TW202517673A - Antibody that binds to c3bbb - Google Patents

Abstract

The present invention relates to anti-C3bBb antibodies and methods of using the same.

Description

Translated fromChinese

與　C3bBb　結合之抗體Antibodies that bind to C3bBb

本發明涉及抗 C3bBb 抗體及其使用方法。The present invention relates to anti-C3bBb antibodies and methods of using the same.

補體系統在老年性黃斑部病變 (AMD) 之疾病生物學中發揮著至關重要的作用 (Cell Mol Life Sci 2021 May；78(10):4487-4505)。替代途徑 C3 轉化酶 (C3bBb) 係補體級聯的關鍵放大因子，並且它係藉由將因子 B (FB) 與補體組分 C3 之 C3b 片段結合並隨後在釋放片段 Ba 之情況下經血漿絲胺酸蛋白酶因子 D (FD) 切割而形成的。與 C3b 結合之剩餘 Bb 片段形成功能性 C3 轉化酶 C3bBb。C3bBb 相對不穩定，半衰期僅有幾分鐘，使其成為不適合抗體生成的標靶。The complement system plays a critical role in the disease biology of age-related macular degeneration (AMD) (Cell Mol Life Sci 2021 May;78(10):4487-4505). The alternative pathway C3 convertase (C3bBb) is a key amplifier of the complement cascade and is formed by binding of factor B (FB) to the C3b fragment of the complement component C3 and subsequent cleavage by the plasma serine protease factor D (FD) with the release of fragment Ba. The remaining Bb fragment bound to C3b forms the functional C3 convertase C3bBb. C3bBb is relatively unstable with a half-life of only a few minutes, making it an unsuitable target for antibody generation.

由於替代途徑在各種病理學中之核心作用，仍需要開發作用於該蛋白水解級聯內的各種補體組分之有效抑制劑。Due to the central role of the alternative pathway in various pathologies, there remains a need to develop effective inhibitors that act on the various complement components within this proteolytic cascade.

本發明涉及一種與人類 C3bBb 特異性結合之抗體。The present invention relates to an antibody that specifically binds to human C3bBb.

本發明進一步涉及一種與人類 C3bBb 結合之抗體，其中該抗體： -       與野生型人類 C3bBb 結合，及/或 -       與重組人類 C3bBb 結合，該重組人類 C3bBb 包含重組因子 B (FB) 蛋白之 Bb 次單元，該重組因子 B (FB) 蛋白包含 D279G 突變及視情況突變 K350N 及/或 M458I；及/或 -       抑制替代途徑；及/或 -       為 C3bBb 活性之促效劑或拮抗劑；及/或 -       與食蟹獼猴 C3bBb 及人類 C3bBb 特異性結合，及/或 -       與非洲綠猴 C3bBb 及人類 C3bBb 特異性結合，及/或 -       藉由 SPR 所測量，在 37°C 以 ≤ 10 nM 之親和力結合，及/或 -       不與備解素競爭 C3bBb 結合，及/或 -       不能穩定 C3 轉化酶。The present invention further relates to an antibody that binds to human C3bBb, wherein the antibody: -       binds to wild-type human C3bBb, and/or-       binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of a recombinant factor B (FB) protein comprising a D279G mutation and, as appropriate, mutations K350N and/or M458I; and/or-       inhibits the alternative pathway; and/or-       is an agonist or antagonist of C3bBb activity; and/or-       specifically binds to cynomolgus macaque C3bBb and human C3bBb, and/or-       binds to African green monkey C3bBb and human specifically binds C3bBb, and/or-       binds with an affinity of ≤ 10 nM at 37°C as measured by SPR, and/or-       does not compete with properdin for C3bBb binding, and/or-       does not stabilize C3 convertase.

在一個態樣中，本發明涉及一種與野生型人類 C3bBb 特異性結合之抗體。In one aspect, the invention relates to an antibody that specifically binds to wild-type human C3bBb.

在另一態樣中，本發明涉及一種與重組人類 C3bBb 特異性結合之抗體，其中 C3bBb 包含重組 FB 蛋白之 Bb 次單元，該重組 FB 蛋白包含 D279G 及視情況地另外的突變 K350N 及/或 M458I。在一個實施例中，該抗體特異性結合包含根據 SEQ ID NO: 492 之重組 FB 蛋白的 Bb 次單元之人類 C3bBb。在一個實施例中，該抗體特異性結合包含根據 SEQ ID NO: 493 之重組 FB 蛋白的 Bb 次單元之人類 C3bBb。In another aspect, the present invention relates to an antibody that specifically binds to recombinant human C3bBb, wherein C3bBb comprises the Bb subunit of a recombinant FB protein, the recombinant FB protein comprising D279G and, as appropriate, additional mutations K350N and/or M458I. In one embodiment, the antibody specifically binds to human C3bBb comprising the Bb subunit of a recombinant FB protein according to SEQ ID NO: 492. In one embodiment, the antibody specifically binds to human C3bBb comprising the Bb subunit of a recombinant FB protein according to SEQ ID NO: 493.

在另一態樣中，本發明涉及一種與人類 C3bBb 之抗原決定基特異性結合之抗體，該抗原決定基包括 C3b 次單元之胺基酸殘基及人類 FB 之 Bb 次單元之胺基酸殘基。在一個實施例中，本發明之抗體與人類 C3bBb 特異性結合，其中該抗體不與 C3bBb 之 (分離的) C3b 次單元特異性結合，並且其中該抗體不與 C3bBb 之 (分離的) Bb 次單元特異性結合。In another aspect, the present invention relates to an antibody that specifically binds to an antigenic determinant of human C3bBb, the antigenic determinant comprising an amino acid residue of the C3b subunit and an amino acid residue of the Bb subunit of human FB. In one embodiment, the antibody of the present invention specifically binds to human C3bBb, wherein the antibody does not specifically bind to the (isolated) C3b subunit of C3bBb, and wherein the antibody does not specifically bind to the (isolated) Bb subunit of C3bBb.

在另一態樣中，本發明涉及一種與人類 C3bBb 結合之抗體，其中該抗體包含選自表 D1 之抗體之重鏈及輕鏈 CDR。在一個實施例中，抗體包含選自表 D1 之抗體之重鏈可變域及輕鏈可變域。In another aspect, the present invention relates to an antibody that binds to human C3bBb, wherein the antibody comprises heavy chain and light chain CDRs of an antibody selected from Table D1. In one embodiment, the antibody comprises a heavy chain variable domain and a light chain variable domain of an antibody selected from Table D1.

在一個實施例中，抗體包含：重鏈可變域 (VH) (a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含 (d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列的 CDR-L3 (對應於抗體 #1，P1AG9426)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含 (d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列的 CDR-L3 (對應於抗體 #2，P1AG9376)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；以及輕鏈可變域(VL)，其包含 (d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列的 CDR-L3 (對應於抗體 #3，P1AG9372)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含 (d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列的 CDR-L3 (對應於抗體 #4，P1AG9420)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含 (d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列的 CDR-L3 (對應於抗體 #5，P1AG9391)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；以及輕鏈可變域(VL)，其包含 (d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列的 CDR-L3 (對應於抗體 #6，P1AH1205)；或重鏈可變域 (VH) (a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含 (d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列的 CDR-L3 (對應抗體 #7，P1AH1199)。In one embodiment, the antibody comprises: a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 449; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 450; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 451; and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 452; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 453; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 454 (corresponding to antibody #1, P1AG9426); or a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 455; (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 461; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 462; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 463; and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 464; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 465; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 466 (corresponding to antibody #2, P1AG9376); or a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 467; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 468; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 469; NO:463; and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO:464; (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO:465; and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO:466 (corresponding to antibody #3, P1AG9372); or a heavy chain variable domain (VH) (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO:467; (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO:468; and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO:469; and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO:464; (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO:465; and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO:466 (corresponding to antibody #3, P1AG9372). NO:470; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:471; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:472 (corresponding to antibody #4, P1AG9420); or a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:473; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:474; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:475; and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:476; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:477; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:478. (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:481; and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:482; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:483; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:484 (corresponding to antibody #5, P1AG9391). #6, P1AH1205); or a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:485; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:486; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:487; and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:488; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:489; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:490 (corresponding antibody #7, P1AH1199).

在一個實施例中，抗體包含：包含 SEQ ID NO:1 之 VH 域及包含 SEQ ID NO:2 之 VL 域 (對應於抗體 #1，P1AG9426)；或包含 SEQ ID NO:3 之 VH 域及包含 SEQ ID NO:4 之 VL 域 (對應於抗體 #2，P1AG9376)；或包含 SEQ ID NO:5 之 VH 域及包含 SEQ ID NO:6 之 VL 域 (對應於抗體 #3，P1AG9372)；或包含 SEQ ID NO:7 之 VH 域及包含 SEQ ID NO:8 之 VL 域 (對應於抗體 #4，P1AG9420)；或包含 SEQ ID NO:9 之 VH 域及包含 SEQ ID NO:10 之 VL 域 (對應於抗體 #5，P1AG9391)；或包含 SEQ ID NO:11 之 VH 域及包含 SEQ ID NO:12 之 VL 域 (對應於抗體 #6，P1AH1205)；或包含 SEQ ID NO:13 之 VH 域及包含 SEQ ID NO:14 之 VL 域 (對應於抗體 #7，P1AH1199)。In one embodiment, the antibody comprises: a VH domain comprising SEQ ID NO: 1 and a VL domain comprising SEQ ID NO: 2 (corresponding to antibody #1, P1AG9426); or a VH domain comprising SEQ ID NO: 3 and a VL domain comprising SEQ ID NO: 4 (corresponding to antibody #2, P1AG9376); or a VH domain comprising SEQ ID NO: 5 and a VL domain comprising SEQ ID NO: 6 (corresponding to antibody #3, P1AG9372); or a VH domain comprising SEQ ID NO: 7 and a VL domain comprising SEQ ID NO: 8 (corresponding to antibody #4, P1AG9420); or a VH domain comprising SEQ ID NO: 9 and a VL domain comprising SEQ ID NO: 10 (corresponding to antibody #5, P1AG9391); or a VH domain comprising SEQ ID NO: 11 and a VL domain comprising SEQ ID NO: 12 (corresponding to antibody #6, P1AG9392); ID NO: 11 and a VL domain comprising SEQ ID NO: 12 (corresponding to antibody #6, P1AH1205); or a VH domain comprising SEQ ID NO: 13 and a VL domain comprising SEQ ID NO: 14 (corresponding to antibody #7, P1AH1199).

此外，本發明涉及一種與本發明之抗體競爭結合野生型人類 C3bBb 之抗體。In addition, the present invention relates to an antibody that competes with the antibody of the present invention for binding to wild-type human C3bBb.

本發明亦涉及一種與本發明之抗體競爭結合重組人類 C3bBb 之抗體，該重組人類 C3bBb 包含重組 FB 蛋白之 Bb 次單元，該重組 FB 蛋白包含 D279G 及視情況地另外的突變 K350N 及/或 M458I。The present invention also relates to an antibody that competes with the antibody of the present invention for binding to recombinant human C3bBb, wherein the recombinant human C3bBb comprises the Bb subunit of the recombinant FB protein, wherein the recombinant FB protein comprises D279G and, optionally, the additional mutations K350N and/or M458I.

本發明之另一態樣係經分離之核酸，該經分離之核酸編碼本發明之抗體。Another aspect of the present invention is an isolated nucleic acid encoding the antibody of the present invention.

本發明亦涉及一種宿主細胞，該宿主細胞包含本發明之核酸。The present invention also relates to a host cell comprising the nucleic acid of the present invention.

此外，本發明涉及一種生產與人類 C3bBb 結合的抗體之方法，其包含在適合於抗體之表現的條件下培養本發明之宿主細胞。Furthermore, the present invention relates to a method for producing an antibody that binds to human C3bBb, comprising culturing the host cells of the present invention under conditions suitable for the expression of the antibody.

在另一態樣中，本發明涉及一種包含本發明之抗體的醫藥組成物。In another aspect, the present invention relates to a pharmaceutical composition comprising the antibody of the present invention.

在又一態樣中，本發明涉及本發明之抗體，其使用為藥物。In another aspect, the present invention relates to the antibody of the present invention for use as a drug.

本發明之抗體適合於藉由結合 C3bBb 來抑制替代途徑。本發明之抗體可能能夠在結合時抑制替代途徑而不穩定 C3bBb，從而避免 C3bBb 之累積。此外，本發明之抗體可以對 C3bBb 複合物具有特異性，但不表現出與其各個次單元的顯著抗原結合。The antibodies of the present invention are suitable for inhibiting the alternative pathway by binding to C3bBb. The antibodies of the present invention may be able to inhibit the alternative pathway without stabilizing C3bBb upon binding, thereby avoiding the accumulation of C3bBb. In addition, the antibodies of the present invention may be specific for the C3bBb complex but do not show significant antigenic binding to its individual subunits.

本文所揭示之抗體可以適合於療法，特定而言眼部血管疾病之治療。The antibodies disclosed herein may be suitable for therapy, in particular the treatment of ocular vascular diseases.

本發明之抗體提供了若干允許其治療應用的有價值的性質，如高親和力及有利於延長持續時間的高穩定性。此外，本發明之抗體有利於以具有適合眼部應用之黏度的高濃度液體調配物提供。The antibodies of the present invention provide several valuable properties that allow for their therapeutic applications, such as high affinity and high stability that facilitates prolonged duration. In addition, the antibodies of the present invention are advantageously provided in high concentration liquid formulations with viscosities suitable for ocular applications.

1.定義「受體人框架」為本文中之目的是如下述定義的衍生自人免疫球蛋白框架或人共通框架、包含輕鏈可變域 (VL) 框架或重鏈可變域 (VH) 框架的胺基酸序列之框架。「衍生自 (derived from)」人免疫球蛋白框架或人共通框架的受體人框架可包含與此等為相同的胺基酸序列，或其可含有胺基酸序列的變更。在一些態樣中，胺基酸變更數目為 10 或更少、9 或更少、8 或更少、7 或更少、6 或更少、5 或更少、4 或更少、3 或更少、或 2 或更少。在一些態樣中，VL 受體人框架與 VL 人免疫球蛋白框架序列或人共通框架序列的序列相同。1.Definitions "Acceptor human framework" is for purposes herein a framework derived from a human immunoglobulin framework or a human common framework, comprising an amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human common framework may comprise the same amino acid sequence as these, or it may contain changes in the amino acid sequence. In some aspects, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some aspects, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human common framework sequence.

「親和力」係指分子 (例如抗體) 之單一結合位點與其結合配偶體 (例如抗原) 之間的非共價交互作用總和的強度。除非另有說明，否則如本文中所使用的「結合親和力」，係指反映結合對成員 (例如抗體及抗原) 之間 1:1 交互作用之內在結合親和力。分子 X 對於其配偶體 Y 之親和力通常可藉由解離常數 (KD) 來表示。可以藉由本領域已知的習知方法測量親和力，包括彼等本文所述之方法。下面描述了用於測量結合親和力的具體說明性和例示性方法。與人類 C3bBb 結合之抗體具有 ≤ 1μM、≤ 100 nM、≤ 10 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM 或 ≤ 0.001 nM 之解離常數 (K_D)，在一個實施例中為 10^-6M 或更小，在一個實施例中為 10^-7M 或更小，在一個實施例中為 10^-8M 或更小，在一個實施例中為 10^-8M 至 10^-13M，在一個實施例中為 10^-9M 至 10^-13M)。當抗體具有 1μM 或更小之 KD 時，稱該抗體與人類 C3bBb「特異性結合」。在某些態樣中，抗人類 C3bBb 抗體與人類 C3bBb 之抗原決定基結合，該抗原決定基在來自不同物種之人類 C3bBb 中為保守的。"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, "binding affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (KD). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary methods for measuring binding affinity are described below. The antibody that binds to human C3bBb has a dissociation constant (_KD ) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM, in one embodiment^10-6 M or less, in one embodiment^10-7 M or less, in one embodiment^10-8 M or less, in one embodiment^10-8 M to^10-13 M, in one embodiment^10-9 M to^10-13 M). An antibody is said to "specifically bind" to human C3bBb when it has a KD of 1 μM or less. In certain aspects, the anti-human C3bBb antibody binds to an epitope of human C3bBb that is conserved among human C3bBb from different species.

先天性免疫系統之組成部分，亦即來自典型及替代途徑的不同元件在本文中根據其在本領域中的標準含義來提及，並且本文中所使用之術語包括先天性免疫系統的各個天然組成部分的重組變異體，其維持功能並且可以包括包含標籤及/或標籤之變異體。Components of the innate immune system, i.e., the various elements from the classical and alternative pathways, are referred to herein according to their standard meaning in the art, and the terms used herein include recombinant variants of each natural component of the innate immune system that maintain function and may include variants comprising tags and/or tags.

簡而言之，如本文所使用之術語「C3bBb」係指藉由 C3 片段 (「C3b」) 與因子 B (「FB」) 結合並隨後在釋放片段 Ba 之情況下經血漿絲胺酸蛋白酶因子 D (「FD」) 切割而形成的替代途徑 C3 轉化酶。如本文所使用之術語「C3b」係指由補體組分 3 (C3) 的替代途徑切割產生的兩個元件中之較大者，另一者為 C3a。術語「C3 轉化酶」係指補體系統的絲胺酸蛋白酶並且可以指替代途徑 C3 轉化酶 (C3bBb) 或典型及凝集素途徑 C3 轉化酶 (C4bC2b)。術語「人類因子 B」或「FB」係指在人類中由 CFB 基因編碼之補體因子 B。術語「人類因子 D」係指在人類中由 CFD 基因編碼之補體因子 D。如本文所使用之術語「C5 轉化酶」係指替代途徑 C5 轉化酶 (C3bBbC3b)。Briefly, the term "C3bBb" as used herein refers to the alternative pathway C3 convertase formed by the binding of a C3 fragment ("C3b") to factor B ("FB") and subsequent cleavage by the plasma serine protease factor D ("FD") with the release of fragment Ba. The term "C3b" as used herein refers to the larger of the two elements resulting from the alternative pathway cleavage of complement component 3 (C3), the other being C3a. The term "C3 convertase" refers to the serine protease of the complement system and may refer to the alternative pathway C3 convertase (C3bBb) or the classical and lectin pathway C3 convertases (C4bC2b). The term "human factor B" or "FB" refers to complement factor B encoded by the CFB gene in humans. The term "human factor D" refers to complement factor D encoded by the CFD gene in humans. The term "C5 convertase" as used herein refers to the alternative pathway C5 convertase (C3bBbC3b).

術語「抗體篩選」係指用於鑑定與標靶抗原特異性結合之抗體的技術。用於鑑定抗體之各種技術係本領域已知的，諸如向基因轉殖動物投予免疫原性標靶抗原、基於融合瘤的方法、或分離選自噬菌體展示文庫之可變域序列。術語「噬菌體文庫淘選」係指用於鑑定對標靶抗原具有所期望之結合特性之噬菌體展示變異體的親和力選擇技術。The term "antibody screening" refers to techniques used to identify antibodies that specifically bind to a target antigen. Various techniques for identifying antibodies are known in the art, such as administration of immunogenic target antigens to transgenic animals, fusion tumor-based methods, or isolation of variable domain sequences selected from phage display libraries. The term "phage library panning" refers to affinity selection techniques used to identify phage-displayed variants with desired binding properties to a target antigen.

本文中之術語「抗體」以最廣義使用且涵蓋各種抗體結構，包括但不限於單株抗體、多株抗體、多特異性抗體 (例如，雙特異性抗體) 及抗體片段，只要其等展示出所期望之抗原結合活性即可。The term "antibody" herein is used in the broadest sense and covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments, as long as they exhibit the desired antigen-binding activity.

「抗體片段」係指除完整抗體以外的分子，其包含結合完整抗體所結合抗原之完整抗體的一部分。抗體片段之實例包括但不限於 Fv、Fab、Fab'、Fab'-SH、F(ab')₂；雙抗體 (diabody)；線性抗體；單鏈抗體分子 (例如，scFv 及 scFab)；單域抗體 (dAb)；及由抗體片段所形成之多特異性抗體。關於某些抗體片段的綜述，參見 Holliger 及 Hudson, Nature Biotechnology 23:1126-1136 (2005)。"Antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds to an antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')₂ ; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAb); and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

術語「抗原決定基 (epitope)」表示抗人類 C3bBb 抗體與之結合的抗原上的位點，無論是蛋白性的還是非蛋白性的。本發明之抗體所結合之抗原決定基包含非連續胺基酸，並且因此為構形抗原決定基。The term "epitope" refers to the site on the antigen to which the anti-human C3bBb antibody binds, whether proteinaceous or non-proteinaceous. The epitope to which the antibodies of the present invention bind comprises non-consecutive amino acids and is therefore a conformational epitope.

篩選與特定抗原決定基結合的抗體 (亦即，與相同抗原決定基結合者) 可使用本技術領域的常規方法進行，諸如例如但不限於丙胺酸掃描、肽印漬 (參見 Meth. Mol. Biol. 248 (2004) 443-463)、肽切割分析、抗原決定基切除、抗原決定基萃取、抗原的化學修飾 (參見 Prot. Sci. 9 (2000) 487-496)、交叉阻斷 (參見「Antibodies」, Harlow 及 Lane (Cold Spring Harbor Press, Cold Spring Harb., NY)。在本文所使用之某些實施例中，藉由低溫電子顯微鏡鑑定抗體之抗原決定基。Screening for antibodies that bind to a specific antigenic determinant (i.e., those that bind to the same antigenic determinant) can be performed using conventional methods in the art, such as, for example, but not limited to, alanine scanning, peptide blotting (see Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, antigenic determinant excision, antigenic determinant extraction, chemical modification of antigens (see Prot. Sci. 9 (2000) 487-496), cross-blocking (see "Antibodies", Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY). In certain embodiments used herein, the antigenic determinant of the antibody is identified by cryogenic electron microscopy.

此外，競爭性結合可用於容易判定抗體是否與本發明之參考抗人類 C3bBb 抗體競爭結合人類 C3bBb。例如，「與本發明之參考抗人類 C3bBb 抗體競爭結合之抗體」係指在競爭測定中將參考抗人類 C3bBb 抗體與其抗原之結合阻斷 50% 或更多的抗體，且反之，參考抗體在競爭測定中將該抗體與其抗原之結合阻斷 50% 或更多。In addition, competitive binding can be used to easily determine whether an antibody competes with a reference anti-human C3bBb antibody of the present invention for binding to human C3bBb. For example, "an antibody that competes for binding with a reference anti-human C3bBb antibody of the present invention" refers to an antibody that blocks the binding of the reference anti-human C3bBb antibody to its antigen by 50% or more in a competitive assay, and conversely, the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competitive assay.

在一些態樣中，如藉由競爭性結合測定測量，如果一個抗體的 1 倍、5 倍、10 倍、20 倍或 100 倍的過量抑制另一抗體的結合至少 50%、至少 75%、至少 90% 或甚至 99% 或更多，則認為兩個抗體競爭結合人類 C3bBb (參見，例如，Junghans 等人，Cancer Res. 50 (1990) 1495-1502)。In some aspects, two antibodies are considered to compete for binding to human C3bBb if a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antibody inhibits binding of the other antibody by at least 50%, at least 75%, at least 90%, or even 99% or more as measured by a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).

抗體之「類別 (class)」係指為其重鏈所具有的恆定域或恆定區之類型。有五大類抗體：IgA、IgD、IgE、IgG及IgM，且此等類別中之若干者可進一步分成子類（同型），例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。在某些態樣，抗體屬於 IgG1 同型。在某些態樣中，抗體屬於具有 P329G、L234A 及 L235A 突變之 IgG1 同型，以減少 Fc 區效應功能。在其他態樣，抗體屬於 IgG2 同型。在某些態樣，該抗體屬 IgG4 同型，在鉸鏈區中具有 S228P 突變以改善 IgG4 抗體之穩定性。對應於不同類別之免疫球蛋白的重鏈恆定域分別稱為 α、δ、ε、γ 及 μ。基於其恆定域之胺基酸序列，抗體之輕鏈可經分配為兩種類型之一，稱為 kappa (κ) 及 lambda (λ)。如本申請案中所使用之術語「衍生自人類來源之恆定區」或「人類恆定區」表示亞類 IgG1、IgG2、IgG3 或 IgG4 之人類抗體的恆定重鏈區及/或恆定輕鏈 κ 或 λ 區。此等恆定區在現有技術中為人類所熟知，且例如描述於以下文獻中：Kabat, E.A. 等人，Sequences of Proteins of Immunological Interest，第 5 版，Public Health Service, National Institutes of Health, Bethesda, MD (1991) (亦參見例如 Johnson, G. 與 Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218；Kabat, E.A. 等人，Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788)。除非本文另有說明，否則恆定區中胺基酸殘基之編號係根據 EU 編號系統 (亦稱為 Kabat 之 EU 索引) 進行，如以下文獻中所述：Kabat, E.A. 等人, Sequences of Proteins of Immunological Interest, 第 5 版 Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242。The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In some aspects, the antibody is of the IgG1 isotype. In some aspects, the antibody is of the IgG1 isotype with P329G, L234A, and L235A mutations to reduce Fc region effector function. In other aspects, the antibody is of the IgG2 isotype. In some aspects, the antibody is of the IgG4 isotype with an S228P mutation in the hinge region to improve the stability of the IgG4 antibody. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively. The light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain. As used in this application, the term "constant region derived from human sources" or "human constant region" refers to the constant heavy chain region and/or the constant light chain κ or λ region of a human antibody of subclass IgG1, IgG2, IgG3 or IgG4. Such constant regions are well known in the art and are described, for example, in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, for example, Johnson, G. and Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218; Kabat, E.A. et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). Unless otherwise indicated herein, the numbering of amino acid residues in the constant regions is according to the EU numbering system (also known as Kabat's EU index) as described in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

「效應功能 (effector function)」，係指歸因於抗體的 Fc 區域的那些生物活性，其隨抗體同型而變化。抗體效用功能的實例包括：C1q 結合和補體依賴性細胞毒性 (CDC)；Fc 受體結合；抗體依賴性細胞媒介的細胞毒性 (ADCC)；吞噬作用；細胞表面受體 (例如 B 細胞受體) 的下調；以及 B 細胞活化。"Effector function" refers to those biological activities attributed to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

藥劑例如醫藥組成物的「治療有效量」係指在所需之給藥劑量和時間段內有效實現所需的治療或預防效果的量。A "therapeutically effective amount" of a pharmaceutical agent, such as a pharmaceutical composition, refers to an amount effective to achieve the desired therapeutic or preventive effect when administered in the amount and for the period of time required.

本文中的術語「Fc 區域」，用於定義包含至少一部分恆定區域的免疫球蛋白重鏈的 C 端區域。該術語包括天然序列 Fc 區域和變異體 Fc 區域。在一個態樣中，人 IgG 重鏈 Fc 區從 Cys226 或從 Pro230 延伸至重鏈的羧基端。但是，由宿主細胞產生的抗體可能經歷重鏈 C 端的一種或多種，特別是一種或兩種胺基酸之轉譯後切割。因此，由宿主細胞藉由表現編碼全長重鏈的特異性核酸分子所產生之抗體可包括該全長重鏈，或者可包括該全長重鏈的經切割之變異體。重鏈的最後兩個 C 端胺基酸為甘胺酸 (G446) 及離胺酸 (K447，EU 編號系統)。因此，可以存在或可以不存在 Fc 區域之 C 端離胺酸 (Lys447) 或 C 端甘胺酸 (Gly446) 及離胺酸 (Lys447)。除非另有說明，否則包括 Fc 區域之重鏈之胺基酸序列在本文中表示不含 C 端甘胺酸-離胺酸二肽。在一個態樣中，包含在根據本發明之抗體中的包括如本文所指明之 Fc 區的重鏈包含另外的 C 端甘胺酸-離胺酸二肽 (G446 及 K447，EU 編號系統)。在一個態樣中，包含在根據本發明之抗體中的包括如本文所指明之 Fc 區的重鏈包含另外的 C 端甘胺酸殘基 (G446，根據 EU 索引編號)。除非本文另有說明，否則 Fc 區或恆定區中胺基酸殘基之編號根據 EU 編號系統 (也稱為 EU 指數) 進行，如 Kabat 等人所述 (Sequences of Proteins of Immunological Interest, 第 5 版 Public Health Service, National Institutes of Health, Bethesda, MD, 1991)。The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two amino acids at the C-terminus of the heavy chain. Therefore, antibodies produced by host cells by expressing specific nucleic acid molecules encoding full-length heavy chains may include the full-length heavy chain, or may include cleaved variants of the full-length heavy chain. The last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering system). Thus, the C-terminal lysine (Lys447) or C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified, the amino acid sequence of the heavy chain including the Fc region is herein indicated as being free of the C-terminal glycine-lysine dipeptide. In one aspect, the heavy chain including the Fc region as specified herein contained in the antibody according to the present invention comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447, EU numbering system). In one embodiment, the heavy chain comprising the Fc region as specified herein contained in the antibody according to the present invention comprises an additional C-terminal glycine residue (G446, numbered according to the EU index). Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or the constant region is according to the EU numbering system (also called EU index) as described by Kabat et al. (Sequences of Proteins of Immunological Interest, 5th edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

「框架」或「FR」係指互補決定區 (CDR) 之外的可變域殘基。可變域之 FR 通常由四個 FR 域組成：FR1、FR2、FR3、及 FR4。因此，CDR 及 FR 序列通常以如下順序出現在 VH (或 VL) 中：FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4。"Framework" or "FR" refers to the variable domain residues outside the complementary determining regions (CDRs). The FR of a variable domain is usually composed of four FR domains: FR1, FR2, FR3, and FR4. Therefore, CDR and FR sequences usually appear in the following order in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

術語「全長抗體」、「完整抗體」及「全抗體」在本文中可互換使用，係指具有與天然抗體結構實質上類似的結構或具有包含本文所定義之 Fc 區域的重鏈之抗體。The terms "full length antibody", "intact antibody" and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain comprising an Fc region as defined herein.

術語「宿主細胞」、「宿主細胞株」及「宿主細胞培養物」可互換使用且係指已向其中引入外源性核酸的細胞，其包括此等細胞的子代細胞。宿主細胞包括「轉化子」和「轉化細胞」，其包括原代轉化細胞及由其衍生的子代細胞，而與傳代次數無關。子代細胞之核酸含量可能與親代細胞不完全相同，但可能含有突變。本文中包括具有與原始轉化細胞中篩選或選擇的功能或生物活性相同的功能或生物活性的突變子代細胞。The terms "host cell," "host cell strain," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages. The nucleic acid content of the progeny cells may not be exactly the same as that of the parent cell, but may contain mutations. Mutant progeny cells having the same function or biological activity as that screened or selected in the original transformed cell are included herein.

「人抗體 (human antibody)」為具有胺基酸序列之抗體，該胺基酸序列對應於由人或人體細胞產生或自利用人抗體譜系 (antibody repertoire) 或其他人抗體編碼序列之非人來源衍生之抗體之胺基酸序列。人抗體的該定義特定地排除包含非人抗原結合殘基之人源化抗體。A "human antibody" is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell or derived from a non-human source utilizing the human antibody repertoire or other human antibody encoding sequences. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen binding residues.

「人共通框架」是代表一系列人免疫球蛋白 VL 或 VH 框架序列中最常見的胺基酸殘基的框架。通常，人免疫球蛋白 VL 或 VH 序列的選擇來自可變域序列的次群組。通常，序列之次群組為如 Kabat 等人, Sequences of Proteins of Immunological Interest，第五版，NIH Publication 91-3242, Bethesda MD (1991), 第 1-3 卷中之次群組。在一個態樣中，對於 VL，亞組係如 Kabat 等人在上述文獻中所述之亞組 κ I。在一個態樣中，對於 VH，亞組係如 Kabat 等人在上述文獻中所述之亞組 III。A "human common framework" is a framework that represents the most common amino acid residues in a set of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Typically, the subgroups of sequences are as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one aspect, for VL, the subgroup is subgroup κ I as described in Kabat et al., supra. In one aspect, for VH, the subgroup is subgroup III as described in Kabat et al., supra.

如本文所用，術語「高變區」或「HVR」係指抗體可變域中序列高變並決定抗原結合特異性的各個區域，例如「互補決定區」(「CDR」)。As used herein, the term "hypervariable region" or "HVR" refers to the regions of the antibody variable domain whose sequences are highly variable and which determine the antigen binding specificity, such as the "complementary determining region" ("CDR").

通常，抗體包括六個 CDR：三個在 VH 中 (CDR-H1、CDR-H2、CDR-H3)，及三個在 VL 中 (CDR-L1、CDR-L2、CDR-L3)。在本文中，例示性 CDR 包括： a)     (a) 存在於胺基酸殘基 26-32 (L1)、50-52 (L2)、91-96 (L3)、26-32 (H1)、53-55 (H2) 及 96-101 (H3) 處之超變環 (Chothia 及 Lesk，J. Mol. Biol. 196:901-917 (1987))； b)     (b) 存在於胺基酸殘基 24-34 (L1)、50-56 (L2)、89-97 (L3)、31-35b (H1)、50-65 (H2) 及 95-102 (H3) 處之 CDR (Kabat 等人，Sequences of Proteins of Immunological Interest，第 5 版 Public Health Service，National Institutes of Health，Bethesda, MD (1991))；及 c)     存在於胺基酸殘基 27c-36 (L1)、46-55 (L2)、89-96 (L3)、30-35b (H1)、47-58 (H2) 及 93-101 (H3) 處之抗原觸點 (MacCallum 等人，J. Mol. Biol. 262: 732-745 (1996))。Typically, antibodies include six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). As used herein, exemplary CDRs include:a)     (a) hypervariable loops present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));b)     (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health Health, Bethesda, MD (1991)); andc)     Antigenic contacts at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)).

除非另有說明，否則 CDR 根據 Kabat 等人之上述文獻中所述之方法確定。本領域之技術人員將理解，也可以根據 Chothia 之上述文獻、McCallum 之上述文獻中所述之方法或任何其他科學上接受之命名系統確定 CDR 名稱。Unless otherwise indicated, CDRs were determined according to the method described in Kabat et al., supra. Those skilled in the art will appreciate that CDR names may also be determined according to the method described in Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

「受試者」或「個體」為哺乳動物。哺乳動物包括但不限於馴養的動物 (例如牛、綿羊、貓、狗和馬)、靈長類動物 (例如人及非人類靈長類動物諸如猴)、兔以及囓齒動物 (例如小鼠及大鼠)。在某些態樣中，個體或個體為人類。A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the individual or subject is a human.

「分離的」抗體是從其自然環境的組分中分離出來之抗體。在一些態樣中，將抗體純化至大於 95% 或 99% 純度，藉由 (例如) 電泳 (例如 SDS-PAGE、等電聚焦 (IEF)、毛細管電泳) 或層析 (例如，離子交換或反相 HPLC) 方法測定。關於評估抗體純度之方法的綜述，參見例如 Flatman 等人，J. Chromatogr. B 848:79-87 (2007)。An "isolated" antibody is one that is separated from the components of its natural environment. In some aspects, the antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

術語「核酸分子」或「多核苷酸」包括任何包含核苷酸聚合物的化合物及/或物質。各核苷酸由鹼基具體而言嘌呤或嘧啶鹼基 (亦即，胞嘧啶 (C)、鳥嘌呤 (G)、腺嘌呤 (A)、胸腺嘧啶 (T) 或尿嘧啶 (U))、糖 (亦即，去氧核糖或核糖) 及磷酸基團構成。通常，核酸分子係藉由鹼基之序列來描述，其中該等鹼基表示核酸分子之一級結構 (線性結構)。鹼基之序列通常由 5' 至 3' 表示。在本文中，術語核酸分子包括：去氧核糖核酸 (DNA)，其包括例如互補 DNA (cDNA) 及基因組 DNA；核糖核酸 (RNA)，特定而言信使 RNA (mRNA)；DNA 或 RNA 的合成形式；以及包含兩個或更多個這些分子的混合聚合物。核酸分子可以是線性或環狀的。此外，術語核酸分子包括正義股及反義股，以及單股形式及雙股形式。此外，本文所述之核酸分子可包含天然存在或非天然存在之核苷酸。非天然存在之核苷酸的實例包括帶有經衍生之醣、磷酸鹽主鏈鍵聯或經化學修飾之殘基的經修飾之核苷酸鹼基。核酸分子亦涵蓋適於作為在活體外及/或在活體內 (例如在宿主或患者體中) 直接表現本發明抗體之載體的 DNA 及 RNA 分子。此類 DNA (例如，cDNA) 或 RNA (例如，mRNA) 載體可為未修飾的或經修飾的。例如，mRNA 可經化學修飾以增強 RNA 載體之穩定性及/或所編碼之分子的表現，使得 mRNA 可被注射入個體體內以生成抗體 (參見例如 Stadler 等人，Nature Medicine 2017，線上發表於 2017 年 6 月 12 日，doi:10.1038/nm.4356 或 EP 2 101 823 B1)。The term "nucleic acid molecule" or "polynucleotide" includes any compound and/or substance comprising a nucleotide polymer. Each nucleotide is composed of a base, specifically a purine or pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e., deoxyribose or ribose) and a phosphate group. Typically, nucleic acid molecules are described by the sequence of bases, wherein the bases represent the primary structure (linear structure) of the nucleic acid molecule. The sequence of bases is usually represented from 5' to 3'. As used herein, the term nucleic acid molecule includes: deoxyribonucleic acid (DNA), including, for example, complementary DNA (cDNA) and genomic DNA; ribonucleic acid (RNA), specifically messenger RNA (mRNA); synthetic forms of DNA or RNA; and mixed polymers comprising two or more of these molecules. Nucleic acid molecules can be linear or circular. In addition, the term nucleic acid molecule includes sense and antisense strands, as well as single-stranded and double-stranded forms. In addition, the nucleic acid molecules described herein may contain naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugars, phosphate backbone linkages or chemically modified residues. Nucleic acid molecules also encompass DNA and RNA molecules suitable as carriers for directly expressing the antibodies of the present invention in vitro and/or in vivo (e.g., in a host or patient). Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors may be unmodified or modified. For example, mRNA can be chemically modified to enhance the stability of the RNA vector and/or the expression of the encoded molecule, so that the mRNA can be injected into an individual to produce antibodies (see, e.g., Stadler et al., Nature Medicine 2017, published online June 12, 2017, doi:10.1038/nm.4356 or EP 2 101 823 B1).

「分離的」核酸係指已經與其天然環境的組分分離的核酸分子。分離的核酸包括通常包含核酸分子之細胞中所含之核酸分子，但是核酸分子存在於染色體外或與自然染色體位置不同之染色體位置。An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells that normally contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from the natural chromosomal location.

「經分離之編碼抗人類 C3bBb 抗體的核酸」係指編碼抗人類 C3bBb 抗體重鏈及輕鏈 (或其片段) 之一種或多種核酸分子，包括在單個載體或單獨抗體中之此等核酸分子，並且此等核酸分子存在於宿主細胞中的一個或多個位置。"Isolated nucleic acid encoding an anti-human C3bBb antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains of an anti-human C3bBb antibody (or fragments thereof), including such nucleic acid molecules in a single vector or a separate antibody, and such nucleic acid molecules are present at one or more locations in a host cell.

如本文所用之術語「單株抗體」係指獲自實質上同源抗體群體之抗體，即包含群體的個別抗體是相同的及/或結合相同的抗原決定基，除了例如含有天然生成之突變或於單株抗體製劑生產過程中產生的可能的變異體抗體之外，此等變異體通常係以少量存在。與通常包括針對不同決定位 (抗原決定基) 之不同抗體之多株抗體製劑相反，單株抗體製劑之每個單株抗體係針對於抗原上的單一決定位。因此，修飾詞「單株」表示抗體之特徵係獲自實質上同質之抗體群體，且不應解釋為需要藉由任何特定方法產生抗體。例如，意欲根據本發明使用的單株抗體可藉由多種技術來製造，包括但不限於融合瘤方法、重組 DNA 方法、噬菌體展示方法、及利用包含全部或部分人免疫球蛋白基因座之轉殖基因動物之方法，本文描述此等方法及用於製備單株抗體之其他例示性方法。The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical and/or bind to the same antigenic determinant, except for possible variant antibodies that contain naturally occurring mutations or that arise during the production of the monoclonal antibody preparation, such variants are generally present in small amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (antigenic determinants), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the characteristics of the antibody are obtained from a substantially homogeneous antibody population, and should not be interpreted as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use in accordance with the present invention may be produced by a variety of techniques, including but not limited to fusion tumor methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, these methods and other exemplary methods for preparing monoclonal antibodies are described herein.

術語「藥品仿單」用於指涉通常包含在治療性產品的商業包裝中的說明，該說明包含有關使用此等治療性產品的適應症、用法、劑量、投予途徑、組合療法、禁忌症及/或警告等資訊。The term "product leaflet" is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, routes of administration, combination therapy, contraindications and/or warnings for the use of such therapeutic products.

相對於參照多肽序列所述之「胺基酸序列同一性百分比 (%)」，是指候選序列中胺基酸殘基與參照多肽序列中之胺基酸殘基相同之百分比，在比對序列並引入差異後 (如有必要)，可實現最大的序列同一性百分比，並且不考慮將任何保守取代作為序列同一性之一部分。為確定胺基酸序列同一性百分比之目的而進行的比對可透過本領域中技術範圍內之各種方式實現，例如，使用公開可用的電腦軟體諸如 BLAST、BLAST-2、Clustal W、Megalign (DNASTAR) 軟件或 FASTA 程式套件實現。熟習此項技術者可判定用於比對序列之適當參數，包括在所比較之序列的全長上達成最大比對所需之任何演算法。可替代地，可使用序列比較電腦程式 ALIGN-2 生成同一性百分比值。ALIGN-2 序列比較電腦程式由建南德克公司開發，並且其源代碼已與用戶文檔一起歸檔在位於美國華盛頓特區 20559 的美國著作權局，其已經注冊 (美國版權註冊號 TXU510087) 並在 WO 2001/007611 中有所描述。"Percent amino acid sequence identity (%)" relative to a reference polypeptide sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing differences (if necessary) to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in various ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software, or the FASTA suite of programs. One skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve maximum alignment over the full length of the sequences being compared. Alternatively, percent identity values may be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was developed by ALIGN-2, Inc., and its source code is filed with user documentation in the U.S. Copyright Office, Washington, D.C. 20559, registered (U.S. Copyright Registration No. TXU510087) and described in WO 2001/007611.

除非另有說明，否則出於本文之目的，使用 FASTA 套件 36.3.8c 版或更高版本的 ggsearch 程式及 BLOSUM50 比較矩陣來生成胺基酸序列同一性百分比值。FASTA 程式包由以下作者開發：W. R. W. R. Pearson 及 D. J. Lipman、 (1988), “Improved Tools for Biological Sequence Analysis”, PNAS 85:2444-2448；W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258；及 Pearson 等人(1997) (Genomics 46:24-36)，並可從以下網址公開存取：www.fasta.bioch.virginia.edu/fasta_www2/fasta_down.shtml 或 www.ebi.ac.uk/Tools/sss/fasta。可替代地，可使用透過 fasta.bioch.virginia.edu/fasta_www2/index.cgi 存取的公用伺服器，使用 ggsearch (global protein:protein) 程式和預設選項 (BLOSUM50; open: -10; ext: -2; Ktup = 2) 比較序列，以確保執行全局而不是局部比對。胺基酸同一性百分比提供於輸出比對標題中。Unless otherwise noted, for the purposes of this article, percent amino acid sequence identity values were generated using the ggsearch program from the FASTA suite, version 36.3.8c or later, and the BLOSUM50 comparison matrix. The FASTA package was developed by W. R. W. R. Pearson and D. J. Lipman, (1988), “Improved Tools for Biological Sequence Analysis”, PNAS 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et al. (1997) (Genomics 46:24-36) and is publicly accessible at www.fasta.bioch.virginia.edu/fasta_www2/fasta_down.shtml or www.ebi.ac.uk/Tools/sss/fasta. Alternatively, sequences can be compared using a public server accessed through fasta.bioch.virginia.edu/fasta_www2/index.cgi using the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure that a global rather than a local alignment is performed. The percentage of amino acid identity is provided in the output alignment header.

術語「醫藥組成物」或「醫藥調配物」係指以下製劑，其形式為允許其中所含之活性成分的生物活性有效，並且不含對組成物將投予之個體具有不可接受之毒性的其他組分。The term "pharmaceutical composition" or "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective and that contains no other components that are unacceptably toxic to the subject to which the composition is to be administered.

「醫藥上可接受之載劑」是指醫藥組成物或調配物中除對個體無毒之活性成分以外的成分。 醫藥上可接受之載劑包括但不限於緩衝劑、賦形劑、穩定劑或防腐劑。"Pharmaceutically acceptable carriers" refer to ingredients in pharmaceutical compositions or formulations other than active ingredients that are non-toxic to individuals. Pharmaceutically acceptable carriers include but are not limited to buffers, excipients, stabilizers or preservatives.

如本文中所使用的「治療」(及其語法變異體，諸如「治療過程」或「治療中」)，係指試圖改變受治療個體之疾病自然病程的臨床干預，並且可進行預防或在臨床病理過程中執行。期望之治療效果包括但不限於預防疾病之發生或複發、減輕症狀、減輕疾病之任何直接或間接病理後果、預防轉移、降低疾病進展之速度、改善或減輕疾病狀態、緩解或改善預後。在一些態樣中，本發明之抗體用於延遲疾病之發展或減慢疾病之進展。As used herein, "treatment" (and grammatical variants such as "treatment" or "treating") refers to clinical intervention that attempts to alter the natural course of a disease in the individual being treated, and can be performed preventively or during the course of clinical pathology. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, ameliorating or reducing the disease state, relieving or improving prognosis. In some aspects, the antibodies of the present invention are used to delay the development of a disease or slow the progression of a disease.

術語「可變區 (variable region)」或「可變域 (variable domain)」係指參與抗體與抗原結合的抗體重鏈或輕鏈之域。天然抗體之重鏈及輕鏈 (分別為 VH 及 VL) 之可變域通常具有類似的結構，且每個域均包含四個保守性骨架區 (FR) 及三個互補決定區 (CDR)。(參見例如，Kindt 等人，Kuby Immunology，第 6 版，W.H. Freeman and Co.，第 91 頁 (2007)。)單個 VH 或 VL 域可能足以賦予抗原結合特異性。此外，可以使用 VH 或 VL 域從結合抗原的抗體中分離結合特定抗原的抗體，以分別篩選互補 VL 或 VH 域的文庫。例如參見 Portolano 等人，J. Immunol. 150:880-887 (1993)；Clarkson 等人，Nature 352:624-628 (1991)。The term "variable region" or "variable domain" refers to a domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, and each domain comprises four conserved framework regions (FRs) and three complementary determining regions (CDRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, VH or VL domains can be used to separate antibodies that bind a specific antigen from antibodies that bind the antigen to screen libraries for complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

如本文所用，術語「載體」是指一種核酸分子，其能夠傳送與其連接之另一種核酸。該術語包括作為自我複製核酸結構之載體以及併入已引入該宿主細胞的基因體中的載體。某些載體能夠指導與其可操作地連接的核酸的表現。這些載體在本文中稱為「表現載體」。2.具體實施方式As used herein, the term "vector" refers to a nucleic acid molecule that is capable of transporting another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of the host cell that has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. These vectors are referred to herein as "expression vectors."2.Specific Implementation Methods

在一個態樣中，本發明部分基於提供與人類 C3bBb 特異性結合之抗體，該抗體係在使用穩定化 C3bBb 複合物篩選後獲得的。在某些態樣中，提供了與人類 C3bBb 結合之抗體。本發明之抗體可用於例如疾病諸如眼部疾病，例如老年性黃斑部病變之診斷、預防或治療。A.例示性抗C3bBb抗體In one aspect, the invention is based in part on providing antibodies that specifically bind to human C3bBb, which are obtained after screening using stabilized C3bBb complexes. In certain aspects, antibodies that bind to human C3bBb are provided. The antibodies of the invention can be used, for example, in the diagnosis, prevention or treatment of diseases such as eye diseases, such as age-related macular degeneration.A.Exemplary Anti-C3bBbAntibodies

在一個態樣中，本發明提供一種與人類 C3bBb 特異性結合之抗體。在另一態樣中，本發明提供一種與人類 C3bBb 特異性結合之抗體，該人類 C3bBb 包含具有 D279G 突變的因子 B (FB) 之 Bb 次單元。在一個實施例中，該抗體與包含具有 SEQ ID NO: 492 之胺基酸序列的因子 B (FB) 之 Bb 次單元的人類 C3bBb 結合。In one aspect, the present invention provides an antibody that specifically binds to human C3bBb. In another aspect, the present invention provides an antibody that specifically binds to human C3bBb, wherein the human C3bBb comprises the Bb subunit of factor B (FB) having a D279G mutation. In one embodiment, the antibody binds to human C3bBb comprising the Bb subunit of factor B (FB) having an amino acid sequence of SEQ ID NO: 492.

在另一態樣中，本發明提供一種與人類 C3bBb 特異性結合之抗體，該人類 C3bBb 包含具有 D279G、K350N 及 M458I 突變的因子 B (FB) 之 Bb 次單元。在一個實施例中，該抗體與包含具有 SEQ ID NO: 493 之胺基酸序列的因子 B (FB) 之 Bb 次單元的人類 C3bBb 結合。In another aspect, the present invention provides an antibody that specifically binds to human C3bBb, which comprises a Bb subunit of factor B (FB) having mutations D279G, K350N, and M458I. In one embodiment, the antibody binds to human C3bBb comprising a Bb subunit of factor B (FB) having an amino acid sequence of SEQ ID NO: 493.

在另一態樣中，本發明提供一種與人類 C3bBb 結合之抗體，其中該抗體： -       與野生型人類 C3bBb 結合，及/或 -       與重組人類 C3bBb 結合，該重組人類 C3bBb 包含重組因子 B (FB) 蛋白之 Bb 次單元，該重組因子 B (FB) 蛋白包含 D279G 突變及視情況突變 K350N 及/或 M458I；及/或 -       抑制替代途徑；及/或 -       為 C3bBb 活性之促效劑或拮抗劑；及/或 -       與食蟹獼猴 C3bBb 及人類 C3bBb 特異性結合，及/或 -       與非洲綠猴 C3bBb 及人類 C3bBb 特異性結合，及/或 -       藉由 SPR 所測量，在 37°C 以 ≤ 10 nM 之親和力結合。In another embodiment, the present invention provides an antibody that binds to human C3bBb, wherein the antibody: -       binds to wild-type human C3bBb, and/or-       binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of a recombinant factor B (FB) protein, the recombinant factor B (FB) protein comprising a D279G mutation and, as appropriate, mutations K350N and/or M458I; and/or-       inhibits the alternative pathway; and/or-       is an agonist or antagonist of C3bBb activity; and/or-       specifically binds to cynomolgus macaque C3bBb and human C3bBb, and/or-       binds to African green monkey C3bBb and human C3bBb specifically binds, and/or-       binds with an affinity of ≤ 10 nM at 37°C as measured by SPR.

本發明之抗體可以藉由使用穩定化 C3bBb 進行篩選來提供，該穩定化 C3bBb 係使用具有 D279G 及視情況地另外的突變 K350N 及/或 M458I 的重組 FB 蛋白提供的。野生型 C3bBb 係一種快速衰減的分子，其需要穩定化才能用於抗體篩選目的。本發明之發明者能夠將 C3bBb 複合物之半衰期從約 5 分鐘增加至 11 小時，這允許在噬菌體文庫淘選中使用穩定化之複合物來產生抗體。The antibodies of the present invention can be provided by screening using stabilized C3bBb provided using recombinant FB protein with D279G and optionally the additional mutations K350N and/or M458I. Wild-type C3bBb is a rapidly decaying molecule that requires stabilization for antibody screening purposes. The inventors of the present invention were able to increase the half-life of the C3bBb complex from approximately 5 minutes to 11 hours, which allows the use of the stabilized complex to generate antibodies in phage library panning.

因此，本發明之抗體與穩定化 C3bBb，特定而言包含具有 D279G 突變及視情況地突變 K350N 及/或 M458I 的因子 B (FB) 之 Bb 次單元之 C3bBb 特異性結合。在一個實施例中，本發明之抗體與包含具有 D279G、K350N 及 M458I 突變的因子 B (FB) (較佳地具有 SEQ ID NO: 493 之胺基酸序列的 FB) 之 Bb 次單元的穩定化 C3bBb 特異性結合。Therefore, the antibodies of the present invention specifically bind to stabilized C3bBb, in particular, C3bBb comprising a Bb subunit of factor B (FB) having a D279G mutation and, optionally, mutations K350N and/or M458I. In one embodiment, the antibodies of the present invention specifically bind to stabilized C3bBb comprising a Bb subunit of factor B (FB) having D279G, K350N and M458I mutations (preferably a FB having the amino acid sequence of SEQ ID NO: 493).

因此，本發明的一個態樣係結合人類 C3bBb 之抗體，該人類 C3bBb 包含具有 D279G、K350N 及 M458I 突變的重組因子 B (FB) (較佳地具有 SEQ ID NO: 493 之胺基酸序列的 FB) 之 Bb 次單元，其抑制替代途徑。Thus, one aspect of the invention is an antibody that binds to human C3bBb comprising a Bb subunit of a recombinant factor B (FB) having D279G, K350N, and M458I mutations (preferably a FB having the amino acid sequence of SEQ ID NO: 493), which inhibits the alternative pathway.

而且，本發明之抗體特異性結合野生型人類 C3bBb (實例 14)，並且能夠抑制替代途徑 (實例 9)。Furthermore, the antibodies of the present invention specifically bind to wild-type human C3bBb (Example 14) and are capable of inhibiting the alternative pathway (Example 9).

本發明之抗體結合人類 C3bBb 上的抗原決定基，該抗原決定基包括人類 C3bBb 之 C3b 次單元之胺基酸殘基及 Bb 次單元之胺基酸殘基。這可以藉由使用穩定化 C3bBb 作為目標抗原篩選抗體來實現，例如藉由本文所述之方法。The antibodies of the present invention bind to an antigenic determinant on human C3bBb, which antigenic determinant includes amino acid residues of the C3b subunit and amino acid residues of the Bb subunit of human C3bBb. This can be achieved by screening antibodies using stabilized C3bBb as a target antigen, for example, by the methods described herein.

本發明之抗體的抗原決定基可以藉由本領域已知的方法來鑑定，例如藉由低溫電子顯微鏡。藉由抗體與 C3bBb (實例 4) 的三聚體複合物的低溫電子顯微鏡分析本發明之 P1AF8499 (#20，參見實例 2 及 4)。如圖 1 所示，該抗原決定基係包括人類 C3bBb 之 C3b 次單元之胺基酸殘基及 Bb 次單元之胺基酸殘基的構形抗原決定基，這導致該抗體與 C3bBb 特異性結合，而對其次單元 C3b 及 Bb 不顯示相關的結合活性。使用低溫電子顯微鏡來鑑定本發明之抗體所結合之胺基酸 (實例 4 的表 E5)。The antigenic determinant of the antibody of the present invention can be identified by methods known in the art, such as by cryogenic electron microscopy. P1AF8499 of the present invention (#20, see Examples 2 and 4) was analyzed by cryogenic electron microscopy of the trimeric complex of the antibody and C3bBb (Example 4). As shown in Figure 1, the antigenic determinant is a conformational antigenic determinant including amino acid residues of the C3b subunit and amino acid residues of the Bb subunit of human C3bBb, which results in the antibody specifically binding to C3bBb, while not showing relevant binding activity to its subunits C3b and Bb. Cryogenic electron microscopy was used to identify the amino acids bound by the antibody of the present invention (Table E5 of Example 4).

在本發明的一個態樣，抗體結合在野生型人類 C3bBb 上包含下列胺基酸殘基之抗原決定基，藉由低溫電子顯微鏡所檢測，較佳地使用根據實例 4 之方法檢測： -       C3b 次單元：Arg444、Lys534、Gly539、Ser540、Val524、Lys544、Gly546、Gln547、Ser548、Arg551、Gln557、Gln558、Thr560、Lys562、Glu564、Glu758、Pro759、Lys761、Asn762、Ile764、Leu768、Asn770、Asp797，以及 -       Bb 次單元：Tyr465、Lys473、Ile474、Ser475、Ile477、Gly482、His483、Lys513、Val514、Ser515、Lys520、Arg521、Asp522、Glu610 及 Lys613。In one aspect of the invention, the antibody binds to an antigenic determinant comprising the following amino acid residues on wild-type human C3bBb, as detected by cryogenic electron microscopy, preferably using the method according to Example 4: -       C3b subunit: Arg444, Lys534, Gly539, Ser540, Val524, Lys544, Gly546, Gln547, Ser548, Arg551, Gln557, Gln558, Thr560, Lys562, Glu564, Glu758, Pro759, Lys761, Asn762, Ile764, Leu768, Asn770, Asp797, and -       Bb Subunits: Tyr465, Lys473, Ile474, Ser475, Ile477, Gly482, His483, Lys513, Val514, Ser515, Lys520, Arg521, Asp522, Glu610 and Lys613.

在一個實施例中，抗體結合與具有以下之抗體結合的抗原決定基相同或重疊的抗原決定基：SEQ ID NO: 39 之 VH 域及 SEQ ID NO: 30 之 VL 域。In one embodiment, the antibody binds to an antigenic determinant that is the same as or overlaps with an antigenic determinant that binds to the antibody having: a VH domain of SEQ ID NO: 39 and a VL domain of SEQ ID NO: 30.

以噬菌體文庫淘選及直接產生的抗體的進一步工程化來完成與人類 C3bBb 結合之抗體的篩選，從而產生被鑑定為與穩定化 C3bBb 結合之多種抗體。抗體之 VH 及 VL 域之胺基酸序列如表 D1 所示。表D1：抗 C3bBb 抗體之可變重鏈域及可變輕鏈域之胺基酸序列號#標識符VH (SEQ ID NO:)VL (SEQ ID NO:)1P1AG9426IgG122P1AG9376IgG343P1AG9372IgG564P1AG9420IgG785P1AG9391IgG9106P1AH1205Fab11127P1AH1199Fab13148C3bBb.P045.072Fab15169C3bBb.P045.236Fab171810C3bBb.P045.225Fab192011C3bBb.P048.152Fab212212C3bBb.P048.061Fab232413C3bBb.P048.127Fab252614C3bBb.P048.241Fab272815C3bBb.P048.230Fab293016C3bBb.P048.204Fab313217C3bBb.P048.333Fab333418C3bBb.P053.095Fab353619C3bBb.P055.015Fab373820P1AF8499Fab394021GQ-5_1Fab414222GQ-11_1Fab434423PT5622.F19Fab454624PT5624.P06Fab474825PT5624.M09Fab495026PT5626.M10Fab515227PT5626.C10Fab535428PT5628.E16Fab555629PT5630.D05Fab575830PT5630.A20Fab596031PT5632.A13Fab616232PT5634.N13Fab636433PT5634.M24Fab656634PT5636.P22Fab676835PT5625.G07Fab697036PT5627.M20Fab717237PT5627.M12Fab737438PT5629.F09Fab757639PT5629.H08Fab777840PT5631.D21Fab798041PT5633.I03Fab818242PT5635.C08Fab838443PT5639.G15Fab858644PT5622.A20Fab878845PT5622.C12Fab899046PT5622.G24Fab919247PT5622.I20Fab939448PT5622.J24Fab959649PT5624.A21Fab979850PT5624.B10Fab9910051PT5624.N05Fab10110252PT5624.P11Fab10310453PT5626.A12Fab10510654PT5626.N08Fab10710855PT5626.N18Fab10911056PT5626.O09Fab11111257PT5628.B13Fab11311458PT5628.C21Fab11511659PT5628.E12Fab11711860PT5628.I07Fab11912061PT5628.P14Fab12112262PT5630.G05Fab12312463PT5630.K04Fab12512664PT5630.M11Fab12712865PT5630.N06Fab12913066PT5630.O08Fab13113267PT5632.A10Fab13313468PT5632.A15Fab13513669PT5632.B15Fab13713870PT5632.D11Fab13914071PT5632.J23Fab14114272PT5634.A17Fab14314473PT5634.A21Fab14514674PT5634.K10Fab14714875PT5634.M16Fab14915076PT5634.N11Fab15115277PT5634.P19Fab15315478PT5636.A16Fab15515679PT5636.D21Fab15715880PT5636.M03Fab15916081PT5636.N13Fab16116282PT5636.P11Fab16316483PT5636.P15Fab16516684PT5638.C06Fab16716885PT5638.C20Fab16917086PT5638.E14Fab17117287PT5638.J23Fab17317488PT5638.O14Fab17517689PT5638.P12Fab17717890PT5623.E21Fab17918091PT5623.F17Fab18118292PT5623.G08Fab18318493PT5623.H05Fab18518694PT5623.O08Fab18718895PT5625.A05Fab18919096PT5625.B14Fab19119297PT5625.C15Fab19319498PT5625.G05Fab19519699PT5625.L22Fab197198100PT5625.O14Fab199200101PT5627.I21Fab201202102PT5629.F04Fab203204103PT5629.L22Fab205206104PT5629.L24Fab207208105PT5629.M15Fab209210106PT5631.H06Fab211212107PT5631.K12Fab213214108PT5631.N17Fab215216109PT5631.P07Fab217218110PT5633.E09Fab219220111PT5633.G19Fab221222112PT5635.F04Fab223224113PT5635.L21Fab225226114PT5635.O15Fab227228115PT5637.B23Fab229230116PT5637.C20Fab231232117PT5637.K09Fab233234118PT5637.L15Fab235236119PT5637.M03Fab237238120PT5637.P15Fab239240121PT5639.B15Fab241242122PT5639.P05Fab243244123PT5625.G07_22.F19_2Fab245246124PT5625.G07_24.M09_1Fab247248125PT5625.G07_24.P06_2Fab249250126PT5625.G07_26.C10_1Fab251252127PT5625.G07_26.M10_2Fab253254128PT5625.G07_28.E16_1Fab255256129PT5625.G07_30.A20_1Fab257258130PT5625.G07_32.A13_2Fab259260131PT5625.G07_34.M24_1Fab261262132PT5625.G07_34.N13_3Fab263264133PT5625.G07_36.P22_1Fab265266134PT5627.M20_24.M09_1Fab267268135PT5627.M20_24.P06_1Fab269270136PT5627.M20_26.C10_1Fab271272137PT5627.M20_26.M10_2Fab273274138PT5627.M20_28.E16_2Fab275276139PT5627.M20_30.D05_1Fab277278140PT5627.M20_32.A13_1Fab279280141PT5627.M20_34.M24_2Fab281282142PT5627.M20_34.N13_4Fab283284143PT5627.M20_36.P22_1Fab285286144PT5627.M12_22.F19_1Fab287288145PT5627.M12_24.M09_1Fab289290146PT5627.M12_26.M10_2Fab291292147PT5627.M12_32.A13_2Fab293294148PT5627.M12_34.M24_2Fab295296149PT5627.M12_34.N13_1Fab297298150PT5629.F09_26.C10_1Fab299300151PT5629.F09_28.E16_1Fab301302152PT5629.F09_30.A20_1Fab303304153PT5629.F09_30.D05_1Fab305306154PT5629.F09_32.A13_3Fab307308155PT5629.F09_36.P22_2Fab309310156PT5629.H08_22.F19_4Fab311312157PT5629.H08_24.M09_4Fab313314158PT5629.H08_24.P06_2Fab315316159PT5629.H08_26.C10_1Fab317318160PT5629.H08_26.M10_1Fab319320161PT5629.H08_28.E16_2Fab321322162PT5629.H08_30.A20_2Fab323324163PT5629.H08_30.D05_1Fab325326164PT5629.H08_32.A13_1Fab327328165PT5629.H08_34.M24_2Fab329330166PT5629.H08_34.N13_2Fab331332167PT5629.H08_36.P22_4Fab333334168PT5631.D21_22.F19_2Fab335336169PT5631.D21_24.M09_1Fab337338170PT5631.D21_24.P06_4Fab339340171PT5631.D21_26.C10_1Fab341342172PT5631.D21_26.M10_4Fab343344173PT5631.D21_28.E16_3Fab345346174PT5631.D21_30.A20_4Fab347348175PT5631.D21_30.D05_1Fab349350176PT5631.D21_32.A13_4Fab351352177PT5631.D21_34.M24_4Fab353354178PT5631.D21_34.N13_2Fab355356179PT5631.D21_36.P22_3Fab357358180PT5633.I03_22.F19_1Fab359360181PT5633.I03_24.M09_1Fab361362182PT5633.I03_24.P06_4Fab363364183PT5633.I03_26.C10_1Fab365366184PT5633.I03_26.M10_4Fab367368185PT5633.I03_28.E16_4Fab369370186PT5633.I03_30.A20_1Fab371372187PT5633.I03_30.D05_1Fab373374188PT5633.I03_32.A13_1Fab375376189PT5633.I03_34.M24_2Fab377378190PT5633.I03_34.N13_1Fab379380191PT5633.I03_36.P22_2Fab381382192PT5635.C08_22.F19_1Fab383384193PT5635.C08_24.M09_1Fab385386194PT5635.C08_24.P06_1Fab387388195PT5635.C08_26.C10_1Fab389390196PT5635.C08_26.M10_2Fab391392197PT5635.C08_28.E16_1Fab393394198PT5635.C08_30.A20_1Fab395396199PT5635.C08_30.D05_3Fab397398200PT5635.C08_32.A13_3Fab399400201PT5635.C08_34.M24_2Fab401402202PT5635.C08_34.N13_1Fab403404203PT5635.C08_36.P22_1Fab405406204PT5639.G15_22.F19_2Fab407408205PT5639.G15_24.P06_1Fab409410206PT5639.G15_24.M09_4Fab411412207PT5639.G15_26.M10_3Fab413414208PT5639.G15_28.E16_1Fab415416209PT5639.G15_30.A20_1Fab417418210PT5639.G15_30.D05_1Fab419420211PT5639.G15_34.N13_4Fab421422212PT5639.G15_34.M24_3Fab423424213PT5639.G15_36.P22_3Fab425426214PT5625.G07_30.D05_1Fab427428215PT5627.M12_26.C10_1Fab429430216PT5627.M12_30.A20_2Fab431432217PT5629.F09_34.N13_3Fab433434衍生自抗體篩選之抗體Screening of antibodies that bind to human C3bBb was accomplished by panning with a phage library and further engineering of the directly generated antibodies, resulting in a variety of antibodies that were identified as binding to stabilized C3bBb. The amino acid sequences of the VH and VL domains of the antibodies are shown in Table D1.TableD1: Amino acid sequence numbers of the variable heavy and variable light domains of anti-C3bBb antibodies#IdentifierVH (SEQ ID NO:)VL (SEQ ID NO:) 1 P1AG9426 IgG 1 2 2 P1AG9376 IgG 3 4 3 P1AG9372 IgG 5 6 4 P1AG9420 IgG 7 8 5 P1AG9391 IgG 9 10 6 P1AH1205 Fab 11 12 7 P1AH1199 Fab 13 14 8 C3bBb.P045.072 Fab 15 16 9 C3bBb.P045.236 Fab 17 18 10 C3bBb.P045.225 Fab 19 20 11 C3bBb.P048.152 Fab twenty one twenty two 12 C3bBb.P048.061 Fab twenty three twenty four 13 C3bBb.P048.127 Fab 25 26 14 C3bBb.P048.241 Fab 27 28 15 C3bBb.P048.230 Fab 29 30 16 C3bBb.P048.204 Fab 31 32 17 C3bBb.P048.333 Fab 33 34 18 C3bBb.P053.095 Fab 35 36 19 C3bBb.P055.015 Fab 37 38 20 P1AF8499 Fab 39 40 twenty one GQ-5_1 Fab 41 42 twenty two GQ-11_1 Fab 43 44 twenty three PT5622.F19 Fab 45 46 twenty four PT5624.P06 Fab 47 48 25 PT5624.M09 Fab 49 50 26 PT5626.M10 Fab 51 52 27 PT5626.C10 Fab 53 54 28 PT5628.E16 Fab 55 56 29 PT5630.D05 Fab 57 58 30 PT5630.A20 Fab 59 60 31 PT5632.A13 Fab 61 62 32 PT5634.N13 Fab 63 64 33 PT5634.M24 Fab 65 66 34 PT5636.P22 Fab 67 68 35 PT5625.G07 Fab 69 70 36 PT5627.M20 Fab 71 72 37 PT5627.M12 Fab 73 74 38 PT5629.F09 Fab 75 76 39 PT5629.H08 Fab 77 78 40 PT5631.D21 Fab 79 80 41 PT5633.I03 Fab 81 82 42 PT5635.C08 Fab 83 84 43 PT5639.G15 Fab 85 86 44 PT5622.A20 Fab 87 88 45 PT5622.C12 Fab 89 90 46 PT5622.G24 Fab 91 92 47 PT5622.I20 Fab 93 94 48 PT5622.J24 Fab 95 96 49 PT5624.A21 Fab 97 98 50 PT5624.B10 Fab 99 100 51 PT5624.N05 Fab 101 102 52 PT5624.P11 Fab 103 104 53 PT5626.A12 Fab 105 106 54 PT5626.N08 Fab 107 108 55 PT5626.N18 Fab 109 110 56 PT5626.O09 Fab 111 112 57 PT5628.B13 Fab 113 114 58 PT5628.C21 Fab 115 116 59 PT5628.E12 Fab 117 118 60 PT5628.I07 Fab 119 120 61 PT5628.P14 Fab 121 122 62 PT5630.G05 Fab 123 124 63 PT5630.K04 Fab 125 126 64 PT5630.M11 Fab 127 128 65 PT5630.N06 Fab 129 130 66 PT5630.O08 Fab 131 132 67 PT5632.A10 Fab 133 134 68 PT5632.A15 Fab 135 136 69 PT5632.B15 Fab 137 138 70 PT5632.D11 Fab 139 140 71 PT5632.J23 Fab 141 142 72 PT5634.A17 Fab 143 144 73 PT5634.A21 Fab 145 146 74 PT5634.K10 Fab 147 148 75 PT5634.M16 Fab 149 150 76 PT5634.N11 Fab 151 152 77 PT5634.P19 Fab 153 154 78 PT5636.A16 Fab 155 156 79 PT5636.D21 Fab 157 158 80 PT5636.M03 Fab 159 160 81 PT5636.N13 Fab 161 162 82 PT5636.P11 Fab 163 164 83 PT5636.P15 Fab 165 166 84 PT5638.C06 Fab 167 168 85 PT5638.C20 Fab 169 170 86 PT5638.E14 Fab 171 172 87 PT5638.J23 Fab 173 174 88 PT5638.O14 Fab 175 176 89 PT5638.P12 Fab 177 178 90 PT5623.E21 Fab 179 180 91 PT5623.F17 Fab 181 182 92 PT5623.G08 Fab 183 184 93 PT5623.H05 Fab 185 186 94 PT5623.O08 Fab 187 188 95 PT5625.A05 Fab 189 190 96 PT5625.B14 Fab 191 192 97 PT5625.C15 Fab 193 194 98 PT5625.G05 Fab 195 196 99 PT5625.L22 Fab 197 198 100 PT5625.O14 Fab 199 200 101 PT5627.I21 Fab 201 202 102 PT5629.F04 Fab 203 204 103 PT5629.L22 Fab 205 206 104 PT5629.L24 Fab 207 208 105 PT5629.M15 Fab 209 210 106 PT5631.H06 Fab 211 212 107 PT5631.K12 Fab 213 214 108 PT5631.N17 Fab 215 216 109 PT5631.P07 Fab 217 218 110 PT5633.E09 Fab 219 220 111 PT5633.G19 Fab 221 222 112 PT5635.F04 Fab 223 224 113 PT5635.L21 Fab 225 226 114 PT5635.O15 Fab 227 228 115 PT5637.B23 Fab 229 230 116 PT5637.C20 Fab 231 232 117 PT5637.K09 Fab 233 234 118 PT5637.L15 Fab 235 236 119 PT5637.M03 Fab 237 238 120 PT5637.P15 Fab 239 240 121 PT5639.B15 Fab 241 242 122 PT5639.P05 Fab 243 244 123 PT5625.G07_22.F19_2 Fab 245 246 124 PT5625.G07_24.M09_1 Fab 247 248 125 PT5625.G07_24.P06_2 Fab 249 250 126 PT5625.G07_26.C10_1 Fab 251 252 127 PT5625.G07_26.M10_2 Fab 253 254 128 PT5625.G07_28.E16_1 Fab 255 256 129 PT5625.G07_30.A20_1 Fab 257 258 130 PT5625.G07_32.A13_2 Fab 259 260 131 PT5625.G07_34.M24_1 Fab 261 262 132 PT5625.G07_34.N13_3 Fab 263 264 133 PT5625.G07_36.P22_1 Fab 265 266 134 PT5627.M20_24.M09_1 Fab 267 268 135 PT5627.M20_24.P06_1 Fab 269 270 136 PT5627.M20_26.C10_1 Fab 271 272 137 PT5627.M20_26.M10_2 Fab 273 274 138 PT5627.M20_28.E16_2 Fab 275 276 139 PT5627.M20_30.D05_1 Fab 277 278 140 PT5627.M20_32.A13_1 Fab 279 280 141 PT5627.M20_34.M24_2 Fab 281 282 142 PT5627.M20_34.N13_4 Fab 283 284 143 PT5627.M20_36.P22_1 Fab 285 286 144 PT5627.M12_22.F19_1 Fab 287 288 145 PT5627.M12_24.M09_1 Fab 289 290 146 PT5627.M12_26.M10_2 Fab 291 292 147 PT5627.M12_32.A13_2 Fab 293 294 148 PT5627.M12_34.M24_2 Fab 295 296 149 PT5627.M12_34.N13_1 Fab 297 298 150 PT5629.F09_26.C10_1 Fab 299 300 151 PT5629.F09_28.E16_1 Fab 301 302 152 PT5629.F09_30.A20_1 Fab 303 304 153 PT5629.F09_30.D05_1 Fab 305 306 154 PT5629.F09_32.A13_3 Fab 307 308 155 PT5629.F09_36.P22_2 Fab 309 310 156 PT5629.H08_22.F19_4 Fab 311 312 157 PT5629.H08_24.M09_4 Fab 313 314 158 PT5629.H08_24.P06_2 Fab 315 316 159 PT5629.H08_26.C10_1 Fab 317 318 160 PT5629.H08_26.M10_1 Fab 319 320 161 PT5629.H08_28.E16_2 Fab 321 322 162 PT5629.H08_30.A20_2 Fab 323 324 163 PT5629.H08_30.D05_1 Fab 325 326 164 PT5629.H08_32.A13_1 Fab 327 328 165 PT5629.H08_34.M24_2 Fab 329 330 166 PT5629.H08_34.N13_2 Fab 331 332 167 PT5629.H08_36.P22_4 Fab 333 334 168 PT5631.D21_22.F19_2 Fab 335 336 169 PT5631.D21_24.M09_1 Fab 337 338 170 PT5631.D21_24.P06_4 Fab 339 340 171 PT5631.D21_26.C10_1 Fab 341 342 172 PT5631.D21_26.M10_4 Fab 343 344 173 PT5631.D21_28.E16_3 Fab 345 346 174 PT5631.D21_30.A20_4 Fab 347 348 175 PT5631.D21_30.D05_1 Fab 349 350 176 PT5631.D21_32.A13_4 Fab 351 352 177 PT5631.D21_34.M24_4 Fab 353 354 178 PT5631.D21_34.N13_2 Fab 355 356 179 PT5631.D21_36.P22_3 Fab 357 358 180 PT5633.I03_22.F19_1 Fab 359 360 181 PT5633.I03_24.M09_1 Fab 361 362 182 PT5633.I03_24.P06_4 Fab 363 364 183 PT5633.I03_26.C10_1 Fab 365 366 184 PT5633.I03_26.M10_4 Fab 367 368 185 PT5633.I03_28.E16_4 Fab 369 370 186 PT5633.I03_30.A20_1 Fab 371 372 187 PT5633.I03_30.D05_1 Fab 373 374 188 PT5633.I03_32.A13_1 Fab 375 376 189 PT5633.I03_34.M24_2 Fab 377 378 190 PT5633.I03_34.N13_1 Fab 379 380 191 PT5633.I03_36.P22_2 Fab 381 382 192 PT5635.C08_22.F19_1 Fab 383 384 193 PT5635.C08_24.M09_1 Fab 385 386 194 PT5635.C08_24.P06_1 Fab 387 388 195 PT5635.C08_26.C10_1 Fab 389 390 196 PT5635.C08_26.M10_2 Fab 391 392 197 PT5635.C08_28.E16_1 Fab 393 394 198 PT5635.C08_30.A20_1 Fab 395 396 199 PT5635.C08_30.D05_3 Fab 397 398 200 PT5635.C08_32.A13_3 Fab 399 400 201 PT5635.C08_34.M24_2 Fab 401 402 202 PT5635.C08_34.N13_1 Fab 403 404 203 PT5635.C08_36.P22_1 Fab 405 406 204 PT5639.G15_22.F19_2 Fab 407 408 205 PT5639.G15_24.P06_1 Fab 409 410 206 PT5639.G15_24.M09_4 Fab 411 412 207 PT5639.G15_26.M10_3 Fab 413 414 208 PT5639.G15_28.E16_1 Fab 415 416 209 PT5639.G15_30.A20_1 Fab 417 418 210 PT5639.G15_30.D05_1 Fab 419 420 211 PT5639.G15_34.N13_4 Fab 421 422 212 PT5639.G15_34.M24_3 Fab 423 424 213 PT5639.G15_36.P22_3 Fab 425 426 214 PT5625.G07_30.D05_1 Fab 427 428 215 PT5627.M12_26.C10_1 Fab 429 430 216 PT5627.M12_30.A20_2 Fab 431 432 217 PT5629.F09_34.N13_3 Fab 433 434Antibodies derived from antibody screening

本文所揭示之 217 種抗體中之各種均作為一項發明揭示，由其 6 個 CDR 來定義，該 6 個 CDR 衍生自表 D1 所示的其 VH 域胺基酸序列及其 VL 胺基酸序列之胺基酸序列。可替代地，本發明之抗體的特徵在於具有如表 D1 中所示之 VH 胺基酸序列的 VH 域及具有如表 D1 中所示之 VL 胺基酸序列的 VL 域。Each of the 217 antibodies disclosed herein is disclosed as an invention, defined by its 6 CDRs derived from the amino acid sequences of its VH domain amino acid sequence and its VL amino acid sequence as shown in Table D1. Alternatively, the antibodies of the invention are characterized by a VH domain having a VH amino acid sequence as shown in Table D1 and a VL domain having a VL amino acid sequence as shown in Table D1.

本發明的一個態樣係與人類 C3bBb 特異性結合之抗體，該人類 C3bBb 包含表 D1 的抗體中任一者的一組六個 CDR。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。One aspect of the present invention is an antibody that specifically binds to human C3bBb, wherein the human C3bBb comprises a set of six CDRs of any of the antibodies in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any of the antibodies in Table D1.

在一個態樣中，本發明涉及選自如表 D1 的第一列中所示之抗體 #1 至抗體 #217 的抗體，其中該抗體包含一組六個 CDR，如衍生自如表 D1 中所示之其各自 VH 域胺基酸序列及其各自 VL 胺基酸序列的胺基酸序列。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。In one aspect, the present invention relates to an antibody selected from Antibody #1 to Antibody #217 as shown in the first column of Table D1, wherein the antibody comprises a set of six CDRs, such as amino acid sequences derived from their respective VH domain amino acid sequences and their respective VL amino acid sequences as shown in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any one of the antibodies in Table D1.

在一個態樣中，本發明涉及選自如表 D1 的第一列中所示之抗體 #1 至抗體 #122 的抗體，其中該抗體包含一組六個 CDR，如衍生自如表 D1 中所示之其各自 VH 域胺基酸序列及其各自 VL 胺基酸序列的胺基酸序列。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。In one aspect, the present invention relates to an antibody selected from Antibody #1 to Antibody #122 as shown in the first column of Table D1, wherein the antibody comprises a set of six CDRs, such as amino acid sequences derived from their respective VH domain amino acid sequences and their respective VL amino acid sequences as shown in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any one of the antibodies in Table D1.

在一個態樣中，本發明涉及選自如表 D1 的第一列中所示之抗體 #1 至抗體 #7 及 #22 至 #217 的抗體，其中該抗體包含一組六個 CDR，如衍生自如表 D1 中所示之其各自 VH 域胺基酸序列及其各自 VL 胺基酸序列的胺基酸序列。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。In one aspect, the present invention relates to an antibody selected from Antibody #1 to Antibody #7 and #22 to #217 as shown in the first column of Table D1, wherein the antibody comprises a set of six CDRs, such as amino acid sequences derived from their respective VH domain amino acid sequences and their respective VL amino acid sequences as shown in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any one of the antibodies in Table D1.

在一個態樣中，本發明涉及選自如表 D1 的第一列中所示之抗體 #1 至抗體 #7 及 #22 至 #122 的抗體，其中該抗體包含一組六個 CDR，如衍生自如表 D1 中所示之其各自 VH 域胺基酸序列及其各自 VL 胺基酸序列的胺基酸序列。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。In one aspect, the present invention relates to an antibody selected from Antibody #1 to Antibody #7 and #22 to #122 as shown in the first column of Table D1, wherein the antibody comprises a set of six CDRs, such as amino acid sequences derived from their respective VH domain amino acid sequences and their respective VL amino acid sequences as shown in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any one of the antibodies in Table D1.

在一個態樣中，本發明涉及選自如表 D1 的第一列中所示之抗體 #1 至抗體 #7 的抗體，其中該抗體包含一組六個 CDR，如衍生自如表 D1 中所示之其各自 VH 域胺基酸序列及其各自 VL 胺基酸序列的胺基酸序列。在一個實施例中，抗體包含表 D1 的抗體中任一者的可變輕鏈胺基酸序列及可變重鏈胺基酸序列。In one aspect, the present invention relates to an antibody selected from Antibody #1 to Antibody #7 as shown in the first column of Table D1, wherein the antibody comprises a set of six CDRs, such as amino acid sequences derived from their respective VH domain amino acid sequences and their respective VL amino acid sequences as shown in Table D1. In one embodiment, the antibody comprises a variable light chain amino acid sequence and a variable heavy chain amino acid sequence of any one of the antibodies in Table D1.

在一個態樣中，本發明涉及衍生自如表 D1 的第一列中所示的抗體 #22 的抗體。In one aspect, the invention relates to an antibody derived from antibody #22 as shown in the first column of Table D1.

本發明的另一態樣係與人類 C3bBb 特異性結合之抗體，該人類 C3bBb 包含表 D1 的抗體中任一者的一組 VH 及 VL 域。Another aspect of the present invention is an antibody that specifically binds to human C3bBb, wherein the human C3bBb comprises a set of VH and VL domains of any one of the antibodies in Table D1.

在一個實施例中，抗體包含表 E4 的抗體中任一者的一組六個 CDR。在另一實施例中，抗體包含表 E4 的抗體中任一者的一組 VH 及 VL 域。個別抗體抗體 P1AG9426In one embodiment, the antibody comprises a set of six CDRs of any of the antibodies of Table E4. In another embodiment, the antibody comprises a set of VH and VL domains of any of the antibodies of Table E4.Individual Antibodies Antibody P1AG9426

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列的 CDR-L3 (對應於抗體 #1，P1AG9426)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:449; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:450; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:451; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:452; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:453; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:454 (corresponding to antibody #1, P1AG9426).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:1 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:2 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:1 之 VH 的 CDR 序列及 SEQ ID NO:2 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 1. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 2. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 1 and the CDR sequences of the VL of SEQ ID NO: 2.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:1 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:2 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 1 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 2.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:1 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:1 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:1 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:1 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:1 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:1 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:1 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:1 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 1; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 1. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 1; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 1. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 1; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 1. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 1; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 1.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:2 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:2 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:2 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:2 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:2 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:2 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:2 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:2 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 2; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 2. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 2; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 2. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 2; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 2. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 2; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 2.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:1 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:2 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 1 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 2 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:449; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:450; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:451; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:452; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:453; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:454; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:1; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 2.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:1 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:2 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 1 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 2 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:1 之 VH 序列及 SEQ ID NO:2 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:449; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:450; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:451; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:452; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:453; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:454; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:1; and a VL In one aspect, the antibody comprises a VH domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10 times or increased by up to 10 times compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 2.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:1 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:2 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 1 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 1 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 450 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 451 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:2 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:2 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 2 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 2 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 452 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 453 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 454 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 1. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 1, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 1, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 449; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 450; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 451. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. In certain aspects, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 2, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence in SEQ ID NO: 2, including post-translational modifications of the sequence. In a specific aspect, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 452; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 453; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 454.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:1 及 SEQ ID NO:2 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:435 之重鏈胺基酸序列及 SEQ ID NO:436 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:435 and a light chain amino acid sequence of SEQ ID NO:436.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:435 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:436 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AG9376In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:435, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:436.Antibody P1AG9376

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列的 CDR-L3 (對應於抗體 #2，P1AG9376)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:455; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:456; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:457; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:458; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:459; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:460 (corresponding to antibody #2, P1AG9376).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:3 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:4 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:3 之 VH 的 CDR 序列及 SEQ ID NO:4 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 3. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 4. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 3 and the CDR sequences of the VL of SEQ ID NO: 4.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:3 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:4 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:3 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:4.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:3 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:3 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:3 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:3 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:3 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:3 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:3 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:3 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 3; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 3. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 3; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 3. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 3; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 3. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 3; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 3.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:4 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:4 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:4 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:4 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:4 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:4 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:4 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:4 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 4; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 4. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 4; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 4. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 4; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 4. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 4; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 4.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:3 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:4 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 3 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 4 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:455; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:456; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:457; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:458; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:459; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:460; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:3; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 3. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 4.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:3 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:4 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 3 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 4 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:3 之 VH 序列及 SEQ ID NO:4 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:455; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:456; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:457; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:458; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:459; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:460; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:3; and a VL In one aspect, the antibody comprises a VH domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 3. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 4. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10 times or increased by up to 10 times compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 4.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:3 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:4 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 3 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 3 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 456 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 457 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:4 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:4 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 4 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 4 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 458 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 459 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 460 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 4. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 3, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 3, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 455; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 456; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 457. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 4. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 4. In certain aspects, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 4, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence in SEQ ID NO: 4, including post-translational modifications of the sequence. In a specific aspect, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 458; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 459; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 460.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:3 及 SEQ ID NO:4 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 3 and SEQ ID NO: 4, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:437 之重鏈胺基酸序列及 SEQ ID NO:438 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:437 and a light chain amino acid sequence of SEQ ID NO:438.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:437 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:438 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AG9372In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:437, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:438.Antibody P1AG9372

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列的 CDR-L3 (對應於抗體 #3，P1AG9372)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:461; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:462; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:463; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:464; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:465; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:466 (corresponding to antibody #3, P1AG9372).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:5 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:6 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:5 之 VH 的 CDR 序列及 SEQ ID NO:6 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 5. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 6. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 5 and the CDR sequences of the VL of SEQ ID NO: 6.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:5 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:6 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:5 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:6.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:5 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:5 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:5 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:5 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:5 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:5 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:5 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:5 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:5; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO:5. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:5; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO:5. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 5; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 5. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 5; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 5.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:6 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:6 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:6 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:6 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:6 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:6 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:6 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:6 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 6; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 6. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 6; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 6. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 6; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 6. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 6; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 6.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:5 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:6 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 5 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 6 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:461; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:462; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:463; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:464; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:465; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:466; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:5; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 5. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 6.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:5 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:6 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 5 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 6 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:5 之 VH 序列及 SEQ ID NO:6 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:461; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:462; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:463; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:464; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:465; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:466; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:5; and a VL In one aspect, the antibody comprises a VH domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 5. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10 times or increased by up to 10 times compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 6.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:5 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:6 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 5 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 5 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 462 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 463 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:6 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:6 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 6 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 6 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 464 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 465 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 466 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 5, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 5, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 461; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 462; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 463. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 6. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6. In certain aspects, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 6, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence in SEQ ID NO: 6, including post-translational modifications of the sequence. In a specific aspect, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 464; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 465; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 466.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:5 及 SEQ ID NO:6 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:439 之重鏈胺基酸序列及 SEQ ID NO:440 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:439 and a light chain amino acid sequence of SEQ ID NO:440.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:439 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:440 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AG9420In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:439, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:440.Antibody P1AG9420

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列的 CDR-L3 (對應於抗體 #4，P1AG9420)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:467; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:468; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:469; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:470; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:471; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:472 (corresponding to antibody #4, P1AG9420).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:7 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:8 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:7 之 VH 的 CDR 序列及 SEQ ID NO:8 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 7. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 8. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 7 and the CDR sequences of the VL of SEQ ID NO: 8.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:7 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:8 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:7 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:8.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:7 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:7 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:7 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:7 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:7 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:7 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:7 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:7 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 7; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 7. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 7; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 7. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 7; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 7. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 7; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 7.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:8 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:8 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:8 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:8 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:8 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:8 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:8 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:8 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 8; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 8. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 8; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 8. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 8; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 8. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 8; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 8.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:7 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:8 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 7 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 8 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:467; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:468; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:469; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:470; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:471; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:472; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:7; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:7 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:8 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 7 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 8 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:7 之 VH 序列及 SEQ ID NO:8 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 467; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 468; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 469; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 470; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 471; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 472; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 7; and a VL In one aspect, the antibody comprises a VH domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10 times or increased by up to 10 times compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:7 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:8 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 7 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 7 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 468 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 469 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:8 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:8 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 8 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 8 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 470 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 471 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 472 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 7, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 7, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 467; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 468; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 469. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain aspects, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 8, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence in SEQ ID NO: 8, including post-translational modifications of the sequence. In a specific aspect, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 470; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 471; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 472.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:7 及 SEQ ID NO:8 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:441 之重鏈胺基酸序列及 SEQ ID NO:442 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:441 and a light chain amino acid sequence of SEQ ID NO:442.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:441 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:442 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AG9391In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:441, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:442.Antibody P1AG9391

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列的 CDR-L3 (對應於抗體 #5，P1AG9391)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO:473; (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO:474; (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO:475; (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO:476; (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO:477; and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO:478 (corresponding to antibody #5, P1AG9391).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:9 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:10 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:9 之 VH 的 CDR 序列及 SEQ ID NO:10 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 9. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 10. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 9 and the CDR sequences of the VL of SEQ ID NO: 10.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:9 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:10 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO:9 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO:10.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:9 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:9 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:9 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:9 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:9 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:9 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:9 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:9 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 9; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 9. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 9; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 9. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 9; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 9. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 9; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 9.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:10 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:10 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:10 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:10 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:10 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:10 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:10 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:10 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 10; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 10. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 10; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 10. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 10; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 10. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 10; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 10.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:9 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:10 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 9 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 10 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 473; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 474; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 475; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 476; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 477; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 478; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 9; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 10.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:9 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:10 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 9 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 10 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:9 之 VH 序列及 SEQ ID NO:10 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 473; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 474; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 475; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 476; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 477; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 478; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 9; and a VL In one aspect, the antibody comprises a VH domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10-fold or increased by up to 10-fold compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 9 and the VL sequence of SEQ ID NO: 10.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:9 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:10 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 9 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 9 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 474 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 475 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:10 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:10 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 10 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 10 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 476 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 477 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 478 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 9. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10. In certain aspects, the VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 9, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 9, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from the following: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 473; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 474; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 475. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 10. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10. In certain aspects, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 10, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence in SEQ ID NO: 10, including post-translational modifications of the sequence. In a specific aspect, VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 476; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 477; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 478.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:9 及 SEQ ID NO:10 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:443 之重鏈胺基酸序列及 SEQ ID NO:444 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:443 and a light chain amino acid sequence of SEQ ID NO:444.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:443 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:444 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AH1205In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:443, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:444.Antibody P1AH1205

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列的 CDR-L3 (對應於抗體 #6，P1AH1205)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:479; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:480; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:481; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:482; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:483; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:484 (corresponding to antibody #6, P1AH1205).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:11 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:12 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:11 之 VH 的 CDR 序列及 SEQ ID NO:12 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 11. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 12. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 11 and the CDR sequences of the VL of SEQ ID NO: 12.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:11 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:12 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 11 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 12.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:11 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:11 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:11 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:11 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:11 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:11 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:11 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:11 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 11; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 11. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 11; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 11. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 11; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 11. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 11; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 11.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:12 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:12 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:12 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:12 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:12 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:12 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:12 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:12 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 12; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 12. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 12; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 12. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 12; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 12. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 12; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 12.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:11 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:12 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 11 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 12 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 479; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 480; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 481; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 482; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 483; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 484; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 11; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 11. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 12.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:11 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:12 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 11 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 12 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:11 之 VH 序列及 SEQ ID NO:12 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 479; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 480; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 481; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 482; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 483; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 484; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 11; and a VL In one aspect, the antibody comprises a VH domain that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 11. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 12. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10-fold or increased by up to 10-fold compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 11 and the VL sequence of SEQ ID NO: 12.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:11 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:12 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 11 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 11 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 480 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 481 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:12 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:12 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 12 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 12 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 482 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 483 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 484 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12. In certain aspects, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 11, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 11, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 479; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 480; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 481. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 12. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12. In certain aspects, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 12, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VL sequence of SEQ ID NO: 12, including post-translational modifications of the sequence. In a specific aspect, the VL comprises one, two or three CDRs selected from the following: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 482; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 483; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 484.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:11 及 SEQ ID NO:12 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 11 and SEQ ID NO: 12, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:445 之重鏈胺基酸序列及 SEQ ID NO:446 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:445 and a light chain amino acid sequence of SEQ ID NO:446.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:445 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:446 所包含之輕鏈恆定域胺基酸序列。 抗體 P1AH1199In one embodiment, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:445, and a VL domain as described above and a light chain constant domain amino acid sequence as contained in SEQ ID NO:446.Antibody P1AH1199

在另一態樣中，本發明提供了一種抗體，其包含：(a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列的 CDR-L3 (對應於抗體 #7，P1AH1199)。In another aspect, the present invention provides an antibody comprising: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:485; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:486; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:487; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:488; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:489; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:490 (corresponding to antibody #7, P1AH1199).

在另一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:13 之 VH 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:14 之 VL 的一個或多個 CDR 序列。在另一實施例中，抗 C3bBb 抗體包含 SEQ ID NO:13 之 VH 的 CDR 序列及 SEQ ID NO:14 之 VL 的 CDR 序列。In another aspect, the anti-C3bBb antibody comprises one or more CDR sequences of the VH of SEQ ID NO: 13. In another embodiment, the anti-C3bBb antibody comprises one or more CDR sequences of the VL of SEQ ID NO: 14. In another embodiment, the anti-C3bBb antibody comprises the CDR sequences of the VH of SEQ ID NO: 13 and the CDR sequences of the VL of SEQ ID NO: 14.

在又一態樣中，抗 C3bBb 抗體包含 SEQ ID NO:13 之 VH 域的 CDR-H1、CDR-H2 及 CDR-H3 胺基酸序列及 SEQ ID NO:14 之 VL 域的 CDR-L1、CDR-L2 及 CDR-L3 胺基酸序列。In another aspect, the anti-C3bBb antibody comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NO: 13 and the CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 14.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:13 之 VH 域的一個或多個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:13 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:13 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:13 之 VH 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:13 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:13 之 VH 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:13 之 VH 域的三個重鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:13 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 13; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO: 13. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 13; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 13. In one aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 13; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 13. In another aspect, the anti-C3bBb antibody comprises: three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 13; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 13.

在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:14 之 VL 域的一個或多個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:14 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:14 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:14 之 VL 域之框架胺基酸序列具有至少 85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 的序列同一性。在一個態樣中，抗 C3bBb 抗體包含：SEQ ID NO:14 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:14 之 VL 域之框架胺基酸序列具有至少 95% 的序列同一性。在另一態樣中，抗 C3bBb 抗體包含：SEQ ID NO:14 之 VL 域的三個輕鏈 CDR 胺基酸序列；及框架，該框架與 SEQ ID NO:14 之 VH 域之框架胺基酸序列具有至少 98% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: one or more light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 14; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO: 14. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 14; and a framework having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 14. In one aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 14; and a framework having at least 95% sequence identity with the framework amino acid sequence of the VL domain of SEQ ID NO: 14. In another aspect, the anti-C3bBb antibody comprises: three light chain CDR amino acid sequences of the VL domain of SEQ ID NO: 14; and a framework having at least 98% sequence identity with the framework amino acid sequence of the VH domain of SEQ ID NO: 14.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列的 CDR-L3；及 VH 域，其與 SEQ ID NO:13 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:14 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性。在一方面，VH 域與 SEQ ID NO: 13 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 14 之胺基酸序列具有至少 95% 的序列同一性。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 485; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 486; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 487; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 488; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 489; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 490; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 13; and a VL In one aspect, the VH domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 13. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 14.

在一個態樣中，抗 C3bBb 抗體包含：(a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；(c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；(d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列 CDR-L3；及 VH 域，其與 SEQ ID NO:13 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；及 VL 域，其與 SEQ ID NO:14 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 的序列同一性；其中該抗體與人類 C3bBb 特異性結合。在一方面，VH 域與 SEQ ID NO: 13 之胺基酸序列具有至少 95% 的序列同一性。在一方面，VL 域與 SEQ ID NO: 14 之胺基酸序列具有至少 95% 的序列同一性。在一個態樣中，該抗體與 C3bBb 結合之解離常數 (KD) 相比於包含 SEQ ID NO:13 之 VH 序列及 SEQ ID NO:14 之 VL 序列的抗體之解離常數 (KD) 降低至多 10 倍或增加至多 10 倍。In one aspect, the anti-C3bBb antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 485; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 486; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 487; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 488; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 489; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 490; and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 13; and a VL In one aspect, the antibody comprises a VH domain that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 13. In one aspect, the VL domain has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 14. In one aspect, the antibody binds to C3bBb with a dissociation constant (KD) that is reduced by up to 10-fold or increased by up to 10-fold compared to the dissociation constant (KD) of an antibody comprising the VH sequence of SEQ ID NO: 13 and the VL sequence of SEQ ID NO: 14.

在另一態樣，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，該 VH 序列與 SEQ ID NO:13 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含重鏈可變域 (VH) 序列，其與 SEQ ID NO:14 之胺基酸序列具有至少 95% 的序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VH 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 13 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些態樣中，取代、插入或缺失發生在 CDR 以外的區域中 (亦即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 13 中之 VH 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VH 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO: 486 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO: 487 之胺基酸序列的 CDR-H3。在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:14 之胺基酸序列具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98%、99% 或 100% 序列同一性。在一個態樣中，抗 C3bBb 抗體包含輕鏈可變域 (VL) 序列，其與 SEQ ID NO:14 之胺基酸序列具有至少 95% 序列同一性。在某些態樣中，具有至少 90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性的 VL 序列含有相對於參照序列的取代 (例如，保留式取代)、插入或缺失，但包含該序列之抗 C3bBb 抗體保留與 C3bBb 結合之能力。在某些方面，在 SEQ ID NO: 14 中，總計 1 至 10 個胺基酸被取代、插入及/或缺失。在某些方面，取代、插入或缺失發生在 CDR 以外的區域 (即，在 FR 中)。視情況，抗 C3bBb 抗體包含 SEQ ID NO: 14 中之 VL 序列，其包括該序列之轉譯後修飾。在一個特定態樣中，VL 包含選自以下項的一個、兩個或三個 CDR：(a) 包含 SEQ ID NO: 488 之胺基酸序列的 CDR-L1；(b) 包含 SEQ ID NO: 489 之胺基酸序列的 CDR-L2；及 (c) 包含 SEQ ID NO: 490 之胺基酸序列的 CDR-L3。In another aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13. In one aspect, the anti-C3bBb antibody comprises a heavy chain variable domain (VH) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 14. In certain aspects, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but an anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 13, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitutions, insertions or deletions occur in regions outside of the CDRs (i.e., in the FRs). Optionally, the anti-C3bBb antibody comprises the VH sequence in SEQ ID NO: 13, including post-translational modifications of the sequence. In a specific aspect, VH comprises one, two or three CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 485; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 486; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 487. In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14. In one aspect, the anti-C3bBb antibody comprises a light chain variable domain (VL) sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 14. In certain aspects, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains a substitution (e.g., a conservative substitution), insertion or deletion relative to the reference sequence, but the anti-C3bBb antibody comprising the sequence retains the ability to bind to C3bBb. In certain aspects, in SEQ ID NO: 14, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In certain aspects, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). Optionally, the anti-C3bBb antibody comprises the VL sequence of SEQ ID NO: 14, including post-translational modifications of the sequence. In a specific aspect, the VL comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 488; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 489; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 490.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含上文所提供之態樣中任一者的 VH 序列以及上文所提供之態樣中任一者的 VL 序列。在一個態樣中，該抗體包含分別為 SEQ ID NO:13 及 SEQ ID NO:14 之 VH 及 VL 序列，其包括彼等序列之轉譯後修飾。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a VH sequence of any of the aspects provided above and a VL sequence of any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 13 and SEQ ID NO: 14, respectively, including post-translational modifications of those sequences.

在另一態樣中，提供一種抗 C3bBb 抗體，其中該抗體包含 SEQ OF NO:447 之重鏈胺基酸序列及 SEQ ID NO:448 之輕鏈胺基酸序列。In another aspect, an anti-C3bBb antibody is provided, wherein the antibody comprises a heavy chain amino acid sequence of SEQ OF NO:447 and a light chain amino acid sequence of SEQ ID NO:448.

在一個態樣中，提供一種抗體，其包含如上所述之 VH 域及如 SEQ ID NO:447 中所包含之重鏈恆定域胺基酸序列，以及如上所述之 VL 域及如 SEQ ID NO:448 所包含之輕鏈恆定域胺基酸序列。又一態樣及實施例In one aspect, an antibody is provided, comprising a VH domain as described above and a heavy chain constant domain amino acid sequence as contained in SEQ ID NO:447, and a VL domain as described above and a light chain constant domain amino acid sequenceas contained in SEQ ID NO:448.

在本發明之又一態樣中，根據上述態樣中之任一者的抗人類 C3bBb 抗體為單株抗體，其包括嵌合抗體、人源化抗體或人類抗體。在一個態樣中，抗人類 C3bBb 抗體為抗體片段，例如，Fv、Fab、Fab'、scFv、雙抗體 (diabody) 或 F(ab')2 片段。In another aspect of the present invention, the anti-human C3bBb antibody according to any of the above aspects is a monoclonal antibody, including a chimeric antibody, a humanized antibody or a human antibody. In one aspect, the anti-human C3bBb antibody is an antibody fragment, such as, for example, Fv, Fab, Fab', scFv, diabody or F(ab')2 fragment.

另一方面，抗體為全長抗體，例如本文所定義之完整 IgG1 抗體或其他抗體類別或同型。在一個實施例中，該抗體為全長 IgG1 抗體。In another aspect, the antibody is a full-length antibody, such as a complete IgG1 antibody or other antibody class or isotype as defined herein. In one embodiment, the antibody is a full-length IgG1 antibody.

在一個實施例中，抗體為單價抗體。在一個實施例中，抗體為二價抗體。在一個實施例中，抗體為三價抗體。在一個實施例中，抗體為四價抗體。In one embodiment, the antibody is a monovalent antibody. In one embodiment, the antibody is a divalent antibody. In one embodiment, the antibody is a trivalent antibody. In one embodiment, the antibody is a tetravalent antibody.

在又一態樣中，如以下 1-8 部分所述，根據任一上述態樣之抗人類 C3bBb 抗體可單獨或組合地結合任何特徵：1.抗體親和力In yet another aspect, as described in Sections 1-8 below, the anti-human C3bBb antibody according to any of the above aspects may combine any of the following characteristics alone or in combination:1.Antibody affinity

在某些態樣中，本文提供之抗體具有 ≤ 1μM、≤ 100 nM、≤ 10 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM 或 ≤ 0.001 nM 之解離常數 (KD)。在某些實施例中，本文提供之抗體具有 10^-6M 或更小，在一個實施例中 10^-7M 或更小，在一個實施例中 10^-8M 或更小，在一個實施例中 10^-8M 至 10^-13M，在一個實施例中 10^-9M 至 10^-13M 之解離常數 (KD)。In certain aspects, the antibodies provided herein have a dissociation constant (KD) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM. In certain embodiments, the antibodies provided herein have a dissociation constant (KD) of^10-6 M or less, in one embodiment^10-7 M or less, in one embodiment^10-8 M or less, in one embodiment^10-8 M to^10-13 M, in one embodiment^10-9 M to^10-13 M.

在一個實施例中，藉由 SPR 所測量，該抗體在約 37℃ 以 ≤ 300 pM 之親和力結合人類 C3bBb。在一個實施例中，藉由 SPR 所測量，該抗體在約 37℃ 以約 1 至 300 pM 之親和力結合人類 C3bBb。在一個實施例中，藉由 SPR 所測量，抗體在約 37°C 以約 1 至約 200 pM 之親和力結合人類 C3bBb。In one embodiment, the antibody binds human C3bBb with an affinity of ≤ 300 pM at about 37°C as measured by SPR. In one embodiment, the antibody binds human C3bBb with an affinity of about 1 to 300 pM at about 37°C as measured by SPR. In one embodiment, the antibody binds human C3bBb with an affinity of about 1 to about 200 pM at about 37°C as measured by SPR.

在一個實施例中，藉由 SPR 所測量，該抗體在約 25°C 以 ≤ 100 pM 之親和力結合人類 C3bBb。在一個實施例中，藉由 SPR 所測量，該抗體在約 25°C 以約 1 至 100 pM 之親和力結合人類 C3bBb。在一個實施例中，藉由 SPR 所測量，該抗體在約 25°C 以 ≤ 50 pM 之親和力結合人類 C3bBb。In one embodiment, the antibody binds human C3bBb with an affinity of ≤ 100 pM at about 25°C as measured by SPR. In one embodiment, the antibody binds human C3bBb with an affinity of about 1 to 100 pM at about 25°C as measured by SPR. In one embodiment, the antibody binds human C3bBb with an affinity of ≤ 50 pM at about 25°C as measured by SPR.

在一個態樣中，KD 係使用 BIACORE® 表面電漿子共振測定來測量。在一個實施例中，KD 係如實例 5 中所述測量的。2.抗體片段In one aspect, KD is measured using a BIACORE® surface plasmon resonance assay. In one embodiment, KD is measured as described in Example 5.2.Antibody Fragments

在某些態樣中，本文提供之抗體為抗體片段。In certain aspects, the antibodies provided herein are antibody fragments.

在一個態樣中，抗體片段為 Fab、Fab'、Fab'-SH 或 F(ab')2 片段，特定而言 Fab 片段。木瓜酶對完整抗體之消化產生兩個相同的抗原結合片段，稱為「Fab」片段，其各自包含重鏈和輕鏈可變域 (分別為 VH 和 VL) 及輕鏈之恆定域 (CL) 和重鏈之第一恆定域 (CH1)。因此，術語「Fab 片段」係指包含輕鏈 (包含 VL 域和 CL 域) 及重鏈片段 (包含 VH 域和 CH1 域) 之抗體片段。「Fab’ 片段」與 Fab 片段的區別在於在 CH1 域的羧基末端增加了殘基，其包括來自抗體鉸鏈區的一個或多個半胱胺酸。Fab'-SH 是 Fab' 片段，其中恆定域的半胱胺酸殘基帶有一個游離硫醇基團。胃蛋白酶處理產生一個 F(ab')2 片段，該片段具有兩個抗原結合位點 (兩個 Fab 片段) 及一部分 Fc 區。關於包含補救受體結合抗原決定基殘基且具有增加的活體內半衰期之 Fab 及 F(ab')2 片段的論述，參見美國專利號 5,869,046。In one embodiment, the antibody fragment is a Fab, Fab', Fab'-SH or F(ab')2 fragment, specifically a Fab fragment. Papain digestion of an intact antibody produces two identical antigen-binding fragments, called "Fab" fragments, each of which contains the heavy chain and light chain variable domains (VH and VL, respectively) and the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain. Therefore, the term "Fab fragment" refers to an antibody fragment containing a light chain (including the VL domain and the CL domain) and a heavy chain fragment (including the VH domain and the CH1 domain). The difference between a "Fab' fragment" and a Fab fragment is the addition of a residue at the carboxyl terminus of the CH1 domain, which includes one or more cysteines from the hinge region of the antibody. Fab'-SH is a Fab' fragment in which the cysteine residue of the homeodomain bears a free thiol group. Pepsin treatment yields a F(ab')2 fragment that has two antigen binding sites (two Fab fragments) and a portion of the Fc region. For a discussion of Fab and F(ab')2 fragments that contain salvage receptor binding antigenic determinant residues and have increased in vivo half-lives, see U.S. Patent No. 5,869,046.

在另一態樣中，抗體片段為雙功能抗體、三功能抗體或四功能抗體。「雙抗體」為具有兩個抗原結合位點 (其可為二價或雙特異性的) 之抗體片段。參見例如 EP 404,097；WO 1993/01161；Hudson 等人，Nat. Med. 9:129-134 (2003)；及 Hollinger 等人，Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993)。三功能抗體及四功能抗體亦描述於Hudson等人, Nat. Med. 9:129-134 (2003)中。In another aspect, the antibody fragment is a bifunctional antibody, a trifunctional antibody, or a tetrafunctional antibody. A "bifunctional antibody" is an antibody fragment having two antigen binding sites (which may be bivalent or bispecific). See, e.g., EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Trifunctional antibodies and tetrafunctional antibodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

在又一態樣中，抗體片段為單鏈 Fab 片段。「單鏈 Fab 片段」或「scFab」是由抗體重鏈可變域 (VH)、抗體重鏈恆定域 1 (CH1)、抗體輕鏈可變域 (VL)、抗體輕鏈恆定域 (CL) 及連接子組成的多肽，其中該抗體域及該連接子在 N 端至 C 端方向具有以下序列之一：a) VH-CH1-連接子-VL-CL、b) VL-CL-連接子-VH-CH1、c) VH-CL-連接子-VL-CH1 或 d) VL-CH1-連接子-VH-CL。特定而言，該連接子為至少 30 個胺基酸且較佳地 32 至 50 個胺基酸組成之多肽。該單鏈 Fab 片段通過 CL 域與 CH1 域之間的天然雙硫鍵達到穩定。此外，這些單鏈 Fab 片段可藉由插入半胱胺酸殘基產生鏈間二硫鍵而得到進一步穩定 (例如，根據 Kabat 編號，在變異重鏈之位置 44 及變異輕鏈之位置 100 處插入)。In another aspect, the antibody fragment is a single-chain Fab fragment. "Single-chain Fab fragment" or "scFab" is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein the antibody domain and the linker have one of the following sequences in the N-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 or d) VL-CH1-linker-VH-CL. In particular, the linker is a polypeptide consisting of at least 30 amino acids and preferably 32 to 50 amino acids. The single-chain Fab fragments are stabilized by the native disulfide bonds between the CL domain and the CH1 domain. In addition, these single-chain Fab fragments can be further stabilized by the insertion of cysteine residues to generate interchain disulfide bonds (e.g., at position 44 of the variant heavy chain and at position 100 of the variant light chain according to Kabat numbering).

在另一態樣中，抗體片段為單鏈變異片段 (scFv)。「單鏈變異片段」 或 「scFv」 為抗體之重鏈 (VH) 及輕鏈 (VL) 的可變域之融合蛋白，其藉由連接子連接。特別地，連接子為 10 個至 25 個胺基酸組成之短多肽，並且通常富含甘胺酸以提高柔韌性，並含有絲胺酸或蘇胺酸以提高溶解性，並且可將 VH 之 N 端與 VL 之 C 端連接，或反之亦然。儘管去除了恆定區並引入了連接子，但是該蛋白仍保留了原始抗體的特異性。關於 scFv 片段的綜述，參見例如 Plückthun，The Pharmacology of Monoclonal Antibodies，第 113卷，Rosenburg 及 Moore 編，Springer-Verlag，New York，第 269 頁至第 315 頁 (1994)；亦可參見 WO 93/16185；及美國專利第 5,571,894 號及第 5,587,458 號。In another aspect, the antibody fragment is a single-chain variant fragment (scFv). "Single-chain variant fragment" or "scFv" is a fusion protein of the variable domains of the heavy chain (VH) and light chain (VL) of the antibody, which are connected by a linker. In particular, the linker is a short polypeptide composed of 10 to 25 amino acids, and is usually rich in glycine to improve flexibility, and contains serine or threonine to improve solubility, and can connect the N-terminus of VH to the C-terminus of VL, or vice versa. Despite the removal of the constant region and the introduction of the linker, the protein still retains the specificity of the original antibody. For a general description of scFv fragments, see, e.g., Plückthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458.

在另一態樣中，抗體片段為單域抗體。單域抗體為包含抗體之重鏈可變域之全部或部分或抗體之輕鏈可變域之全部或部分之抗體片段。在某些態樣中，單域抗體為人單域抗體 (Domantis, Inc.，Waltham, MA；參見例如美國第 6,248,516 B1 號專利)。In another aspect, the antibody fragment is a single domain antibody. A single domain antibody is an antibody fragment comprising all or part of the heavy chain variable domain of an antibody or all or part of the light chain variable domain of an antibody. In certain aspects, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1).

抗體片段可藉由各種技術製造，包括但不限於如本文所述之完整抗體之蛋白水解消化以及重組宿主細胞 (例如大腸桿菌) 之重組產生。3.嵌合抗體及人源化抗體Antibody fragments can be produced by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies as described herein and recombinant production in recombinant host cells (e.g., E. coli).3.Chimeric and humanized antibodies

在某些態樣中，本文提供之抗體為嵌合抗體。某些嵌合抗體闡述於例如美國專利第 4,816,567 號；及 Morrison 等人，Proc. Natl. Acad. Sci. USA，81:6851-6855，(1984)) 中。在一個實例中，嵌合抗體包含非人可變區 (例如，來源於小鼠、大鼠、倉鼠、兔或非人類靈長類動物如猴的可變區) 及人恆定區。在又一個實例中，嵌合抗體為「類別轉換」抗體，其中類或子類相比於其親代抗體已發生變更。嵌合抗體包括其抗原結合片段。In certain aspects, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855, (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In another example, a chimeric antibody is a "class-switched" antibody, in which the class or subclass has been changed compared to its parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

在某些態樣中，嵌合抗體為人源化抗體。通常，非人抗體為人源化抗體以降低對人的免疫原性，同時保留親本非人抗體之特異性及親和力。通常，人源化抗體包含一個或多個可變域，其中 CDR (或其部分) 來源於非人抗體，並且 FR (或其部分) 來源於人抗體序列。人源化抗體視情況將包含人恆定區之至少一部分。在一些態樣中，人源化抗體中的一些 FR 殘基經來自非人抗體 (例如衍生 CDR 殘基之抗體) 之對應殘基取代，以例如恢復或改善抗體特異性或親和力。In some aspects, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized antibodies to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Typically, humanized antibodies comprise one or more variable domains, wherein CDR (or a portion thereof) is derived from a non-human antibody, and FR (or a portion thereof) is derived from a human antibody sequence. Humanized antibodies will optionally comprise at least a portion of a human constant region. In some aspects, some FR residues in humanized antibodies are replaced with corresponding residues from a non-human antibody (e.g., an antibody from which CDR residues are derived), for example, to restore or improve antibody specificity or affinity.

人源化抗體及其製備方法綜述於例如 Almagro 和 Fransson，Front. Biosci. 13:1619-1633 (2008) 中，且進一步闡述於例如以下文獻中：Riechmann 等人，Nature 332:323-329 (1988)；Queen 等人，Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989)；美國專利第 5, 821,337 號、第 7,527,791 號、第 6,982,321 號及第 7,087,409 號；Kashmiri 等人，Methods 36:25-34 (2005) (闡述特異性決定區 (SDR) 接枝)；Padlan，Mol. Immunol. 28:489-498 (1991) (闡述「表面重塑」)；Dall’Acqua 等人，Methods 36:43-60 (2005) (闡述「FR 改組」)；及 Osbourn 等人，Methods 36:61-68 (2005)；以及 Klimka 等人，Br. J. Cancer，83:252-260 (2000) (闡述 FR 改組的「導向選擇」法)。Humanized antibodies and methods for their preparation are generally described in, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described in, e.g., Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (elaborating on specificity determining regions (SDRs) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "surface remodeling"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the "guided selection" approach to FR shuffling).

可以用於人源化的人骨架區包括但不限於：使用「最佳匹配」方法選擇的框架區 (例如參見 Sims 等人，J. Immunol. 151:2296 (1993))；衍生自輕鏈或重鏈可變區的特定亞組的人類抗體的共有序列的框架區 (例如參見，Carter 等人，Proc. Natl. Acad. Sci. USA，89:4285 (1992)；及 Presta 等人，J. Immunol.，151:2623 (1993))；人類成熟 (體細胞突變) 框架區或人類種系框架區 (例如參見 Almagro 及 Fransson，Front. Biosci. 13:1619-1633 (2008))；以及衍生自篩選 FR 文庫的框架區 (例如參見，Baca 等人，J. Biol. Chem. 272:10678-10684 (1997) 及 Rosok 等人，J. Biol. Chem. 271:22611-22618 (1996))。4.人抗體Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best match" method (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of a particular subset of light chain or heavy chain variable regions of human antibodies (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al., J. Immunol., 151:2623 (1993)); human mature (somatic cell mutation) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from a screened FR library (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).4.Human antibodies

在某些態樣中，本文提供之抗體為人抗體。可使用此領域中所公知的各種技術生產人抗體。人類抗體一般描述於 van Dijk 及 van de Winkel，Curr. Opin. Pharmacol. 5: 368-74 (2001) 及 Lonberg，Curr. Opin. Immunol. 20:450-459 (2008)。In certain aspects, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

可透過對轉基因動物投予免疫原來製備人抗體，該轉基因動物已被修飾以回應於抗原攻擊而產生完整的人抗體或具有人可變區的完整抗體。此等動物通常包含全部或部分人免疫球蛋白基因座，其取代內源性免疫球蛋白基因座，或存在於染色體外或隨機整合到動物的染色體中。在此等轉基因小鼠中，內源性免疫球蛋白基因座通常已被滅活。有關從基因轉殖動物中獲得人類抗體的方法的綜述，參見 Lonberg，Nat. Biotech. 23:1117-1125 (2005)。亦參見例如美國專利號 6,075,181 及 6,150,584 (闡述 XENOMOUSETM 技術)；美國專利號 5,770,429 (闡述 HUMAB® 技術)；美國專利號 7,041,870 (闡述 K-M MOUSE® 技術)；及美國專利申請公開號 US 2007/0061900 (闡述 VELOCIMOUSE® 技術)。由此等動物產生的來源於完整抗體的人可變區可被進一步修飾，例如透過與不同的人恆定區結合來修飾。Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce complete human antibodies or complete antibodies with human variable regions in response to an antigenic challenge. These animals typically contain all or part of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the chromosomes of the animal. In these transgenic mice, the endogenous immunoglobulin loci are usually inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 (describing XENOMOUSE™ technology); U.S. Patent No. 5,770,429 (describing HUMAB® technology); U.S. Patent No. 7,041,870 (describing K-M MOUSE® technology); and U.S. Patent Application Publication No. US 2007/0061900 (describing VELOCIMOUSE® technology). The human variable regions from intact antibodies generated by these animals can be further modified, for example, by combining with different human constant regions.

人抗體也可透過基於融合瘤的方法進行製備。用於生產人單株抗體的人骨髓瘤和小鼠-人异源骨髓瘤細胞株已有描述。(參見，例如，Kozbor J. Immunol., 133: 3001 (1984)；Brodeur 等人, Monoclonal Antibody Production Techniques and Applications, 第 51-63 頁 (Marcel Dekker, Inc., New York, 1987)；及 Boerner 等人, J. Immunol., 147: 86 (1991).)經由人類 B 細胞融合瘤技術產生的人類抗體亦闡述於 Li 等人，Proc. Natl. Acad. Sci. USA，103:3557-3562 (2006) 中。其他方法包括彼等描述於例如美國專利號 7,189,826 (描述由融合瘤細胞株產生單株人類 IgM 抗體) 及 Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (描述人類-人類融合瘤) 中者。人類融合瘤技術 (三源融合瘤技術) 亦描述於 Vollmers 及 Brandlein, Histology and Histopathology, 20(3):927-937 (2005) 以及 Vollmers 及 Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005) 中。Human antibodies can also be prepared by fusion tumor-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies produced by human B cell fusion tumor technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103: 3557-3562 (2006). Other methods include those described in, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies by hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (tri-source hybridoma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

人抗體也可以藉由分離選自人源性噬菌體展示文庫的可變域序列來產生。然後可以將此等可變域序列與所需的人恆定域結合。下文描述了從抗體文庫中選擇人類抗體的技術。5.源自文庫之抗體Human antibodies can also be generated by isolating variable domain sequences selected from human-derived phage display libraries. These variable domain sequences can then be combined with the desired human constant domains. The following describes techniques for selecting human antibodies from antibody libraries.5.Antibodies from libraries

在某些態樣中，本文所提供之抗體來源於文庫。用於本發明之抗體可藉由篩選組合文庫中具有所期望的一種或多種活性之抗體來分離。用於篩選組合文庫的方法綜述於例如 Lerner 等人的 Nature Reviews 16:498-508 (2016) 中。例如，此領域中已知多種方法用於生成噬菌體展示文庫並篩選此類文庫中具有所期望之結合特性的抗體。此等方法綜述於例如以下文獻中：Frenzel 等人的 mAbs 8:1177-1194 (2016)；Bazan 等人的 Human Vaccines and Immunotherapeutics 8:1817-1828 (2012)；及 Zhao 等人的 Critical Reviews in Biotechnology 36:276-289 (2016)；以及 Hoogenboom 等人的 Methods in Molecular Biology 178:1-37 (O’Brien 等人主編，Human Press，Totowa，NJ，2001)；及 Marks 與 Bradbury 的 Methods in Molecular Biology 248:161-175 (Lo 主編，Human Press，Totowa，NJ，2003)。In certain aspects, the antibodies provided herein are derived from a library. Antibodies used in the present invention can be isolated by screening combinatorial libraries for antibodies having one or more desired activities. Methods for screening combinatorial libraries are summarized in, for example, Lerner et al., Nature Reviews 16:498-508 (2016). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies having desired binding properties. Such methods are reviewed in, for example, Frenzel et al., mAbs 8:1177-1194 (2016); Bazan et al., Human Vaccines and Immunotherapeutics 8:1817-1828 (2012); and Zhao et al., Critical Reviews in Biotechnology 36:276-289 (2016); and Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, 2001); and Marks and Bradbury, Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003).

在某些噬菌體展示方法中，藉由聚合酶鏈反應 (PCR) 分別選殖 VH 及 VL 基因庫，並在噬菌體文庫中隨機重組，然後可按照以下文獻所述篩選抗原結合噬菌體：Winter 等人的 Annual Review of Immunology 12: 433-455 (1994)。噬菌體通常以單鏈 Fv (scFv) 片段或 Fab 片段展示抗體片段。來自免疫源的文庫無需構建融合瘤即可向免疫原提供高親和性抗體。可替代地，可在不進行任何免疫之情況下選殖天然譜系 (例如，來自人類) 以向廣泛範圍之非自體以及自體抗原提供抗體的單一來源，如闡述於 Griffiths 等人的 EMBO Journal 12: 725-734 (1993)。此外，亦可藉由自幹細胞選殖未重排的 V 基因片段，並使用含有隨機序列的 PCR 引子來編碼高度可變 CDR3 區並在活體外完成重排，由此合成天然文庫，如闡述於 Hoogenboom 與 Winter 的 Journal of Molecular Biology 227: 381-388 (1992)。描述人抗體噬菌體庫的專利公開包括例如：美國專利號 5,750,373、7,985,840、7,785,903 及 8,679,490；以及美國專利公開號 2005/0079574、2007/0117126、2007/0237764 及 2007/0292936。In certain phage display methods, VH and VL gene repertoires are cloned separately by polymerase chain reaction (PCR) and randomly recombined in phage libraries, and then the phage can be screened for antigen binding as described in Winter et al. Annual Review of Immunology 12: 433-455 (1994). Phage typically display antibody fragments as single-chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources can provide high-affinity antibodies to the immunogen without the need to construct fusion tumors. Alternatively, natural repertoire lines (e.g., from humans) can be cloned without any immunization to provide a single source of antibodies to a wide range of non-self and self antigens, as described in Griffiths et al. EMBO Journal 12: 725-734 (1993). Alternatively, natural libraries can be synthesized by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode the highly variable CDR3 regions and achieve rearrangement in vitro, as described in Hoogenboom and Winter, Journal of Molecular Biology 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent Nos. 5,750,373, 7,985,840, 7,785,903, and 8,679,490; and U.S. Patent Publication Nos. 2005/0079574, 2007/0117126, 2007/0237764, and 2007/0292936.

用於篩選組合文庫中具有所需活性之抗體的此領域中所公知方法的其他實例包括核醣體和 mRNA 展示以及用於細菌、哺乳動物細胞、昆蟲細胞或酵母細胞上的抗體展示和選擇的方法。酵母表面展示方法綜述於例如 Scholler 等人的 Methods in Molecular Biology 503:135-56 (2012) 及 Cherf 等人的 Methods in Molecular biology 1319:155-175 (2015) 以及 Zhao 等人的 Methods in Molecular Biology 889:73-84 (2012)。用於核醣體展示之方法描述於例如 He 等人的 Nucleic Acids Research 25:5132-5134 (1997) 及 Hanes 等人的 PNAS 94:4937-4942 (1997) 中。Other examples of methods known in the art for screening combinatorial libraries for antibodies with the desired activity include ribosome and mRNA display and methods for antibody display and selection on bacteria, mammalian cells, insect cells, or yeast cells. Yeast surface display methods are reviewed in, for example, Scholler et al. Methods in Molecular Biology 503:135-56 (2012) and Cherf et al. Methods in Molecular biology 1319:155-175 (2015) and Zhao et al. Methods in Molecular Biology 889:73-84 (2012). Methods for ribosome display are described, for example, in He et al., Nucleic Acids Research 25:5132-5134 (1997) and Hanes et al., PNAS 94:4937-4942 (1997).

從人抗體庫分離的抗體或抗體片段在本文中被視作人抗體或人抗體片段。6.多特異性抗體Antibodies or antibody fragments isolated from human antibody libraries are referredto herein as human antibodies or humanantibody fragments.

在某些實施例中，本文提供之抗體為多特異性抗體，例如雙特異性抗體。「多特異性抗體」為對至少兩個不同位點 (亦即不同抗原上之不同抗原決定基或同一抗原上之不同抗原決定基) 具有結合特異性的單株抗體。在某些態樣中，多特異性抗體具有三種或更多種結合特異性。在某些態樣中，結合特異性中之一者係針對 C3bBb 的，而其他特異性則係針對任何其他抗原。在某些態樣中，雙特異性抗體可以與人 C3bBb 之兩個 (或更多個) 不同抗原決定基結合。多特異性 (例如，雙特異性) 抗體亦可以用於將細胞毒性劑或細胞定位於表現人 C3bBb 之細胞。多特異性抗體可製成全長抗體或抗體片段。In certain embodiments, the antibodies provided herein are multispecific antibodies, such as bispecific antibodies. A "multispecific antibody" is a monoclonal antibody that has binding specificities for at least two different sites (i.e., different antigenic determinants on different antigens or different antigenic determinants on the same antigen). In certain aspects, a multispecific antibody has three or more binding specificities. In certain aspects, one of the binding specificities is for C3bBb, while the other specificities are for any other antigen. In certain aspects, a bispecific antibody can bind to two (or more) different antigenic determinants of human C3bBb. Multispecific (e.g., bispecific) antibodies can also be used to localize cytotoxic agents or cells to cells expressing human C3bBb. Multispecific antibodies can be prepared as full-length antibodies or antibody fragments.

製備多特異性抗體之技術包括但不限於具有不同特異性之兩個免疫球蛋白重鏈-輕鏈對的重組共表現 (參見 Milstein 及　Cuello, Nature 305: 537 (1983)) 以及「杵-臼」工程化 (參見例如美國專利第 5,731,168 號及 Atwell 等人，J. Mol. Biol. 270:26 (1997))。多特異性抗體亦可藉由以下方法來製備：用於製備抗體 Fc-異型二聚體分子的工程靜電轉向效應 (參見例如 WO 2009/089004)；交聯兩個或更多個抗體或片段 (參見例如美國專利第 4,676,980 號，及 Brennan 等人，Science, 229: 81 (1985))；使用白胺酸拉鍊產生雙特異性抗體 (參見例如，Kostelny 等人，J. Immunol.，148(5):1547-1553 (1992)；及 WO 2011/034605)；使用常用輕鏈技術規避輕鏈錯配問題 (參見例如 WO 98/50431)；使用「雙抗體」技術製備雙特異性抗體片段 (參見例如，Hollinger 等人，Proc. Natl. Acad. Sci. USA，90:6444-6448 (1993))；以及使用單鏈 Fv (sFv) 二聚體 (參見例如 Gruber 等人，J. Immunol.，152:5368 (1994))；以及製備三特異性抗體，如闡述於例如 Tutt 等人 J. Immunol. 147: 60 (1991)。Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305: 537 (1983)) and "knob-and-mortar" engineering (see, e.g., U.S. Patent No. 5,731,168 and Atwell et al., J. Mol. Biol. 270:26 (1997)). Multispecific antibodies can also be prepared by the following methods: engineering electrostatic steering for preparing antibody Fc-heterodimer molecules (see, e.g., WO 2009/089004); cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zipper to generate bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992); and WO 2011/034605); using common light chain technology to circumvent the light chain mispairing problem (see, e.g., WO 98/50431); using "diabody" technology to prepare bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al., J. Immunol. 147:60 (1991).

本文亦包括具有三個或更多個抗原結合位點的工程化之抗體，包括例如「章魚抗體」(Octopus antibodies) 或 DVD-Ig (參見，例如，WO 2001/77342 及 WO 2008/024715)。具有三個或更多個抗原結合位點的多特異性抗體之其他實例可見於 WO 2010/115589、WO 2010/112193、WO 2010/136172、WO 2010/145792 及 WO 2013/026831 中。雙特異性抗體或其抗原結合片段亦包括「雙重作用 FAb」或「DAF」，其包含與人類 C3bBb 以及另一不同抗原或人類 C3bBb 的兩個不同抗原決定基結合之抗原結合位點 (參見，例如，US 2008/0069820 及 WO 2015/095539)。Also included herein are engineered antibodies with three or more antigen binding sites, including, for example, "Octopus antibodies" or DVD-Ig (see, for example, WO 2001/77342 and WO 2008/024715). Other examples of multispecific antibodies with three or more antigen binding sites can be found in WO 2010/115589, WO 2010/112193, WO 2010/136172, WO 2010/145792 and WO 2013/026831. Bispecific antibodies or antigen-binding fragments thereof also include "dual-acting FAbs" or "DAFs," which comprise antigen-binding sites that bind to human C3bBb and another different antigen or two different antigenic determinants of human C3bBb (see, e.g., US 2008/0069820 and WO 2015/095539).

多特異性抗體也可提供為不對稱形式，其包含在一個或多個具有相同抗原特異性之結合臂中交叉的域，即透過交換 VH/VL 域 (參見例如 WO 2009/080252 及 WO 2015/150447)、CH1/CL 域 (參見例如 WO 2009/080253) 或完整的 Fab 臂 (參見例如 WO 2009/080251、WO 2016/016299，另見 Schaefer 等人，PNAS，108 (2011) 1187-1191，及 Klein 等人，MAbs 8 (2016) 1010-20) 實現。在一個態樣中，多特異性抗體包含 cross-Fab 片段。術語「cross-Fab 片段」或「xFab 片段」或「交叉 Fab 片段」 是指其中重鏈和輕鏈之可變區或恆定區發生交換的 Fab 片段。cross-Fab 片段包含由輕鏈可變區 (VL) 和重鏈恆定區 1 (CH1) 構成之多肽鏈以及由重鏈可變區 (VH) 和輕鏈恆定區 (CL) 構成之多肽鏈。還可透過將帶電荷或不帶電荷之胺基酸突變引入域界面引導正確 Fab 配對，從而設計不對稱之 Fab 臂。參見例如 WO 2016/172485。Multispecific antibodies can also be provided in an asymmetric format comprising cross-domains in one or more binding arms with the same antigenic specificity, i.e. by exchanging VH/VL domains (see, e.g., WO 2009/080252 and WO 2015/150447), CH1/CL domains (see, e.g., WO 2009/080253) or complete Fab arms (see, e.g., WO 2009/080251, WO 2016/016299, see also Schaefer et al., PNAS, 108 (2011) 1187-1191, and Klein et al., MAbs 8 (2016) 1010-20). In one aspect, the multispecific antibody comprises a cross-Fab fragment. The term "cross-Fab fragment" or "xFab fragment" or "cross-Fab fragment" refers to a Fab fragment in which the variable or constant regions of the heavy and light chains are exchanged. The cross-Fab fragment comprises a polypeptide chain consisting of a light chain variable region (VL) and a heavy chain constant region 1 (CH1) and a polypeptide chain consisting of a heavy chain variable region (VH) and a light chain constant region (CL). Asymmetric Fab arms can also be designed by introducing charged or uncharged amino acid mutations into the domain interface to direct the correct Fab pairing. See, for example, WO 2016/172485.

用於多特異性抗體之各種其他分子形式為本技術領域中已知的並且包括在本文中 (參見例如 Spiess 等人，Mol Immunol 67 (2015) 95-106)。Various other molecular formats for multispecific antibodies are known in the art and are included herein (see, e.g., Spiess et al., Mol Immunol 67 (2015) 95-106).

亦包括於本文中的特定類型之多特異性抗體為雙特異性抗體，該雙特異性抗體經設計為同時與標靶細胞 (例如，腫瘤細胞) 上之表面抗原以及與 T 細胞受體 (TCR) 複合物之活化、不變組分 (諸如 CD3) 結合，用於重定向 T 細胞以毒殺標靶細胞。因此，在某些態樣中，本文所提供之抗體為多特異性抗體，特定而言雙特異性抗體，其中結合特異性中之一者係針對人 C3bBb，而另一者係針對 CD3。Also included herein are specific types of multispecific antibodies that are bispecific antibodies that are designed to bind simultaneously to a surface antigen on a target cell (e.g., a tumor cell) and to an activating, invariant component of the T cell receptor (TCR) complex (e.g., CD3) for redirecting T cells to kill the target cell. Thus, in certain aspects, the antibodies provided herein are multispecific antibodies, particularly bispecific antibodies, in which one of the binding specificities is to human C3bBb and the other is to CD3.

可用於此目的之雙特異性抗體形式之實例包括但不限於所謂「BiTE」(雙特異性 T 細胞接合物) 分子，其中，兩個 scFv 分子透過柔性連接子融合 (參見例如 WO 2004/106381、WO 2005/061547、WO 2007/042261 及 WO 2008/119567；Nagorsen 及 Bäuerle，Exp Cell Res 317, 1255-1260 (2011))；雙抗體 (Holliger 等人，Prot Eng 9, 299-305 (1996)) 及其衍生物，諸如串聯雙抗體 (「TandAb」；Kipriyanov 等人，J Mol Biol 293, 41-56 (1999))；「DART」(雙親和性重定位) 分子，其基於雙抗體形式，但具有 C 端二硫鍵以供進一步穩定 (Johnson 等人，J Mol Biol 399, 436-449 (2010))，以及所謂三功能抗體 (triomab)，它們為完整的小鼠/大鼠 IgG 雜合分子 (參見 Seimetz 等人的綜述：Cancer Treat Rev 36, 458-467 (2010))。本文所包括之特定 T 細胞雙特異性抗體形式描述於：WO 2013/026833；WO 2013/026839；WO 2016/020309；及 Bacac 等人 Oncoimmunology 5(8) (2016) e1203498。7.抗體變異體Examples of bispecific antibody formats that can be used for this purpose include, but are not limited to, so-called "BiTE" (bispecific T cell engager) molecules, in which two scFv molecules are fused via a flexible linker (see, e.g., WO 2004/106381, WO 2005/061547, WO 2007/042261, and WO 2008/119567; Nagorsen and Bäuerle, Exp Cell Res 317, 1255-1260 (2011)); diabodies (Holliger et al., Prot Eng 9, 299-305 (1996)) and their derivatives, such as tandem diabodies ("TandAb"; Kipriyanov et al., J Mol Biol 293, 41-56 (1999)); "DART" (dual affinity repositioning) molecules, which are based on the diabody format but have a C-terminal disulfide bond for further stabilization (Johnson et al., J Mol Biol 399, 436-449 (2010)), and so-called triomabs, which are complete mouse/rat IgG hybrid molecules (see Seimetz et al. for a review: Cancer Treat Rev 36, 458-467 (2010)). Specific T cell bispecific antibody formats included herein are described in: WO 2013/026833; WO 2013/026839; WO 2016/020309; and Bacac et al. Oncoimmunology 5(8) (2016) e1203498.7.Antibody variants

在某些態樣中，考慮到本文提供之抗體的胺基酸序列變異體。例如，可能希望改變抗體的結合親和力及/或其他生物學特性。可藉由將適當的修飾引入編碼抗體的核苷酸序列中，或藉由肽合成來製備抗體之胺基酸序列變異體。此等修飾包括例如抗體之胺基酸序列中的殘基的缺失及/或插入及/或取代。可實施缺失、插入及取代之任意組合以得到最終構建體，前提條件是最終構建體具有所期望之特徵，例如抗原結合特徵。a)取代、插入及缺失變異體In certain aspects, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to alter the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of antibodies may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions may be performed to obtain the final construct, provided that the final construct has the desired characteristics, such as antigen binding characteristics.a)Substitution, insertion, and deletion variants

在某些態樣中，提供具有一個或多個胺基酸取代的抗體變異體。取代誘變的目標位點包括 CDR 和 FR。保留取代顯示於表 D2 之「較佳取代」標題下。表 1 中之「例示性取代」標題下提供了更多實質性變更，並且下文將參考胺基酸側鏈類別進行進一步描述。可將胺基酸取代引入所關注抗體中，並篩選具有所期望的活性之產物，例如，保留/改善的抗原結合特徵、降低的免疫原性或改善的 ADCC 或 CDC。表D2：胺基酸取代原始殘基例示性取代較佳取代Ala (A)Val；Leu；IleValArg (R)Lys；Gln；AsnLysAsn (N)Gln；His；Asp；Lys；ArgGlnAsp (D)Glu；AsnGluCys (C)Ser；AlaSerGln (Q)Asn；GluAsnGlu (E)Asp；GlnAspGly (G)AlaAlaHis (H)Asn；Gln；Lys；ArgArgIle (I)Leu；Val；Met；Ala；Phe；正白胺酸LeuLeu (L)正白胺酸；Ile；Val；Met；Ala；PheIleLys (K)Arg；Gln；AsnArgMet (M)Leu；Phe；IleLeuPhe (F)Trp；Leu；Val；Ile；Ala；TyrTyrPro (P)AlaAlaSer (S)ThrThrThr (T)Val；SerSerTrp (W)Tyr；PheTyrTyr (Y)Trp；Phe；Thr；SerPheVal (V)Ile；Leu；Met；Phe；Ala；正白胺酸LeuIn certain aspects, antibody variants having one or more amino acid substitutions are provided. Target sites for substitution-induced mutagenesis include CDRs and FRs. Conservative substitutions are shown in Table D2 under the heading "Preferred Substitutions". More substantial changes are provided under the heading "Exemplary Substitutions" in Table 1 and are further described below with reference to amino acid side chain categories. Amino acid substitutions can be introduced into the antibodies of interest and the products screened for desired activity, e.g., retained/improved antigen binding characteristics, reduced immunogenicity, or improved ADCC or CDC.TableD2: Amino Acid SubstitutionsOriginal ResidueExemplary substitutionsBetter replacement Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn(N) Gln; His; Asp; Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn；Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; nor-leucine Leu Leu (L) nor-leucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; nor-leucine Leu

胺基酸可根據常見的側鏈特性進行分組： (1) 疏水性：正白胺酸，Met，Ala，Val，Leu，Ile； (2) 中性親水性：Cys、Ser、Thr、Asn、Gln； (3) 酸性：Asp，Glu； (4) 鹼性：His，Lys，Arg; (5) 影響鏈取向之殘基：Gly，Pro； (6) 芳香族：Trp，Tyr，Phe。Amino acids can be grouped according to common side chain properties:(1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;(2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;(3) Acidic: Asp, Glu;(4) Basic: His, Lys, Arg;(5) Residues that affect chain orientation: Gly, Pro;(6) Aromatic: Trp, Tyr, Phe.

非保守取代需要將這些類別中之一類的成員交換為另一類的成員。Non-conservative substitutions will entail exchanging a member of one of these classes for a member of another class.

一種類型的取代變異體涉及取代一個或多個親代抗體 (例如，人源化或人抗體) 之高度可變區殘基。通常，選擇用於進一步研究之所得變異體將相對於親代抗體在某些生物學特性 (例如提高親和性、降低免疫原性) 上具有修飾 (例如，改善) 及/或基本上保留親代抗體之某些生物學特性。例示性取代變異體為親和力成熟的抗體，其可以方便地產生，例如，使用基於噬菌體展示的親和力成熟技術，例如本文所述的那些。簡而言之，取代一個或多個。CDR 殘基發生突變，並且變異體抗體在噬菌體上展示並篩選出特定的生物學活性 (例如，結合親和性)。One type of substitution variant involves replacing one or more highly variable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, the resulting variant selected for further study will have modifications (e.g., improvements) and/or substantially retain certain biological properties of the parent antibody relative to the parent antibody (e.g., increased affinity, reduced immunogenicity). Exemplary substitution variants are affinity-matured antibodies, which can be conveniently produced, for example, using affinity maturation techniques based on phage display, such as those described herein. In short, one or more CDR residues are mutated, and the variant antibody is displayed on phage and screened for specific biological activity (e.g., binding affinity).

可以在 CDR 中進行更改 (例如，取代)，以改善抗體親和性。此等改變可在 CDR 「熱點」中進行，亦即在體細胞成熟過程中發生高頻突變之由密碼子編碼的殘基 (例如，參見，Chowdhury，Methods Mol. Biol. 207:179-196 (2008))，及/或與抗原接觸的殘基，並測試所得變異體 VH 或 VL 之結合親和力。藉由構築並自二級庫中重新選擇來達成親和力成熟已闡述於例如 Hoogenboom 等人，Methods in Molecular Biology 178:1-37 (O'Brien 等人編輯，Human Press，Totowa，NJ，(2001)) 中。在親和性成熟之某些態樣中，通過多種方法 (例如，易錯 PCR、鏈改組或寡核苷酸定向誘變) 將多樣性引入選擇用於成熟的變異基因中。然後創建第二文庫。然後篩選該文庫，以識別具有所需之親和性的任何抗體變異體。引入多樣性的另一種方法是 CDR 定向方法，其中將若干 CDR 殘基 (例如，每次 4-6 個殘基) 隨機化。可通過例如丙胺酸掃描誘變或建模以特異性識別參與抗原結合的 CDR 殘基。特別地，CDR-H3 和 CDR-L3 經常成為靶點。Changes (e.g., substitutions) can be made in the CDRs to improve antibody affinity. Such changes can be made in CDR "hotspots," i.e., residues encoded by codons that undergo high frequency mutations during somatic maturation (e.g., see, Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries has been described, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In certain aspects of affinity maturation, diversity is introduced into the variant genes selected for maturation by various methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide directed mutagenesis). A second library is then created. This library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity is the CDR-directed approach, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues that participate in antigen binding can be specifically identified by, for example, alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

在某些態樣中，在一個或多個 CDR 內可能發生取代、插入或缺失，只要此等修改不顯著降低抗體以結合抗原的能力即可。例如，可在 CDR 中實施基本上不降低結合親和力的保留式修改 (例如，本文所提供之保留取代)。例如，此等修改可能在 CDR 中之抗原接觸殘基之外。在上文提供之某些 VH 和 VL 序列變異體中，每個 CDR 均未改變，或包含不超過一個、兩個或三個胺基酸取代。In certain aspects, substitutions, insertions or deletions may occur within one or more CDRs, as long as such modifications do not significantly reduce the ability of the antibody to bind to the antigen. For example, conservative modifications (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be implemented in the CDRs. For example, such modifications may be outside of antigen contact residues in the CDRs. In certain VH and VL sequence variants provided above, each CDR is unchanged or contains no more than one, two or three amino acid substitutions.

如由 Cunningham 及 Wells (1989) Science, 244:1081-1085 所描述，用於鑑別可被靶向誘變之抗體殘基或區域之一種有用的方法稱為「丙胺酸掃描誘變」。在該方法中，殘基或標靶殘基組 (例如，帶電荷的殘基，諸如 arg、asp、his、lys 及 glu) 係經鑑定並且由中性或帶負電荷的胺基酸 (例如，丙胺酸或聚丙胺酸) 替換以判定抗體與抗原之交互作用是否受到影響。可在胺基酸位置引入更多取代，表明對初始取代具有良好的功能敏感性。可替代地或另外地，可使用抗原-抗體複合物之晶體結構來識別抗體與抗原之間的接觸點。此等接觸殘基和鄰近殘基可靶向或消除為取代的候選物。可篩選變異體以判定它們是否含有所需之特性。As described by Cunningham and Wells (1989) Science, 244:1081-1085, a useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis." In this method, residues or target residue groups (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. More substitutions can be introduced at amino acid positions, showing good functional sensitivity to the initial substitutions. Alternatively or additionally, the crystal structure of the antigen-antibody complex can be used to identify the contact points between the antibody and the antigen. These contact residues and neighboring residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they contain the desired properties.

胺基酸序列插入包括胺基及/或羧基末端融合體之長度，從一個殘基到包含一百個或更多殘基之多肽，以及單個或多個胺基酸殘基的序列內插入。末端插入的實例包括具有 N 端甲硫胺醯基殘基的抗體。抗體分子之其他插入變異體包括與抗體的 N 端或 C 端融合的酶 (例如，對於 ADEPT (針對抗體之酶前藥治療)) 或提高抗體血清半衰期之多肽。b)醣基化變異體Amino acid sequence insertions include amino and/or carboxyl terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertion variants of the antibody molecule include enzymes fused to the N-terminus or C-terminus of the antibody (e.g., for ADEPT (antibody-directed enzyme prodrug therapy)) or polypeptides that increase the serum half-life of the antibody.b)Glycosylation variants

在某些態樣中，本文所提供之抗體係經改變以增加或減少抗體經醣基化之程度。抗體中的醣基化位點之添加或缺失可藉由改變胺基酸序列以使得產生或去除一個或多個醣基化位點而方便地實現。In certain aspects, the antibodies provided herein are altered to increase or decrease the degree to which the antibody is glycosylated. The addition or deletion of glycosylation sites in an antibody can be conveniently achieved by altering the amino acid sequence so that one or more glycosylation sites are generated or removed.

當抗體包含 Fc 區時，可改變接附至其的寡醣。由哺乳動物細胞產生的天然抗體通常包含分支的雙觸角寡醣，該寡醣通常藉由 N-鍵結接附至 Fc 區之 CH2 域的 Asn297。例如參見 Wright 等人，TIBTECH 15:26-32 (1997)。寡醣可包括各種碳水化合物，例如甘露醣、N-乙醯基葡醣胺 (GlcNAc)、半乳醣及唾液酸以及在雙觸角寡醣結構之「莖」中接附至 GlcNAc 的岩藻醣。在一些態樣中，可對本發明之抗體中的寡醣進行修飾，以產生具有某些改善之特性的抗體變異體。When the antibody comprises an Fc region, the oligosaccharides attached thereto may be varied. Natural antibodies produced by mammalian cells typically comprise branched bitactinic oligosaccharides that are typically attached to Asn297 of the CH2 domain of the Fc region by an N-bond. See, for example, Wright et al., TIBTECH 15:26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the bitactinic oligosaccharide structure. In some aspects, the oligosaccharides in the antibodies of the present invention may be modified to produce antibody variants having certain improved properties.

在一個態樣中，提供具有非岩藻醣基化寡醣的抗體變異體，亦即缺少 (直接或間接地) 接附至 Fc 區的岩藻醣之寡醣結構。此等非岩藻醣基化寡醣 (也稱為「去岩藻醣基化」寡醣) 特定而言在雙天線型寡醣結構的莖中缺少與第一 GlcNAc 連接之岩藻醣殘基的 N-連接寡醣。在一個態樣中，提供了與天然或親本抗體相比在 Fc 區域中具有增加比例的非岩藻醣基化寡醣的抗體變異體。例如，非岩藻醣基化寡醣的比例可以為至少約 20%、至少約 40%、至少約 60%、至少約 80% 或甚至約 100% (即不存在岩藻醣基化寡醣)。非岩藻醣基化寡醣之百分比係缺少岩藻糖殘基之寡醣相對於附接至 Asn 297 (例如復合物、雜合及高甘露糖結構) 的所有寡醣的總和之 (平均) 量，該百分比藉由 MALDI-TOF 質譜測得，如 WO 2006/082515 中所闡述。Asn297 係指位於 Fc 區域位置 297 附近之天冬醯胺酸殘基 (Fc 區域殘基的 EU 編號)；但是，Asn297 也可以位於位置 297 上游或下游大約 ±3 個胺基酸處，即由於抗體之微小序列變化而介於位置 294 和 300 之間。此等在 Fc 區域中具有增加的比例的非岩藻醣基化寡糖的抗體可具有改善的 FcγRIIIa 受體結合及/或改善的效應功能，特定而言改善的 ADCC 功能。參見例如 US 2003/0157108；US 2004/0093621。In one aspect, antibody variants are provided that have non-fucosylated oligosaccharides, i.e., oligosaccharide structures that lack (directly or indirectly) fucose attached to the Fc region. These non-fucosylated oligosaccharides (also referred to as "defucosylated" oligosaccharides) are specifically N-linked oligosaccharides that lack a fucose residue linked to the first GlcNAc in the stem of the double antenna oligosaccharide structure. In one aspect, antibody variants are provided that have an increased proportion of non-fucosylated oligosaccharides in the Fc region compared to a native or parent antibody. For example, the proportion of non-fucosylated oligosaccharides may be at least about 20%, at least about 40%, at least about 60%, at least about 80% or even about 100% (i.e., no fucosylated oligosaccharides are present). The percentage of non-fucosylated oligosaccharides is the (average) amount of oligosaccharides lacking a fucose residue relative to the sum of all oligosaccharides attached to Asn 297 (e.g., complex, hybrid and high mannose structures), as measured by MALDI-TOF mass spectrometry, as described in WO 2006/082515. Asn297 refers to the asparagine residue located near position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300 due to minor sequence variations of the antibody. Such antibodies with an increased proportion of non-fucosylated oligosaccharides in the Fc region may have improved FcγRIIIa receptor binding and/or improved effector function, in particular improved ADCC function. See, e.g., US 2003/0157108; US 2004/0093621.

能夠產生具有減少的岩藻醣基化之抗體之細胞株的實例包括缺乏蛋白質岩藻醣基化之 Lec13 CHO 細胞 (Ripka 等人，Arch. Biochem. Biophys. 249:533-545 (1986)；US 2003/0157108；及 WO 2004/056312，尤其在實例 11 中)；及剔除細胞株，諸如剔除 α-1,6-岩藻醣基轉移酶基因 FUT8 的 CHO 細胞 (例如參見 Yamane-Ohnuki 等人，Biotech. Bioeng. 87:614-622 (2004)；Kanda, Y. 等人，Biotechnol. Bioeng.，94(4):680-688 (2006)；及 WO 2003/085107)；或 GDP-岩藻醣合成或轉運蛋白活性降低或消失的細胞 (例如參見 US2004259150、US2005031613、US2004132140、US2004110282)。Examples of cell lines capable of producing antibodies with reduced fucosylation include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US 2003/0157108; and WO 2004/056312, particularly in Example 11); and knockout cell lines, such as CHO cells knocked out for the α-1,6-fucosyltransferase gene FUT8 (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87:614-622 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688). (2006); and WO 2003/085107); or cells in which GDP-fucose synthesis or transporter activity is reduced or absent (see, for example, US2004259150, US2005031613, US2004132140, US2004110282).

在又一態樣中，抗體變異體被提供有二等分之寡醣，例如，其中連接至抗體之 Fc 區域的雙天線型寡醣被 GlcNAc 平分。此等抗體變異體可具有如上所述之減少的岩藻醣基化及/或改善的 ADCC 功能。此等抗體變異體之實例描述於例如：Umana 等人，Nat Biotechnol 17，176-180 (1999)；Ferrara 等人，Biotechn Bioeng 93，851-861 (2006)；WO 99/54342；WO 2004/065540、WO 2003/011878。In another aspect, the antibody variant is provided with a bisected oligosaccharide, for example, wherein the bivalent oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function as described above. Examples of such antibody variants are described in, for example: Umana et al., Nat Biotechnol 17, 176-180 (1999); Ferrara et al., Biotechn Bioeng 93, 851-861 (2006); WO 99/54342; WO 2004/065540, WO 2003/011878.

亦提供了在寡醣上具有至少一個連接至 Fc 區域之半乳糖殘基的抗體變異體。此等抗體變異體可具有改善的 CDC 功能。此等抗體變異體描述於例如 WO 1997/30087、WO 1998/58964 及 WO 1999/22764 中。c) Fc區變異體Antibody variants having at least one galactose residue on the oligosaccharide linked to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087, WO 1998/58964 and WO 1999/22764.c) Fcregion variants

在某些態樣中，可在本文所提供之抗體的 Fc 區域中引入一個或多個胺基酸修飾，從而產生 Fc 區變異體。Fc 區變異體可包含人 Fc 區域序列 (例如，人 IgG1、IgG2、IgG3 或 IgG4 Fc 區)，其包含在一個或多個胺基酸位置處的胺基酸修飾 (例如，取代)。In certain aspects, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

在某些態樣中，本發明考慮一種具有一部分但非全部效應功能的抗體變異體，使其成為所期望之候選以用於以下應用：其中抗體活體內半衰期係重要的，但某些效應功能 (諸如補體依賴性細胞毒性 (CDC) 及抗體依賴性細胞媒介之細胞毒性 (ADCC)) 係不必要或有害的。可實施活體外及/或活體內細胞毒性測定以確認 CDC 及/或 ADCC 活性之降低/耗乏。舉例而言，可實施 Fc 受體 (FcR) 結合測定以確保抗體缺乏 FcγR 結合 (因此可能缺乏 ADCC 活性)，但保留 FcRn 結合能力。介導 ADCC 的主要細胞 NK 細胞僅表現 FcγRIII，而單核細胞表現 FcγRI、FcγRII 及 FcγRIII。FcR 在造血細胞上之表現匯總於 Ravetch 及 Kinet 的論文 (Annu. Rev. Immunol. 9: 457-492 (1991)) 之第 464 頁的表 3 中。用於評估目標分子之 ADCC 活性的活體外檢定的非限制性實例闡述於美國專利第 5,500,362 號 (例如參見，Hellstrom, I. 等人，Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) 及 Hellstrom, I 等人，Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985)；5,821,337 (參見 Bruggemann, M. 等人，J. Exp. Med. 166:1351-1361 (1987)) 中。可替代地，可採用非放射性測定方法 (參見例如：用於流式細胞術的 ACTI™ 非放射性細胞毒性測定 (CellTechnology，Inc. Mountain View，CA)；及 CytoTox 96® 非放射性細胞毒性測定 (Promega，Madison，WI))。用於此等測定的有用的效應細胞包括外周血單核細胞 (PBMC) 及自然殺手 (NK) 細胞。可替代地或另外地，可在例如諸如 Clynes 等人 Proc. Nat’l Acad. Sci. USA95:652-656 (1998) 中揭示的動物模型中在活體內評定目標分子之 ADCC 活性。還可實施 C1q 結合測定以確認該抗體無法結合 C1q 並因此缺乏 CDC 活性。參見，例如，WO 2006/029879 及 WO 2005/100402 中的 C1q 及 C3c 結合 ELISA。為評定補體活化，可進行 CDC 測定 (例如參見 Gazzano-Santoro 等人，J. Immunol. Methods 202:163 (1996)；Cragg, M.S. 等人，Blood 101:1045-1052 (2003)；及 Cragg, M.S. 與 M.J. Glennie，Blood 103:2738-2743 (2004))。FcRn 結合和體內清除率/半衰期確定也可使用此領域中所公知的方法進行 (參見例如 Petkova, S.B. 等人，Int'l. Immunol. 18(12):1759-1769 (2006)；WO 2013/120929 Al)。In certain aspects, the present invention contemplates an antibody variant that has some but not all effector functions, making it a desirable candidate for use in applications where the in vivo half-life of the antibody is important, but certain effector functions (such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)) are unnecessary or detrimental. In vitro and/or in vivo cytotoxicity assays can be performed to confirm reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity), but retains FcRn binding ability. NK cells, the primary cells mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet (Annu. Rev. Immunol. 9: 457-492 (1991)). Non-limiting examples of in vitro assays for evaluating ADCC activity of target molecules are described in U.S. Pat. Nos. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be employed (see, e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, ADCC activity of the target molecule can be assessed in vivo in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody is unable to bind to C1q and therefore lacks CDC activity. See, e.g., WO 2006/029879 and WO 2005/100402 for C1q and C3c binding ELISAs. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determination can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int'l. Immunol. 18(12):1759-1769 (2006); WO 2013/120929 Al).

效應子功能下降的抗體包括一個或多個 Fc 區域殘基 238、265、269、270、297、327 和 329 被取代之抗體 (美國第 6,737,056 號專利)。此等 Fc 突變體包括具有在胺基酸位置 265、269、270、297 及 327 中的兩者或更多者處的取代之 Fc 突變體，包括所謂的「DANA」Fc 突變體，其中殘基 265 及 297 被丙胺酸取代 (美國專利號 7,332,581)。Antibodies with reduced effector function include antibodies in which one or more of the Fc region residues 238, 265, 269, 270, 297, 327 and 329 are substituted (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant, in which residues 265 and 297 are substituted with alanine (U.S. Patent No. 7,332,581).

描述了某些與 FcR 之結合得到改善或減弱的抗體變異體。(參見例如美國專利第 6,737,056 號；WO 2004/056312；及 Shields 等人，J. Biol. Chem. 9(2):6591-6604 (2001).)Certain antibody variants with improved or reduced binding to FcRs have been described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

在某些態樣中，抗體變異體包含具有一個或多個胺基酸取代的 Fc 區域，這些取代改善了 ADCC，例如 Fc 區域的位置 298、333 及/或 334 (殘基的 EU 編號) 處之取代。In certain aspects, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333 and/or 334 (EU numbering of residues) of the Fc region.

在某些態樣中，抗體變異體包含具有一個或多個胺基酸取代的 Fc 區，這些取代減弱了 FcγR 結合，例如 Fc 區的位置 234 及 235 (殘基的 EU 編號) 處之取代。在一個態樣中，取代為 L234A 及 L235A (LALA)。在某些方面，抗體變異體進一步包含 Fc 區中之 D265A 及/或 P329G，其來源於人 IgG1 Fc 區。一方面，取代為 Fc 區中的 L234A、L235A 和 P329G (LALA-PG)，其來源於人 IgG1 Fc 區。參見例如 WO 2012/130831。另一方面，取代為 Fc 區中的 L234A、L235A 和 D265A (LALA-DA)，其來源於人 IgG1 Fc 區。In certain aspects, the antibody variant comprises an Fc region with one or more amino acid substitutions that reduce FcγR binding, such as substitutions at positions 234 and 235 (EU numbering of residues) of the Fc region. In one aspect, the substitutions are L234A and L235A (LALA). In certain aspects, the antibody variant further comprises D265A and/or P329G in the Fc region, which are derived from a human IgG1 Fc region. In one aspect, the substitutions are L234A, L235A and P329G (LALA-PG) in the Fc region, which are derived from a human IgG1 Fc region. See, e.g., WO 2012/130831. On the other hand, the substitutions were L234A, L235A, and D265A (LALA-DA) in the Fc region, which was derived from the human IgG1 Fc region.

在一些態樣中，在 Fc 區域中進行修改，得到修改 (亦即改善或減少) 之 C1q 結合及/或補體依賴性細胞毒性 (CDC)，例如，如闡述於美國專利第 6,194,551 號、WO 99/51642 及 Idusogie 等人 J. Immunol. 164: 4178-4184 (2000)。In some aspects, modifications are made in the Fc region resulting in modified (i.e., improved or reduced) C1q binding and/or complement-dependent cytotoxicity (CDC), e.g., as described in U.S. Patent No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

具有更長半衰期並改良了與新生兒 Fc 受體 (FcRn) (其負責將母體 IgG 轉移給胎兒，參見 Guyer 等人，J. Immunol. 117:587 (1976) 及 Kim 等人，J. Immunol. 24:249 (1994)) 之結合的抗體闡述於 US2005/0014934 (Hinton 等人) 中。那些抗體包含其中具有一個或多個取代之 Fc 區域，其改善了 Fc 區域與 FcRn 之結合。此類 Fc 變異體包括在一個或多個 Fc 區域殘基上發生取代之 Fc 變異體：238、252、254、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424 或 434，例如 Fc 區域殘基 434 之取代 (參見例如美國專利號 7,371,826；Dall'Acqua, W.F. 等人，J. Biol. Chem. 281 (2006) 23514-23524)。Antibodies with longer half-lives and improved binding to the neonatal Fc receptor (FcRn) (which is responsible for the transfer of maternal IgG to the fetus, see Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in US2005/0014934 (Hinton et al.). Those antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, such as substitution of Fc region residue 434 (see, e.g., U.S. Pat. No. 7,371,826; Dall'Acqua, W.F. et al., J. Biol. Chem. 281 (2006) 23514-23524).

對人 Fc-人 FcRn 複合物的研究表明，殘基 I253、S254、H435 和 Y436 對於相互作用至關重要 (Firan, M. 等人，Int. Immunol. 13 (2001) 993；Shields, R.L. 等人，J. Biol. Chem. 276 (2001) 6591-6604)。在 Yeung, Y.A. 等人 (J. Immunol. 182 (2009) 7667-7671) 中，已經報導並研究了殘基 248 至 259 及 301 至 317 及 376 至 382 及 424 至 437 的各種突變體。Studies on the human Fc-human FcRn complex have shown that residues I253, S254, H435 and Y436 are essential for the interaction (Firan, M. et al., Int. Immunol. 13 (2001) 993; Shields, R.L. et al., J. Biol. Chem. 276 (2001) 6591-6604). In Yeung, Y.A. et al. (J. Immunol. 182 (2009) 7667-7671), various mutants of residues 248 to 259, 301 to 317, 376 to 382 and 424 to 437 have been reported and studied.

在某些態樣中，抗體變異體包含具有一個或多個胺基酸取代的 Fc 區，該等取代降低 FcRn 結合，例如 Fc 區之位置 253、及/或 310、及/或 435 (殘基的 EU 編號) 處之取代。在某些態樣中，抗體變異體包含 Fc 區域，該 Fc 區域具有在位置 253、310 及 435 處之胺基酸取代。在一個態樣中，取代為 Fc 區域中之 I253A、H310A 及 H435A，其來源於人 IgG1 Fc 區域。參見例如 Grevys, A 等人，J. Immunol. 194 (2015) 5497-5508。In certain aspects, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcRn binding, such as substitutions at positions 253, and/or 310, and/or 435 (EU numbering of residues) of the Fc region. In certain aspects, the antibody variant comprises an Fc region having amino acid substitutions at positions 253, 310, and 435. In one aspect, the substitutions are I253A, H310A, and H435A in the Fc region, which are derived from a human IgG1 Fc region. See, e.g., Grevys, A et al., J. Immunol. 194 (2015) 5497-5508.

在某些態樣中，抗體變異體包含具有一個或多個胺基酸取代的 Fc 區，該等取代降低 FcRn 結合，例如 Fc 區之位置 310、及/或 433、及/或 436 (殘基的 EU 編號) 處之取代。在某些態樣中，抗體變異體包含 Fc 區域，該 Fc 區域具有在位置 310、433 及 436 處之胺基酸取代。在一個態樣中，取代為 Fc 區域中之 H310A、H433A 及 Y436A，其來源於人 IgG1 Fc 區域。(參見例如 WO 2014/177460 Al)。In certain aspects, the antibody variant comprises an Fc region having one or more amino acid substitutions that reduce FcRn binding, such as substitutions at positions 310, and/or 433, and/or 436 (EU numbering of residues) of the Fc region. In certain aspects, the antibody variant comprises an Fc region having amino acid substitutions at positions 310, 433, and 436. In one aspect, the substitutions are H310A, H433A, and Y436A in the Fc region, which are derived from a human IgG1 Fc region. (See, e.g., WO 2014/177460 Al).

在某些態樣中，抗體變異體包含具有一個或多個胺基酸取代的 Fc 區，該等取代增加 FcRn 結合，例如 Fc 區之位置 252、及/或 254、及/或 256 (殘基的 EU 編號) 處之取代。在某些態樣中，抗體變異體包含 Fc 區，該 Fc 區具有在位置 252、254 及 256 處之胺基酸取代。在一個態樣中，取代為 Fc 區域中之 M252Y、S254T 及 T256E，其來源於人 IgG1 Fc 區域。亦參見 Duncan & Winter，Nature 322:738-40 (1988)；美國專利號 5,648,260；美國專利號 5,624,821；及 WO 94/29351，其中涉及 Fc 區變異體之其他實例。In certain aspects, the antibody variant comprises an Fc region having one or more amino acid substitutions that increase FcRn binding, such as substitutions at positions 252, and/or 254, and/or 256 (EU numbering of residues) of the Fc region. In certain aspects, the antibody variant comprises an Fc region having amino acid substitutions at positions 252, 254, and 256. In one aspect, the substitutions are M252Y, S254T, and T256E in the Fc region, which is derived from a human IgG1 Fc region. See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351 for other examples of Fc region variants.

如本文所報告之抗體的重鏈之 C 末端可為以胺基酸殘基 PGK 結尾的完整 C 末端。重鏈的 C 端可以是縮短的 C 端，其中一個或兩個 C 端胺基酸殘基已被去除。於一個優選態樣中，重鏈之 C 端是縮短的 C 端結尾 PG。在本文所報告的所有態樣中之一態樣中，一種包含重鏈的抗體包括本文所指定之 C 端 CH3 域，其包含 C 端甘胺酸-離胺酸二肽 (G446 和 K447，胺基酸位置的 EU 指數編號)。在本文所報告的所有態樣中之一態樣中，一種包含重鏈的抗體包括本文所指定之 C 端 CH3 域，其包含 C 端甘胺酸殘基 (G446，胺基酸位置的 EU 指數編號)。d)半胱胺酸工程化抗體變異體The C-terminus of the heavy chain of the antibody as reported herein may be a complete C-terminus ending with the amino acid residue PGK. The C-terminus of the heavy chain may be a shortened C-terminus, in which one or both C-terminal amino acid residues have been removed. In a preferred embodiment, the C-terminus of the heavy chain is a shortened C-terminus ending with PG. In one embodiment of all embodiments reported herein, an antibody comprising a heavy chain includes a C-terminal CH3 domain as specified herein, which comprises a C-terminal glycine-lysine dipeptide (G446 and K447, EU index numbering of amino acid positions). In one embodiment of all the embodiments reported herein, an antibody comprising a heavy chain comprises a C-terminal CH3 domain as specified herein, comprising a C-terminal glycine residue (G446, EU index numbering of amino acid positions).d)Cysteine engineered antibody variants

在某些態樣中，可以期望創建半胱胺酸工程化抗體，例如 THIOMABTM 抗體，其中抗體之一個或多個殘基被半胱胺酸殘基取代。在特定態樣中，取代殘基出現在抗體之可進入的位點。透過用半胱胺酸取代那些殘基，反應性硫醇基團由此被定位在抗體之可進入的位點，並可用於使抗體與其他部分 (例如藥物部分或連接子-藥物部分) 結合，以形成免疫結合物，如本文進一步所述。半胱胺酸工程化抗體可按照例如美國專利號 7,521,541、8,30,930、7,855,275、9,000,130 或 WO 2016040856 所屬的方法產生。e)抗體衍生物In certain aspects, it may be desirable to create cysteine engineered antibodies, such as THIOMAB™ antibodies, in which one or more residues of the antibody are replaced with cysteine residues. In particular aspects, the substituted residues occur at accessible sites of the antibody. By replacing those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and can be used to bind the antibody to other moieties (e.g., drug moieties or linker-drug moieties) to form immunoconjugates, as further described herein. Cysteine engineered antibodies can be produced, for example, according to the methods of U.S. Patent Nos. 7,521,541, 8,30,930, 7,855,275, 9,000,130, or WO 2016040856.e)Antibody Derivatives

在某些態樣中，本文所提供之抗體可經進一步修飾以含有本領域中已知且容易獲得的另外的非蛋白質部分。適用於抗體之衍生化的部分包括但不限於水溶性聚合物。水溶性聚合物之非限制性實例包括但不限於聚乙二醇 (PEG)、乙二醇/丙二醇共聚物、羧甲基纖維素、葡聚醣、聚乙烯醇、聚乙烯基吡咯啶酮、聚-1,3-二氧戊環、聚-1,3,6-三㗁𠮿、乙烯/馬來酸酐共聚物、聚胺基酸 (均聚物或隨機共聚物) 以及葡聚醣或聚(n-乙烯基吡咯啶酮)聚乙二醇、丙二醇均聚物、聚環氧丙烷/環氧乙烷共聚物、聚氧乙烯化多元醇 (例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛由於其水中之穩定性而可能在製造中具有優勢。該聚合物可具有任何分子量，且可聚支鏈或無支鏈。連接至抗體的聚合物之數量可以變化，並且如果連接的聚合物超過一種，則它們可以為相同或不同之分子。通常，用於衍生化的聚合物之數量及/或類型可基於以下考慮因素來判定，此等考慮因素包括但不限於待改善之抗體的特定性質或功能、抗體衍生物是否將用於指定條件下的治療中等。8.免疫結合物In certain aspects, the antibodies provided herein may be further modified to contain additional non-protein moieties known in the art and readily available. Suitable derivatized moieties for antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-triazine, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers) and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. Generally, the amount and/or type of polymer used for derivatization may be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, whether the antibody derivative will be used in therapy under specified conditions, etc.8.Immunoconjugates

本發明亦提供了包含本文之抗人類 C3bBb 抗體的免疫結合物，其結合 (化學鍵合) 至一種或多種治療劑，諸如細胞毒性劑、化學治療劑、藥物、生長抑制劑、毒素 (例如，來源於細菌、真菌、植物或動物之蛋白毒素、酶活性毒素或其片段) 或放射性同位素。The present invention also provides immunoconjugates comprising an anti-human C3bBb antibody herein conjugated (chemically bonded) to one or more therapeutic agents, such as a cytotoxic agent, a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin or a fragment thereof derived from bacteria, fungi, plants or animals), or a radioactive isotope.

在一個態樣中，免疫結合物為抗體-藥物結合物 (ADC)，其中抗體與上述治療劑中之一者或多者結合。通常使用連接子將抗體連結至一種或多種治療劑。ADC 技術概述 (包括治療劑及藥物以及連接體之實例) 陳述於 Pharmacol Review 68:3-19 (2016) 中。In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC), in which the antibody is conjugated to one or more of the above therapeutic agents. A linker is typically used to link the antibody to the one or more therapeutic agents. An overview of ADC technology, including examples of therapeutic agents and drugs and linkers, is described in Pharmacol Review 68:3-19 (2016).

在另一個實施例中，免疫複合體包括綴合至酶活性毒素或其片段的本文所述之抗體，該酶活性毒素或其片段包括但不限於白喉 A 鏈、白喉毒素之非結合活性片段、外毒素 A 鏈 (來源於銅綠假單胞菌)、蓖麻毒蛋白 A 鏈、相思子毒素 A 鏈、莫迪素 A 鏈、α-八疊球菌、油桐蛋白、香石竹毒蛋白、美洲商陸蛋白 (PAPI、PAPII 和 PAP-S)、苦瓜抑制因子、薑黃素、巴豆毒素、肥皂草抑制劑、白樹毒素、米托菌素、局限曲菌素、酚黴素、伊諾黴素和單端孢黴烯族毒素。In another embodiment, the immune complex comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria chain A, non-binding active fragments of diphtheria toxin, exotoxin chain A (from Pseudomonas aeruginosa), ricin chain A, abrin A chain, modisin A chain, alpha-octadecene, Aleurites fordii proteins, Dianthus caryophyllus proteins, Pokeweed proteins (PAPI, PAPII and PAP-S), Momordica charantia inhibitory factor, curcumin, crotonin, saponin, smilax glabra toxin, mitocin, restrictocin, phenomycin, enomycin and trichothecenes.

在另一態樣中，免疫結合物包含結合至放射性原子以形成放射性結合物的本文所述之抗體。多種放射性同位素可用於產生放射性結合物。實例包括 At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212 及 Lu 放射性同位素。當放射性結合物用於檢測時，它可包含用於閃爍顯像研究之放射性原子，例如 tc99m 或 I123，或用於核磁共振 (NMR) 成像 (亦稱為磁共振成像，mri) 之自旋標記物，例如碘-123 (再次)、碘-131、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵。In another aspect, the immunoconjugate comprises an antibody described herein bound to a radioactive atom to form a radioactive conjugate. A variety of radioisotopes can be used to produce radioactive conjugates. Examples include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and Lu radioisotopes. When the radioactive conjugate is used for detection, it can include a radioactive atom used for scintillation imaging studies, such as tc99m or I123, or a spin label used for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 (again), iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

抗體與細胞毒性劑之複合體可使用多種雙功能蛋白偶合劑進行製備，該雙功能蛋白偶合劑諸如 N-琥珀醯亞胺基-3-(2-吡啶基二硫代)丙酸酯 (SPDP)、琥珀醯亞胺基-4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸酯 (SMCC)、亞胺基硫烷 (IT)、亞胺基酸酯的雙功能衍生物 (諸如己二酸二甲酯鹽酸鹽 (HCl))、活性酯 (諸如雙琥珀醯亞胺辛二酸)、醛 (諸如戊二醛)、雙疊氮化合物 (諸如雙(對疊氮基苯甲醯基)己二胺)、雙重氮衍生物 (諸如雙-(對重氮苯甲醯基)-乙二胺)、二異氰酸酯 (諸如甲苯 2,6-二異氰酸酯) 及雙活性氟化合物 (諸如 1,5-二氟-2,4-二硝基苯)。舉例而言，蓖麻毒蛋白免疫毒素可按照 Vitetta 等人 (Science 238:1098 (1987)) 所闡述的方法進行製備。用於放射性核苷酸與抗體之結合的一種例示性螯合劑為碳-14 標記之 1-異硫氰酸苄基-3-甲基二亞乙基三胺五乙酸 (MX-DTPA)。參見 WO 94/11026。連接子可為促進細胞中細胞毒性藥物釋放的「可切割連接子」。舉例而言，可使用酸不穩定之連接子、對肽酶敏感之連接子、光不穩定之連接子、二甲基連接子或含雙硫鍵之連接子 (Chari 等人，Cancer Res. 52:127-131 (1992)；美國專利第 5,208,020 號)。The complex of the antibody and the cytotoxic agent can be prepared using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-cis-butylenediimidomethyl) cyclohexane-1-carboxylate (SMCC), imidosulfane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipate hydrochloride (HCl)), active esters (such as bis-succinimidyl suberate), aldehydes (such as glutaraldehyde), bis-diazo compounds (such as bis-(p-azidobenzoyl)hexanediamine), bis-diazo derivatives. (e.g., bis-(p-diazobenzyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared according to the method described by Vitetta et al. (Science 238:1098 (1987)). An exemplary chelator for conjugation of radionucleotides to antibodies is carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA). See WO 94/11026. The linker can be a "cleavable linker" that promotes release of the cytotoxic drug in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-bond-containing linker can be used (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020).

本文之免疫結合物或 ADC 明確考慮但不限於此類用交聯劑試劑製得之複合體，該等交聯劑試劑包括但不限於 (例如，自 Pierce Biotechnology, Inc., Rockford, IL., U.S.A) 可商購獲得之 BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC 及磺基-SMPB 以及 SVSB (琥珀醯亞胺基-(4-乙烯碸)苯甲酸酯)。B.重組方法及組成物The immunoconjugates or ADCs herein specifically contemplate, but are not limited to, such complexes made with crosslinking reagents, including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfonate)benzoate) commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., USA).B.Recombination Methods and Compositions

抗體可使用重組方法及組成物來生產，例如按照 US 4,816,567 中所述。對於此等方法，提供了一種或多種編碼抗體的分離之核酸。Antibodies can be produced using recombinant methods and compositions, for example as described in US 4,816,567. For these methods, one or more isolated nucleic acids encoding the antibodies are provided.

如果是天然抗體或天然抗體片段，則需要兩個核酸，一個用於輕鏈或其片段，且另一個用於重鏈或其片段。此等核酸編碼包含 VL 之胺基酸序列及/或包含抗體的 VH 的胺基酸序列 (例如，抗體之輕鏈及/或重鏈)。這些核酸可以在同一表現載體上，也可以在不同表現載體上。In the case of a natural antibody or a natural antibody fragment, two nucleic acids are required, one for the light chain or a fragment thereof and the other for the heavy chain or a fragment thereof. These nucleic acids encode the amino acid sequence comprising the VL and/or the amino acid sequence comprising the VH of the antibody (e.g., the light chain and/or the heavy chain of the antibody). These nucleic acids may be on the same expression vector or on different expression vectors.

如果是具有異二聚體重鏈的雙特異性抗體，需要四個核酸，一個用於第一輕鏈，一個用於第一重鏈 (其包含第一異源單體 Fc 區多肽)，一個用於第二輕鏈，且一個用於第二重鏈 (其包含第二異源單體 Fc 區多肽)。這四個核酸可包含在一個或多個核酸分子或表現載體中。此等核酸編碼包含第一 VL 之胺基酸序列、及/或包含第一 VH (包括第一異源 Fc 區域) 之胺基酸序列、及/或包含第二 VL 之胺基酸序列、及/或包含第二 VH (包括抗體之第二異源 Fc 區域) 之胺基酸序列 (例如，抗體之第一及/或第二輕鏈、及/或第一及/或第二重鏈)。這些核酸可以在同一表現載體上，也可以在不同表現載體上，通常這些核酸位於兩個或三個表現載體上，即一個載體可包含一個以上的這些核酸。這些雙特異性抗體的實例是 CrossMabs (參見例如 Schaefer, W. 等人，PNAS，108 (2011) 11187-1191)。例如，異源單體重鏈之一包含所謂「杵突變」 (T366W，視情況地為 S354C 或 Y349C 之一)，且另一個包含所謂「臼突變」 (T366S、L368A 及 Y407V，以及視情況的 Y349C 或 S354C) (參見例如 Carter, P. 等人，Immunotechnol.2 (1996) 73) (根據 EU 索引編號)。In the case of a bispecific antibody with heterodimeric heavy chains, four nucleic acids are required, one for the first light chain, one for the first heavy chain (which comprises the first heterologous monomeric Fc region polypeptide), one for the second light chain, and one for the second heavy chain (which comprises the second heterologous monomeric Fc region polypeptide). These four nucleic acids can be contained in one or more nucleic acid molecules or expression vectors. These nucleic acids encode an amino acid sequence comprising a first VL, and/or an amino acid sequence comprising a first VH (comprising a first heterologous Fc region), and/or an amino acid sequence comprising a second VL, and/or an amino acid sequence comprising a second VH (comprising a second heterologous Fc region of the antibody) (e.g., the first and/or second light chains, and/or the first and/or second heavy chains of the antibody). These nucleic acids can be on the same expression vector or on different expression vectors. Usually, these nucleic acids are located on two or three expression vectors, that is, one vector can contain more than one of these nucleic acids. Examples of these bispecific antibodies are CrossMabs (see, for example, Schaefer, W. et al., PNAS, 108 (2011) 11187-1191). For example, one of the heterologous monomer rechains comprises a so-called "knob mutation" (T366W, and optionally one of S354C or Y349C), and the other comprises a so-called "hole mutation" (T366S, L368A and Y407V, and optionally Y349C or S354C) (see, e.g., Carter, P. et al., Immunotechnol. 2 (1996) 73) (numbering according to the EU index).

在一個態樣中，提供編碼抗體的分離之核酸，該抗體用於如本文所報告的方法中。In one aspect, an isolated nucleic acid encoding an antibody for use in a method as reported herein is provided.

在一個態樣中，提供一種製備抗人類 C3bBb 抗體之方法，其中該方法包含在適合於表現抗體之條件下培養包含如上文提供之一種或多種編碼抗體的核酸的宿主細胞，並視情況自宿主細胞 (或宿主細胞培養基) 回收抗體。In one aspect, a method for preparing an anti-human C3bBb antibody is provided, wherein the method comprises culturing a host cell comprising one or more antibody-encoding nucleic acids as provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

對於抗人類 C3bBb 抗體之重組產生，將例如上述之編碼抗體之核酸分離並插入到一種或多種載體中，以在宿主細胞中進一步選殖及/或表現。此等核酸可使用習用方法 (例如，藉由使用能夠與編碼抗體重鏈及輕鏈的基因特異性結合的寡核苷酸探針) 輕易地分離並定序，或藉由重組方法或化學合成來產生。For recombinant production of anti-human C3bBb antibodies, nucleic acids encoding the antibodies, such as those described above, are isolated and inserted into one or more vectors for further propagation and/or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional methods (e.g., by using oligonucleotide probes that specifically bind to genes encoding the heavy and light chains of the antibody), or produced by recombinant methods or chemical synthesis.

適用於選殖或表現編碼抗體之載體的宿主細胞包括本文所述之原核或真核細胞。例如，抗體可能在細菌中產生，特別是在無需醣基化和 Fc 效應功能的情況下。有關抗體片段和多肽在細菌中之表現，參見例如 US 5,648,237、US 5,789,199 及 US 5,840,523。(另請參見 Charlton, K.A.，在：Methods in Molecular Biology，第 248 卷，Lo, B.K.C. (編輯)，Humana Press, Totowa, NJ (2003), 第 245-254 頁，其中描述了抗體片段在大腸桿菌中之表現。)在表現後，抗體可與可溶性部分中的細菌細胞糊分離，並可進一步經純化。Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly where glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, US 5,648,237, US 5,789,199, and US 5,840,523. (See also Charlton, K.A., In: Methods in Molecular Biology, Vol. 248, Lo, B.K.C. (ed.), Humana Press, Totowa, NJ (2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibodies can be separated from the bacterial cell paste in the soluble fraction and can be further purified.

除原核生物以外，真核微生物 (如絲狀真菌或酵母菌) 也為合適的抗體編碼載體的選殖或表現宿主，包括其醣基化途徑已被「人源化」的真菌和酵母菌株，從而導致具有部分或完全人醣基化型態的抗體的產生。參見 Gerngross, T.U.，Nat. Biotech. 22 (2004) 1409-1414；及 Li, H. 等人，Nat. Biotech. 24 (2006) 210-215。In addition to prokaryotes, eukaryotic microorganisms (such as filamentous fungi or yeast) are also suitable hosts for the cloning or expression of antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized", resulting in the production of antibodies with partially or fully human glycosylation patterns. See Gerngross, T.U., Nat. Biotech. 22 (2004) 1409-1414; and Li, H. et al., Nat. Biotech. 24 (2006) 210-215.

用於表現 (醣基化) 抗體的合適的宿主細胞也來源於多細胞生物 (無脊椎動物及脊椎動物)。無脊椎動物細胞之實例包括植物及昆蟲細胞。已鑑定出許多桿狀病毒株，它們可以與昆蟲細胞結合使用，特定而言用於轉染草地貪夜蛾 (Spodoptera frugiperda) 細胞。Suitable host cells for the expression of (glycosylated) antibodies also come from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. A number of bacilliform virus strains have been identified that can be used in conjunction with insect cells, specifically for transfection of Spodoptera frugiperda cells.

植物細胞培養物亦可以用作宿主。參見，例如，US 5,959,177、US 6,040,498、US 6,420,548、US 7,125,978 及 US 6,417,429 (描述在基因轉殖植物中產生抗體的 PLANTIBODIESTM 技術)。Plant cell cultures can also be used as hosts. See, for example, US 5,959,177, US 6,040,498, US 6,420,548, US 7,125,978 and US 6,417,429 (describing the PLANTIBODIES™ technology for producing antibodies in genetically modified plants).

脊椎動物細胞也可用為宿主。例如，可使用適於在懸浮液中生長的哺乳動物細胞株。可用的哺乳動物宿主細胞株的其他實例包括：由 SV40 (COS-7) 轉化的猴腎 CV1 系；人胚胎腎系 (如例如 Graham, F.L. 等人，J. Gen Virol. 36 (1977) 59-74 中所述之 293 或 293T 細胞)；幼地鼠腎細胞 (BHK)；小鼠睾丸支持細胞 (如例如 Mather, J.P.，Biol. Reprod. 23 (1980) 243-252 中所述之 TM4 細胞)；猴腎細胞 (CV1)；非洲綠猴腎細胞 (VERO-76)；人宮頸癌細胞 (HeLa)；犬腎細胞 (MDCK)；buffalo 大鼠肝細胞 (BRL 3A)；人類肺細胞 (W138)；人類肝細胞 (Hep G2)；小鼠乳腺腫瘤細胞 (MMT 060562)；TRI 細胞 (如例如 Mather, J.P. 等人，Annals N.Y.Acad. Sci. 383 (1982) 44-68 所述)；MRC 5 細胞；及 FS4 細胞。其他可用的哺乳動物宿主細胞株包括中國倉鼠卵巢 (CHO) 細胞，包括 DHFR- CHO 細胞 (Urlaub, G. 等人，Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220)；及骨髓瘤細胞株，例如 Y0、NS0 和 Sp2/0。有關某些適用於抗體生產的哺乳動物宿主細胞株的綜述，參見例如：Yazaki, P. 及 Wu, A.M., Methods in Molecular Biology, 第 248 卷, Lo, B.K.C. (主編)，Humana Press, Totowa, NJ (2004), 第 255-268 頁。Vertebrate cells can also be used as hosts. For example, mammalian cell strains adapted to growth in suspension can be used. Other examples of useful mammalian host cell lines include: monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (such as 293 or 293T cells as described, for example, in Graham, F.L. et al., J. Gen Virol. 36 (1977) 59-74); baby hamster kidney cells (BHK); mouse testicular Sertoli cells (such as TM4 cells as described, for example, in Mather, J.P., Biol. Reprod. 23 (1980) 243-252); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HeLa); canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse breast tumor cells (MMT 060562); TRI cells (as described, for example, in Mather, J.P. et al., Annals N.Y. Acad. Sci. 383 (1982) 44-68); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub, G. et al., Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220); and myeloma cell lines, such as Y0, NS0, and Sp2/0. For a review of some mammalian host cell lines suitable for antibody production, see, e.g., Yazaki, P. and Wu, A.M., Methods in Molecular Biology, Vol. 248, Lo, B.K.C. (Ed.), Humana Press, Totowa, NJ (2004), pp. 255-268.

在一個態樣中，宿主細胞為真核細胞，例如中國倉鼠卵巢 (CHO) 細胞或淋巴樣細胞 (例如，Y0、NS0、Sp20 細胞)。C.測定In one aspect, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., Y0, NS0, Sp20 cell).C.Assay

可採用此領域中所習知的各種檢定對本文所提供之抗 C3bBb 抗體的物理/化學特性及/或生物活性進行鑑定、篩選或表徵。1.結合測定及其他測定The physical/chemical properties and/or biological activities of the anti-C3bBb antibodies provided herein can be identified, screened or characterized using a variety of assays known in the art.1.Binding Assays and Other Assays

在一個態樣中，例如藉由已知方法諸如 ELISA、西方墨點等，檢測本發明之抗體的抗原結合活性。In one embodiment, the antigen binding activity of the antibody of the present invention is detected by known methods such as ELISA, Western blot, etc.

在另一態樣中，競爭測定可用於鑑定與本發明之抗體競爭結合至 C3bBb 的抗體。在某些態樣中，此競爭性抗體結合與本發明之抗體結合者相同之抗原決定基 (例如，線性或構形抗原決定基)。用於圖譜建立抗體結合的抗原決定基的詳細例示性方法提供於 Morris (1996)「Epitope Mapping Protocols」載於 Methods in Molecular Biology 第 66 卷 (Humana Press, Totowa, NJ)。In another aspect, competition assays can be used to identify antibodies that compete with the antibodies of the invention for binding to C3bBb. In certain aspects, the competing antibody binds to the same epitope (e.g., a linear or conformational epitope) as the antibody of the invention. Detailed exemplary methods for mapping epitopes to which antibodies bind are provided in Morris (1996) "Epitope Mapping Protocols" in Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).

在例示性競爭測定中，將固定化 C3bBb 置於包含與 C3bBb 結合之第一標記抗體 (例如，本發明之抗體) 及第二無標記抗體 (正在測試其與第一抗體競爭與 C3bBb 結合的能力) 的溶液中孵化。第二抗體可存在於融合瘤上清液中。作為對照，將固定化 C3bBb 置於包含第一標記抗體但不包含第二未標記抗體的溶液中進行孵育。在允許第一抗體與 C3bBb 結合的條件下孵化後，去除多餘的未結合抗體，並測量與固定化 C3bBb 相關聯之標記物的量。如果試驗樣品中與固定化 C3bBb 相關的標記物的數量相對於對照樣品而言明顯減少，則表明第二抗體正在與第一抗體競爭與 C3bBb 的結合。參見 Harlow 及 Lane (1988) Antibodies:A Laboratory Manual 第 14 章 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)。2.活性測定In an exemplary competition assay, immobilized C3bBb is incubated in a solution containing a first labeled antibody (e.g., an antibody of the present invention) that binds to C3bBb and a second unlabeled antibody (which is being tested for its ability to compete with the first antibody for binding to C3bBb). The second antibody may be present in the fusion tumor supernatant. As a control, immobilized C3bBb is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow binding of the first antibody to C3bBb, excess unbound antibody is removed and the amount of label associated with immobilized C3bBb is measured. If the amount of label associated with immobilized C3bBb in the test sample is significantly reduced relative to the control sample, this indicates that the secondary antibody is competing with the primary antibody for binding to C3bBb. See Harlow and Lane (1988) Antibodies: A Laboratory Manual Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).2.Activity Assay

在一個態樣中，提供用於鑑定抑制抗 C3bBb 抗體之生物學活性的檢定。生物活性可包括例如抑制調節 C3 轉化酶蛋白複合物的形成、穩定性、活性及解離以及影響與其他蛋白 (例如備解素或補體因子 I) 的相互作用。亦提供於體內及/或體外具有此等生物活性之抗體。In one aspect, assays are provided for identifying biological activities that inhibit anti-C3bBb antibodies. Biological activities may include, for example, inhibition of the formation, stability, activity, and dissociation of the C3 convertase protein complex, as well as affecting interactions with other proteins (e.g., properdin or complement factor I). Antibodies having such biological activities in vivo and/or in vitro are also provided.

在某些態樣中，對本發明之抗體進行了此等生物學活性試驗。D.用於診斷和檢測之方法及組成物In certain aspects, the antibodies of the present invention are subjected to such biological activity assays.D.Methods and compositions for diagnosis and detection

在某些態樣中，本文所提供之抗 C3bBb 抗體中之任一者皆可用於檢測生物樣品中 C3bBb 的存在。如本文所用的術語「檢測」，涵蓋定量或定性檢測。In certain aspects, any of the anti-C3bBb antibodies provided herein can be used to detect the presence of C3bBb in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection.

在一個態樣中，提供了一種用於診斷或檢測方法中的抗 C3bBb 抗體。在又一態樣中，提供了一種檢測生物樣品中是否存在 C3bBb 的方法。在某些態樣中，該方法包含在允許抗 C3bBb 抗體與 C3bBb 結合的條件下使生物樣品與如本文所述之抗 C3bBb 抗體接觸，並檢測抗 C3bBb 抗體與 C3bBb 之間是否形成複合物。此方法可為活體外或活體內方法。在一個態樣中，使用抗 C3bBb 抗體來選擇適格於使用抗 C3bBb 抗體進行治療的個體，例如，其中 C3bBb 為用於選擇患者的生物標記。In one aspect, an anti-C3bBb antibody for use in a diagnostic or detection method is provided. In another aspect, a method for detecting the presence of C3bBb in a biological sample is provided. In certain aspects, the method comprises contacting the biological sample with an anti-C3bBb antibody as described herein under conditions that allow the anti-C3bBb antibody to bind to C3bBb, and detecting whether a complex is formed between the anti-C3bBb antibody and C3bBb. This method can be an in vitro or in vivo method. In one aspect, an anti-C3bBb antibody is used to select individuals suitable for treatment with the anti-C3bBb antibody, for example, where C3bBb is a biomarker for selecting patients.

在某些態樣中，提供經標記之抗 C3bBb 抗體。標記包括但不限於直接檢測的標記或部分 (例如螢光、發色、電子緻密、化學發光和放射性標記)，以及間接檢測 (例如，透過酶促反應或分子相互作用) 的部分，例如酶或配體。例示性標記包括但不限於：放射性同位素³²P、¹⁴C、¹²⁵I、³H 及¹³¹I；螢光團，例如稀土螯合物或螢光素及其衍生物；玫瑰紅及其衍生物；丹磺醯基；繖形酮；螢光素酶，例如螢火蟲螢光素酶和細菌螢光素酶 (美國專利號 4,737,456)；螢光素；2,3-二氫鄰苯二甲二酮；辣根過氧化物酶 (HRP)；鹼性磷酸酶；β-半乳糖苷酶；葡糖澱粉酶；溶菌酶；醣類氧化酶，例如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脫氫酶；雜環氧化酶，例如尿酸酶和黃嘌呤氧化酶，與採用過氧化氫氧化染料前身 (例如 HRP、乳過氧化酶或微過氧化酶) 的酶結合使用；生物素/抗生物素蛋白；旋轉標記；噬菌體標記；穩定自由基等。E.醫藥組成物In certain aspects, a labeled anti-C3bBb antibody is provided. Labels include, but are not limited to, directly detectable labels or moieties (e.g., fluorescent, chromogenic, electrophoretic, chemiluminescent, and radioactive labels), as well as moieties that are indirectly detected (e.g., via an enzymatic reaction or molecular interaction), such as enzymes or ligands. Exemplary labels include, but are not limited to, radioactive isotopes³² P,¹⁴ C,¹²⁵ I,³ H, and¹³¹ I; fluorophores, such as rare earth chelates or luciferin and its derivatives; Rose Bengal and its derivatives; Dansyl; Umbelliferone; luciferase, such as firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456); luciferin; 2,3-dihydrophthalenedione; horseradish peroxidase (HRP); alkaline phosphatase; β-galactosidase; glucosidase; lysozyme; carbohydrate oxidase, such as glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase; heterocyclic oxidase, such as uricase and xanthine oxidase, and oxidation of dye precursors (such as HRP, lactoperoxidase or microperoxidase) using hydrogen peroxide Enzyme binding; biotin/antibiotin protein; rotation labeling; phage labeling; stable free radicals, etc.E.Pharmaceutical composition

在又一態樣中，提供了包含本文所提供之任何抗體的醫藥組成物，例如用於以下任何治療方法。在一個態樣中，醫藥組成物包含本文所提供之任何抗體和醫藥上可接受之載劑。在另一態樣中，醫藥組成物包含本文所提供之任何抗體及至少一種另外治療劑 (如下文所述)。In yet another aspect, a pharmaceutical composition comprising any antibody provided herein is provided, for example, for use in any of the following treatment methods. In one aspect, the pharmaceutical composition comprises any antibody provided herein and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises any antibody provided herein and at least one additional therapeutic agent (as described below).

如本文所述之抗 C3bBb 抗體的醫藥組成物 (調配物) 可藉由將該抗體與本領域之技術人員已知的醫藥上可接受之載劑或賦形劑組合來製備。參見例如 Remington's Pharmaceutical Sciences 第 16 版，Osol, A. 主編 (1980), Shire S., Monoclonal Antibodies:Meeting the Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product, 第 1 版, Woodhead Publishing (2015), §4 以及 Falconer R.J., Biotechnology Advances (2019), 37, 107412。如本文所述之抗 C3bBb 抗體的例示性醫藥組成物為凍乾的、水性的、冷凍的等。The pharmaceutical compositions (formulations) of the anti-C3bBb antibodies described herein can be prepared by combining the antibody with a pharmaceutically acceptable carrier or excipient known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980), Shire S., Monoclonal Antibodies: Meeting the Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product, 1st edition, Woodhead Publishing (2015), §4 and Falconer R.J., Biotechnology Advances (2019), 37, 107412. Exemplary pharmaceutical compositions of the anti-C3bBb antibodies described herein are lyophilized, aqueous, frozen, etc.

醫藥上可接受之載劑在採用的劑量及濃度下通常對接受者無毒，且包括但不限於：緩衝劑，諸如組胺酸、磷酸鹽、檸檬酸鹽、醋酸鹽及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑 (諸如十八烷基二甲基苄基氯化銨；氯化六羥季銨；氯化苄烷銨；氯化苯索寧；苯酚、丁醇或苄醇；對羥苯甲酸烷基酯，諸如對羥苯甲酸甲酯或對羥苯甲酸丙酯；鄰苯二酚；間苯二酚；環己醇；3-戊醇；及間甲酚)；低分子量 (小於約 10 個殘基) 多肽；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯烷酮；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸；單醣、雙醣及其他碳水化合物，包括葡萄糖、甘露糖或糊精；螯合劑 (諸如 EDTA)；糖，諸如蔗糖、甘露醇、海藻糖或山梨糖醇；成鹽抗衡離子，諸如鈉；金屬複合物 (例如，鋅蛋白複合物)；及/或非離子界面活性劑，諸如聚乙二醇 (PEG)。Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as histidine, phosphates, citrates, acetates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexahydroxyquaternary ammonium chloride; benzylammonium chloride; benzathonine chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; o-catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspartic acid, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG).

本文所述之醫藥組成物還可包含適合於所治療的特定適應症的多於一種活性成分，較佳地，為那些相互無不利影響的具有互補活性成分。此等活性成分適宜地以對預期目的有效的量組合存在。The pharmaceutical compositions described herein may also contain more than one active ingredient suitable for the specific indication to be treated, preferably, those having complementary active ingredients that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts effective for the intended purpose.

用於活體內投予之醫藥組成物通常係無菌的。無菌性可易於例如透過無菌濾膜過濾來實現。F.治療方法及投予途徑Pharmaceutical compositions for intravenous administration are generally sterile. Sterility can be easily achieved, for example, by filtration through a sterile filter membrane.F.Treatment Methods and Administration Routes

本文所提供之任何抗 C3bBb 抗體皆可用於治療方法中。Any anti-C3bBb antibody provided herein can be used in a method of treatment.

在一個態樣中，提供一種用為藥物的抗 C3bBb 抗體。在又一態樣中，提供了一種用於治療眼部疾病之抗 C3bBb 抗體。在一個實施例中，眼部疾病選自 AMD (在一個實施例中為濕性 AMD、乾性 AMD、中期 AMD、晚期 AMD 及地圖狀萎縮 (GA)、黃斑退化、黃斑部水腫、DME (在一個實施例中為局部性、非中心性 DME 及瀰漫性、涉及中心的 DME)、視網膜病變、糖尿病性視網膜病變 (DR) (在一個實施例中為增生性 DR (PDR)、非增生性 DR (NPDR) 及高海拔 DR)、其他與缺血相關的視網膜病變、ROP、視網膜靜脈阻塞 (RVO) (在一個實施例中為中心 (CRVO) 及分支 (BRVO) 形式)、CNV (在一個實施例中為近視 CNV)、視網膜新血管形成、與視網膜新血管形成相關的疾病、視網膜血管新生、與視網膜/脈絡膜血管新生相關的疾病、中心性漿液視網膜病變 (CSR)、病理性近視、逢希伯-林道病、眼部組織胞漿菌病、FEVR、柯氏症、諾里氏病、與骨質疏鬆-假性神經膠質瘤症候群 (OPPG) 相關的視網膜異常、結膜下出血、紅腫、眼血管新生疾病、血管新生性青光眼、色素性視網膜炎 (RP)、高血壓性視網膜病變、視網膜血管瘤增生、黃斑部毛細血管擴張、虹膜血管新生、眼內血管新生、視網膜病變、黃斑部囊樣水腫 (CME)、管脈炎、視乳頭水腫、視網膜炎，包括但不限於 CMV 視網膜炎、眼黑色素瘤、視網膜母細胞瘤、結膜炎 (在一個實施例中為感染性結膜炎及非感染性 (例如，過敏性) 結膜炎)、萊伯先天性黑蒙症 (亦稱為萊伯氏先天性黑蒙症或 LCA)、眼色素層炎 (包括感染性及非感染性眼色素層炎)、脈絡膜炎 (在一個實施例中為多灶性脈絡膜炎)、眼組織胞漿菌病、瞼緣炎、乾眼症、眼外傷、修格倫氏病及其他眼科疾病，其中該疾病或疾病與血管新生、血管滲漏、及/或視網膜水腫或視網膜萎縮相關。在一個實施例中，眼部疾病選自 AMD (在一個實施例中，為濕性 AMD、乾性 AMD、中期 AMD、晚期 AMD 及地圖狀萎縮 (GA))、黃斑退化、黃斑部水腫、DME (在一個實施例中，為局部性、非中心性 DME 及瀰漫性、涉及中心的 DME)、視網膜病變、糖尿病性視網膜病變 (DR) (在一個實施例中，為增生性 DR (PDR)、非增生性 DR (NPDR) 及高海拔 DR)。在一個實施例中，眼部疾病來自 AMD，在一個實施例中為濕性 AMD。In one aspect, an anti-C3bBb antibody for use as a medicament is provided. In another aspect, an anti-C3bBb antibody for use in treating an ocular disease is provided. In one embodiment, the ocular disease is selected from AMD (in one embodiment, wet AMD, dry AMD, intermediate AMD, advanced AMD, and geographic atrophy (GA), macular degeneration, macular edema, DME (in one embodiment, localized, non-central DME and diffuse, centrally involved DME), retinopathy, diabetic retinopathy (DR) (in one embodiment, proliferative DR (PDR), non-proliferative DR (NPDR) and high altitude DR), other ischemia-related retinopathy, ROP, retinal vein occlusion (RVO) (in one embodiment, central (CRVO) and branch (BRVO) forms), CNV (in one embodiment, myopia CNV), retinal neovascularization, diseases associated with retinal neovascularization, retinal angiogenesis, diseases associated with retinal/choroidal angiogenesis, central serous retinopathy (CSR), pathological myopia, Feng Heber-Lindau disease, ocular histoplasmosis, FEVR, Koch disease, Norrie's disease, retinal abnormalities associated with osteoporosis-pseudoglioma syndrome (OPPG), subconjunctival hemorrhage, erythema, ocular angiogenesis diseases, angiogenic glaucoma, pigmentary retinitis (RP), hypertensive retinopathy, retinal angiomatous proliferation, macular capillary dilatation, iris angiogenesis, intraocular angiogenesis, retinopathy, cystoid macular edema (CME), papillitis, papilledema, retinitis, including but not limited to CMV retinitis, ocular melanoma, retinoblastoma, conjunctivitis (in one embodiment, infectious conjunctivitis and non-infectious (e.g., allergic) conjunctivitis), Leber congenital amaurosis (also known as Leber's congenital amaurosis or LCA), uveitis (including infectious and non-infectious uveitis), choroiditis (in one embodiment, multifocal choroiditis), ocular histoplasmosis, blepharitis, dry eye, ocular trauma, Sjogren's disease and other ophthalmic diseases, wherein the disease or disease is associated with angiogenesis, vascular leakage, and/or retinal edema or retinal atrophy. In one embodiment, the ocular disease is selected from AMD (in one embodiment, wet AMD, dry AMD, intermediate AMD, advanced AMD and geographic atrophy (GA)), macular degeneration, macular edema, DME (in one embodiment, localized, non-central DME and diffuse, centrally involved DME), retinopathy, diabetic retinopathy (DR) (in one embodiment, proliferative DR (PDR), non-proliferative DR (NPDR) and high altitude DR). In one embodiment, the eye disease is from AMD, in one embodiment wet AMD.

在某些態樣中，提供一種用於治療方法中的抗 C3bBb 抗體。在某些態樣中，本發明提供一種在治療患有眼部疾病的個體之方法中使用的抗 C3bBb 抗體，該方法包含向個體投予有效量之抗 C3bBb 抗體。在一個此類態樣中，該方法進一步包含向該個體投予有效量之至少一種另外的治療劑 (例如，一種、兩種、三種、四種、五種或六種另外的治療劑)，例如，如下文所述。In certain aspects, an anti-C3bBb antibody for use in a method of treatment is provided. In certain aspects, the present invention provides an anti-C3bBb antibody for use in a method of treating an individual suffering from an ocular disease, the method comprising administering to the individual an effective amount of the anti-C3bBb antibody. In one such aspect, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents), e.g., as described below.

在又一態樣中，本發明提供抗 C3bBb 抗體在製造或製備藥物中之用途。在一個態樣中，藥物用於治療眼部疾病。在又一態樣中，藥物在治療眼部疾病之方法中使用，該方法包含向患有眼部疾病的個體投予有效量之藥物。在一個此等態樣中，該方法進一步包含將有效量之至少一種另外治療劑 (例如，如下文所述) 投予個體。根據上述任一態樣中的「個體」可以是人。In another aspect, the present invention provides the use of an anti-C3bBb antibody in the manufacture or preparation of a medicament. In one aspect, the medicament is used to treat an eye disease. In another aspect, the medicament is used in a method of treating an eye disease, the method comprising administering an effective amount of the medicament to an individual suffering from the eye disease. In one of these aspects, the method further comprises administering an effective amount of at least one additional therapeutic agent (e.g., as described below) to the individual. According to any of the above aspects, the "individual" can be a human.

在又一態樣中，本發明提供一種用於治療眼部疾病之方法。在一個態樣中，該方法包含向患有此眼部疾病的個體投予有效量之抗 C3bBb 抗體。在一個此類樣態中，如下所述，該方法進一步包含向個體投予有效量之至少一種另外的治療劑。根據上述任一態樣中的「個體」可以是人。In another aspect, the present invention provides a method for treating an ocular disease. In one aspect, the method comprises administering an effective amount of an anti-C3bBb antibody to an individual suffering from the ocular disease. In one such aspect, as described below, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual. According to any of the above aspects, the "individual" can be a human.

在又一態樣中，本發明提供包含本文所提供之抗 C3bBb 抗體中之任一者的醫藥組成物，其例如用於上述治療方法中之任一者。在一個態樣中，醫藥組成物包含本文所提供之抗 C3bBb 抗體中之任一者及醫藥上可接受之載劑。在另一態樣中，醫藥組成物包含本文所提供之抗 C3bBb 抗體中之任一者及至少一種另外的治療劑，例如，如下文所述。In yet another aspect, the invention provides a pharmaceutical composition comprising any of the anti-C3bBb antibodies provided herein, e.g., for use in any of the above-described treatment methods. In one aspect, the pharmaceutical composition comprises any of the anti-C3bBb antibodies provided herein and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises any of the anti-C3bBb antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.

本發明之抗體可單獨投予或用於聯合治療。例如，聯合治療包括投予本發明之抗體並投予至少一種另外的治療劑 (例如，一種、兩種、三種、四種、五種或六種另外的治療劑)。 在某些態樣中，聯合療法包含投予本發明之抗體並投予至少一種另外的治療劑，諸如 VEGF-拮抗劑。The antibodies of the invention may be administered alone or in combination therapy. For example, the combination therapy includes administering an antibody of the invention and administering at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents). In certain aspects, the combination therapy includes administering an antibody of the invention and administering at least one additional therapeutic agent, such as a VEGF-antagonist.

任何合適的 AMD 治療劑皆可作為另外的治療劑與如本文所提供之與人類 C3bBb 結合之抗體聯合投予以用於治療眼部病症 (例如，AMD、DME、DR、RVO 或 GA)，包括但不限於 VEGF 拮抗劑，例如抗 VEGF 抗體 (例如 LUCENTIS® (蘭尼單抗)、RTH-258 (原 ESBA-1008，抗 VEGF 單鏈抗體片段；Novartis) 或雙特異性抗 VEGF 抗體 (例如，抗 VEGF/抗血管生成素 2 雙特異性抗體，諸如氟西匹單抗 (Faricimab) 或 zifibancimig；Roche))、可溶性 VEGF 受體融合蛋白 (例如，EYLEA® (阿柏西普))、抗 VEGF DARPin® (例如，abicipar pegol；Molecular Partners AG/Allergan) 或抗 VEGF 適體 (例如，MACUGEN® (哌加他尼鈉))；源自血小板之生長因子 (PDGF) 拮抗劑，例如，抗 PDGF 抗體，抗 PDGFR 抗體 (例如，REGN2176-3)、抗 PDGF-BB peg 化適體 (例如 FOVISTA®；Ophthotech/Novartis)、可溶性 PDGFR 受體融合蛋白或雙重 PDGF/VEGF 拮抗劑 (例如，小分子抑制劑 (例如，DE-120 (Santen) 或 X-82 (TyrogeneX)) 或雙特異性抗 PDGF/抗 VEGF 抗體))；與光動力治療合用之 VISUDYNE® (維替泊芬)；抗氧化劑；補體系統拮抗劑，例如，補體因子 C5 拮抗劑 (例如，小分子抑制劑 (例如，ARC-1905；Opthotech) 或抗 C5 抗體 (例如，LFG-316；Novartis)、備解素拮抗劑 (例如，抗備解素抗體，例如，CLG-561；Alcon) 或補體因子 D 拮抗劑 (例如，抗補體因子 D 抗體，例如，蘭帕麗珠單抗 (lampalizumab)；Roche))；C3 阻斷肽 (例如，APL-2,，Appellis)；視覺週期休試劑 (例如，依米司他鹽酸鹽 (emixustat hydrochloride))；角鯊胺 (例如，OHR-102；Ohr Pharmaceutical)；維生素及礦物質補充劑 (例如，彼等揭示於 Age-Related Eye Disease Study 1 (AREDS1；鋅及/或抗氧化劑) 及 Study 2 (AREDS2；鋅、抗氧化劑、葉黃素、玉米黃素及/或 ω-3 脂肪酸))；基於細胞之治療，例如，NT-501 (Renexus)；PH-05206388 (Pfizer)、huCNS-SC 細胞移植 (StemCells)、CNTO-2476 (臍帶幹細胞系；Janssen)、OpRegen (RPE 細胞之懸浮液；Cell Cure Neurosciences) 或 MA09-hRPE 細胞移植 (Ocata Therapeutics)；組織因子拮抗劑 (例如，hI-con1；Iconic Therapeutics)；α-腎上腺素性受體促效劑 (例如，酒石酸溴莫尼定 (brimonidine tartrate)；Allergan)；肽疫苗 (例如，S-646240；Shionogi)；類澱粉蛋白 β 拮抗劑 (例如，抗 β 類澱粉蛋白單株抗體，例如，GSK-933776)；S1P 拮抗劑 (例如，抗 S1P 抗體，例如，iSONEP™；Lpath Inc)；ROBO4 拮抗劑 (例如，抗 ROBO4 抗體，例如，DS-7080a；Daiichi Sankyo)；表現內皮抑素及血管抑素之慢病毒載體 (例如，RetinoStat) 及其組合。於一些情況下，AMD 治療劑 (包括前述任意 AMD 治療劑) 可共同調配。例如，抗 PDGFR 抗體 REGN2176-3 可與阿柏西普 (EYLEA®) 共同調配。在一些情況下，此共調配物可與本發明之與人類 C3bBb 結合之抗體組合投予。於一些情況下，該眼部病症為 AMD (例如，濕性 AMD)。Any suitable AMD therapeutic agent can be administered as an additional therapeutic agent in combination with an antibody that binds to human C3bBb as provided herein for the treatment of an ocular disorder (e.g., AMD, DME, DR, RVO, or GA), including but not limited to VEGF antagonists, such as anti-VEGF antibodies (e.g., LUCENTIS® (ranibizumab), RTH-258 (formerly ESBA-1008, an anti-VEGF single chain antibody fragment; Novartis) or bispecific anti-VEGF antibodies (e.g., anti-VEGF/anti-angiopoietin 2 bispecific antibodies, such as faricimab or zifibancimig; Roche)), soluble VEGF receptor fusion proteins (e.g., EYLEA® (aflibercept)), anti-VEGF DARPin® (e.g., abicipar pegol; Molecular Partners AG/Allergan) or anti-VEGF aptamer (e.g., MACUGEN® (pegaptanib sodium)); platelet-derived growth factor (PDGF) antagonists, e.g., anti-PDGF antibodies, anti-PDGFR antibodies (e.g., REGN2176-3), anti-PDGF-BB pegylated aptamers (e.g., FOVISTA®; Ophthotech/Novartis), soluble PDGFR receptor fusion proteins, or dual PDGF/VEGF antagonists (e.g., small molecule inhibitors (e.g., DE-120 (Santen) or X-82 (TyrogeneX)) or bispecific anti-PDGF/anti-VEGF antibodies); VISUDYNE® (verteporfin); antioxidants; complement system antagonists, e.g., complement factor C5 antagonists (e.g., small molecule inhibitors (e.g., ARC-1905; Opthotech) or anti-C5 antibodies (e.g., LFG-316; Novartis), properdin antagonists (e.g., anti-properdin antibodies, e.g., CLG-561; Alcon), or complement factor D antagonists (e.g., anti-complement factor D antibodies, e.g., lampalizumab; Roche)); C3 blocking peptides (e.g., APL-2, Appellis); visual cycle resting agents (e.g., emixustat hydrochloride); squalamide (e.g., OHR-102; Ohr Pharmaceutical); vitamin and mineral supplements (e.g., those disclosed in Age-Related Eye Disease Study 1 (AREDS1; zinc and/or antioxidants) and Study 2 (AREDS2; zinc, antioxidants, lutein, zeaxanthin, and/or omega-3 fatty acids)); cell-based therapies, e.g., NT-501 (Renexus); PH-05206388 (Pfizer), huCNS-SC cell transplantation (StemCells), CNTO-2476 (umbilical cord stem cell line; Janssen), OpRegen (suspension of RPE cells; Cell Cure Neurosciences), or MA09-hRPE cell transplantation (Ocata Therapeutics); tissue factor antagonists (e.g., hI-con1; Iconic Therapeutics); alpha-adrenaline receptor agonists (e.g., brimonidine tartrate; Allergan); peptide vaccines (e.g., S-646240; Shionogi); beta-amyloid protein antagonists (e.g., anti-beta-amyloid protein monoclonal antibodies, e.g., GSK-933776); S1P antagonists (e.g., anti-S1P antibodies, e.g., iSONEP™; Lpath Inc); ROBO4 antagonists (e.g., anti-ROBO4 antibodies, e.g., DS-7080a; Daiichi Sankyo); lentiviral vectors expressing endostatin and angiostatin (e.g., RetinoStat) and combinations thereof. In some cases, AMD therapeutics (including any of the aforementioned AMD therapeutics) can be co-formulated. For example, the anti-PDGFR antibody REGN2176-3 can be co-formulated with aflibercept (EYLEA®). In some cases, this co-formulation can be administered in combination with an antibody of the invention that binds to human C3bBb. In some cases, the ocular disorder is AMD (e.g., wet AMD).

任何合適的 DME 及/或 DR 治療劑皆可與本發明之與人類 C3bBb 結合之抗體聯合投予，以用於治療眼部病症 (例如，AMD、DME、DR、RVO 或 GA)，包括但不限於 VEGF 拮抗劑 (例如，LUCENTIS® 或 EYLEA®)、皮質類固醇 (例如，皮質類固醇植入物 (例如，OZURDEX® (地塞米松玻璃體內植入物) 或 ILUVIEN® (丙酮氟洛皮質醇玻璃體內植入物)) 或經調配用於藉由玻璃體內注射投予之皮質類固醇 (例如，丙酮特安皮質醇)) 或其組合。於一些情況下，該眼部病症為 DME 及/或 DR。Any suitable DME and/or DR therapeutic agent may be administered in combination with an antibody that binds to human C3bBb of the invention for treating an ocular disorder (e.g., AMD, DME, DR, RVO, or GA), including but not limited to VEGF antagonists (e.g., LUCENTIS® or EYLEA®), corticosteroids (e.g., corticosteroid implants (e.g., OZURDEX® (dexamethasone intravitreal implant) or ILUVIEN® (floxacin intravitreal implant)) or corticosteroids formulated for administration by intravitreal injection (e.g., floxacin)), or combinations thereof. In some instances, the ocular disorder is DME and/or DR.

如本文所提供之與人類 C3bBb 結合之抗體可與療法或外科方法聯合投予以用於治療眼部病症 (例如，DME、DR、AMD、RVO 或 GA)，該療法或外科方法包括，例如，雷射光凝 (例如，全視網膜光凝 (PRP))、隱結雷射作用、黃斑裂孔手術、黃斑轉位手術、可植入袖珍望遠鏡、PHI-運動血管造影 (亦稱為微雷射治療及分支血管治療 (feeder vessel treatment))、光子束治療、微刺激治療、視網膜脫落及玻璃體手術、鞏膜屈曲 (scleral buckle)、黃斑下手術、經瞳孔熱療、光系統 I 治療、RNA 干擾 (RNAi) 之使用、體外流變過程 (亦稱為膜差濾及流變治療)、微晶片植入、幹細胞治療、基因替換治療、核糖核酸酵素基因治療 (包括用於缺氧反應元件之基因治療，Oxford Biomedica；Lentipak，Genetix；以及 PDEF 基因治療，GenVec)、光受器/視網膜細胞移植 (包括可移植視網膜上皮細胞，Diacrin, Inc.；視網膜細胞移植物，例如，Astellas Pharma US, Inc., ReNeuron, CHA Biotech)、針灸術及其組合。Antibodies that bind to human C3bBb as provided herein can be administered in conjunction with therapeutic or surgical procedures for the treatment of ocular disorders (e.g., DME, DR, AMD, RVO, or GA), including, for example, laser photocoagulation (e.g., panretinal photocoagulation (PRP)), retinal laser treatment, macular hole surgery, macular translocation surgery, implantable mini-telescopes, PHI-motion angiography (also known as microlaser therapy and feeder vessel treatment), photon beam therapy, microstimulation therapy, retinal detachment and vitrectomy, scleral buckle, submacular surgery, transpupillary thermal therapy, optical system I therapy, use of RNA interference (RNAi), in vitro rheological processes (also known as membrane filtration and rheotherapy), microchip implantation, stem cell therapy, gene replacement therapy, ribonuclease gene therapy (including gene therapy for hypoxia response element, Oxford Biomedica; Lentipak, Genetix; and PDEF gene therapy, GenVec), photoreceptor/retinal cell transplantation (including transplantable retinal epithelial cells, Diacrin, Inc.; retinal cell transplants, e.g., Astellas Pharma US, Inc., ReNeuron, CHA Biotech), acupuncture, and combinations thereof.

上文述及之此等聯合療法涵蓋聯合投予 (其中兩種或多種治療劑包括在同一或單獨的調配物中)，以及單獨投予，在這種情況下，本發明之與人類 C3bBb 結合之抗體之投予可在投予另外一種或多種治療劑之前、同時及/或之後發生。在一個實施例中，本發明之與人類 C3bBb 結合之抗體之投予及另外的治療劑之投予彼此在約一個、兩個、三個、四個或五個月內或者在約一週、兩週或三週內或者在約一天、兩天、三天、四天、五天或六天內。Such combination therapies described above encompass co-administration (where two or more therapeutic agents are included in the same or separate formulations), as well as separate administration, in which case administration of an antibody that binds to human C3bBb of the invention can occur before, simultaneously with, and/or after administration of the other therapeutic agent or agents. In one embodiment, administration of an antibody that binds to human C3bBb of the invention and administration of the other therapeutic agent are within about one, two, three, four, or five months of each other, or within about one, two, three, four, five, or six days of each other.

本發明之抗體 (及任何其他治療劑) 可透過任何合適的方式投予，包括腸胃外、肺內和鼻內投予，並且如果需要局部治療，則可以採用病灶內投予。腸胃道外輸注包括肌肉內、靜脈內、動脈內、腹膜內或皮下投予。投予可藉由任何合適的途徑進行，例如藉由注射，諸如靜脈內或皮下注射，部分取決於短暫投予抑或是長期投予。本文中考慮各種給藥方案，其包括但不限於在多種時間點單次或多次投予、快速注射投予及脈衝輸注。The antibodies of the present invention (and any other therapeutic agents) may be administered by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and if local treatment is desired, intralesional administration may be employed. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term. Various dosing regimens are contemplated herein, including but not limited to single or multiple administrations at various time points, rapid injection administration, and pulse infusion.

本發明之抗體將按照與良好醫學實踐一致的方式進行配製、給藥和施用。在這種情況下，所慮及之因素包括待治療之特定病症、待治療之特定哺乳動物、個別患者的臨床病症、病症之原因、遞送藥劑的部位、投予方法、投予日程及醫療從業者已知的其他因素。該抗體並非必須、但可以視情況與一種或多種目前用於預防或治療所述疾病之藥劑一起配製。此等其他藥劑的有效量取決於醫藥組成物中存在之抗體的量、疾病或治療的類型以及上文討論的其他因素。這些藥物通常以與本文中所述相同的劑量和投予途徑，或本文中所述劑量的約 1% 至 99%，或以經驗上/臨床上確定為適當的任意劑量及藉由任意途徑使用。The antibodies of the present invention will be formulated, dosed, and applied in a manner consistent with good medical practice. In this context, factors to be considered include the specific condition to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to medical practitioners. The antibody need not be, but may be optionally, formulated with one or more agents currently used to prevent or treat the disease in question. The effective amount of such other agents depends on the amount of the antibody present in the pharmaceutical composition, the type of disease or treatment, and the other factors discussed above. These drugs are generally used in the same dosages and by any route as described herein, or about 1% to 99% of the dosages described herein, or in any dosage and by any route determined empirically/clinically to be appropriate.

對於疾病的預防或治療，本發明之抗體的適當劑量 (單獨使用或與一種或多種其他其他治療劑組合使用) 將取決於待治療的疾病的類型、抗體的類型、疾病的嚴重度和病程、為了預防或是治療的目的施用該抗體、之前的治療、患者的臨床病史和對該抗體的反應及主治醫師的判斷。在一次或一系列的治療中適宜地對患者投予抗體。對於在幾天或更長時間內重複給藥，視病症而定，治療通常將持續直至出現所需的疾病症狀抑制。藉由習用技術及測定很容易監測此治療的進展。3.本發明之具體實施例For the prevention or treatment of disease, the appropriate dose of the antibody of the present invention (used alone or in combination with one or more other therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is being administered for preventive or therapeutic purposes, previous treatments, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is appropriately administered to the patient in one or a series of treatments. For repeated dosing over several days or longer, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. The progress of this treatment is easily monitored by conventional techniques and assays.3.Specific embodiments of the present invention

下文中列述本發明之具體實施例。 1. 一種與人類 C3bBb 特異性結合之抗體。 2. 一種與人類 C3bBb 結合之抗體，其中該抗體： - 與野生型人類 C3bBb 結合；及/或 - 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:491 之因子 B (FB) 之 Bb 次單元； - 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:492 之因子 B (FB) 之 Bb 次單元；及/或 - 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:493 之因子 B (FB) 之 Bb 次單元；及/或 - 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含重組因子 B (FB) 蛋白之 Bb 次單元，該重組因子 B (FB) 蛋白包含 D279G 突變及視情況的突變 K350N 及/或 M458I； - 抑制替代途徑；及/或 - 為 C3bBb 活性之促效劑或拮抗劑；及/或 - 與食蟹獼猴 C3bBb 及人類 C3bBb 特異性結合，及/或 - 與非洲綠猴 C3bBb 及人類 C3bBb 特異性結合，及/或 - 藉由 SPR 所測量，在 37°C 以 ≤ 300 pM 之親和力結合。 3. 一種與重組人類 C3bBb 特異性結合之抗體，該重組人類 C3bBb 包含具有 D279G 突變及視情況地另外的突變 K350N 及/或 M458I 之 FB 蛋白之 Bb 次單元。 4. 一種與重組人類 C3bBb 結合之抗體，該重組人類 C3bBb 包含根據 SEQ ID NO:491 之因子 B (FB) 之 Bb 次單元。 5. 一種與重組人類 C3bBb 結合之抗體，該重組人類 C3bBb 包含根據 SEQ ID NO:492 之因子 B (FB) 之 Bb 次單元。 6. 一種與重組人類 C3bBb 結合之抗體，該重組人類 C3bBb 包含根據 SEQ ID NO:493 之因子 B (FB) 之 Bb 次單元。 7. 一種與人類 C3bBb 之抗原決定基特異性結合之抗體，該抗原決定基包括人類 C3bBb 之 C3b 次單元之胺基酸殘基及 Bb 次單元之胺基酸殘基。 8. 一種與人類 C3bBb 結合之抗體，其與藉由低溫電子顯微鏡術所檢測的在 C3bBb 上包含下列胺基酸殘基之抗原決定基結合： - C3b 次單元：Arg444、Lys534、Gly539、Ser540、Val524、Lys544、Gly546、Gln547、Ser548、Arg551、Gln557、Gln558、Thr560、Lys562、Glu564、Glu758、Pro759、Lys761、Asn762、Ile764、Leu768、Asn770、Asp797，以及 - Bb 次單元：Tyr465、Lys473、Ile474、Ser475、Ile477、Gly482、His483、Lys513、Val514、Ser515、Lys520、Arg521、Asp522、Glu610 及 Lys613。 9. 一種與具有 SEQ ID NO: 39 之 VH 域及 SEQ ID NO: 40 之 VL 域之抗體 (P1AF8499) 結合相同或重疊抗原決定基之抗體。 10. 一種與人類 C3bBb 結合之抗體，其中該抗體包含選自表 D1 之抗體之重鏈及輕鏈 CDR。 11. 一種與人類 C3bBb 結合之抗體，其中該抗體包含選自表 D1 之抗體之重鏈可變域及輕鏈可變域。 12. 如前述實施例中任一項之抗體，其包含一組六個 CDR，在一個實施例中包含一組 VH 及 VL 域，作為選自表 D1 的抗體 #1 至抗體 #217 的抗體。 13. 如前述實施例中任一項之抗體，其包含一組六個 CDR，在一個實施例中包含一組 VH 及 VL 域，作為選自表 D1 的抗體 #1 至抗體 #122 的抗體。 14. 如前述實施例中任一項之抗體，其包含一組六個 CDR，在一個實施例中包含一組 VH 及 VL 域，作為選自表 D1 的抗體 #1 至抗體 #7 及抗體 #22 至抗體 #217 的抗體。 15. 如前述實施例中任一項之抗體，其包含一組六個 CDR，在一個實施例中包含一組 VH 及 VL 域，作為選自表 D1 的抗體 #1 至抗體 #7 的抗體。 16. 如前述實施例中任一項之抗體，其包含 i) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列的 CDR-L3 (對應於抗體 #1，P1AG9426)； ii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列的 CDR-L3 (對應於抗體 #2，P1AG9376)； iii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列的 CDR-L3 (對應於抗體 #3，P1AG9372)； iv) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列的 CDR-L3 (對應於抗體 #4，P1AG9420)； v) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列的 CDR-L3 (對應於抗體 #5，P1AG9391)； vi) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列的 CDR-L3 (對應於抗體 #6，P1AH1205)；或 vii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列的 CDR-L3 (對應於抗體 #7，P1AH1199)。 17. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 1 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 2 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 18. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 3 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 4 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 19. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 5 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 6 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 20. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 7 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 8 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 21. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 9 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 10 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 22. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 11 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 12 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 23. 如前述實施例中任一項之抗體，其包含選自由以下所組成之群組的序列 (a) VH 序列，其與 SEQ ID NO: 13 之胺基酸序列具有至少 95% 的序列同一性； (b) VL 序列，其與 SEQ ID NO: 14 之胺基酸序列具有至少 95% 的序列同一性；及 (c) 如 (a) 中所定義之 VH 序列及如 (b) 中所定義之 VL 序列。 24. 如前述實施例中任一項之抗體，其包含 i) 包含 SEQ ID NO:1 之 VH 域及包含 SEQ ID NO:2 之 VL 域 (對應於抗體 #1，P1AG9426)； ii) 包含 SEQ ID NO:3 之 VH 域及包含 SEQ ID NO:4 之 VL 域 (對應於抗體 #2，P1AG9376)； iii) 包含 SEQ ID NO:5 之 VH 域及包含 SEQ ID NO:6 之 VL 域 (對應於抗體 #3，P1AG9372)； iv) 包含 SEQ ID NO:7 之 VH 域及包含 SEQ ID NO:8 之 VL 域 (對應於抗體 #4，P1AG9420)； v) 包含 SEQ ID NO:9 之 VH 域及包含 SEQ ID NO:10 之 VL 域 (對應於抗體 #5，P1AG9391)； vi) 包含 SEQ ID NO:11 之 VH 域及包含 SEQ ID NO:12 之 VL 域 (對應於抗體 #6，P1AH1205)；或 vii) 包含 SEQ ID NO:13 之 VH 域及包含 SEQ ID NO:14 之 VL 域 (對應於抗體 #7，P1AH1199)。 25. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:435 之重鏈及 SEQ ID NO:436 之輕鏈。 26. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:437 之重鏈及 SEQ ID NO:438 之輕鏈。 27. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:439 之重鏈及 SEQ ID NO:440 之輕鏈。 28. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:441 之重鏈及 SEQ ID NO:442 之輕鏈。 29. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:443 之重鏈及 SEQ ID NO:444 之輕鏈。 30. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:445 之重鏈及 SEQ ID NO:446 之輕鏈。 31. 如前述實施例中任一項之抗體，其包含 SEQ ID NO:447 之重鏈及 SEQ ID NO:447 之輕鏈。 32. 如前述實施例中任一項之抗體，其為單株抗體。 33. 如前述實施例中任一項之抗體，其為人類抗體。 34. 如前述實施例中任一項之抗體，其中該抗體包含具有 VH3 框架之 VH 域及具有 Vkappa1 框架之 VL 域。 35. 如前述實施例中任一項之抗體，其中該抗體包含 IgG 同型之人類恆定區。 36. 如前述實施例中任一項之抗體，其為結合人類 C3bBb 之抗體片段。 37. 如前述實施例中任一項之抗體，其為全長 IgG1 抗體。 38. 如前述實施例中任一項之抗體，其中藉由 SPR 所測量，該抗體以 ≤ 300 pM 之親和力結合人類 C3bBb。 39. 如前述實施例中任一項之抗體，其中該抗體為多特異性抗體。 40. 一種抗體，其與如前述實施例中任一項之抗體競爭結合人類 C3bBb。 41. 一種經分離之核酸，其編碼如前述實施例中任一項之抗體。 42. 一種經分離之宿主細胞，其包含如實施例 42 之核酸。 43. 一種生產與人 C3bBb 結合的抗體之方法，其包含在適合於抗體之表現的條件下培養如實施例 42 之宿主細胞。 44. 如實施例第 43 項所述之方法，其進一步包含自該宿主細胞回收該抗體。 45. 一種抗體，其藉由如實施例第 43 項所述之方法來生產。 46. 一種醫藥組成物，其包含如實施例第 1 項至第 40 項中任一項所述之抗體以及醫藥上可接受之載劑。 47. 如實施例第 46 項所述之醫藥組成物，其進一步包含另外治療劑。 48. 如實施例 1 至 40 中任一項之抗體或如實施例 46 至 47 中任一項之醫藥組成物，其用為藥物。 49. 如實施例 1 至 40 中任一項之抗體或如實施例 46 至 47 中任一項之醫藥組成物，其用於治療眼部疾病。 50. 如實施例 1 至 40 中任一項之抗體或如實施例 46 至 47 中任一項之醫藥組成物在製造用於治療眼部疾病之藥物中的用途。 51. 一種治療患有眼部疾病之個體的方法，該方法包含向該個體投予有效量之如實施例 1 至 40 中任一項之抗體或如實施例 46 至 47 中任一項之醫藥組成物。胺基酸序列說明#標識符域序列SEQ ID NO: 011P1AG9426VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 021P1AG9426VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 032P1AG9376VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 042P1AG9376VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 053P1AG9372VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 063P1AG9372VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 074P1AG9420VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 084P1AG9420VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 095P1AG9391VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 105P1AG9391VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 116P1AH1205VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 126P1AH1205VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 137P1AH1199VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 147P1AH1199VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 158C3bBb.P045.072VHKLQLVESGGGLVKPGGSLRLSCAASGRRFGVqDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWGYFDQWGQGTLVTVSSSEQ ID NO: 168C3bBb.P045.072VLAIQMTQSPSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGIIGNVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 179C3bBb.P045.236VHYGQLVESGGGLVKPGGSLRLSCAATGTLFSKqDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDWGYFDHWGQGTLVTVSSSEQ ID NO: 189C3bBb.P045.236VLAIQMTQSPSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGVQGSVPSRFSGSGSHEDYTLTISSLQQEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 1910C3bBb.P045.225VHDPQLVESGGGLVKPGGSLRLSCAARGLHFNNTDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWGYFDWWGQGTLVTVSSSEQ ID NO: 2010C3bBb.P045.225VLAIQMTQSPSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGLKGGVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 2111C3bBb.P048.152VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKSGSKGYAQNVPGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 2211C3bBb.P048.152VLHDIQMTQSPSSLSASVGDRVTITCDADFGISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGGSFTLTISSLQPEDFATYYCQQYGVHPFTFGQGTKVEIKSEQ ID NO: 2312C3bBb.P048.061VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSTDINPKIGGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 2412C3bBb.P048.061VLAIQMTQSPSSLSASVGDRVTITCQGSWLISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYGGRLLTFGQGTKVEIKSEQ ID NO: 2513C3bBb.P048.127VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSTEYNTKVYGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 2613C3bBb.P048.127VLHQMTQSPSSLSASVGDRVTITCDGEWDISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGRDFTLTISSLQPEDFATYYCQQYNRMYFTFGQGTKVEIKSEQ ID NO: 2714C3bBb.P048.241VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNNNFTGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 2814C3bBb.P048.241VLHINQMTQSPSSLSASVGDRVTITCQAKWVISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDGTFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 2915C3bBb.P048.230VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNNKFHGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 3015C3bBb.P048.230VLHYIQMTQSPSSLSASVGDRVTITCQGNAFISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGDDFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 3116C3bBb.P048.204VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWFNRNFAGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 3216C3bBb.P048.204VLGHVQMTQSPSSLSASVGDRVTITCQAEDEISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDASFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 3317C3bBb.P048.333VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNDKFKGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 3417C3bBb.P048.333VLHINQMTQSPSSLSASVGDRVTITCNSTEFISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDQEFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 3518C3bBb.P053.095VHRKQLVESGGGLVQPGGSLRLSCAAHGSLVSRNDMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDVDYMDLWGQGTLVTVSSSEQ ID NO: 3618C3bBb.P053.095VLAIQMTQSPSSLSASVGDRVTITCQASYWLNSELAWYQQKPGKAPKLLIFDGDQTWFGVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 3719C3bBb.P055.015VHGQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAEYASKVYGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 3819C3bBb.P055.015VLDYQMTQSPSSLSASVGDRVTITCEAHSQISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGPDFTLTISSLQPEDFATYYCQQYNDFWLTFGQGTKVEIKSEQ ID NO: 3920P1AF8499VHEVQLVESGGGLVQPGGSLRLSCAASGFSWEHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 4020P1AF8499VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 4121GQ-5_1VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 4221GQ-5_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 4322GQ-11_1VHEVQLVESGGGLVQPGGSLRLSCAASGFSWEHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 4422GQ-11_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 4523PT5622.F19VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 4623PT5622.F19VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 4724PT5624.P06VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 4824PT5624.P06VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 4925PT5624.M09VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 5025PT5624.M09VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 5126PT5626.M10VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 5226PT5626.M10VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 5327PT5626.C10VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 5427PT5626.C10VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 5528PT5628.E16VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 5628PT5628.E16VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 5729PT5630.D05VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 5829PT5630.D05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 5930PT5630.A20VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 6030PT5630.A20VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 6131PT5632.A13VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 6231PT5632.A13VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 6332PT5634.N13VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 6432PT5634.N13VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 6533PT5634.M24VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 6633PT5634.M24VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 6734PT5636.P22VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 6834PT5636.P22VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 6935PT5625.G07VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 7035PT5625.G07VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 7136PT5627.M20VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 7236PT5627.M20VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 7337PT5627.M12VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 7437PT5627.M12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 7538PT5629.F09VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 7638PT5629.F09VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 7739PT5629.H08VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 7839PT5629.H08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 7940PT5631.D21VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 8040PT5631.D21VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 8141PT5633.I03VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 8241PT5633.I03VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 8342PT5635.C08VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 8442PT5635.C08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 8543PT5639.G15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 8643PT5639.G15VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 8744PT5622.A20VHEVQLVESGGGLVQPGGSLRLSCAASGFRWDKYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 8844PT5622.A20VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 8945PT5622.C12VHRVQLVESGGGLVQPGGSLRLSCAASGFTYEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 9045PT5622.C12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 9146PT5622.G24VHGVQLVESGGGLVQPGGSLRLSCAASGFRYDIYAMSWVRQAPGKGLEWVGEISPEGNHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 9246PT5622.G24VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 9347PT5622.I20VHKVQLVESGGGLVQPGGSLRLSCAASGYTYDIYAMSWVRQAPGKGLEWVGEISPDGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDHWGQGTLVTVSSSEQ ID NO: 9447PT5622.I20VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 9548PT5622.J24VHKVQLVESGGGLVQPGGSLRLSCAASGYRYEHYAMSWVRQAPGKGLEWVGSISPKGQHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDVWGQGTLVTVSSSEQ ID NO: 9648PT5622.J24VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 9749PT5624.A21VHKVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPKGEHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDGWGQGTLVTVSSSEQ ID NO: 9849PT5624.A21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 9950PT5624.B10VHKVQLVESGGGLVQPGGSLRLSCAASGFHYDIYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 10050PT5624.B10VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 10151PT5624.N05VHGVQLVESGGGLVQPGGSLRLSCAASGFKYEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 10251PT5624.N05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 10352PT5624.P11VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDQWGQGTLVTVSSSEQ ID NO: 10452PT5624.P11VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 10553PT5626.A12VHRVQLVESGGGLVQPGGSLRLSCAASGFKWDHYAMSWVRQAPGKGLEWVGSISPDGNHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 10653PT5626.A12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 10754PT5626.N08VHKVQLVESGGGLVQPGGSLRLSCAASGYKYDHYAMSWVRQAPGKGLEWVGEISPEGNSKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 10854PT5626.N08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 10955PT5626.N18VHKVQLVESGGGLVQPGGSLRLSCAASGFKYEVYAMSWVRQAPGKGLEWVGEISPKGDTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 11055PT5626.N18VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 11156PT5626.O09VHRVQLVESGGGLVQPGGSLRLSCAASGFKWEIYAMSWVRQAPGKGLEWVGDISPDGQTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDHWGQGTLVTVSSSEQ ID NO: 11256PT5626.O09VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 11357PT5628.B13VHQVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 11457PT5628.B13VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 11558PT5628.C21VHRVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDSWGQGTLVTVSSSEQ ID NO: 11658PT5628.C21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 11759PT5628.E12VHKVQLVESGGGLVQPGGSLRLSCAASGYRWDIYAMSWVRQAPGKGLEWVGSISPDGNHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 11859PT5628.E12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 11960PT5628.I07VHKVQLVESGGGLVQPGGSLRLSCAASGFRYDYYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 12060PT5628.I07VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 12161PT5628.P14VHKVQLVESGGGLVQPGGSLRLSCAASGFTWEHYAMSWVRQAPGKGLEWVGSISPDGQHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 12261PT5628.P14VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 12362PT5630.G05VHQVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPDGRHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 12462PT5630.G05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 12563PT5630.K04VHRVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDEWGQGTLVTVSSSEQ ID NO: 12663PT5630.K04VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 12764PT5630.M11VHRVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 12864PT5630.M11VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 12965PT5630.N06VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPKGDTKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 13065PT5630.N06VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 13166PT5630.O08VHKVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDSWGQGTLVTVSSSEQ ID NO: 13266PT5630.O08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 13367PT5632.A10VHRVQLVESGGGLVQPGGSLRLSCAASGFHFDKYAMSWVRQAPGKGLEWVGSISPKGRTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 13467PT5632.A10VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 13568PT5632.A15VHRVQLVESGGGLVQPGGSLRLSCAASGFRWDYYAMSWVRQAPGKGLEWVGSISPDGQHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 13668PT5632.A15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 13769PT5632.B15VHKVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGEISPDGQNKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 13869PT5632.B15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 13970PT5632.D11VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPEGNHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 14070PT5632.D11VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 14171PT5632.J23VHGVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 14271PT5632.J23VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 14372PT5634.A17VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPDGRTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 14472PT5634.A17VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 14573PT5634.A21VHRVQLVESGGGLVQPGGSLRLSCAASGFKFDIYAMSWVRQAPGKGLEWVGEISPDGQSKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 14673PT5634.A21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 14774PT5634.K10VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPKGDNKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 14874PT5634.K10VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 14975PT5634.M16VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGEISPKGDSKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 15075PT5634.M16VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 15176PT5634.N11VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGQDKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 15276PT5634.N11VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 15377PT5634.P19VHKVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 15477PT5634.P19VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 15578PT5636.A16VHKVQLVESGGGLVQPGGSLRLSCAASGFKYDIYAMSWVRQAPGKGLEWVGDISPKGETKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDAWGQGTLVTVSSSEQ ID NO: 15678PT5636.A16VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 15779PT5636.D21VHEVQLVESGGGLVQPGGSLRLSCAASGYKFDKYAMSWVRQAPGKGLEWVGEISPRGDHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWEYFDSWGQGTLVTVSSSEQ ID NO: 15879PT5636.D21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 15980PT5636.M03VHKVQLVESGGGLVQPGGSLRLSCAASGFRWDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 16080PT5636.M03VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 16181PT5636.N13VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPKGNHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 16281PT5636.N13VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 16382PT5636.P11VHEVQLVESGGGLVQPGGSLRLSCAASGFQFDHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDQWGQGTLVTVSSSEQ ID NO: 16482PT5636.P11VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 16583PT5636.P15VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDYYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDGWGQGTLVTVSSSEQ ID NO: 16683PT5636.P15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 16784PT5638.C06VHKVQLVESGGGLVQPGGSLRLSCAASGYTWEHYAMSWVRQAPGKGLEWVGSISPDGRHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 16884PT5638.C06VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 16985PT5638.C20VHKVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPDGDHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 17085PT5638.C20VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 17186PT5638.E14VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 17286PT5638.E14VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 17387PT5638.J23VHEVQLVESGGGLVQPGGSLRLSCAASGWSYDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 17487PT5638.J23VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 17588PT5638.O14VHRVQLVESGGGLVQPGGSLRLSCAASGFRWDYYAMSWVRQAPGKGLEWVGSISPDGEHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 17688PT5638.O14VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 17789PT5638.P12VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDYYAMSWVRQAPGKGLEWVGSISPKGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDIWGQGTLVTVSSSEQ ID NO: 17889PT5638.P12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 17990PT5623.E21VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 18090PT5623.E21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 18191PT5623.F17VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 18291PT5623.F17VLAIQMTQSPSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDEPYTFGQGTKLEIKSEQ ID NO: 18392PT5623.G08VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 18492PT5623.G08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 18593PT5623.H05VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 18693PT5623.H05VLAIQMTQSPSSLSASVGDRVTITCQSTLWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYKETPYTFGQGTKLEIKSEQ ID NO: 18794PT5623.O08VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 18894PT5623.O08VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 18995PT5625.A05VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 19095PT5625.A05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 19196PT5625.B14VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 19296PT5625.B14VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSEEEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 19397PT5625.C15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 19497PT5625.C15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYKETPYTFGQGTKLEIKSEQ ID NO: 19598PT5625.G05VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 19698PT5625.G05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 19799PT5625.L22VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 19899PT5625.L22VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 199100PT5625.O14VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 200100PT5625.O14VLAIQMTQSPSSLSASVGDRVTITCQSQLWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 201101PT5627.I21VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 202101PT5627.I21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYREDPYTFGQGTKLEIKSEQ ID NO: 203102PT5629.F04VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 204102PT5629.F04VLAIQMTQSPSSLSASVGDRVTITCQVSHWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 205103PT5629.L22VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 206103PT5629.L22VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRqTPYTFGQGTKLEIKSEQ ID NO: 207104PT5629.L24VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 208104PT5629.L24VLAIQMTQSPSSLSASVGDRVTITCQSqFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYESEPYTFGQGTKLEIKSEQ ID NO: 209105PT5629.M15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 210105PT5629.M15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSWDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 211106PT5631.H06VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 212106PT5631.H06VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 213107PT5631.K12VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 214107PT5631.K12VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 215108PT5631.N17VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 216108PT5631.N17VLAIQMTQSPSSLSASVGDRVTITCQSTLWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSWDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 217109PT5631.P07VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 218109PT5631.P07VLAIQMTQSPSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYKDTPYTFGQGTKLEIKSEQ ID NO: 219110PT5633.E09VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 220110PT5633.E09VLAIQMTQSPSSLSASVGDRVTITCQAqHWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 221111PT5633.G19VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 222111PT5633.G19VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 223112PT5635.F04VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 224112PT5635.F04VLAIQMTQSPSSLSASVGDRVTITCQAHYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 225113PT5635.L21VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 226113PT5635.L21VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 227114PT5635.O15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 228114PT5635.O15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 229115PT5637.B23VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 230115PT5637.B23VLAIQMTQSPSSLSASVGDRVTITCQSQLWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 231116PT5637.C20VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 232116PT5637.C20VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREDPYTFGQGTKLEIKSEQ ID NO: 233117PT5637.K09VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 234117PT5637.K09VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 235118PT5637.L15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 236118PT5637.L15VLAIQMTQSPSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 237119PT5637.M03VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 238119PT5637.M03VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 239120PT5637.P15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 240120PT5637.P15VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 241121PT5639.B15VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 242121PT5639.B15VLAIQMTQSPSSLSASIGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDIPWELPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 243122PT5639.P05VHGQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 244122PT5639.P05VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYETPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 245123PT5625.G07_22.F19_2VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 246123PT5625.G07_22.F19_2VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 247124PT5625.G07_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 248124PT5625.G07_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 249125PT5625.G07_24.P06_2VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 250125PT5625.G07_24.P06_2VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 251126PT5625.G07_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 252126PT5625.G07_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 253127PT5625.G07_26.M10_2VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 254127PT5625.G07_26.M10_2VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 255128PT5625.G07_28.E16_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 256128PT5625.G07_28.E16_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 257129PT5625.G07_30.A20_1VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 258129PT5625.G07_30.A20_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 259130PT5625.G07_32.A13_2VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 260130PT5625.G07_32.A13_2VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 261131PT5625.G07_34.M24_1VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 262131PT5625.G07_34.M24_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 263132PT5625.G07_34.N13_3VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 264132PT5625.G07_34.N13_3VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 265133PT5625.G07_36.P22_1VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 266133PT5625.G07_36.P22_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 267134PT5627.M20_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 268134PT5627.M20_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 269135PT5627.M20_24.P06_1VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 270135PT5627.M20_24.P06_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 271136PT5627.M20_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 272136PT5627.M20_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 273137PT5627.M20_26.M10_2VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 274137PT5627.M20_26.M10_2VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 275138PT5627.M20_28.E16_2VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 276138PT5627.M20_28.E16_2VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 277139PT5627.M20_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 278139PT5627.M20_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 279140PT5627.M20_32.A13_1VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 280140PT5627.M20_32.A13_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 281141PT5627.M20_34.M24_2VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 282141PT5627.M20_34.M24_2VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 283142PT5627.M20_34.N13_4VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 284142PT5627.M20_34.N13_4VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 285143PT5627.M20_36.P22_1VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 286143PT5627.M20_36.P22_1VLAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 287144PT5627.M12_22.F19_1VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 288144PT5627.M12_22.F19_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 289145PT5627.M12_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 290145PT5627.M12_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 291146PT5627.M12_26.M10_2VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 292146PT5627.M12_26.M10_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 293147PT5627.M12_32.A13_2VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 294147PT5627.M12_32.A13_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 295148PT5627.M12_34.M24_2VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 296148PT5627.M12_34.M24_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 297149PT5627.M12_34.N13_1VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 298149PT5627.M12_34.N13_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 299150PT5629.F09_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 300150PT5629.F09_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 301151PT5629.F09_28.E16_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 302151PT5629.F09_28.E16_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 303152PT5629.F09_30.A20_1VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 304152PT5629.F09_30.A20_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 305153PT5629.F09_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 306153PT5629.F09_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 307154PT5629.F09_32.A13_3VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 308154PT5629.F09_32.A13_3VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 309155PT5629.F09_36.P22_2VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 310155PT5629.F09_36.P22_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 311156PT5629.H08_22.F19_4VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 312156PT5629.H08_22.F19_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 313157PT5629.H08_24.M09_4VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 314157PT5629.H08_24.M09_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 315158PT5629.H08_24.P06_2VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 316158PT5629.H08_24.P06_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 317159PT5629.H08_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 318159PT5629.H08_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 319160PT5629.H08_26.M10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 320160PT5629.H08_26.M10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 321161PT5629.H08_28.E16_2VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 322161PT5629.H08_28.E16_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 323162PT5629.H08_30.A20_2VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 324162PT5629.H08_30.A20_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 325163PT5629.H08_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 326163PT5629.H08_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 327164PT5629.H08_32.A13_1VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 328164PT5629.H08_32.A13_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 329165PT5629.H08_34.M24_2VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 330165PT5629.H08_34.M24_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 331166PT5629.H08_34.N13_2VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 332166PT5629.H08_34.N13_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 333167PT5629.H08_36.P22_4VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 334167PT5629.H08_36.P22_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 335168PT5631.D21_22.F19_2VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 336168PT5631.D21_22.F19_2VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 337169PT5631.D21_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 338169PT5631.D21_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 339170PT5631.D21_24.P06_4VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 340170PT5631.D21_24.P06_4VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 341171PT5631.D21_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 342171PT5631.D21_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 343172PT5631.D21_26.M10_4VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 344172PT5631.D21_26.M10_4VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 345173PT5631.D21_28.E16_3VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 346173PT5631.D21_28.E16_3VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 347174PT5631.D21_30.A20_4VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 348174PT5631.D21_30.A20_4VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 349175PT5631.D21_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 350175PT5631.D21_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 351176PT5631.D21_32.A13_4VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 352176PT5631.D21_32.A13_4VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 353177PT5631.D21_34.M24_4VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 354177PT5631.D21_34.M24_4VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 355178PT5631.D21_34.N13_2VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 356178PT5631.D21_34.N13_2VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 357179PT5631.D21_36.P22_3VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 358179PT5631.D21_36.P22_3VLAIQMTQSPSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 359180PT5633.I03_22.F19_1VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 360180PT5633.I03_22.F19_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 361181PT5633.I03_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 362181PT5633.I03_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 363182PT5633.I03_24.P06_4VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 364182PT5633.I03_24.P06_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 365183PT5633.I03_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 366183PT5633.I03_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 367184PT5633.I03_26.M10_4VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 368184PT5633.I03_26.M10_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 369185PT5633.I03_28.E16_4VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 370185PT5633.I03_28.E16_4VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 371186PT5633.I03_30.A20_1VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 372186PT5633.I03_30.A20_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 373187PT5633.I03_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 374187PT5633.I03_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 375188PT5633.I03_32.A13_1VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 376188PT5633.I03_32.A13_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 377189PT5633.I03_34.M24_2VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 378189PT5633.I03_34.M24_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 379190PT5633.I03_34.N13_1VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 380190PT5633.I03_34.N13_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 381191PT5633.I03_36.P22_2VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 382191PT5633.I03_36.P22_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 383192PT5635.C08_22.F19_1VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 384192PT5635.C08_22.F19_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 385193PT5635.C08_24.M09_1VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 386193PT5635.C08_24.M09_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 387194PT5635.C08_24.P06_1VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 388194PT5635.C08_24.P06_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 389195PT5635.C08_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 390195PT5635.C08_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 391196PT5635.C08_26.M10_2VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 392196PT5635.C08_26.M10_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 393197PT5635.C08_28.E16_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 394197PT5635.C08_28.E16_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 395198PT5635.C08_30.A20_1VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 396198PT5635.C08_30.A20_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 397199PT5635.C08_30.D05_3VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 398199PT5635.C08_30.D05_3VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 399200PT5635.C08_32.A13_3VHRVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 400200PT5635.C08_32.A13_3VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 401201PT5635.C08_34.M24_2VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 402201PT5635.C08_34.M24_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 403202PT5635.C08_34.N13_1VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 404202PT5635.C08_34.N13_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 405203PT5635.C08_36.P22_1VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 406203PT5635.C08_36.P22_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 407204PT5639.G15_22.F19_2VHEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 408204PT5639.G15_22.F19_2VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 409205PT5639.G15_24.P06_1VHQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 410205PT5639.G15_24.P06_1VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 411206PT5639.G15_24.M09_4VHKVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 412206PT5639.G15_24.M09_4VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 413207PT5639.G15_26.M10_3VHRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 414207PT5639.G15_26.M10_3VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 415208PT5639.G15_28.E16_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 416208PT5639.G15_28.E16_1VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 417209PT5639.G15_30.A20_1VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 418209PT5639.G15_30.A20_1VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 419210PT5639.G15_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 420210PT5639.G15_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 421211PT5639.G15_34.N13_4VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 422211PT5639.G15_34.N13_4VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 423212PT5639.G15_34.M24_3VHEVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 424212PT5639.G15_34.M24_3VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 425213PT5639.G15_36.P22_3VHRVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 426213PT5639.G15_36.P22_3VLAIQMTQSPSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 427214PT5625.G07_30.D05_1VHKVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 428214PT5625.G07_30.D05_1VLAIQMTQSPSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 429215PT5627.M12_26.C10_1VHRVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 430215PT5627.M12_26.C10_1VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 431216PT5627.M12_30.A20_2VHKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 432216PT5627.M12_30.A20_2VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 433217PT5629.F09_34.N13_3VHKVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 434217PT5629.F09_34.N13_3VLAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 4351P1AG9426HCQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 4361P1AG9426LCAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4372P1AG9376HCKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 4382P1AG9376LCAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4393P1AG9372HCEVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 4403P1AG9372LCAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4414P1AG9420HCRVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 4424P1AG9420LCAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4435P1AG9391HCQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 4445P1AG9391LCAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4456P1AH1205HCKVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 4466P1AH1205LCAIQMTQSPSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4477P1AH1199HCQVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 4487P1AH1199LCAIQMTQSPSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4491P1AG9426HCDR1GFKYDVYAMSSEQ ID NO: 4501P1AG9426HCDR2EISPRGDSKYYNTKFIDSEQ ID NO: 4511P1AG9426HCDR3DWEYFDNSEQ ID NO: 4521P1AG9426LCDR1QASYWLSNYLASEQ ID NO: 4531P1AG9426LCDR2DGDIPYSEQ ID NO: 4541P1AG9426LCDR3QQYRETPYTSEQ ID NO: 4552P1AG9376HCDR1GFKWEHYAMSSEQ ID NO: 4562P1AG9376HCDR2SISPRGDHKYYNTKFIDSEQ ID NO: 4572P1AG9376HCDR3DWDYFDRSEQ ID NO: 4582P1AG9376LCDR1QSQFWLSNYLASEQ ID NO: 4592P1AG9376LCDR2DGDLPYSEQ ID NO: 4602P1AG9376LCDR3QQYREEPYTSEQ ID NO: 4613P1AG9372HCDR1GFRFDIYAMSSEQ ID NO: 4623P1AG9372HCDR2EISPDGRTKYYNTKFIDSEQ ID NO: 4633P1AG9372HCDR3DWEYFDNSEQ ID NO: 4643P1AG9372LCDR1QSQFWLSNYLASEQ ID NO: 4653P1AG9372LCDR2DGDLPYSEQ ID NO: 4663P1AG9372LCDR3QQYREEPYTSEQ ID NO: 4674P1AG9420HCDR1GFRYDHYAMSSEQ ID NO: 4684P1AG9420HCDR2SISPRGNHKYYNTKFIDSEQ ID NO: 4694P1AG9420HCDR3DWDYFDHSEQ ID NO: 4704P1AG9420LCDR1QASYWLSNYLASEQ ID NO: 4714P1AG9420LCDR2DGDIPYSEQ ID NO: 4724P1AG9420LCDR3QQYRETPYTSEQ ID NO: 4735P1AG9391HCDR1GFKYDVYAMSSEQ ID NO: 4745P1AG9391HCDR2EISPRGDSKYYNTKFIDSEQ ID NO: 4755P1AG9391HCDR3DWEYFDNSEQ ID NO: 4765P1AG9391LCDR1QASYWLSNYLASEQ ID NO: 4775P1AG9391LCDR2DGDIPWSEQ ID NO: 4785P1AG9391LCDR3QQYRDTPYTSEQ ID NO: 4796P1AH1205HCDR1GFKWEHYAMSSEQ ID NO: 4806P1AH1205HCDR2SISPRGDHKYYNTKFIDSEQ ID NO: 4816P1AH1205HCDR3DWDYFDRSEQ ID NO: 4826P1AH1205LCDR1QSQFWLSNYLASEQ ID NO: 4836P1AH1205LCDR2DGDLPYSEQ ID NO: 4846P1AH1205LCDR3QQYREEPYTSEQ ID NO: 4857P1AH1199HCDR1GFKYDVYAMSSEQ ID NO: 4867P1AH1199HCDR2EISPRGDSKYYNTKFIDSEQ ID NO: 4877P1AH1199HCDR3DWEYFDNSEQ ID NO: 4887P1AH1199LCDR1QASYWLSNYLASEQ ID NO: 4897P1AH1199LCDR2DGDIPWSEQ ID NO: 4907P1AH1199LCDR3QQYRDTPYTSEQ ID NO: 491帶有 His 標籤及精確位點的人類因子 B wt (FB)HHHHHHGSLEVLFQGPGGTPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 492帶有 D279G 的人類 FB，帶有 His 標籤及精確位點HHHHHHGSLEVLFQGPGGTPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSGSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 493帶有 D279G、K350N 及 M458I 的人類 FB，帶有 His 標籤及精確位點HHHHHHGSLEVLFQGPGGTPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSGSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLNSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDIENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 494補體因子 DILGGREAEAHARPYMASVQLNGAHLCGGVLVAEQWVLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSQPDTIDHDLLLLQLSEKATLGPAVRPLPWQRVDRDVAPGTLCDVAGWGIVNHAGRRPDSLQHVLLPVLDRATCNRRTHHDGAITERLMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTRVASYAAWIDSVLSEQ ID NO: 495補體 C3 β 鏈 (C3b)SPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVHDFPGKKLVLSSEKTVLTPATNHMGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKVVLVSLQSGYLFIQTDKTIYTPGSTVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSLSSQNQLGVLPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNEKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEVVLSRKVLLDGVQNPRAEDLVGKSLYVSATVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKQELSEAEQATRTMQALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMDRAHEAKIRYYTYLIMNKGRLLKAGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGASGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDKGVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGVFSDAGLTFTSSSGQQTAQRAELQCPQPAARRRRSVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLMNIFLKDSITTWEILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVIVPLKTGLQEVEVKAAVYHHFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQVPDTESETRILLQGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDETEQWEKFGLEKRQGALELIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLISLQEAKDICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFLTTAKDKNRWEDPGKQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQYQKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKDQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCLAFKVHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQKSDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDEYIMAIEQTIKSGSDEVQVGQQRTFISPIKCREALKLEEKKHYLMWGLSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQDLGAFTESMVVFGCPNSEQ ID NO: 496人 C3aSVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARASHLGLARSEQ ID NO: 497食蟹獼猴 C3bPMYSMITPNVLRLESEETVVLEAHDANGDVPVTVTVHDFPGKKLVLSSEKTVLTPATSHMGSVTIRIPANKEFKSEKGHNKFVTVQATFGAQVVEKVVLVSLQSGYLFIQTDKTIYTPGSTVLCRIFTVNHKLLPVGRTVVVNIENPDGIPVKQDSLSSQNQFGILPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNQKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIQIEDGSGDAVLSRKVLLDGVQNPRPEDLVGKSLYVSVTVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDAVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKRELSEAEQATRTMEAQPYSTVGNSNNYLHLSVPRAELRPGETLNVNFLLRMDRTQEAKIRYYTYLIMNKGKLLKVGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGANGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPLPGQQMTLKIEGDHGARVGLVAVDKGVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGVFSDAGLTFASSSGQQTAQRAELQCPQPATRRRRSVQLAEKRMDKVGQYPKELRKCCEHGMRENPMRFSCQRRTRYITLDEACKKAFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWKIEELKEAPKNGISTKLMNIFLKDSITTWEILAVSLSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATAKRRHQQTVTIPPKSSLSVPYVIVPLKTGQQEVEVKAAVYHFFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGQEGVQREDVPPADLSDQVPDTESETRILLQGTPVAQMTEDAIDAERLKHLIVTPSGCGEQNMITMTPTVIAVHYLDETEQWEKFGPEKRQGALELIKKGYTQQLAFRQPSSAFAAFLNRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMTGGFRNTNEKDMALTAFVLISLQEAKEICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAAYALAQMGRLKGPLLNKFLTTAKDKNRWEEPGQQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQYQKDVPDHKELNLDVSLQLPSRSSKIIHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKGQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMMTGFVPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCIAFKVHQYFNVELIQPGAVKVYAYYNLAESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQKLDDKVTLEERLDKACEPGVDYVYKTRLVKAQLSNDFDEYIMAIEQIIKSGSDEVQVGQQRTFISPIKCREALKLEERKHYLMWGLSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQDLGTFTENMVVFGCPNSEQ ID NO: 498食蟹獼猴因子 D (FD)ILGGREAEAHARPYMASVQVNGEHLCGGVLVAEQWVLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSRPDTIDHDLLLLQLSEKATLGPAVRPLPWQRVDRDVEPGTLCDVAGWGIVSHAGRRPDRLQHVLLPVLDRATCNRRTHHDGAITQRMMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTRVASYAAWIDSLEVLFQGPGSHHHHHHSEQ ID NO: 499食蟹獼猴因子 B WTHHHHHHGSLEVLFQGPGGTPLSSAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLQTQDRKTVKKAECRAIRCPRPQDFENGEYRPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSRYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHSPGEQQKRRIILDPSGSMNIYLVLDGSDSIGAGNFTGAKKCLVNLIEKVASYGVKPRYALVTYATYPRIWVKVSDQESSNADWVTKKLSEINYEDHKLKSGTNTKRALQAVYSMMSWPEDIPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVDQVNINALASKKDNEQHVFKVKDMENLEDVFFQMIDESQSLSLCGMVWEHTTGTDYHKQPWQAKISVTRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGKKRDLEIEKVLFHPDYNISGKKEAGIPEFYDYDVALIKLKKKLNYDPTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHVNLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 500食蟹獼猴因子 B 三突變體 (D279G_K350N_M458I)HHHHHHGSLEVLFQGPGGTPLSSAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLQTQDRKTVKKAECRAIRCPRPQDFENGEYRPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSRYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHSPGEQQKRRIILDPSGSMNIYLVLDGSGSIGAGNFTGAKKCLVNLIEKVASYGVKPRYALVTYATYPRIWVKVSDQESSNADWVTKKLSEINYEDHKLNSGTNTKRALQAVYSMMSWPEDIPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVDQVNINALASKKDNEQHVFKVKDIENLEDVFFQMIDESQSLSLCGMVWEHTTGTDYHKQPWQAKISVTRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGKKRDLEIEKVLFHPDYNISGKKEAGIPEFYDYDVALIKLKKKLNYDPTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHVNLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 501人類因子 B (wt，不含訊號肽)TPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 502人類恆定輕鏈域 CLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 503人類恆定重鏈域 CH1ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 504人類因子 B (wt，含訊號肽)MGSNLSPQLCLMPFILGLLSGGVTTTPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFL實例Specific embodiments of the present invention are described below.1. An antibody that specifically binds to human C3bBb.2. An antibody that binds to human C3bBb, wherein the antibody: - binds to wild-type human C3bBb; and/or - binds to recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:491; - binds to recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:492; and/or - binds to recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:493; and/or - binds to recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:494; Bb subunit of a recombinant factor B (FB) protein comprising the D279G mutation and, as appropriate, the mutations K350N and/or M458I;- inhibits the alternative pathway; and/or- is an agonist or antagonist of C3bBb activity; and/or- specifically binds to cynomolgus macaque C3bBb and human C3bBb, and/or- specifically binds to African green monkey C3bBb and human C3bBb, and/or- binds with an affinity of ≤ 300 pM at 37°C as measured by SPR. 3. An antibody that specifically binds to recombinant human C3bBb, comprising the Bb subunit of the FB protein having the D279G mutation and, as appropriate, the additional mutations K350N and/or M458I.4. An antibody that specifically binds to recombinant human C3bBb, comprising the Bb subunit of factor B (FB) according to SEQ ID NO:491.5. An antibody that specifically binds to recombinant human C3bBb, comprising the Bb subunit of factor B (FB) according to SEQ ID NO:492.6. An antibody that binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:493.7. An antibody that specifically binds to an antigenic determinant of human C3bBb, the antigenic determinant comprising amino acid residues of the C3b subunit and amino acid residues of the Bb subunit of human C3bBb.8. An antibody that binds to human C3bBb, which binds to an antigenic determinant comprising the following amino acid residues on C3bBb as detected by cryogenic electron microscopy: - C3b subunit: Arg444, Lys534, Gly539, Ser540, Val524, Lys544, Gly546, Gln547, Ser548, Arg551, Gln557, Gln558, Thr560, Lys562, Glu564, Glu758, Pro759, Lys761, Asn762, Ile764, Leu768, Asn770, Asp797, and - Bb Subunits: Tyr465, Lys473, Ile474, Ser475, Ile477, Gly482, His483, Lys513, Val514, Ser515, Lys520, Arg521, Asp522, Glu610 and Lys613.9. An antibody that binds to the same or overlapping antigenic determinant as an antibody (P1AF8499) having a VH domain of SEQ ID NO: 39 and a VL domain of SEQ ID NO: 40.10. An antibody that binds to human C3bBb, wherein the antibody comprises heavy chain and light chain CDRs of an antibody selected from Table D1.11. An antibody that binds to human C3bBb, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain selected from an antibody in Table D1.12. An antibody as in any of the preceding embodiments, comprising a set of six CDRs, in one embodiment comprising a set of VH and VL domains, as an antibody selected from Antibody #1 to Antibody #217 in Table D1.13. An antibody as in any of the preceding embodiments, comprising a set of six CDRs, in one embodiment comprising a set of VH and VL domains, as an antibody selected from Antibody #1 to Antibody #122 in Table D1.14. An antibody as in any of the preceding embodiments, comprising a set of six CDRs, in one embodiment comprising a set of VH and VL domains, as an antibody selected from Antibody #1 to Antibody #7 and Antibody #22 to Antibody #217 of Table D1.15. An antibody as in any of the preceding embodiments, comprising a set of six CDRs, in one embodiment comprising a set of VH and VL domains, as an antibody selected from Antibody #1 to Antibody #7 of Table D1.16. An antibody as in any of the above embodiments, comprisingi) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:449; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:450; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:451; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:452; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:453; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:454 (corresponding to antibody #1, P1AG9426);ii) a heavy chain variable domain (VH) (a) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:455; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:456; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:457; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:458; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:459; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:460 (corresponding to antibody #2, P1AG9376);iii) heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:461; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:462 ; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:463; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:464; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:465; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:466 (corresponding to antibody #3, P1AG9372);iv) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:467; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:468; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:469 CDR-H3; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:470; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:471; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:472 (corresponding to antibody #4, P1AG9420);v) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:473; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:474; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:475; and a light chain variable domain (VL) comprising: (d) CDR-L2 comprising the amino acid sequence of SEQ ID NO:476 (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:477; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:478 (corresponding to antibody #5, P1AG9391);vi) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:479; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:480; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:481; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:482; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:483; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:484 (corresponding to antibody #6, P1AH1205); orvii) a heavy chain variable domain (VH) (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:485; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:486; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:487; and a light chain variable domain (VL) comprising: (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:488; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:489; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:490 (corresponding to antibody #6, P1AH1205); #7, P1AH1199).17. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 2; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).18. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 3;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 4; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).19. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 5;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 6; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).20. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).21. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 10; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).22. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 11;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 12; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).23. An antibody as in any of the preceding embodiments, comprising a sequence selected from the group consisting of(a) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 13;(b) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 14; and(c) a VH sequence as defined in (a) and a VL sequence as defined in (b).24. An antibody as in any of the above embodiments, comprisingi) a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2 (corresponding to antibody #1, P1AG9426);ii) a VH domain comprising SEQ ID NO:3 and a VL domain comprising SEQ ID NO:4 (corresponding to antibody #2, P1AG9376);iii) a VH domain comprising SEQ ID NO:5 and a VL domain comprising SEQ ID NO:6 (corresponding to antibody #3, P1AG9372);iv) a VH domain comprising SEQ ID NO:7 and a VL domain comprising SEQ ID NO:8 (corresponding to antibody #4, P1AG9420);v) a VH domain comprising SEQ ID NO:9 and a VL domain comprising SEQ ID NO:10 VL domain (corresponding to antibody #5, P1AG9391);vi) a VH domain comprising SEQ ID NO:11 and a VL domain comprising SEQ ID NO:12 (corresponding to antibody #6, P1AH1205); orvii) a VH domain comprising SEQ ID NO:13 and a VL domain comprising SEQ ID NO:14 (corresponding to antibody #7, P1AH1199).25. An antibody as in any of the preceding embodiments, comprising a heavy chain of SEQ ID NO:435 and a light chain of SEQ ID NO:436.26. An antibody as in any of the preceding embodiments, comprising a heavy chain of SEQ ID NO:437 and a light chain of SEQ ID NO:438.27. An antibody as in any of the above embodiments, comprising a heavy chain of SEQ ID NO:439 and a light chain of SEQ ID NO:440.28. An antibody as in any of the above embodiments, comprising a heavy chain of SEQ ID NO:441 and a light chain of SEQ ID NO:442.29. An antibody as in any of the above embodiments, comprising a heavy chain of SEQ ID NO:443 and a light chain of SEQ ID NO:444.30. An antibody as in any of the above embodiments, comprising a heavy chain of SEQ ID NO:445 and a light chain of SEQ ID NO:446.31. An antibody as in any of the preceding embodiments, comprising a heavy chain of SEQ ID NO:447 and a light chain of SEQ ID NO:447.32. An antibody as in any of the preceding embodiments, which is a monoclonal antibody.33. An antibody as in any of the preceding embodiments, which is a human antibody.34. An antibody as in any of the preceding embodiments, wherein the antibody comprises a VH domain having a VH3 framework and a VL domain having a Vkappa1 framework.35. An antibody as in any of the preceding embodiments, wherein the antibody comprises a human constant region of the IgG isotype.36. An antibody as in any of the preceding embodiments, which is an antibody fragment that binds to human C3bBb.37. The antibody of any of the preceding embodiments, which is a full-length IgG1 antibody.38. The antibody of any of the preceding embodiments, wherein the antibody binds to human C3bBb with an affinity of ≤ 300 pM as measured by SPR.39. The antibody of any of the preceding embodiments, wherein the antibody is a multispecific antibody.40. An antibody that competes with the antibody of any of the preceding embodiments for binding to human C3bBb.41. An isolated nucleic acid encoding the antibody of any of the preceding embodiments.42. An isolated host cell comprising the nucleic acid of embodiment 42.43. A method for producing an antibody that binds to human C3bBb, comprising culturing the host cell of Example 42 under conditions suitable for the expression of the antibody.44. The method of Example 43, further comprising recovering the antibody from the host cell.45. An antibody produced by the method of Example 43.46. A pharmaceutical composition comprising the antibody of any one of Examples 1 to 40 and a pharmaceutically acceptable carrier.47. The pharmaceutical composition of Example 46, further comprising an additional therapeutic agent.48. The antibody of any one of Examples 1 to 40 or the pharmaceutical composition of any one of Examples 46 to 47, for use as a drug.49. The antibody of any one of Examples 1 to 40 or the pharmaceutical composition of any one of Examples 46 to 47, for use in treating eye diseases.50. Use of the antibody of any one of Examples 1 to 40 or the pharmaceutical composition of any one of Examples 46 to 47 in the manufacture of a drug for treating eye diseases.51. A method for treating an individual suffering from an ocular disease, the method comprising administering to the individual an effective amount of an antibody according to any one of Examples 1 to 40 or a pharmaceutical composition according to any one of Examples 46 to 47.Amino acid sequence description# Identifier domain sequenceSEQ ID NO: 01 1 P1AG9426 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 02 1 P1AG9426 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 03 2 P1AG9376 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 04 2 P1AG9376 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 05 3 P1AG9372 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 06 3 P1AG9372 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 07 4 P1AG9420 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 08 4 P1AG9420 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 09 5 P1AG9391 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 10 5 P1AG9391 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 11 6 P1AH1205 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 12 6 P1AH1205 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 13 7 P1AH1199 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 14 7 P1AH1199 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 15 8 C3bBb.P045.072 VH KLQLVESGGGLVKPGGSLRLSCAASGRRFGVqDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWGYFDQWGQGTLVTVSSSEQ ID NO: 16 8 C3bBb.P045.072 V L AIQMTQSPSSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGIIGNVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 17 9 C3bBb.P045.236 VH YGQLVESGGGLVKPGGSLRLSCAATGTLFSKqDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDWGYFDHWGQGTLVTVSSSEQ ID NO: 18 9 C3bBb.P045.236 V L AIQMTQSPSSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGVQGSVPSRFSGSGSHEDYTLTISSLQQEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 19 10 C3bBb.P045.225 VH DPQLVESGGGLVKPGGSLRLSCAARGLHFNNTDMSWVRQAPGKGLEWVGSISPKGDHKYLNTKFIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWGYFDWWGQGTLVTVSSSEQ ID NO: 20 10 C3bBb.P045.225 V L AIQMTQSPSSSLSASVGDRVTITCHGSYWLSSEVAWYQQKPGKAPKLLIYDGNGLKGGVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYHPYTFGHGTKVEIKSEQ ID NO: 21 11 C3bBb.P048.152 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKSGSKGYAQNVPGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 22 11 C3bBb.P048.152 V L HDIQMTQSPSSSLSASVGDRVTITCDADFGISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGGSFTLTISSLQPEDFATYYCQQYGVHPFTFGQGTKVEIKSEQ ID NO: 23 12 C3bBb.P048.061 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSTDINPKIGGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 24 12 C3bBb.P048.061 V L AIQMTQSPSSSLSASVGDRVTITCQGSWLISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYGGRLLTFGQGTKVEIKSEQ ID NO: 25 13 C3bBb.P048.127 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSTEYNTKVYGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 26 13 C3bBb.P048.127 V L HQMTQSPSSSLSASVGDRVTITCDGEWDISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGRDFTLTISSLQPEDFATYYCQQYNRMYFTFGQGTKVEIKSEQ ID NO: 27 14 C3bBb.P048.241 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNNNFTGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 28 14 C3bBb.P048.241 V L HINQMTQSPSSSLSASVGDRVTITCQAKWVISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDGTFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 29 15 C3bBb.P048.230 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNNKFHGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 30 15 C3bBb.P048.230 V L HYIQMTQSPSSSLSASVGDRVTITCQGNAFISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGDDFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 31 16 C3bBb.P048.204 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWFNRNFAGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 32 16 C3bBb.P048.204 V L GHVQMTQSPSSSLSASVGDRVTITCQAEDEISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDASFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 33 17 C3bBb.P048.333 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAWYNDKFKGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 34 17 C3bBb.P048.333 V L HINQMTQSPSSSLSASVGDRVTITCNSTEFISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSDQEFTLTISSLQPEDFATYYCQQYDWWPYTFGQGTKVEIKSEQ ID NO: 35 18 C3bBb.P053.095 VH RKQLVESGGGLVQPGGSLRLSCAAHGSLVSRNDMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDVDYMDLWGQGTLVTVSSSEQ ID NO: 36 18 C3bBb.P053.095 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLNSELAWYQQKPGKAPKLLIFDGDQTWFGVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 37 19 C3bBb.P055.015 VH GQLVESGGGLVKPGGSLRLSCKASGFYWGPGAMSWVRQAPGKGLEWVGSISPKGGSAEYASKVYGRFTISRDNNQDTLYLQMNSLRAEDTAVYYCARDIGFFDTWGQGTLVTVSSSEQ ID NO: 38 19 C3bBb.P055.015 V L DYQMTQSPSSSLSASVGDRVTITCEAHSQISNYLAWYQQKPGKAPKLLIFDAKYRAPEVPSRFSGSGSGPDFTLTISSLQPEDFATYYCQQYNDFWLTFGQGTKVEIKSEQ ID NO: 39 20 P1AF8499 VH EVQLVESGGGLVQPGGSLRLSCAASGFSWEHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 40 20 P1AF8499 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 41 twenty one GQ-5_1 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 42 twenty one GQ-5_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 43 twenty two GQ-11_1 VH EVQLVESGGGLVQPGGSLRLSCAASGFSWEHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 44 twenty two GQ-11_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 45 twenty three PT5622.F19 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 46 twenty three PT5622.F19 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 47 twenty four PT5624.P06 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 48 twenty four PT5624.P06 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 49 25 PT5624.M09 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 50 25 PT5624.M09 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 51 26 PT5626.M10 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 52 26 PT5626.M10 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 53 27 PT5626.C10 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 54 27 PT5626.C10 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 55 28 PT5628.E16 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 56 28 PT5628.E16 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 57 29 PT5630.D05 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 58 29 PT5630.D05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 59 30 PT5630.A20 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 60 30 PT5630.A20 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 61 31 PT5632.A13 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 62 31 PT5632.A13 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 63 32 PT5634.N13 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 64 32 PT5634.N13 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 65 33 PT5634.M24 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 66 33 PT5634.M24 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 67 34 PT5636.P22 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 68 34 PT5636.P22 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 69 35 PT5625.G07 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 70 35 PT5625.G07 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 71 36 PT5627.M20 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 72 36 PT5627.M20 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 73 37 PT5627.M12 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 74 37 PT5627.M12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 75 38 PT5629.F09 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 76 38 PT5629.F09 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 77 39 PT5629.H08 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 78 39 PT5629.H08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 79 40 PT5631.D21 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 80 40 PT5631.D21 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 81 41 PT5633.I03 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 82 41 PT5633.I03 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 83 42 PT5635.C08 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 84 42 PT5635.C08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 85 43 PT5639.G15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 86 43 PT5639.G15 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 87 44 PT5622.A20 VH EVQLVESGGGLVQPGGSLRLSCAASGFRWDKYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 88 44 PT5622.A20 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 89 45 PT5622.C12 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 90 45 PT5622.C12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 91 46 PT5622.G24 VH GVQLVESGGGLVQPGGSLRLSCAASGFRYDIYAMSWVRQAPGKGLEWVGEISPEGNHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 92 46 PT5622.G24 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 93 47 PT5622.I20 VH KVQLVESGGGLVQPGGSLRLSCAASGYTYDIYAMSWVRQAPGKGLEWVGEISPDGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDHWGQGTLVTVSSSEQ ID NO: 94 47 PT5622.I20 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 95 48 PT5622.J24 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYEHYAMSWVRQAPGKGLEWVGSISPKGQHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDVWGQGTLVTVSSSEQ ID NO: 96 48 PT5622.J24 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 97 49 PT5624.A21 VH KVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPKGEHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDGWGQGTLVTVSSSEQ ID NO: 98 49 PT5624.A21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 99 50 PT5624.B10 VH KVQLVESGGGLVQPGGSLRLSCAASGFHYDIYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 100 50 PT5624.B10 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 101 51 PT5624.N05 VH GVQLVESGGGLVQPGGSLRLSCAASGFKYEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 102 51 PT5624.N05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 103 52 PT5624.P11 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDQWGQGTLVTVSSSEQ ID NO: 104 52 PT5624.P11 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 105 53 PT5626.A12 VH RVQLVESGGGLVQPGGSLRLSCAASGFKWDHYAMSWVRQAPGKGLEWVGSISPDGNHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 106 53 PT5626.A12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 107 54 PT5626.N08 VH KVQLVESGGGLVQPGGSLRLSCAASGYKYDHYAMSWVRQAPGKGLEWVGEISPEGNSKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 108 54 PT5626.N08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 109 55 PT5626.N18 VH KVQLVESGGGLVQPGGSLRLSCAASGFKYEVYAMSWVRQAPGKGLEWVGEISPKGDTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 110 55 PT5626.N18 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 111 56 PT5626.O09 VH RVQLVESGGGLVQPGGSLRLSCAASGFKWEIYAMSWVRQAPGKGLEWVGDISPDGQTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDHWGQGTLVTVSSSEQ ID NO: 112 56 PT5626.O09 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 113 57 PT5628.B13 VH QVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 114 57 PT5628.B13 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 115 58 PT5628.C21 VH RVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDSWGQGTLVTVSSSEQ ID NO: 116 58 PT5628.C21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 117 59 PT5628.E12 VH KVQLVESGGGLVQPGGSLRLSCAASGYRWDIYAMSWVRQAPGKGLEWVGSISPDGNHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 118 59 PT5628.E12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 119 60 PT5628.I07 VH KVQLVESGGGLVQPGGSLRLSCAASGFRYDYYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 120 60 PT5628.I07 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 121 61 PT5628.P14 VH KVQLVESGGGLVQPGGSLRLSCAASGFTWEHYAMSWVRQAPGKGLEWVGSISPDGQHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 122 61 PT5628.P14 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 123 62 PT5630.G05 VH QVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPDGRHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 124 62 PT5630.G05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 125 63 PT5630.K04 VH RVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDEWGQGTLVTVSSSEQ ID NO: 126 63 PT5630.K04 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 127 64 PT5630.M11 VH RVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 128 64 PT5630.M11 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 129 65 PT5630.N06 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPKGDTKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 130 65 PT5630.N06 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 131 66 PT5630.O08 VH KVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDSWGQGTLVTVSSSEQ ID NO: 132 66 PT5630.O08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 133 67 PT5632.A10 VH RVQLVESGGGLVQPGGSLRLSCAASGFHFDKYAMSWVRQAPGKGLEWVGSISPKGRTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 134 67 PT5632.A10 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 135 68 PT5632.A15 VH RVQLVESGGGLVQPGGSLRLSCAASGFRWDYYAMSWVRQAPGKGLEWVGSISPDGQHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 136 68 PT5632.A15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 137 69 PT5632.B15 VH KVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGEISPDGQNKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 138 69 PT5632.B15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 139 70 PT5632.D11 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPEGNHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 140 70 PT5632.D11 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 141 71 PT5632.J23 VH GVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPDGRHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 142 71 PT5632.J23 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 143 72 PT5634.A17 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPDGRTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 144 72 PT5634.A17 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 145 73 PT5634.A21 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFDIYAMSWVRQAPGKGLEWVGEISPDGQSKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDNWGQGTLVTVSSSEQ ID NO: 146 73 PT5634.A21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 147 74 PT5634.K10 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGEISPKGDNKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 148 74 PT5634.K10 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 149 75 PT5634.M16 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGEISPKGDSKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 150 75 PT5634.M16 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 151 76 PT5634.N11 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGQDKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDTWGQGTLVTVSSSEQ ID NO: 152 76 PT5634.N11 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 153 77 PT5634.P19 VH KVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 154 77 PT5634.P19 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 155 78 PT5636.A16 VH KVQLVESGGGLVQPGGSLRLSCAASGFKYDIYAMSWVRQAPGKGLEWVGDISPKGETKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDAWGQGTLVTVSSSEQ ID NO: 156 78 PT5636.A16 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 157 79 PT5636.D21 VH EVQLVESGGGLVQPGGSLRLSCAASGYKFDKYAMSWVRQAPGKGLEWVGEISPRGDHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWEYFDSWGQGTLVTVSSSEQ ID NO: 158 79 PT5636.D21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 159 80 PT5636.M03 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 160 80 PT5636.M03 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 161 81 PT5636.N13 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPKGNHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 162 81 PT5636.N13 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 163 82 PT5636.P11 VH EVQLVESGGGLVQPGGSLRLSCAASGFQFDHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDQWGQGTLVTVSSSEQ ID NO: 164 82 PT5636.P11 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 165 83 PT5636.P15 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDYYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDGWGQGTLVTVSSSEQ ID NO: 166 83 PT5636.P15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 167 84 PT5638.C06 VH KVQLVESGGGLVQPGGSLRLSCAASGYTWEHYAMSWVRQAPGKGLEWVGSISPDGRHKYYNTKFIDRFTISRDDDKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 168 84 PT5638.C06 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 169 85 PT5638.C20 VH KVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPDGDHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 170 85 PT5638.C20 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 171 86 PT5638.E14 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 172 86 PT5638.E14 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 173 87 PT5638.J23 VH EVQLVESGGGLVQPGGSLRLSCAASGWSYDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 174 87 PT5638.J23 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 175 88 PT5638.O14 VH RVQLVESGGGLVQPGGSLRLSCAASGFRWDYYAMSWVRQAPGKGLEWVGSISPDGEHKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWDYFDTWGQGTLVTVSSSEQ ID NO: 176 88 PT5638.O14 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 177 89 PT5638.P12 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDYYAMSWVRQAPGKGLEWVGSISPKGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDIWGQGTLVTVSSSEQ ID NO: 178 89 PT5638.P12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 179 90 PT5623.E21 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 180 90 PT5623.E21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 181 91 PT5623.F17 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 182 91 PT5623.F17 V L AIQMTQSPSSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRDEPYTFGQGTKLEIKSEQ ID NO: 183 92 PT5623.G08 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 184 92 PT5623.G08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 185 93 PT5623.H05 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 186 93 PT5623.H05 V L AIQMTQSPSSSLSASVGDRVTITCQSTLWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYKETPYTFGQGTKLEIKSEQ ID NO: 187 94 PT5623.O08 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 188 94 PT5623.O08 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 189 95 PT5625.A05 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 190 95 PT5625.A05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 191 96 PT5625.B14 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 192 96 PT5625.B14 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSEEEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 193 97 PT5625.C15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 194 97 PT5625.C15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYKETPYTFGQGTKLEIKSEQ ID NO: 195 98 PT5625.G05 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 196 98 PT5625.G05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 197 99 PT5625.L22 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 198 99 PT5625.L22 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 199 100 PT5625.O14 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 200 100 PT5625.O14 V L AIQMTQSPSSSLSASVGDRVTITCQSQLWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 201 101 PT5627.I21 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 202 101 PT5627.I21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYREDPYTFGQGTKLEIKSEQ ID NO: 203 102 PT5629.F04 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 204 102 PT5629.F04 V L AIQMTQSPSSSLSASVGDRVTITCQVSHWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 205 103 PT5629.L22 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 206 103 PT5629.L22 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRqTPYTFGQGTKLEIKSEQ ID NO: 207 104 PT5629.L24 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 208 104 PT5629.L24 V L AIQMTQSPSSSLSASVGDRVTITCQSqFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYESEPYTFGQGTKLEIKSEQ ID NO: 209 105 PT5629.M15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 210 105 PT5629.M15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSWDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 211 106 PT5631.H06 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 212 106 PT5631.H06 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 213 107 PT5631.K12 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 214 107 PT5631.K12 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 215 108 PT5631.N17 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 216 108 PT5631.N17 V L AIQMTQSPSSSLSASVGDRVTITCQSTLWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGSGSWDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 217 109 PT5631.P07 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 218 109 PT5631.P07 V L AIQMTQSPSSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYKDTPYTFGQGTKLEIKSEQ ID NO: 219 110 PT5633.E09 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 220 110 PT5633.E09 V L AIQMTQSPSSSLSASVGDRVTITCQAqHWLSNYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 221 111 PT5633.G19 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 222 111 PT5633.G19 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 223 112 PT5635.F04 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 224 112 PT5635.F04 V L AIQMTQSPSSSLSASVGDRVTITCQAHYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 225 113 PT5635.L21 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 226 113 PT5635.L21 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 227 114 PT5635.O15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 228 114 PT5635.O15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 229 115 PT5637.B23 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 230 115 PT5637.B23 V L AIQMTQSPSSSLSASVGDRVTITCQSQLWLSNYLAWYQQKPGKAPKLLIFDGDLPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 231 116 PT5637.C20 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 232 116 PT5637.C20 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREDPYTFGQGTKLEIKSEQ ID NO: 233 117 PT5637.K09 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 234 117 PT5637.K09 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 235 118 PT5637.L15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 236 118 PT5637.L15 V L AIQMTQSPSSSLSASVGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRSEPYTFGQGTKLEIKSEQ ID NO: 237 119 PT5637.M03 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 238 119 PT5637.M03 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 239 120 PT5637.P15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 240 120 PT5637.P15 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 241 121 PT5639.B15 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 242 121 PT5639.B15 V L AIQMTQSPSSLSASIGDRVTITCQSQYWLSNYLAWYQQKPGKAPKLLIFDGDIPWELPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 243 122 PT5639.P05 VH GQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMTWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDEWGQGTLVTVSSSEQ ID NO: 244 122 PT5639.P05 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDLPYETPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 245 123 PT5625.G07_22.F19_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 246 123 PT5625.G07_22.F19_2 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 247 124 PT5625.G07_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 248 124 PT5625.G07_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 249 125 PT5625.G07_24.P06_2 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 250 125 PT5625.G07_24.P06_2 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 251 126 PT5625.G07_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 252 126 PT5625.G07_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 253 127 PT5625.G07_26.M10_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 254 127 PT5625.G07_26.M10_2 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 255 128 PT5625.G07_28.E16_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 256 128 PT5625.G07_28.E16_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 257 129 PT5625.G07_30.A20_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 258 129 PT5625.G07_30.A20_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 259 130 PT5625.G07_32.A13_2 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 260 130 PT5625.G07_32.A13_2 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 261 131 PT5625.G07_34.M24_1 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 262 131 PT5625.G07_34.M24_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 263 132 PT5625.G07_34.N13_3 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 264 132 PT5625.G07_34.N13_3 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 265 133 PT5625.G07_36.P22_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 266 133 PT5625.G07_36.P22_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 267 134 PT5627.M20_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 268 134 PT5627.M20_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 269 135 PT5627.M20_24.P06_1 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 270 135 PT5627.M20_24.P06_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 271 136 PT5627.M20_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 272 136 PT5627.M20_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 273 137 PT5627.M20_26.M10_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 274 137 PT5627.M20_26.M10_2 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 275 138 PT5627.M20_28.E16_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 276 138 PT5627.M20_28.E16_2 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 277 139 PT5627.M20_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 278 139 PT5627.M20_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 279 140 PT5627.M20_32.A13_1 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 280 140 PT5627.M20_32.A13_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 281 141 PT5627.M20_34.M24_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 282 141 PT5627.M20_34.M24_2 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 283 142 PT5627.M20_34.N13_4 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 284 142 PT5627.M20_34.N13_4 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 285 143 PT5627.M20_36.P22_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 286 143 PT5627.M20_36.P22_1 V L AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIKSEQ ID NO: 287 144 PT5627.M12_22.F19_1 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 288 144 PT5627.M12_22.F19_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 289 145 PT5627.M12_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 290 145 PT5627.M12_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 291 146 PT5627.M12_26.M10_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 292 146 PT5627.M12_26.M10_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 293 147 PT5627.M12_32.A13_2 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 294 147 PT5627.M12_32.A13_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 295 148 PT5627.M12_34.M24_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 296 148 PT5627.M12_34.M24_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 297 149 PT5627.M12_34.N13_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 298 149 PT5627.M12_34.N13_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 299 150 PT5629.F09_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 300 150 PT5629.F09_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 301 151 PT5629.F09_28.E16_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 302 151 PT5629.F09_28.E16_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 303 152 PT5629.F09_30.A20_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 304 152 PT5629.F09_30.A20_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 305 153 PT5629.F09_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 306 153 PT5629.F09_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 307 154 PT5629.F09_32.A13_3 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 308 154 PT5629.F09_32.A13_3 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 309 155 PT5629.F09_36.P22_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 310 155 PT5629.F09_36.P22_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 311 156 PT5629.H08_22.F19_4 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 312 156 PT5629.H08_22.F19_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 313 157 PT5629.H08_24.M09_4 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 314 157 PT5629.H08_24.M09_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 315 158 PT5629.H08_24.P06_2 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 316 158 PT5629.H08_24.P06_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 317 159 PT5629.H08_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 318 159 PT5629.H08_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 319 160 PT5629.H08_26.M10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 320 160 PT5629.H08_26.M10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 321 161 PT5629.H08_28.E16_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 322 161 PT5629.H08_28.E16_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 323 162 PT5629.H08_30.A20_2 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 324 162 PT5629.H08_30.A20_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 325 163 PT5629.H08_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 326 163 PT5629.H08_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 327 164 PT5629.H08_32.A13_1 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 328 164 PT5629.H08_32.A13_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 329 165 PT5629.H08_34.M24_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 330 165 PT5629.H08_34.M24_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 331 166 PT5629.H08_34.N13_2 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 332 166 PT5629.H08_34.N13_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 333 167 PT5629.H08_36.P22_4 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 334 167 PT5629.H08_36.P22_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 335 168 PT5631.D21_22.F19_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 336 168 PT5631.D21_22.F19_2 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 337 169 PT5631.D21_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 338 169 PT5631.D21_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 339 170 PT5631.D21_24.P06_4 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 340 170 PT5631.D21_24.P06_4 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 341 171 PT5631.D21_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 342 171 PT5631.D21_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 343 172 PT5631.D21_26.M10_4 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 344 172 PT5631.D21_26.M10_4 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 345 173 PT5631.D21_28.E16_3 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 346 173 PT5631.D21_28.E16_3 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 347 174 PT5631.D21_30.A20_4 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 348 174 PT5631.D21_30.A20_4 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 349 175 PT5631.D21_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 350 175 PT5631.D21_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 351 176 PT5631.D21_32.A13_4 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 352 176 PT5631.D21_32.A13_4 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 353 177 PT5631.D21_34.M24_4 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 354 177 PT5631.D21_34.M24_4 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 355 178 PT5631.D21_34.N13_2 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 356 178 PT5631.D21_34.N13_2 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 357 179 PT5631.D21_36.P22_3 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 358 179 PT5631.D21_36.P22_3 V L AIQMTQSPSSSLSASVGDRVTITCQSSHWLSNYLAWYQQKPGKAPKLLIFDGDLPWEVPSRFSGSGSEDEYTLTISSLQPEDFATYYCQQYRYTPYTFGQGTKLEIKSEQ ID NO: 359 180 PT5633.I03_22.F19_1 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 360 180 PT5633.I03_22.F19_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 361 181 PT5633.I03_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 362 181 PT5633.I03_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 363 182 PT5633.I03_24.P06_4 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 364 182 PT5633.I03_24.P06_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 365 183 PT5633.I03_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 366 183 PT5633.I03_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 367 184 PT5633.I03_26.M10_4 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 368 184 PT5633.I03_26.M10_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 369 185 PT5633.I03_28.E16_4 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 370 185 PT5633.I03_28.E16_4 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 371 186 PT5633.I03_30.A20_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 372 186 PT5633.I03_30.A20_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 373 187 PT5633.I03_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 374 187 PT5633.I03_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 375 188 PT5633.I03_32.A13_1 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 376 188 PT5633.I03_32.A13_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 377 189 PT5633.I03_34.M24_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 378 189 PT5633.I03_34.M24_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 379 190 PT5633.I03_34.N13_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 380 190 PT5633.I03_34.N13_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 381 191 PT5633.I03_36.P22_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 382 191 PT5633.I03_36.P22_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEDYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 383 192 PT5635.C08_22.F19_1 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 384 192 PT5635.C08_22.F19_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 385 193 PT5635.C08_24.M09_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 386 193 PT5635.C08_24.M09_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 387 194 PT5635.C08_24.P06_1 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 388 194 PT5635.C08_24.P06_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 389 195 PT5635.C08_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 390 195 PT5635.C08_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 391 196 PT5635.C08_26.M10_2 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 392 196 PT5635.C08_26.M10_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 393 197 PT5635.C08_28.E16_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 394 197 PT5635.C08_28.E16_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 395 198 PT5635.C08_30.A20_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 396 198 PT5635.C08_30.A20_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 397 199 PT5635.C08_30.D05_3 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 398 199 PT5635.C08_30.D05_3 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 399 200 PT5635.C08_32.A13_3 VH RVQLVESGGGLVQPGGSLRLSCAASGYRWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDYWGQGTLVTVSSSEQ ID NO: 400 200 PT5635.C08_32.A13_3 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 401 201 PT5635.C08_34.M24_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 402 201 PT5635.C08_34.M24_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 403 202 PT5635.C08_34.N13_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 404 202 PT5635.C08_34.N13_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 405 203 PT5635.C08_36.P22_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 406 203 PT5635.C08_36.P22_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEVPSRFSGSGSHEEYTLTISSLQPEDFATYYCQQYRSTPYTFGQGTKLEIKSEQ ID NO: 407 204 PT5639.G15_22.F19_2 VH EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 408 204 PT5639.G15_22.F19_2 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 409 205 PT5639.G15_24.P06_1 VH QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 410 205 PT5639.G15_24.P06_1 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 411 206 PT5639.G15_24.M09_4 VH KVQLVESGGGLVQPGGSLRLSCAASGFRWEHYAMSWVRQAPGKGLEWVGEISPDGDTKYYNTKFIDRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 412 206 PT5639.G15_24.M09_4 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 413 207 PT5639.G15_26.M10_3 VH RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTLVTVSSSEQ ID NO: 414 207 PT5639.G15_26.M10_3 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 415 208 PT5639.G15_28.E16_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTYDHYAMSWVRQAPGKGLEWVGEISPRGNTKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 416 208 PT5639.G15_28.E16_1 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 417 209 PT5639.G15_30.A20_1 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 418 209 PT5639.G15_30.A20_1 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 419 210 PT5639.G15_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 420 210 PT5639.G15_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 421 211 PT5639.G15_34.N13_4 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 422 211 PT5639.G15_34.N13_4 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 423 212 PT5639.G15_34.M24_3 VH EVQLVESGGGLVQPGGSLRLSCAASGFQWDHYAMSWVRQAPGKGLEWVGEISPRGDTKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWEYFDYWGQGTLVTVSSSEQ ID NO: 424 212 PT5639.G15_34.M24_3 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 425 213 PT5639.G15_36.P22_3 VH RVQLVESGGGLVQPGGSLRLSCAASGFKFEHYAMSWVRQAPGKGLEWVGEISPKGDHKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDRWGQGTLVTVSSSEQ ID NO: 426 213 PT5639.G15_36.P22_3 V L AIQMTQSPSSSLSASVGDRVTITCQSTHWLSAYLAWYQQKPGKAPKLLIFDGDIPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNEPYTFGQGTKLEIKSEQ ID NO: 427 214 PT5625.G07_30.D05_1 VH KVQLVESGGGLVQPGGSLRLSCAASGYRYDKYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 428 214 PT5625.G07_30.D05_1 V L AIQMTQSPSSSLSASVGDRVTITCQAQYWLSNYLAWYQQKPGKAPKLLIFDGDLPYEVPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYRNTPYTFGQGTKLEIKSEQ ID NO: 429 215 PT5627.M12_26.C10_1 VH RVQLVESGGGLVQPGGSLRLSCAASGFTWDHYAMSWVRQAPGKGLEWVGSISPKGDHKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 430 215 PT5627.M12_26.C10_1 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 431 216 PT5627.M12_30.A20_2 VH KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTLVTVSSSEQ ID NO: 432 216 PT5627.M12_30.A20_2 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIKSEQ ID NO: 433 217 PT5629.F09_34.N13_3 VH KVQLVESGGGLVQPGGSLRLSCAASGFTYDAYAMSWVRQAPGKGLEWVGEISPRGESKYYNTKFIDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTLVTVSSSEQ ID NO: 434 217 PT5629.F09_34.N13_3 V L AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIKSEQ ID NO: 435 1 P1AG9426 HC QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 436 1 P1AG9426 LC AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 437 2 P1AG9376 HC KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 438 2 P1AG9376 LC AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 439 3 P1AG9372 HC EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMSWVRQAPGKGLEWVGEISPDGRTKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 440 3 P1AG9372 LC AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 441 4 P1AG9420 HC RVQLVESGGGLVQPGGSLRLSCAASGFRYDHYAMSWVRQAPGKGLEWVGSISPRGNHKYYNTKFIDRFTISRDDEKNTLYLQMNSLRAEDTAVYYCARDWDYFDHWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 442 4 P1AG9420 LC AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPYEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRETPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 443 5 P1AG9391 HC QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPSEQ ID NO: 444 5 P1AG9391 LC AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 445 6 P1AH1205 HC KVQLVESGGGLVQPGGSLRLSCAASGFKWEHYAMSWVRQAPGKGLEWVGSISPRGDHKYYNTKFIDRFTISRDNDKNTLYLQMNSLRAEDTAVYYCARDWDYFDRWGQGT LVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 446 6 P1AH1205 LC AIQMTQSPSSSLSASVGDRVTITCQSQFWLSNYLAWYQQKPGKAPKLLIFDGDLPYERPSRFSGSGSHDEYTLTISSLQPEDFATYYCQQYREEPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 447 7 P1AH1199 HC QVQLVESGGGLVQPGGSLRLSCAASGFKYDVYAMSWVRQAPGKGLEWVGEISPRGDSKYYNTKFIDRFTISRDNEKNTLYLQMNSLRAEDTAVYYCARDWEYFDNWGQGT LVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 448 7 P1AH1199 LC AIQMTQSPSSSLSASVGDRVTITCQASYWLSNYLAWYQQKPGKAPKLLIFDGDIPWEIPSRFSGGSHEEYTLTISSLQPEDFATYYCQQYRDTPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 449 1 P1AG9426 HCDR1 GFKYDVYAMSSEQ ID NO: 450 1 P1AG9426 HCDR2 EISPRGDSKYYNTKFIDSEQ ID NO: 451 1 P1AG9426 HCDR3 DWYFSEQ ID NO: 452 1 P1AG9426 LCDR1 QASYWLSNYLASEQ ID NO: 453 1 P1AG9426 LCDR2 DGDIPYSEQ ID NO: 454 1 P1AG9426 LCDR3 QQYRETPYTSEQ ID NO: 455 2 P1AG9376 HCDR1 GFKWEHYAMSSEQ ID NO: 456 2 P1AG9376 HCDR2 SISPRGDHKYYNTKFIDSEQ ID NO: 457 2 P1AG9376 HCDR3 DWDYFDRSEQ ID NO: 458 2 P1AG9376 LCDR1 QSQFWLSNYLASEQ ID NO: 459 2 P1AG9376 LCDR2 DGDLPSEQ ID NO: 460 2 P1AG9376 LCDR3 QQYREEPYTSEQ ID NO: 461 3 P1AG9372 HCDR1 GFRFDIYAMSSEQ ID NO: 462 3 P1AG9372 HCDR2 EISPDGRTKYYNTKFIDSEQ ID NO: 463 3 P1AG9372 HCDR3 DWYFSEQ ID NO: 464 3 P1AG9372 LCDR1 QSQFWLSNYLASEQ ID NO: 465 3 P1AG9372 LCDR2 DGDLPSEQ ID NO: 466 3 P1AG9372 LCDR3 QQYREEPYTSEQ ID NO: 467 4 P1AG9420 HCDR1 GFRYDHYAMSSEQ ID NO: 468 4 P1AG9420 HCDR2 SISPRGNHKYYNTKFIDSEQ ID NO: 469 4 P1AG9420 HCDR3 DWDYSEQ ID NO: 470 4 P1AG9420 LCDR1 QASYWLSNYLASEQ ID NO: 471 4 P1AG9420 LCDR2 DGDIPYSEQ ID NO: 472 4 P1AG9420 LCDR3 QQYRETPYTSEQ ID NO: 473 5 P1AG9391 HCDR1 GFKYDVYAMSSEQ ID NO: 474 5 P1AG9391 HCDR2 EISPRGDSKYYNTKFIDSEQ ID NO: 475 5 P1AG9391 HCDR3 DWYFSEQ ID NO: 476 5 P1AG9391 LCDR1 QASYWLSNYLASEQ ID NO: 477 5 P1AG9391 LCDR2 DGDIPWSEQ ID NO: 478 5 P1AG9391 LCDR3 QQYRDTPYTSEQ ID NO: 479 6 P1AH1205 HCDR1 GFKWEHYAMSSEQ ID NO: 480 6 P1AH1205 HCDR2 SISPRGDHKYYNTKFIDSEQ ID NO: 481 6 P1AH1205 HCDR3 DWDYFDRSEQ ID NO: 482 6 P1AH1205 LCDR1 QSQFWLSNYLASEQ ID NO: 483 6 P1AH1205 LCDR2 DGDLPSEQ ID NO: 484 6 P1AH1205 LCDR3 QQYREEPYTSEQ ID NO: 485 7 P1AH1199 HCDR1 GFKYDVYAMSSEQ ID NO: 486 7 P1AH1199 HCDR2 EISPRGDSKYYNTKFIDSEQ ID NO: 487 7 P1AH1199 HCDR3 DWYFSEQ ID NO: 488 7 P1AH1199 LCDR1 QASYWLSNYLASEQ ID NO: 489 7 P1AH1199 LCDR2 DGDIPWSEQ ID NO: 490 7 P1AH1199 LCDR3 QQYRDTPYTSEQ ID NO: 491 Human factor B wt (FB) with His tag and precise site HHHHHHGSLEVLFQGPGGTPWSLARPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLT LRGSQRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVII LMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYD YDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKV KDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 492 Human FB with D279G, with His tag and precise location HHHHHHGSLEVLFQGPGGTPWSLARPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLT LRGSQRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSGSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVII LMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYD YDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKV KDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 493 Human FB with D279G, K350N and M458I, with His tag and precise location HHHHHHGSLEVLFQGPGGTPWSLARPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLT LRGSQRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSGSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLNSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVII LMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDIENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYD YDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKV KDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 494 Complement factor D ILGGREAEAHARPYMASVQLNGAHLCGGVLVAEQWVLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSQPDTIDHDLLLLQLSEKATLGPAVRPLPWQRV DRDVAPGTLCDVAGWGIVNHAGRRPDSLQHVLLPVLDRATCNRRTHHDGAITERLMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTRVASYAAWIDSVLSEQ ID NO: 495 Complement C3 β chain (C3b) SPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVHDFPGKKLVLSSEKTVLTPATNHMGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKVVLVS LQSGYLFIQTDKTIYTPGSTVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSLSSQNQLGVLPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEY VLPSFEVIVEPTEKFYYIYNEKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEVVLSRKVLLDGVQNPRAEDLVGKSLYVSAT VILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKQELS EAEQATRTMQALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMDRAHEAKIRYYTYLIMNKGRLLKAGRQVREPGQDLVVLPLSITTDFIPSFRLVAY YTLIGASGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDKGVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAG VFSDAGLTFTSSSGQQTAQRAELQCPQPAARRRRSVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLMNIFLKDSITTWEILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRN EQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVIVPLKTGLQEVEVKAAVYHHFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQVPDTESETRILLQGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDETEQWEKFGLEKRQGALE LIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLI SLQEAKDICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFLTTAKDKNRWEDPGKQLYNVEATSYALLALLQLKDFDFVPPV VRWLNEQRYYGGGYGSTQATFMVFQALAQYQKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKD QLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDD CLAFKVHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEDGKLNKLCRDELCRCAEENCFIQKSDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDE YIMAIEQTIKSGSDEVQVGQQRTFISPIKCREALKLEEKKHYLMWGLSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQDLGAFTESMVVFGCPNSEQ ID NO: 496 Human C3a SVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARASHLGLARSEQ ID NO: 497 Cynomolgus macaque C3b PMYSMITPNVLRLESEETVVLEAHDANGDVPVTVTVHDFPGKKLVLSSEKTVLTPATSHMGSVTIRIPANKEFKSEKGHNKFVTVQATFGAQVVEKVVLVSL QSGYLFIQTDKTIYTPGSTVLCRIFTVNHKLLPVGRTVVVNIENPDGIPVKQDSLSSQNQFGILPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYV LPSFEVIVEPTEKFYYIYNQKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIQIEDSGDAVLSRKVLLDGVQNPRPEDLVGKSLYVSVTV ILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDAVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKRELSE AEQATRTMEAQPYSTVGNSNNYLHLSVPRAELRPGETLNVNFLLRMDRTQEAKIRYYTYLIMNKGKLLKVGRQVREPGQDLVVLPLSITTDFIPSFRLVAYY TLIGANGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPLPGQQMTLKIEGDHGARVGLVAVDKGVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGV FSDAGLTFASSSGQQTAQRAELQCPQPATRRRRSVQLAEKRMDKVGQYPKELRKCCEHGMRENPMRFSCQRRTRYITLDEACKKAFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWKIEELKEAPKNGISTKLMNIFLKDSITTWEILAVSLSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNE QVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATAKRRHQQTVTIPPKSSLSVPYVIVPLKTGQQEVEVKAAVYHFFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGQEGVQREDVPPADLSDQVPDTESETRILLQGTPVAQMTEDAIDAERLKHLIVTPSGCGEQNMITMTPTVIAVHYLDETEQWEKFGPEKRQGALEL IKKGYTQQLAFRQPSSAFAAFLNRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMTGGFRNTNEKDMALTAFVLIS LQEAKEICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAAYALAQMGRLKGPLLNKFLTTAKDKNRWEEPGQQLYNVEATSYALLALLQLKDFDFVPPVV RWLNEQRYYGGGYGSTQATFMVFQALAQYQKDVPDHKELNLDVSLQLPSRSSKIIHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKGQ LTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMMTGFVPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDC IAFKVHQYFNVELIQPGAVKVYAYYNLAESCTRFYHPKEDGKLNKLCRDELCRCAEENCFIQKLDDKVTLEERLDKACEPGVDYVYKTRLVKAQLSNDFDE YIMAIEQIIKSGSDEVQVGQQRTFISPIKCREALKLEERKHYLMWGLSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQDLGTFTENMVVFGCPNSEQ ID NO: 498 Cynomolgus macaque factor D (FD) ILGGREAEAHARPYMASVQVNGEHLCGGVLVAEQWVLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSRPDTIDHDLLLLQLSEKATLGPAVRPLPWQRVDRDVEPG TLCDVAGWGIVSHAGRRPDRLQHVLLPVLDRATCNRRTHHDGAITQRMMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTRVASYAAWIDSLEVLFQGPGSHHHHHHSEQ ID NO: 499 Cynomolgus macaque factor B WT HHHHHHGSLEVLFQGPGGTPLSSAQPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLQTQDRKTVKKAECRAIRCPRPQDFENGEYRPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSRYRLEDSVTYHCSRGLT LRGSQRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHSPGEQQKRRIILDPSGSMNIYLVLDGSDSIGAGNFTGAKKCLVNLIEKVASYGVKPRYALVTYATYPRIWVKVSDQESSNADWVTKKLSEINYEDHKLKSGTNTKRALQAVYSMMSWPEDIPPEGWNRTRHVII LMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVDQVNINALASKKDNEQHVFKVKDMENLEDVFFQMIDESQSLSLCGMVWEHTTGTDYHKQPWQAKISVTRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGKKRDLEIEKVLFHPDYNISGKKEAGIPEFYDY DVALIKLKKKLNYDPTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHVNLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 500 Cynomolgus macaque factor B triple mutant (D279G_K350N_M458I) HHHHHHGSLEVLFQGPGGTPLSSAQPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLQTQDRKTVKKAECRAIRCPRPQDFENGEYRPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSRYRLEDSVTYHCSRGLT LRGSQRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHSPGEQQKRRIILDPSGSMNIYLVLDGSGSIGAGNFTGAKKCLVNLIEKVASYGVKPRYALVTYATYPRIWVKVSDQESSNADWVTKKLSEINYEDHKLNSGTNTKRALQAVYSMMSWPEDIPPEGWNRTRHVII LMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVDQVNINALASKKDNEQHVFKVKDIENLEDVFFQMIDESQSLSLCGMVWEHTTGTDYHKQPWQAKISVTRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGKKRDLEIEKVLFHPDYNISGKKEAGIPEFYDY DVALIKLKKKLNYDPTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHVNLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 501 Human factor B (wt, without signal peptide) TPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHCSRGLTLRGSQRRTCQEGG SWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNM GGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVAL IKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKD ISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLSEQ ID NO: 502 Human constant light chain domain CL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 503 Human constant heavy chain domain CH1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDSEQ ID NO: 504 Human factor B (wt, with signal peptide) MGSNLSPQLCLMPFILGLLSGGVTTTPWSLARPQGCSLEGVEIKGGSFRLLQEGQALEYVCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDSVTYHC SRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDVPPEGWNRTRH VIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFY DYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDK VKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFLExamples

提供以下實例以幫助理解本發明，但本發明之真實範圍在所附申請專利範圍中闡明。應當理解的是，在不脫離本發明之精神的前提下，可以對所提出的步驟進行修改。實例1：人類C3bBb複合物的穩定化The following examples are provided to aid in understanding the present invention, but the true scope of the present invention is set forth in the appended claims. It should be understood that modifications may be made to the steps set forth without departing from the spirit of the present invention.Example1:Stabilization ofhumanC3bBb complex

野生型 C3bBb 係一種快速衰減的複合物，不適合用於抗體發現目的。為了評定因子 B (FB) 次單元內不同突變對 C3bBb 穩定性之影響，在 FB 蛋白中引入以下突變：D279G、K350N 及 M458I。未突變之 FB 示於 SEQ ID NO: 491，具有 D279G 突變之 FB 示於 SEQ ID NO: 492，並且具有 D279G、K350N 及 M458I 突變之 FB 示於 SEQ ID NO: 493。突變的編號係基於具有訊號肽的人類因子 B 之胺基酸序列 (SEQ ID NO: 504)。藉由對塗有 C3b 的感測器進行生物層干涉測量 (BLI) 分析來評定所描述的不同 C3bBb 變異體的組裝及衰減。使用BLI進行穩定性檢測：a) 鎂離子存在下之 C3bBb 組裝Wild-type C3bBb is a rapidly decaying complex that is not suitable for antibody discovery purposes. To assess the effects of different mutations within the Factor B (FB) subunit on the stability of C3bBb, the following mutations were introduced into the FB protein: D279G, K350N, and M458I. The unmutated FB is shown in SEQ ID NO: 491, the FB with the D279G mutation is shown in SEQ ID NO: 492, and the FB with the D279G, K350N, and M458I mutations is shown in SEQ ID NO: 493. The numbering of the mutations is based on the amino acid sequence of human Factor B with a signal peptide (SEQ ID NO: 504). The assembly and attenuation of the different C3bBb variants described were assessed by biolithography interferometry (BLI) analysis of sensors coated with C3b.Stability assaysusingBLI : a) C3bBb assembly in the presence of magnesium ions

為了分析如此形成之具有不同 Bb 次單元的 C3bBb 複合物的穩定性，藉由將血漿純化之 C3b (補體技術) 在 5 摩爾過量馬來亞醯胺-PEG3-生物素 (Thermo Fisher Scientific) 存在下於 4°C 孵育越夜，隨後在 Zeba 旋轉柱 40K (Thermo Fisher Scientific) 上純化，在半胱胺酸 1010 處對 C3b 進行生物素化。此材料用於以高密度 (5nm BLI訊號) 將鏈黴親和素功能化 BLI 感測器 (SA 感測器；Fortebio) 加載到 Octet RED 384 裝置 (Fortebio) 中。藉由將載入 C3b 之感測器曝露於不同的重組因子 B 變異體 (亦即未突變之 SEQ ID NO: 491；SEQ ID NO: 492 之 D279G 變異體；SEQ ID NO: 493 之 D279G K350N M458I 三重變異體)在 HBS-T(Mg) 緩衝液 (150mM NaCl、10mM HEPES、1mM MgCl₂、0.005% Tween20. pH 7.4) 中之 54 nM 血漿純化因子 D (補體技術) 存在下於 22°C 來組裝 C3bBb。在使轉化酶達到平衡 12 分鐘後，將感測器轉移至 200µl HBS-T(Mg) 緩衝液中，引發組裝的 C3bBb 之解離。轉化酶衰減持續三個小時。To analyze the stability of the C3bBb complexes with different Bb subunits thus formed, C3b was biotinylated at cysteine 1010 by incubating plasma-purified C3b (complement technology) in the presence of 5 molar excess of maleimide-PEG3-biotin (Thermo Fisher Scientific) at 4°C overnight and subsequently purified on a Zeba spin column 40K (Thermo Fisher Scientific). This material was used to load streptavidin-functionalized BLI sensors (SA sensors; Fortebio) at high density (5 nm BLI signal) into an Octet RED 384 device (Fortebio). C3bBb was assembled by exposing the C3b-loaded sensor to different recombinant Factor B variants (i.e., unmutated SEQ ID NO: 491; D279G variant of SEQ ID NO: 492; D279G K350N M458I triple variant of SEQ ID NO: 493) in the presence of 54 nM plasma purified Factor D (complement technique) in HBS-T(Mg) buffer (150 mM NaCl, 10 mM HEPES,₁ mM MgCl2, 0.005% Tween20. pH 7.4) at 22°C. After allowing the convertase to equilibrate for 12 minutes, the sensor was transferred to 200 µl of HBS-T(Mg) buffer to trigger dissociation of assembled C3bBb. Convertase decay continued for three hours.

在減去從省略 C3b 加載步驟的平行參考感測器記錄的訊號並減去省略因子 B 及因子 D 的對照感測器後，使用 XLfit (IDBS 軟體)將解離相的資料擬合為雙指數 ((A*exp(((-1)*B)*x)))+(C*exp(((-1)*D)*x))，允許組裝的轉化酶群體中存在異質性。主要物種的半衰期 (= LN(2)/B) 及相對重要性報告於表E1。b) Ni 離子存在下之 C3bBb 組裝After subtracting the signal recorded from a parallel reference sensor in which the C3b loading step was omitted and subtracting the control sensor in which factors B and D were omitted, the data from the dissociation phase were fit to a biexponential ((A*exp(((-1)*B)*x)))+(C*exp(((-1)*D)*x)) using XLfit (IDBS software), allowing for heterogeneity in the assembled convertase population. The half-lives (= LN(2)/B) and relative importance of the major species are reported inTableE1. b) Assembly of C3bBb in the presence of Ni ions

在另一項實驗中，在因子 B VWA 中配位的結構 Mg²⁺離子取代 Ni²⁺，以進一步穩定 C3 轉化酶。使用與先前實驗相同的設定來探索對 C3bBb 複合物穩定性之影響，不同之處在於使用 HBS-T(Ni) 緩衝液 (150mM NaCl、10mM HEPES、1mM NiCl₂、0.005% Tween20. pH 7.4) 代替 HBS-T(Mg)。In another experiment, structural Mg²⁺ ions coordinated in Factor B VWA replaced Ni²⁺ to further stabilize C3 convertase. The same setup as the previous experiment was used to explore the effect on C3bBb complex stability, except that HBS-T(Ni) buffer (150mM NaCl, 10mM HEPES, 1mM NiCl₂ , 0.005% Tween20. pH 7.4) was used instead of HBS-T(Mg).

BLI 跡線的校正與鎂存在下的實驗相同。與含有 Mg²⁺的 C3bBb 複合物不同，在解離過程中僅檢測到一種物種，並使用單指數衰減 (A*exp(((-1)*B)*x)) 進行分析。在使用不同 Bb 蛋白 (亦即野生型 Bb、單突變 Bb D279G 及三重突變 Bb D279G、K350N 及 M458I) 組裝 C3bBb 過程中添加 Ni²⁺離子對 C3bBb 複合物形成之影響顯示於表E1。表E1：藉由 BLI 所測量的使用不同 Bb 蛋白形成之 C3bBb 複合物之 t1/2包含在C3bBb複合物中之Bbt 1/2主要物種之盛行率wt FB, Mg²⁺4 分 46 秒93%FB (D279G), Mg²⁺1 小時 03 分97%FB (D279G, K350N 及 M458I), Mg²⁺1 小時 59 分93%wt FB, Ni²⁺0 小時 29 分100%FB (D279G), Ni²⁺3 小時 18 分100%FB (D279G, K350N 及 M458I), Ni²⁺11 小時 18 分100%The calibration of the BLI traces was the same as for the experiments in the presence of magnesium. Unlike the C3bBb complexes containing Mg²⁺ , only one species was detected during the dissociation and was analyzed using a single exponential decay (A*exp(((-1)*B)*x)). The effect of the addition of Ni²⁺ ions on the formation of C3bBb complexes during the assembly of C3bBb using different Bb proteins (i.e., wild-type Bb, single mutant Bb D279G, and triple mutants Bb D279G, K350N, and M458I) is shown inTableE1 .TableE1: t1/2 of C3bBb complexes formed using different Bb proteins measured by BLIBbcontained in theC3bBbcomplext 1/2Prevalence of major species wt FB, Mg²⁺ 4 minutes 46 seconds 93% FB (D279G), Mg²⁺ 1 hour 03 minutes 97% FB (D279G, K350N and M458I), Mg²⁺ 1 hour 59 minutes 93% wt FB, Ni²⁺ 0 hours 29 minutes 100% FB (D279G), Ni²⁺ 3 hours 18 minutes 100% FB (D279G, K350N and M458I), Ni²⁺ 11 hours and 18 minutes 100%

雖然在鎂離子存在下形成之野生型 C3bBb 複合物具有小於五分鐘之半衰期，但藉由 FB 之 Bb 次單元內的突變的穩定化，並藉由在 Ni²⁺離子存在下形成進一步穩定化 C3bBb 導致半衰期達至 11 小時 15 分鐘 (相當於 675 分鐘，這相當於 C3bBb 半衰期增加了 135 倍以上)。用於抗體發現的穩定化C3bBb複合物之組裝及純化Although the wild-type C3bBb complex formed in the presence of magnesium ions has a half-life of less than five minutes, stabilization by mutations within the Bb subunit of FB and further stabilization of C3bBb by formation in the presence of Ni²⁺ ions resulted in a half-life of 11 hours 15 minutes (equivalent to 675 minutes, which is equivalent to a more than 135-fold increase in the half-life of C3bBb). Assembly and purification of stabilizedC3bBbcomplexesfor antibody discovery

藉由在 0.4 mM EZ-Link HPDP-生物素 (Thermo Fisher Scientific) 存在下於室溫孵育血漿純化之 C3b (補體技術) 2 小時，隨後在 NAP-10 管柱 (Thermo Fisher Scientific) 上純化，在半胱胺酸 1010 處對 C3b 進行生物素化。將生物素化之 C3b 以 1:1 之摩爾比與 hu 因子 B (亦即未突變之 SEQ ID NO: 491；SEQ ID NO: 492 之 D279G 變異體；SEQ ID NO: 493 之 D279G K350N M458I 三重變異體)混合，另外添加 NiSO₄直至最終濃度為 5 mM。於室溫預孵育 10 分鐘後，以 1 (C3b): 1 (因子 B): 0.02 (因子 D) 之摩爾比添加因子 D (補體技術) 並在反應緩衝液 (20 mM Hepes、150 mM NaCl、5 mM NiSO₄pH 7.4) 於室溫再孵育 10 分鐘。隨後立即於室溫在儲存緩衝液 (20 mM Hepes、150 mM NaCl、1 mM NiSO₄pH 7.4) 中藉由粒徑排阻層析法 Superdex200 (Cytavia) 純化。實例2：使用穩定化C3bBb複合物進行抗體篩選C3b was biotinylated at cysteine 1010 by incubating plasma purified C3b (complement technology) in the presence of 0.4 mM EZ-Link HPDP-biotin (Thermo Fisher Scientific) at room temperature for 2 hours, followed by purification on a NAP-10 column (Thermo Fisher Scientific). Biotinylated C3b was mixed with hu factor B (i.e., unmutated SEQ ID NO: 491; D279G variant of SEQ ID NO: 492; D279G K350N M458I triple variant of SEQ ID NO: 493) at a 1:1 molar ratio, and NiSO₄ was added to a final concentration of 5 mM. After pre-incubation at room temperature for 10 minutes, factor D (complement technology) was added at a molar ratio of 1 (C3b): 1 (factor B): 0.02 (factor D) and incubated for another 10 minutes at room temperature in reaction buffer (20 mM Hepes, 150 mM NaCl, 5 mM NiSO₄ pH 7.4). Immediately thereafter, purification was performed by size exclusion chromatography Superdex200 (Cytavia) in storage buffer (20 mM Hepes, 150 mM NaCl, 1 mM NiSO₄ pH 7.4) at room temperature.Example2: Antibody screeningusing stabilizedC3bBbcomplex

如下篩選特異性結合穩定化 C3bBb 複合物之抗體：淘選The antibodies that specifically bind to the stabilized C3bBb complex were screened asfollows :

對於初始選擇，噬菌體文庫淘選進行 4 輪，其中第一輪用預先固定在 Dynabeads M-280 鏈黴親和素 (Thermofisher 目錄號 11206D) 上的 800 nM 生物素化之 C3bBb 三突變體-HPDP (其中 C3bBb 係在鎳離子存在下使用 SEQ ID NO: 493 之 FB 形成的) 進行。使用溶液中的 150 nM 生物素化之標靶進行第 2 至 4 輪淘選，隨後在 SpeedBead 磁性中性親和素包被顆粒 (Cytiva，目錄號 78152104010350，第2 輪及第 4 輪) 或 Dynabeads M-280 鏈黴親和素 (第 3 輪) 上捕獲噬菌體上的 Fab/標靶複合物。簡而言之，在第一輪淘選中，將噬菌體/標靶/珠複合物用 HBS-NT + NiSO₄(0,01M HEPES pH7.4；0,15M NaCl；補充有 0.1% Tween-20 及 1mM NiSO4 之 Cytiva 目錄 BR-1006-70) 洗滌 2 次並用 HBS-N + NiSO₄(0,01M HEPES pH7.4；0,15M NaCl；補充有 1mM NiSO₄之 Cytiva 目錄 BR-1006-70) 洗滌 1 次。在第 2、3 及 4 輪淘選中，用 HBS-NT + NiSO₄洗滌噬菌體/標靶/珠複合物 5 次並用 1x HBS-N + NiSO₄洗滌 2 次。根據標準方案，使用 100mM DTT 從 M-280 珠粒上洗脫捕獲的帶有標靶特異性 Fab 的噬菌體複製，用於感染對數期 TG1 大腸桿菌細胞，並使用 M13 K07 輔助噬菌體拯救。篩選For the initial selection, phage library panning was performed for 4 rounds, the first of which was performed with 800 nM biotinylated C3bBb triple mutant-HPDP (where C3bBb was formed using FB of SEQ ID NO: 493 in the presence of nickel ions) pre-immobilized on Dynabeads M-280 streptavidin (Thermofisher catalog number 11206D). Panning rounds 2 to 4 were performed using 150 nM biotinylated target in solution, followed by capture of Fab/target complexes on phage on SpeedBead magnetic neutravidin-coated particles (Cytiva, Cat. No. 78152104010350, rounds 2 and 4) or Dynabeads M-280 streptavidin (round 3). Briefly, in the first round of panning, the phage/target/bead complex was washed twice with HBS-NT + NiSO₄ (0,01M HEPES pH7.4; 0,15M NaCl; Cytiva catalog BR-1006-70 supplemented with 0.1% Tween-20 and 1mM NiSO 4) and once with HBS-N + NiSO₄ (0,01M HEPES pH7.4; 0,15M NaCl; Cytiva catalog BR-1006-70 supplemented with 1mM NiSO₄ ). In the 2nd, 3rd and 4th rounds of panning, the phage/target/bead complex was washed 5 times with HBS-NT + NiSO₄ and 2 times with 1x HBS-N + NiSO₄ . Captured phage copies carrying target-specific Fab were eluted from M-280 beads using 100 mM DTT, used to infect log-phase TG1 E. coli cells, andrescued using M13 K07 as a facilitator of phage rescue according to standard protocols.

為了篩選選擇輸出，從感染的 TG1 大腸桿菌細胞中製備了相應選擇輪次的多複製質體小量製備物。將質體重新格式化以在大腸桿菌上清液中產生在 Fab CH1 域的 C 末端帶有 T7 標記的可溶性 Fab。將編碼 T7 標記的 Fab 的連接多複製質體轉化到 TG1 大腸桿菌細胞 (Zymo Research 目錄號 T3017) 中，並將單菌落挑到微量滴定盤中。可溶性 Fab 在微量滴定盤中表現，並且藉由離心來澄清上清液。To screen the selection output, multi-copy plasmid minipreps of the corresponding selection rounds were prepared from infected TG1 E. coli cells. The plasmids were reformatted to produce soluble Fab with a T7 tag at the C-terminus of the Fab CH1 domain in the E. coli supernatant. The ligated multi-copy plasmid encoding the T7-tagged Fab was transformed into TG1 E. coli cells (Zymo Research Catalog No. T3017) and single colonies were picked into microtiter plates. The soluble Fab was expressed in microtiter plates and the supernatant was clarified by centrifugation.

藉由不同的 ELISA 測定分析抗體與 C3bBb 之結合，以分析對由具有三個突變 D279G、K350N 及 M458I 的因子 B 形成的 C3bBb 之結合 (本文稱為「C3bBb 三突變體 Elisa」)，以及評估與補體系統的不同相關組分 (亦即 C3、C3a、C3b 及因子 B、Ba、Bb) 之結合的對照。簡而言之，使用以下方案：C3bBb三突變體Elisa緩衝液：Binding of the antibodies to C3bBb was analyzed by different ELISA assays to analyze binding to C3bBb formed by factor B with three mutations D279G, K350N and M458I (referred to herein as the "C3bBb triple mutant ELISA"), as well as controls to evaluate binding to different relevant components of the complement system (i.e., C3, C3a, C3b and factors B, Ba, Bb). Briefly, the following protocol was used:C3bBbtriple mutantELISA buffer:

使用含有 150 mM NaCl、0.5% BSA 及 0.1% Tween20 之 50 mM Hepes pH 7,4 作為 ELISA 之稀釋劑。使用含有 0,1% Tween20 之 PBS 作為洗滌緩衝液。 方法：50 mM Hepes pH 7,4 containing 150 mM NaCl, 0.5% BSA and 0.1% Tween20 was used as diluent for ELISA. PBS containing 0,1% Tween20 was used as washing buffer.Methods:

將 20 µl 之 500 ng/ml 人類 C3bBb-人類因子 B 三突變體 (D279G_M350N_M458I)-Cys-HPDP-生物素、1:3000 小鼠抗人類 kappa HRP (Southern Biotek 9230-05) 及 1:2000 小鼠 IgG 抗 T7 標籤 HRP (Novagen 69048-3) 之混合物添加至 Microcoat 鏈黴親和素包被的 384 孔微孔板 (Microcoat 11974998001)。將 25 µl 樣品添加至板並於室溫孵育 1 小時。孵育後，使用 Biotek EL406 洗滌器以 90 µl/孔洗滌緩衝液洗滌板，並添加 30 µl TMB (3,3′,5,5′-3,3,5,5-四甲基聯苯胺，Roche 11835033001)。於室溫孵育 5 分鐘後，使用 EnVision 多模式讀板儀 (Perkin Elmer) 在 370 nm 處測量光密度 (OD)。C3、C3a、C3b反篩選Elisa緩衝液：20 µl of a mixture of 500 ng/ml human C3bBb-human factor B triple mutant (D279G_M350N_M458I)-Cys-HPDP-biotin, 1:3000 mouse anti-human kappa HRP (Southern Biotek 9230-05) and 1:2000 mouse IgG anti-T7 tag HRP (Novagen 69048-3) was added to a Microcoat streptavidin-coated 384-well microplate (Microcoat 11974998001). 25 µl of sample was added to the plate and incubated at room temperature for 1 hour. After incubation, the plates were washed with 90 µl/well wash buffer using a Biotek EL406 washer and 30 µl TMB (3,3′,5,5′-3,3,5,5-tetramethylbenzidine, Roche 11835033001) was added. After incubation at room temperature for 5 minutes, the optical density (OD) was measured at 370 nm using an EnVision multi-mode plate reader (Perkin Elmer).C3,C3a,C3bcounterscreeningElisa buffer:

使用含 150 mM NaCl 之 50 mM Hepes pH 7,4 作為包被緩衝液。使用含有 150 mM NaCl、0.5% BSA 及 0,1% Tween20 之 50 mM Hepes pH 7,4 的 2% BSA 溶液作為封閉緩衝液。使用含有 150 mM NaCl、0.5% BSA 及 0.1% Tween20 之 50 mM Hepes pH 7,4 作為 ELISA 之稀釋劑。使用含有 0,1% Tween20 之 PBS 作為洗滌緩衝液。 方法：Use 50 mM Hepes pH 7,4 with 150 mM NaCl as coating buffer. Use 2% BSA solution in 50 mM Hepes pH 7,4 with 150 mM NaCl, 0.5% BSA and 0.1% Tween20 as blocking buffer. Use 50 mM Hepes pH 7,4 with 150 mM NaCl, 0.5% BSA and 0.1% Tween20 as ELISA diluent. Use PBS with 0.1% Tween20 as washing buffer.Methods:

將透明的 384 孔 Nunc MaxiSorp 板 (Nunc，464718) 用 25 µl 在包被緩衝液中之 5 nM 人類 C3 (補體技術，A113)、5 nM 人類 C3a (補體技術，A118) 及 2.5 nM 人類 C3b (補體技術，A114) 之混合物包被並於室溫孵育 1 小時。在 EL406 Biotek 洗滌器上以 90 µl/孔洗滌緩衝液洗滌一次後，添加 90 µl 封閉緩衝液並於室溫孵育 30 分鐘。在 EL406 Biotek 洗滌器上以 90 µl/孔洗滌緩衝液洗滌板 3 次後，將 25 µl 樣品添加至板並於室溫孵育 1 小時。如上所述洗滌板後，添加 25 µl 檢測混合物 (1:3000 小鼠抗人類 kappa HRP (Southern Biotek 9230-05) 及 1:2000 小鼠 IgG 抗 T7 標籤 HRP (Novagen 69048-3)。於室溫孵育 1 小時後，使用 Biotek EL406 洗滌器以 90 µl/孔洗滌緩衝液洗滌板 6 次，並添加 30 µl TMB (3,3′,5,5′-3,3,5,5-四甲基聯苯胺，Roche 11835033001)。於室溫孵育 5 分鐘後，使用 EnVision 多模式讀板儀 (Perkin Elmer) 在 370 nm 處測量光密度 (OD)。因子B、Ba、Bb反篩選Elisa緩衝液：Clear 384-well Nunc MaxiSorp plates (Nunc, 464718) were coated with 25 µl of a mixture of 5 nM human C3 (Complement Technologies, A113), 5 nM human C3a (Complement Technologies, A118), and 2.5 nM human C3b (Complement Technologies, A114) in coating buffer and incubated at room temperature for 1 hour. After washing once with 90 µl/well of wash buffer on an EL406 Biotek washer, 90 µl of blocking buffer was added and incubated at room temperature for 30 minutes. After washing the plate three times with 90 µl/well wash buffer on an EL406 Biotek washer, 25 µl of sample was added to the plate and incubated for 1 hour at room temperature. After washing the plates as described above, 25 µl of detection mix (1:3000 mouse anti-human kappa HRP (Southern Biotek 9230-05) and 1:2000 mouse IgG anti-T7 tag HRP (Novagen 69048-3)) were added. After incubation at room temperature for 1 hour, the plates were washed 6 times with 90 µl/well wash buffer using a Biotek EL406 washer and 30 µl of TMB (3,3′,5,5′-3,3,5,5-tetramethylbenzidine, Roche 11835033001) was added. After incubation at room temperature for 5 minutes, the optical density (OD) was measured at 370 nm using an EnVision multimode plate reader (Perkin Elmer).FactorsB,Ba,Bbback screeningElisa buffer:

使用含 150 mM NaCl 之 50 mM Hepes pH 7,4 作為包被緩衝液。使用含有 150 mM NaCl、0.5% BSA 及 0,1% Tween20 之 50 mM Hepes pH 7,4 的 2% BSA 溶液作為封閉緩衝液。使用含有 150 mM NaCl、0.5% BSA 及 0.1% Tween20 之 50 mM Hepes pH 7,4 作為 ELISA 之稀釋劑。使用含有 0,1% Tween20 之 PBS 作為洗滌緩衝液。 方法：Use 50 mM Hepes pH 7,4 with 150 mM NaCl as coating buffer. Use 2% BSA solution in 50 mM Hepes pH 7,4 with 150 mM NaCl, 0.5% BSA and 0.1% Tween20 as blocking buffer. Use 50 mM Hepes pH 7,4 with 150 mM NaCl, 0.5% BSA and 0.1% Tween20 as ELISA diluent. Use PBS with 0.1% Tween20 as washing buffer.Methods:

將透明的 384 孔 Nunc MaxiSorp 板 (Nunc，464718) 用 25 µl 在包被緩衝液中之 10 nM 人類因子 B (補體技術，A135)、5 nM 人類 Ba (補體技術，A154) 及 10 nM 人類 Bb (補體技術，A155) 之混合物包被並於室溫孵育 1 小時。在 EL406 Biotek 洗滌器上以 90 µl/孔洗滌緩衝液洗滌一次後，添加 90 µl 封閉緩衝液並於室溫孵育 30 分鐘。在 EL406 Biotek 洗滌器上以 90 µl/孔洗滌緩衝液洗滌板 3 次後，將 25 µl 樣品添加至板並於室溫孵育 1 小時。如上所述洗滌板後，在樣品區添加 25 µl 檢測混合物 (1:3000 小鼠抗人類 kappa HRP (Southern Biotek 9230-05) 及 1:2000 小鼠 IgG 抗 T7 標籤 HRP (Novagen 69048-3)。於室溫孵育 1 小時後，使用 Biotek EL406 洗滌器以 90 µl/孔洗滌緩衝液洗滌板 6 次，並添加 30 µl TMB (3,3′,5,5′-3,3,5,5-四甲基聯苯胺，Roche 11835033001)。於室溫孵育 5 分鐘後，使用 EnVision 多模式讀板儀 (Perkin Elmer) 在 370 nm 處測量光密度 (OD)。實例3：C3bBb抗體的鑑定及抗原結合Clear 384-well Nunc MaxiSorp plates (Nunc, 464718) were coated with 25 µl of a mixture of 10 nM human factor B (Complement Technologies, A135), 5 nM human Ba (Complement Technologies, A154), and 10 nM human Bb (Complement Technologies, A155) in coating buffer and incubated at room temperature for 1 hour. After washing once with 90 µl/well of wash buffer on an EL406 Biotek washer, 90 µl of blocking buffer was added and incubated at room temperature for 30 minutes. After washing the plate three times with 90 µl/well wash buffer on an EL406 Biotek washer, 25 µl of sample was added to the plate and incubated for 1 hour at room temperature. After washing the plate as described above, 25 µl of detection mix (1:3000 mouse anti-human kappa HRP (Southern Biotek 9230-05) and 1:2000 mouse IgG anti-T7 tag HRP (Novagen 69048-3)) was added to the sample area. After incubation at room temperature for 1 hour, the plate was washed 6 times with 90 µl/well wash buffer using a Biotek EL406 washer and 30 µl TMB (3,3′,5,5′-3,3,5,5-tetramethylbenzidine, Roche 11835033001) was added. After incubation at room temperature for 5 minutes, the optical density (OD) was measured at 370 nm using an EnVision multi-mode plate reader (Perkin Elmer).Example3:Identification and antigen binding ofC3bBb antibodies

如實例 2 所述，從淘選及篩選中鑑定顯示出與 C3bBb 結合之活性的多種抗體分子，並視情況地，對如此衍生的抗體分子進行進一步工程化。As described in Example 2, a variety of antibody molecules that exhibit binding activity to C3bBb are identified from panning and screening, and the antibody molecules thus derived are further engineered, as appropriate.

所有抗體最初表現為包含 SEQ ID NO:502 之恆定輕鏈域及 SEQ ID NO:503 之恆定重鏈域之 Fab 片段。表E2包括 VH 及 VL 胺基酸序列之概述。表E2：實例 2 中鑑定之抗體的胺基酸序列。#標識符VH胺基酸序列(SEQ ID NO:)VL胺基酸序列(SEQ ID NO:)1P1AG9426122P1AG9376343P1AG9372564P1AG9420785P1AG93919106P1AH120511127P1AH119913148C3bBb.P045.07215169C3bBb.P045.236171810C3bBb.P045.225192011C3bBb.P048.152212212C3bBb.P048.061232413C3bBb.P048.127252614C3bBb.P048.241272815C3bBb.P048.230293016C3bBb.P048.204313217C3bBb.P048.333333418C3bBb.P053.095353619C3bBb.P055.015373820P1AF8499394021GQ-5_1414222GQ-11_1434423PT5622.F19454624PT5624.P06474825PT5624.M09495026PT5626.M10515227PT5626.C10535428PT5628.E16555629PT5630.D05575830PT5630.A20596031PT5632.A13616232PT5634.N13636433PT5634.M24656634PT5636.P22676835PT5625.G07697036PT5627.M20717237PT5627.M12737438PT5629.F09757639PT5629.H08777840PT5631.D21798041PT5633.I03818242PT5635.C08838443PT5639.G15858644PT5622.A20878845PT5622.C12899046PT5622.G24919247PT5622.I20939448PT5622.J24959649PT5624.A21979850PT5624.B109910051PT5624.N0510110252PT5624.P1110310453PT5626.A1210510654PT5626.N0810710855PT5626.N1810911056PT5626.O0911111257PT5628.B1311311458PT5628.C2111511659PT5628.E1211711860PT5628.I0711912061PT5628.P1412112262PT5630.G0512312463PT5630.K0412512664PT5630.M1112712865PT5630.N0612913066PT5630.O0813113267PT5632.A1013313468PT5632.A1513513669PT5632.B1513713870PT5632.D1113914071PT5632.J2314114272PT5634.A1714314473PT5634.A2114514674PT5634.K1014714875PT5634.M1614915076PT5634.N1115115277PT5634.P1915315478PT5636.A1615515679PT5636.D2115715880PT5636.M0315916081PT5636.N1316116282PT5636.P1116316483PT5636.P1516516684PT5638.C0616716885PT5638.C2016917086PT5638.E1417117287PT5638.J2317317488PT5638.O1417517689PT5638.P1217717890PT5623.E2117918091PT5623.F1718118292PT5623.G0818318493PT5623.H0518518694PT5623.O0818718895PT5625.A0518919096PT5625.B1419119297PT5625.C1519319498PT5625.G0519519699PT5625.L22197198100PT5625.O14199200101PT5627.I21201202102PT5629.F04203204103PT5629.L22205206104PT5629.L24207208105PT5629.M15209210106PT5631.H06211212107PT5631.K12213214108PT5631.N17215216109PT5631.P07217218110PT5633.E09219220111PT5633.G19221222112PT5635.F04223224113PT5635.L21225226114PT5635.O15227228115PT5637.B23229230116PT5637.C20231232117PT5637.K09233234118PT5637.L15235236119PT5637.M03237238120PT5637.P15239240121PT5639.B15241242122PT5639.P05243244123PT5625.G07_22.F19_2245246124PT5625.G07_24.M09_1247248125PT5625.G07_24.P06_2249250126PT5625.G07_26.C10_1251252127PT5625.G07_26.M10_2253254128PT5625.G07_28.E16_1255256129PT5625.G07_30.A20_1257258130PT5625.G07_32.A13_2259260131PT5625.G07_34.M24_1261262132PT5625.G07_34.N13_3263264133PT5625.G07_36.P22_1265266134PT5627.M20_24.M09_1267268135PT5627.M20_24.P06_1269270136PT5627.M20_26.C10_1271272137PT5627.M20_26.M10_2273274138PT5627.M20_28.E16_2275276139PT5627.M20_30.D05_1277278140PT5627.M20_32.A13_1279280141PT5627.M20_34.M24_2281282142PT5627.M20_34.N13_4283284143PT5627.M20_36.P22_1285286144PT5627.M12_22.F19_1287288145PT5627.M12_24.M09_1289290146PT5627.M12_26.M10_2291292147PT5627.M12_32.A13_2293294148PT5627.M12_34.M24_2295296149PT5627.M12_34.N13_1297298150PT5629.F09_26.C10_1299300151PT5629.F09_28.E16_1301302152PT5629.F09_30.A20_1303304153PT5629.F09_30.D05_1305306154PT5629.F09_32.A13_3307308155PT5629.F09_36.P22_2309310156PT5629.H08_22.F19_4311312157PT5629.H08_24.M09_4313314158PT5629.H08_24.P06_2315316159PT5629.H08_26.C10_1317318160PT5629.H08_26.M10_1319320161PT5629.H08_28.E16_2321322162PT5629.H08_30.A20_2323324163PT5629.H08_30.D05_1325326164PT5629.H08_32.A13_1327328165PT5629.H08_34.M24_2329330166PT5629.H08_34.N13_2331332167PT5629.H08_36.P22_4333334168PT5631.D21_22.F19_2335336169PT5631.D21_24.M09_1337338170PT5631.D21_24.P06_4339340171PT5631.D21_26.C10_1341342172PT5631.D21_26.M10_4343344173PT5631.D21_28.E16_3345346174PT5631.D21_30.A20_4347348175PT5631.D21_30.D05_1349350176PT5631.D21_32.A13_4351352177PT5631.D21_34.M24_4353354178PT5631.D21_34.N13_2355356179PT5631.D21_36.P22_3357358180PT5633.I03_22.F19_1359360181PT5633.I03_24.M09_1361362182PT5633.I03_24.P06_4363364183PT5633.I03_26.C10_1365366184PT5633.I03_26.M10_4367368185PT5633.I03_28.E16_4369370186PT5633.I03_30.A20_1371372187PT5633.I03_30.D05_1373374188PT5633.I03_32.A13_1375376189PT5633.I03_34.M24_2377378190PT5633.I03_34.N13_1379380191PT5633.I03_36.P22_2381382192PT5635.C08_22.F19_1383384193PT5635.C08_24.M09_1385386194PT5635.C08_24.P06_1387388195PT5635.C08_26.C10_1389390196PT5635.C08_26.M10_2391392197PT5635.C08_28.E16_1393394198PT5635.C08_30.A20_1395396199PT5635.C08_30.D05_3397398200PT5635.C08_32.A13_3399400201PT5635.C08_34.M24_2401402202PT5635.C08_34.N13_1403404203PT5635.C08_36.P22_1405406204PT5639.G15_22.F19_2407408205PT5639.G15_24.P06_1409410206PT5639.G15_24.M09_4411412207PT5639.G15_26.M10_3413414208PT5639.G15_28.E16_1415416209PT5639.G15_30.A20_1417418210PT5639.G15_30.D05_1419420211PT5639.G15_34.N13_4421422212PT5639.G15_34.M24_3423424213PT5639.G15_36.P22_3425426214PT5625.G07_30.D05_1427428215PT5627.M12_26.C10_1429430216PT5627.M12_30.A20_2431432217PT5629.F09_34.N13_3433434All antibodies were initially expressed as Fab fragments comprising a constant light chain domain of SEQ ID NO: 502 and a constant heavy chain domain of SEQ ID NO: 503.TableE2 includes a summary of the VH and VL amino acid sequences.TableE2: Amino acid sequences of antibodies identified in Example 2.#IdentifierVHamino acid sequence(SEQ ID NO:)VLamino acid sequence(SEQ ID NO:) 1 P1AG9426 1 2 2 P1AG9376 3 4 3 P1AG9372 5 6 4 P1AG9420 7 8 5 P1AG9391 9 10 6 P1AH1205 11 12 7 P1AH1199 13 14 8 C3bBb.P045.072 15 16 9 C3bBb.P045.236 17 18 10 C3bBb.P045.225 19 20 11 C3bBb.P048.152 twenty one twenty two 12 C3bBb.P048.061 twenty three twenty four 13 C3bBb.P048.127 25 26 14 C3bBb.P048.241 27 28 15 C3bBb.P048.230 29 30 16 C3bBb.P048.204 31 32 17 C3bBb.P048.333 33 34 18 C3bBb.P053.095 35 36 19 C3bBb.P055.015 37 38 20 P1AF8499 39 40 twenty one GQ-5_1 41 42 twenty two GQ-11_1 43 44 twenty three PT5622.F19 45 46 twenty four PT5624.P06 47 48 25 PT5624.M09 49 50 26 PT5626.M10 51 52 27 PT5626.C10 53 54 28 PT5628.E16 55 56 29 PT5630.D05 57 58 30 PT5630.A20 59 60 31 PT5632.A13 61 62 32 PT5634.N13 63 64 33 PT5634.M24 65 66 34 PT5636.P22 67 68 35 PT5625.G07 69 70 36 PT5627.M20 71 72 37 PT5627.M12 73 74 38 PT5629.F09 75 76 39 PT5629.H08 77 78 40 PT5631.D21 79 80 41 PT5633.I03 81 82 42 PT5635.C08 83 84 43 PT5639.G15 85 86 44 PT5622.A20 87 88 45 PT5622.C12 89 90 46 PT5622.G24 91 92 47 PT5622.I20 93 94 48 PT5622.J24 95 96 49 PT5624.A21 97 98 50 PT5624.B10 99 100 51 PT5624.N05 101 102 52 PT5624.P11 103 104 53 PT5626.A12 105 106 54 PT5626.N08 107 108 55 PT5626.N18 109 110 56 PT5626.O09 111 112 57 PT5628.B13 113 114 58 PT5628.C21 115 116 59 PT5628.E12 117 118 60 PT5628.I07 119 120 61 PT5628.P14 121 122 62 PT5630.G05 123 124 63 PT5630.K04 125 126 64 PT5630.M11 127 128 65 PT5630.N06 129 130 66 PT5630.O08 131 132 67 PT5632.A10 133 134 68 PT5632.A15 135 136 69 PT5632.B15 137 138 70 PT5632.D11 139 140 71 PT5632.J23 141 142 72 PT5634.A17 143 144 73 PT5634.A21 145 146 74 PT5634.K10 147 148 75 PT5634.M16 149 150 76 PT5634.N11 151 152 77 PT5634.P19 153 154 78 PT5636.A16 155 156 79 PT5636.D21 157 158 80 PT5636.M03 159 160 81 PT5636.N13 161 162 82 PT5636.P11 163 164 83 PT5636.P15 165 166 84 PT5638.C06 167 168 85 PT5638.C20 169 170 86 PT5638.E14 171 172 87 PT5638.J23 173 174 88 PT5638.O14 175 176 89 PT5638.P12 177 178 90 PT5623.E21 179 180 91 PT5623.F17 181 182 92 PT5623.G08 183 184 93 PT5623.H05 185 186 94 PT5623.O08 187 188 95 PT5625.A05 189 190 96 PT5625.B14 191 192 97 PT5625.C15 193 194 98 PT5625.G05 195 196 99 PT5625.L22 197 198 100 PT5625.O14 199 200 101 PT5627.I21 201 202 102 PT5629.F04 203 204 103 PT5629.L22 205 206 104 PT5629.L24 207 208 105 PT5629.M15 209 210 106 PT5631.H06 211 212 107 PT5631.K12 213 214 108 PT5631.N17 215 216 109 PT5631.P07 217 218 110 PT5633.E09 219 220 111 PT5633.G19 221 222 112 PT5635.F04 223 224 113 PT5635.L21 225 226 114 PT5635.O15 227 228 115 PT5637.B23 229 230 116 PT5637.C20 231 232 117 PT5637.K09 233 234 118 PT5637.L15 235 236 119 PT5637.M03 237 238 120 PT5637.P15 239 240 121 PT5639.B15 241 242 122 PT5639.P05 243 244 123 PT5625.G07_22.F19_2 245 246 124 PT5625.G07_24.M09_1 247 248 125 PT5625.G07_24.P06_2 249 250 126 PT5625.G07_26.C10_1 251 252 127 PT5625.G07_26.M10_2 253 254 128 PT5625.G07_28.E16_1 255 256 129 PT5625.G07_30.A20_1 257 258 130 PT5625.G07_32.A13_2 259 260 131 PT5625.G07_34.M24_1 261 262 132 PT5625.G07_34.N13_3 263 264 133 PT5625.G07_36.P22_1 265 266 134 PT5627.M20_24.M09_1 267 268 135 PT5627.M20_24.P06_1 269 270 136 PT5627.M20_26.C10_1 271 272 137 PT5627.M20_26.M10_2 273 274 138 PT5627.M20_28.E16_2 275 276 139 PT5627.M20_30.D05_1 277 278 140 PT5627.M20_32.A13_1 279 280 141 PT5627.M20_34.M24_2 281 282 142 PT5627.M20_34.N13_4 283 284 143 PT5627.M20_36.P22_1 285 286 144 PT5627.M12_22.F19_1 287 288 145 PT5627.M12_24.M09_1 289 290 146 PT5627.M12_26.M10_2 291 292 147 PT5627.M12_32.A13_2 293 294 148 PT5627.M12_34.M24_2 295 296 149 PT5627.M12_34.N13_1 297 298 150 PT5629.F09_26.C10_1 299 300 151 PT5629.F09_28.E16_1 301 302 152 PT5629.F09_30.A20_1 303 304 153 PT5629.F09_30.D05_1 305 306 154 PT5629.F09_32.A13_3 307 308 155 PT5629.F09_36.P22_2 309 310 156 PT5629.H08_22.F19_4 311 312 157 PT5629.H08_24.M09_4 313 314 158 PT5629.H08_24.P06_2 315 316 159 PT5629.H08_26.C10_1 317 318 160 PT5629.H08_26.M10_1 319 320 161 PT5629.H08_28.E16_2 321 322 162 PT5629.H08_30.A20_2 323 324 163 PT5629.H08_30.D05_1 325 326 164 PT5629.H08_32.A13_1 327 328 165 PT5629.H08_34.M24_2 329 330 166 PT5629.H08_34.N13_2 331 332 167 PT5629.H08_36.P22_4 333 334 168 PT5631.D21_22.F19_2 335 336 169 PT5631.D21_24.M09_1 337 338 170 PT5631.D21_24.P06_4 339 340 171 PT5631.D21_26.C10_1 341 342 172 PT5631.D21_26.M10_4 343 344 173 PT5631.D21_28.E16_3 345 346 174 PT5631.D21_30.A20_4 347 348 175 PT5631.D21_30.D05_1 349 350 176 PT5631.D21_32.A13_4 351 352 177 PT5631.D21_34.M24_4 353 354 178 PT5631.D21_34.N13_2 355 356 179 PT5631.D21_36.P22_3 357 358 180 PT5633.I03_22.F19_1 359 360 181 PT5633.I03_24.M09_1 361 362 182 PT5633.I03_24.P06_4 363 364 183 PT5633.I03_26.C10_1 365 366 184 PT5633.I03_26.M10_4 367 368 185 PT5633.I03_28.E16_4 369 370 186 PT5633.I03_30.A20_1 371 372 187 PT5633.I03_30.D05_1 373 374 188 PT5633.I03_32.A13_1 375 376 189 PT5633.I03_34.M24_2 377 378 190 PT5633.I03_34.N13_1 379 380 191 PT5633.I03_36.P22_2 381 382 192 PT5635.C08_22.F19_1 383 384 193 PT5635.C08_24.M09_1 385 386 194 PT5635.C08_24.P06_1 387 388 195 PT5635.C08_26.C10_1 389 390 196 PT5635.C08_26.M10_2 391 392 197 PT5635.C08_28.E16_1 393 394 198 PT5635.C08_30.A20_1 395 396 199 PT5635.C08_30.D05_3 397 398 200 PT5635.C08_32.A13_3 399 400 201 PT5635.C08_34.M24_2 401 402 202 PT5635.C08_34.N13_1 403 404 203 PT5635.C08_36.P22_1 405 406 204 PT5639.G15_22.F19_2 407 408 205 PT5639.G15_24.P06_1 409 410 206 PT5639.G15_24.M09_4 411 412 207 PT5639.G15_26.M10_3 413 414 208 PT5639.G15_28.E16_1 415 416 209 PT5639.G15_30.A20_1 417 418 210 PT5639.G15_30.D05_1 419 420 211 PT5639.G15_34.N13_4 421 422 212 PT5639.G15_34.M24_3 423 424 213 PT5639.G15_36.P22_3 425 426 214 PT5625.G07_30.D05_1 427 428 215 PT5627.M12_26.C10_1 429 430 216 PT5627.M12_30.A20_2 431 432 217 PT5629.F09_34.N13_3 433 434

從篩選期間鑑定的抗體中，候選 P1AF8499 (表E2中的 #20，包含 VH SEQ ID NO: 39 及 VL SEQ ID NO: 40) 基於其選擇性、轉化酶抑制以及對轉化酶穩定性分布之影響進行選擇，以進行進一步優化。From the antibodies identified during screening, candidate P1AF8499 (#20inTableE2 , comprising VH SEQ ID NO: 39 and VL SEQ ID NO: 40) was selected for further optimization based on its selectivity, invertase inhibition, and effect on invertase stability profile.

為此，創建了兩個噬菌體文庫，其在重鏈 CDR 或輕鏈 CDR 中含有親代候選抗體的多樣化。如實例2所述，針對標靶對文庫進行淘選及篩選。To this end, two phage libraries were created containing diversification of the parental candidate antibodies in either the heavy chain CDRs or the light chain CDRs. The libraries were panned and screened against the target as described inExample2 .

選擇相較於親代分子具有改進特性之候選，並以組合方式將各個分子的重鏈及輕鏈組合成單一分子。親代抗體候選的改良版本係抗體 #1 至 #7 以及抗體 #23 至 #217，如下表E2進一步所示。Candidates with improved properties compared to the parent molecule were selected and the heavy and light chains of each molecule were combined into a single molecule in a combinatorial manner. The improved versions of the parent antibody candidates are antibodies #1 to #7 and antibodies #23 to #217, as further shownin TableE2 below.

藉由不同的 ELISA 測定分析抗體與人類 C3bBb 之結合，如實例2中所述，以分析對由具有三個突變 D279G、K350N 及 M458I 的因子 B 形成的人類 C3bBb 之結合 (本文稱為「C3bBb 三突變體 ELISA」)，以及評估與補體系統的不同相關組分 (亦即 C3、C3a、C3b 及因子 B、Ba、Bb) 之結合的對照。表E3中顯示了如表E2中定義的抗體的不同 ELISA 測定之結果。表E3：使用 C3bBb 三突變體 ELISA 鑑定的表 E2 中抗體的 C3bBb 複合物之抗原結合#標識符C3bBb (D279G/350N/M458I)C3bBb (D279G)C3/C3a/C3bCFB/Ba/Bb陰性對照8C3bBb.P045.0722,9040,023-0,005-0,010-0,0269C3bBb.P045.2361,815-0,0030,0050,000-0,02410C3bBb.P045.2252,6150,0170,027-0,021-0,00311C3bBb.P048.1520,405-0,035-0,007-0,005-0,02512C3bBb.P048.0611,8990,0040,0010,0060,01513C3bBb.P048.1270,1872,423-0,0060,002-0,01014C3bBb.P048.2412,3842,5730,1700,0370,05115C3bBb.P048.2302,6922,6700,2100,0210,01816C3bBb.P048.2041,3411,9430,1260,015-0,01417C3bBb.P048.3332,7862,7580,2740,0340,00818C3bBb.P053.095-0,0060,353-0,0010,0030,00819C3bBb.P055.015-0,0100,860-0,0140,004-0,01423PT5622.F192.78652,8105-0,002-0,0145-0,095524PT5624.P062,933752,761750,01750,05575-0,0282525PT5624.M092,880752,72575-0,0035-0,01025-0,0762526PT5626.M102,72952,4185-0,00175-0,0075-0,0597527PT5626.C102,46452,1365-0,01175-0,0235-0,0727528PT5628.E162,33352,47050,013-0,0215-0,08729PT5630.D052,410752,42475-0,006-0,01625-0,1082530PT5630.A202,149752,280750,013-0,01925-0,0792531PT5632.A132,347252,412250,012-0,02675-0,07932PT5634.N132,580752,257750,0250,02175-0,0642533PT5634.M242,086751,680750,0270,02075-0,0462534PT5636.P222,73852,26650,0490,01650,005535PT5625.G072,265751,43375-0,006-0,01225-0,087536PT5627.M202,097251,480250,009750,01525-0,0187537PT5627.M121,961251,161250,00875-0,00175-0,0567538PT5629.F092,1721,536-0,003-0,015-0,0772539PT5629.H081,8930,930,003-0,003-0,0682540PT5631.D211,5970,671-0,018-0,032-0,08741PT5633.I030,94950,26150,008-0,0175-0,0917542PT5635.C081,6460,676-0,004-0,017-0,0762543PT5639.G151,255250,43425-0,014-0,02575-0,0587544PT5622.A202,41352,2785-0,014-0,0365-0,074545PT5622.C122,50552,5475-0,007-0,0235-0,103546PT5622.G242,71452,38150,0070,0025-0,071547PT5622.I202,67452,51550,0050,0095-0,094548PT5622.J242,68152,59550,0310,00850,019549PT5624.A212,367752,72575-0,0105-0,02625-0,0632550PT5624.B102,684752,79175-0,0095-0,02525-0,0902551PT5624.N052,592752,516750,01050,07275-0,0642552PT5624.P112,676752,781750,02350,02175-0,0062553PT5626.A122,52452,32250,03925-0,0205-0,0457554PT5626.N082,90952,61350,015250,0095-0,0437555PT5626.N182,77452,83550,011250,0015-0,0447556PT5626.O092,69552,41350,000250,0065-0,0497557PT5628.B132,34752,01650,038-0,0255-0,08758PT5628.C212,56152,8435-0,007-0,0285-0,0959PT5628.E122,40152,30750,008-0,0185-0,09360PT5628.I072,33752,53650,014-0,0115-0,08461PT5628.P142,49652,38550,0330,0185-0,02462PT5630.G052,342752,11075-0,009-0,01225-0,1072563PT5630.K041,968751,56875-0,006-0,01325-0,1062564PT5630.M112,537752,350750,0090,00575-0,0932565PT5630.N062,338751,979750,0120,00875-0,0862566PT5630.O082,554752,226750,0030,00475-0,0812567PT5632.A102,113251,100250,009-0,03875-0,08168PT5632.A152,443252,201250,008-0,04475-0,08169PT5632.B152,416252,42125-0,049-0,04375-0,0970PT5632.D112,477252,016250,01-0,02275-0,08171PT5632.J232,176252,173250,047-0,01075-0,06772PT5634.A172,385751,77875-0,014-0,03525-0,0632573PT5634.A212,381752,40675-0,001-0,02225-0,0782574PT5634.K102,555752,82475-0,009-0,02825-0,1072575PT5634.M162,325752,517750,001-0,00225-0,0952576PT5634.N112,460752,318750,0170,00575-0,0762577PT5634.P192,163751,918750,0510,056750,0097578PT5636.A162,41052,2515-0,006-0,0325-0,064579PT5636.D212,08951,5595-0,002-0,0195-0,070580PT5636.M032,34352,08350-0,0195-0,066581PT5636.N132,51652,35150,0380,0165-0,021582PT5636.P112,09551,17850,0340,0315-0,010583PT5636.P152,39052,07150,040,02750,011584PT5638.C061,87751,50450,021-0,0275-0,1082585PT5638.C201,89751,6935-0,006-0,0305-0,1042586PT5638.E142,08251,65250,008-0,0225-0,1032587PT5638.J231,53750,78150,0550,0885-0,0782588PT5638.O142,16351,37950,1080,0135-0,0692589PT5638.P122,18351,30650,0980,0375-0,0292590PT5623.E212,12550,9965-0,0105-0,0165-0,0962591PT5623.F172,13451,1215-0,0075-0,0205-0,0872592PT5623.G082,05151,22850,0165-0,0125-0,0922593PT5623.H051,74550,82050,0005-0,0135-0,0912594PT5623.O082,03550,6395-0,00250,0155-0,0752595PT5625.A052,069751,07475-0,011-0,02125-0,058596PT5625.B141,602750,60975-0,008-0,01525-0,083597PT5625.C151,853750,84275-0,014-0,02225-0,090598PT5625.G051,843750,881750,007-0,01425-0,085599PT5625.L221,387750,453750,003-0,00125-0,0685100PT5625.O141,896750,719750,0160,02175-0,0575101PT5627.I211,115250,421250,00475-0,00375-0,05775102PT5629.F042,0731,086-0,0070,027-0,06525103PT5629.L221,9250,9960,004-0,007-0,06325104PT5629.L241,9290,7240,001-0,004-0,04625105PT5629.M152,2841,2870,0050,002-0,07025106PT5631.H061,2350,3680-0,014-0,081107PT5631.K121,9051,014-0,005-0,017-0,091108PT5631.N171,8250,8720,0150,013-0,046109PT5631.P071,8580,5980,004-0,001-0,007110PT5633.E090,65250,2785-0,013-0,0345-0,09775111PT5633.G190,94950,23750,016-0,0135-0,08475112PT5635.F041,6710,649-0,013-0,022-0,07625113PT5635.L211,8961,3550,01-0,001-0,05725114PT5635.O151,6470,67400,014-0,05125115PT5637.B232,0441,2840,018-0,047-0,1105116PT5637.C201,9721,224-0,011-0,034-0,1155117PT5637.K091,7160,708-0,001-0,023-0,1165118PT5637.L151,9751,2520,025-0,012-0,0965119PT5637.M032,0261,1810,022-0,028-0,1155120PT5637.P152,1421,2920,0370,019-0,0185121PT5639.B151,686250,80525-0,018-0,02675-0,06275122PT5639.P050,940250,349250,0040,00825-0,01175The binding of the antibodies to human C3bBb was analyzed by different ELISA assays, as described inExample2 , to analyze binding to human C3bBb formed by factor B with three mutations D279G, K350N and M458I (referred to herein as the "C3bBb triple mutant ELISA"), as well as to evaluate the binding to different relevant components of the complement system (i.e., C3, C3a, C3b and factors B, Ba, Bb). The results of the different ELISA assays for the antibodies as defined inTableE2 are shown inTableE3 .TableE3: Antigen binding of the C3bBb complex of the antibodies in Table E2 identified using the C3bBb triple mutant ELISA#IdentifierC3bBb (D279G/350N/M458I)C3bBb (D279G)C3/C3a/C3bCFB/Ba/BbNegative control 8 C3bBb.P045.072 2,904 0,023 -0,005 -0,010 -0,026 9 C3bBb.P045.236 1,815 -0,003 0,005 0,000 -0,024 10 C3bBb.P045.225 2,615 0,017 0,027 -0,021 -0,003 11 C3bBb.P048.152 0,405 -0,035 -0,007 -0,005 -0,025 12 C3bBb.P048.061 1,899 0,004 0,001 0,006 0,015 13 C3bBb.P048.127 0,187 2,423 -0,006 0,002 -0,010 14 C3bBb.P048.241 2,384 2,573 0,170 0,037 0,051 15 C3bBb.P048.230 2,692 2,670 0,210 0,021 0,018 16 C3bBb.P048.204 1,341 1,943 0,126 0,015 -0,014 17 C3bBb.P048.333 2,786 2,758 0,274 0,034 0,008 18 C3bBb.P053.095 -0,006 0,353 -0,001 0,003 0,008 19 C3bBb.P055.015 -0,010 0,860 -0,014 0,004 -0,014 twenty three PT5622.F19 2.7865 2,8105 -0,002 -0,0145 -0,0955 twenty four PT5624.P06 2,93375 2,76175 0,0175 0,05575 -0,02825 25 PT5624.M09 2,88075 2,72575 -0,0035 -0,01025 -0,07625 26 PT5626.M10 2,7295 2,4185 -0,00175 -0,0075 -0,05975 27 PT5626.C10 2,4645 2,1365 -0,01175 -0,0235 -0,07275 28 PT5628.E16 2,3335 2,4705 0,013 -0,0215 -0,087 29 PT5630.D05 2,41075 2,42475 -0,006 -0,01625 -0,10825 30 PT5630.A20 2,14975 2,28075 0,013 -0,01925 -0,07925 31 PT5632.A13 2,34725 2,41225 0,012 -0,02675 -0,079 32 PT5634.N13 2,58075 2,25775 0,025 0,02175 -0,06425 33 PT5634.M24 2,08675 1,68075 0,027 0,02075 -0,04625 34 PT5636.P22 2,7385 2,2665 0,049 0,0165 0,0055 35 PT5625.G07 2,26575 1,43375 -0,006 -0,01225 -0,0875 36 PT5627.M20 2,09725 1,48025 0,00975 0,01525 -0,01875 37 PT5627.M12 1,96125 1,16125 0,00875 -0,00175 -0,05675 38 PT5629.F09 2,172 1,536 -0,003 -0,015 -0,07725 39 PT5629.H08 1,893 0,93 0,003 -0,003 -0,06825 40 PT5631.D21 1,597 0,671 -0,018 -0,032 -0,087 41 PT5633.I03 0,9495 0,2615 0,008 -0,0175 -0,09175 42 PT5635.C08 1,646 0,676 -0,004 -0,017 -0,07625 43 PT5639.G15 1,25525 0,43425 -0,014 -0,02575 -0,05875 44 PT5622.A20 2,4135 2,2785 -0,014 -0,0365 -0,0745 45 PT5622.C12 2,5055 2,5475 -0,007 -0,0235 -0,1035 46 PT5622.G24 2,7145 2,3815 0,007 0,0025 -0,0715 47 PT5622.I20 2,6745 2,5155 0,005 0,0095 -0,0945 48 PT5622.J24 2,6815 2,5955 0,031 0,0085 0,0195 49 PT5624.A21 2,36775 2,72575 -0,0105 -0,02625 -0,06325 50 PT5624.B10 2,68475 2,79175 -0,0095 -0,02525 -0,09025 51 PT5624.N05 2,59275 2,51675 0,0105 0,07275 -0,06425 52 PT5624.P11 2,67675 2,78175 0,0235 0,02175 -0,00625 53 PT5626.A12 2,5245 2,3225 0,03925 -0,0205 -0,04575 54 PT5626.N08 2,9095 2,6135 0,01525 0,0095 -0,04375 55 PT5626.N18 2,7745 2,8355 0,01125 0,0015 -0,04475 56 PT5626.O09 2,6955 2,4135 0,00025 0,0065 -0,04975 57 PT5628.B13 2,3475 2,0165 0,038 -0,0255 -0,087 58 PT5628.C21 2,5615 2,8435 -0,007 -0,0285 -0,09 59 PT5628.E12 2,4015 2,3075 0,008 -0,0185 -0,093 60 PT5628.I07 2,3375 2,5365 0,014 -0,0115 -0,084 61 PT5628.P14 2,4965 2,3855 0,033 0,0185 -0,024 62 PT5630.G05 2,34275 2,11075 -0,009 -0,01225 -0,10725 63 PT5630.K04 1,96875 1,56875 -0,006 -0,01325 -0,10625 64 PT5630.M11 2,53775 2,35075 0,009 0,00575 -0,09325 65 PT5630.N06 2,33875 1,97975 0,012 0,00875 -0,08625 66 PT5630.O08 2,55475 2,22675 0,003 0,00475 -0,08125 67 PT5632.A10 2,11325 1,10025 0,009 -0,03875 -0,081 68 PT5632.A15 2,44325 2,20125 0,008 -0,04475 -0,081 69 PT5632.B15 2,41625 2,42125 -0,049 -0,04375 -0,09 70 PT5632.D11 2,47725 2,01625 0,01 -0,02275 -0,081 71 PT5632.J23 2,17625 2,17325 0,047 -0,01075 -0,067 72 PT5634.A17 2,38575 1,77875 -0,014 -0,03525 -0,06325 73 PT5634.A21 2,38175 2,40675 -0,001 -0,02225 -0,07825 74 PT5634.K10 2,55575 2,82475 -0,009 -0,02825 -0,10725 75 PT5634.M16 2,32575 2,51775 0,001 -0,00225 -0,09525 76 PT5634.N11 2,46075 2,31875 0,017 0,00575 -0,07625 77 PT5634.P19 2,16375 1,91875 0,051 0,05675 0,00975 78 PT5636.A16 2,4105 2,2515 -0,006 -0,0325 -0,0645 79 PT5636.D21 2,0895 1,5595 -0,002 -0,0195 -0,0705 80 PT5636.M03 2,3435 2,0835 0 -0,0195 -0,0665 81 PT5636.N13 2,5165 2,3515 0,038 0,0165 -0,0215 82 PT5636.P11 2,0955 1,1785 0,034 0,0315 -0,0105 83 PT5636.P15 2,3905 2,0715 0,04 0,0275 0,0115 84 PT5638.C06 1,8775 1,5045 0,021 -0,0275 -0,10825 85 PT5638.C20 1,8975 1,6935 -0,006 -0,0305 -0,10425 86 PT5638.E14 2,0825 1,6525 0,008 -0,0225 -0,10325 87 PT5638.J23 1,5375 0,7815 0,055 0,0885 -0,07825 88 PT5638.O14 2,1635 1,3795 0,108 0,0135 -0,06925 89 PT5638.P12 2,1835 1,3065 0,098 0,0375 -0,02925 90 PT5623.E21 2,1255 0,9965 -0,0105 -0,0165 -0,09625 91 PT5623.F17 2,1345 1,1215 -0,0075 -0,0205 -0,08725 92 PT5623.G08 2,0515 1,2285 0,0165 -0,0125 -0,09225 93 PT5623.H05 1,7455 0,8205 0,0005 -0,0135 -0,09125 94 PT5623.O08 2,0355 0,6395 -0,0025 0,0155 -0,07525 95 PT5625.A05 2,06975 1,07475 -0,011 -0,02125 -0,0585 96 PT5625.B14 1,60275 0,60975 -0,008 -0,01525 -0,0835 97 PT5625.C15 1,85375 0,84275 -0,014 -0,02225 -0,0905 98 PT5625.G05 1,84375 0,88175 0,007 -0,01425 -0,0855 99 PT5625.L22 1,38775 0,45375 0,003 -0,00125 -0,0685 100 PT5625.O14 1,89675 0,71975 0,016 0,02175 -0,0575 101 PT5627.I21 1,11525 0,42125 0,00475 -0,00375 -0,05775 102 PT5629.F04 2,073 1,086 -0,007 0,027 -0,06525 103 PT5629.L22 1,925 0,996 0,004 -0,007 -0,06325 104 PT5629.L24 1,929 0,724 0,001 -0,004 -0,04625 105 PT5629.M15 2,284 1,287 0,005 0,002 -0,07025 106 PT5631.H06 1,235 0,368 0 -0,014 -0,081 107 PT5631.K12 1,905 1,014 -0,005 -0,017 -0,091 108 PT5631.N17 1,825 0,872 0,015 0,013 -0,046 109 PT5631.P07 1,858 0,598 0,004 -0,001 -0,007 110 PT5633.E09 0,6525 0,2785 -0,013 -0,0345 -0,09775 111 PT5633.G19 0,9495 0,2375 0,016 -0,0135 -0,08475 112 PT5635.F04 1,671 0,649 -0,013 -0,022 -0,07625 113 PT5635.L21 1,896 1,355 0,01 -0,001 -0,05725 114 PT5635.O15 1,647 0,674 0 0,014 -0,05125 115 PT5637.B23 2,044 1,284 0,018 -0,047 -0,1105 116 PT5637.C20 1,972 1,224 -0,011 -0,034 -0,1155 117 PT5637.K09 1,716 0,708 -0,001 -0,023 -0,1165 118 PT5637.L15 1,975 1,252 0,025 -0,012 -0,0965 119 PT5637.M03 2,026 1,181 0,022 -0,028 -0,1155 120 PT5637.P15 2,142 1,292 0,037 0,019 -0,0185 121 PT5639.B15 1,68625 0,80525 -0,018 -0,02675 -0,06275 122 PT5639.P05 0,94025 0,34925 0,004 0,00825 -0,01175

產生七種候選抗體，並進一步表徵了其治療應用的潛力，產生五種抗體作為全長 IgG1 (Mab)，並產生兩種抗體作為 Fab 片段 (參見表E4)。Seven candidate antibodies were generated and their potential for therapeutic applications was further characterized, with five antibodies generated as full-length IgG1 (Mab) and two antibodies generated as Fab fragments (see TableE4) .

所有 Mab 及 Fab 均使用 ExpiCHO 表現系統 (Thermo Fisher Scientific) 在無血清培養基中產生。為了培養 ExpiCHO 細胞，使用了相應的高滴度方案。質體摩爾比係標靶依賴性，輕鏈與重鏈為 1:1 或 1:3。All Mabs and Fabs were produced in serum-free medium using the ExpiCHO Expression System (Thermo Fisher Scientific). For the cultivation of ExpiCHO cells, the corresponding high titer protocol was used. The plasmid molar ratio was target dependent, with a light chain to heavy chain ratio of 1:1 or 1:3.

藉由 Kappa Select (Cytavia)，隨後在 20 mM 組胺酸、140 mM NaCl pH 6.0 中進行粒徑排阻層析法 Superdex200 (Cytavia) 來進行抗體純化。Fab 之純化由 Kappa Select (Cytavia) 開始，隨後為 CaptureSelect CH1-XL (Thermo Fisher Scientific) 步驟，最後由 Superdex200 (Cytavia) 在 20 mM 組胺酸、140 mM NaCl pH 6.0 中完成。表E4：實例2中鑑定的臨床候選抗體的胺基酸序列。#標識符VH胺基酸序列VL胺基酸序列HC胺基酸序列LC胺基酸序列1P1AG9426 (Mab)124354362P1AG9376 (Mab)344374383P1AG9372 (Mab)564394404P1AG9420 (Mab)784414425P1AG9391 (Mab)9104434446P1AH1205 (Fab)11124454467P1AH1199 (Fab)1314447448實例4：藉由冷凍電子顯微鏡分析由本發明之C3bBb及Fab片段形成的三聚體複合物Antibody purification was performed by Kappa Select (Cytavia) followed by size exclusion chromatography Superdex200 (Cytavia) in 20 mM histidine, 140 mM NaCl pH 6.0. Fab purification started with Kappa Select (Cytavia) followed by CaptureSelect CH1-XL (Thermo Fisher Scientific) step and was completed by Superdex200 (Cytavia) in 20 mM histidine, 140 mM NaCl pH 6.0.TableE4: Amino acid sequences of clinical candidate antibodies identified in Example2 .#IdentifierVHamino acid sequenceVLamino acid sequenceHCamino acid sequenceLCamino acid sequence 1 P1AG9426 (Mab) 1 2 435 436 2 P1AG9376 (Mab) 3 4 437 438 3 P1AG9372 (Mab) 5 6 439 440 4 P1AG9420 (Mab) 7 8 441 442 5 P1AG9391 (Mab) 9 10 443 444 6 P1AH1205 (Fab) 11 12 445 446 7 P1AH1199 (Fab) 13 14 447 448Example4: Analysis ofthe trimeric complex formed byC3bBbandFab fragmentsof the present invention by cryo-electron microscopy

藉由電子顯微鏡分析親代抗體 P1AF8499 (#20) 與 C3bBb 複合物的三聚體複合物。簡而言之，遵守以下方案：The trimeric complex of the parental antibody P1AF8499 (#20) and the C3bBb complex was analyzed by electron microscopy. Briefly, the following protocol was followed:

冷凍 EM 網格準備。將人類 C3bBb 三突變體 + Fab P1AF8499 在 20 mM HEPES、150 mM NaCl、1 mM NiSO4、pH 7.4 中的純化重組複合物冷凍在液態氮中 (0.15 mg/ml，0.7 µM)。解凍後，將 3 µl 施加於新近輝光放電的 Quantifoil R1.2/1.3 400 目銅網格 (Plano) 上。將網格 (Whatman 濾紙，1 級) 於 20°C、95% 室濕度下吸乾 4 秒，並使用 EM GP2 速凍機 (Leica) 在液態乙烷中速凍。Frozen EM grid preparation. Purified recombinant complex of human C3bBb triple mutant + Fab P1AF8499 in 20 mM HEPES, 150 mM NaCl, 1 mM NiSO4, pH 7.4 was frozen in liquid nitrogen (0.15 mg/ml, 0.7 µM). After thawing, 3 µl was applied to freshly glow-discharged Quantifoil R1.2/1.3 400 mesh copper grids (Plano). The grids (Whatman filter paper, grade 1) were blotted dry for 4 s at 20°C, 95% room humidity and snap-frozen in liquid ethane using an EM GP2 snap freezer (Leica).

冷凍 EM 資料採集。兩個資料集係在巴塞爾大學 C-CINA 的 FEI Titan Krios (Thermo Fisher Scientific，Waltham，MA，USA) 上收集的，在 300 keV 下操作，並配備 Gatan Quantum-LS 成像能量濾波器 (GIF，20 eV 能量損失窗口；Gatan Inc，Pleasanton，CA，USA)。使用 SerialEM 軟體 [LK1]，使用 K2 Summit 直接電子偵測器 (Gatan Inc) 在計數模式下以 0.82 Å 之物理像素大小及 56 e−/Å2 之總電子劑量總共採集了 7550 部 40 幀的電影。捕獲影像的初始品質檢查由 FOCUS 程式 [LK3] 進行，該程式採用 MotionCor2 程式 [LK2] 來校正幀運動及其劑量加權，並使用 CTFFIND4 程式 [LK4] 來估計 CTF 參數。顯示每幀解析度低於 7 Å 或平均漂移高於 2 Å 之影像被排除在分析之外。Cryo-EM data acquisition. Both data sets were collected on a FEI Titan Krios (Thermo Fisher Scientific, Waltham, MA, USA) at C-CINA, University of Basel, operating at 300 keV and equipped with a Gatan Quantum-LS imaging energy filter (GIF, 20 eV energy loss window; Gatan Inc, Pleasanton, CA, USA). A total of 7550 40-frame movies were acquired in counting mode with a K2 Summit direct electron detector (Gatan Inc) at a physical pixel size of 0.82 Å and a total electron dose of 56 e−/Å2 using SerialEM software [LK1]. An initial quality check of the captured images was performed by the FOCUS program [LK3], which used the MotionCor2 program [LK2] to correct for frame motion and its dose weighting, and the CTFFIND4 program [LK4] to estimate CTF parameters. Images showing a resolution lower than 7 Å per frame or an average drift higher than 2 Å were excluded from the analysis.

冷凍 EM 資料處理。使用 cryoSPARC v3.3 (Structura Biotechnology) 處理影像堆疊。使用 25-4 Å 光譜帶校正了幀運動，並根據影片擬合了對比度傳遞函數 (CTF) 參數。使用最大直徑及特徵直徑分別為 100 及 200 Å 之球形斑點拾取器選擇 CTF 擬合為 4.5 Å 或更好的影像進行顆粒擷取。進行了三輪具有 150 個類別及 384 像素的盒子大小的 2D 分類，以將 C3bBb- P1AF8499 蛋白質顆粒從碎片和其他偽陽性中分類。對剩餘的顆粒進行從頭重建及同質細化以獲得初步的 3D 重建，其用於為另一輪顆粒拾取創建低通濾波模板。重複拾取及分類過程以獲得 497884 個顆粒的顆粒選擇。藉由從頭開始重建為 4 個類別來獲得 3D 異構細化的參考體積，並使用 2500 個批次大小及 4 次完整迭代對顆粒進行進一步分類。選擇含有 172991 個顆粒的最佳結構特徵的一類進行非均勻細化。對於模型構建及圖形準備，使用了銳化地圖。使用 CryoSPARC 中的 blocres 實現，根據局部解析度對地圖進行過濾。Cryo-EM data processing. Image stacks were processed using cryoSPARC v3.3 (Structura Biotechnology). Frame motion was corrected using the 25-4 Å spectral band, and contrast transfer function (CTF) parameters were fitted from the movie. Images with a CTF fit of 4.5 Å or better were selected for particle extraction using a spherical spot picker with a maximum and characteristic diameter of 100 and 200 Å, respectively. Three rounds of 2D classification with 150 classes and a box size of 384 pixels were performed to classify C3bBb- P1AF8499 protein particles from debris and other false positives. The remaining particles were reconstructed ab initio and homogeneously refined to obtain a preliminary 3D reconstruction, which was used to create a low-pass filter template for another round of particle picking. The picking and classification process was repeated to obtain a particle selection of 497,884 particles. A reference volume for 3D heterogeneous refinement was obtained by reconstructing ab initio into 4 classes, and the particles were further classified using a batch size of 2,500 and 4 full iterations. A class with the best structural features of 172,991 particles was selected for heterogeneous refinement. For model building and figure preparation, sharpening maps were used. Using the blocres implementation in CryoSPARC, the map is filtered according to the local resolution.

模型構建。將 C3bBb (PDB 2WIN) 的結構解構為四個獨立的模型 (TED-CUB、B2-MG、C345C 及裂解因子 B)。這些模型作為剛體擬合到冷凍 EM 圖。在對 P1AF8499 進行建模並執行主要與 P1AF8499 CDR 相關的手動調整後，使用具有嚴格二級結構約束 (TC1) 的 phenix.real_space_refinement 工具進行單輪真實空間細化，以校正初始模型與地圖之間的全局結構差異。 該模型在 Coot (TC2) 中透過模型建立及真實空間細化的迭代循環進一步手動調整。Phenix.mtriage 用於計算模型與地圖 FSC 曲線，該曲線與我們從半地圖 FSC 測量中估計的解析度一致。Model building. The structure of C3bBb (PDB 2WIN) was deconstructed into four separate models (TED-CUB, B2-MG, C345C and cleavage factor B). These models were fitted to the cryo-EM map as rigid bodies. After modeling P1AF8499 and performing manual adjustments mainly related to the P1AF8499 CDRs, a single round of real-space refinement was performed using the phenix.real_space_refinement tool with strict secondary structure restraints (TC1) to correct for global structural differences between the initial model and the map. The model was further manually refined in Coot (TC2) through iterative cycles of model building and real-space refinement. Phenix.mtriage is used to compute model and map FSC curves that are consistent with the resolution we estimate from the semi-map FSC measurements.

結果如圖1所示。左側影像顯示 P1AF8499 Fab 片段與 C3bBb 之間形成的三聚體複合物。P1AF8499 所結合之抗原決定基包含來自兩種組分 C3b 及 Bb 之胺基酸 (圖1，右側影像)。因此，與 C3bBb 各個次單元的交叉反應性應該最小化，甚至被排除。藉由定義 P1AF8499 5 Å 內胺基酸殘基的相互作用，鑑定 P1AF8499 Fab 片段所結合的下列抗原決定基：表E5：親代抗體 P1AF8499 Fab 片段所結合的抗原決定基C3bBb 之次單元次單元之 SEQ ID NO:次單元內的胺基酸殘基C3b495Arg444、Lys534、Gly539、Ser540、Val524、Lys544、Gly546、Gln547、Ser548、Arg551、Gln557、Gln558、Thr560、Lys562、Glu564、Glu758、Pro759、Lys761、Asn762、Ile764、Leu768、Asn770、Asp797人類 FB 之 Bb 次單元501Tyr465、Lys473、Ile474、Ser475、Ile477、Gly482、His483、Lys513、Val514、Ser515、Lys520、Arg521、Asp522、Glu610、Lys613實例5：如藉由SPR分析的抗原與人類及食蟹獼猴C3bBb複合物之結合The results are shownin Figure1. The left image shows the trimeric complex formed between the P1AF8499 Fab fragment and C3bBb. The antigenic determinants bound by P1AF8499 contain amino acids from both components, C3b and Bb (Figure1, right image ). Therefore, cross-reactivity with the various subunits of C3bBb should be minimized or even excluded. By defining the interactions of amino acid residues within 5 Å of P1AF8499, the following antigenic determinants bound by the P1AF8499 Fab fragment were identified:TableE5: Epitopes bound by the Fab fragment of the parent antibody P1AF8499 Subunit of C3bBb SEQ ID NO of subunit: Amino acid residues within the subunit C3b 495 Arg444, Lys534, Gly539, Ser540, Val524, Lys544, Gly546, Gln547, Ser548, Arg551, Gln557, Gln 558, Thr560, Lys562, Glu564, Glu758, Pro759, Lys761, Asn762, Ile764, Leu768, Asn770, Asp797 Human FB Bb subunit 501 Tyr465, Lys473, Ile474, Ser475, Ile477, Gly482, His483, Lys513, Val514, Ser515, Lys520, Arg521, Asp522, Glu610, Lys613Example5:Antigen binding to human and cynomolgus macaqueC3bBbcomplexesas analyzed bySPR

使用以下設定藉由 SPR 評定實例 3 之抗體與來自不同物種的 C3bBb 之抗原結合：The antibodies of Example 3 were evaluated for antigen binding to C3bBb from different species by SPR using the following setup:

Biacore T200 系統以 1x HBS-P+ 緩衝液 (10 mM HEPES、150 mM NaCl 及 0.05% v/v 界面活性劑 P20) 打底，該緩衝液由 10x 儲備液 (Cytiva BR100671) 製備。將 CAP 晶片 (生物素 CAPture KIT 的一部分 - Cytiva 28920233) 對接至系統並平衡越夜。人類C3bBb結合特性The Biacore T200 system was primed with 1x HBS-P+ buffer (10 mM HEPES, 150 mM NaCl and 0.05% v/v surfactant P20) prepared from 10x stock buffer (Cytiva BR100671). A CAP chip (part of the Biotin CAPture KIT - Cytiva 28920233) was docked to the system and equilibrated overnight.HumanC3bBbbinding properties

在下文，描述對人類 C3bBb 複合物之測量。將運行緩衝液改為補充有 5 mM NiSO₄的 HBS-P+，以獲得 C3bBb 複合物的穩定化，該複合物在每個循環中從頭開始構建在晶片表面上。流通池 (FC) 1 及 2 用作活性 FC。將樣品室溫度設定為 12°C，而分析溫度分別定義為 25°C 及 37°C，取決於測定步驟。每個分析週期以未稀釋之 CAP 試劑 (生物素 CAPture KIT 的一部分 - Cytiva 28920233) 之注射開始，以 5 µl/min 持續 300 秒，流過兩個 FC。將生物素化之 C3b 以 9 nM 及 10 µl/min 注射至 FC 1 及 2，分別持續 30 秒 (IgG 分析) 及 60 秒 (Fab 分析)。對每個 FC 分別進行注射，以在兩個 FC 上獲得相當的水平。將 D-生物素 (Invitrogen B20656) 以 50 µM 及 10 µl/min 注射到兩個 FC 中 60 秒，以封閉剩餘的生物素結合位點。 將 FB 三突變體以 100 nM 及 5 µl/min 注射到 FC 2 中 300 秒，以在 FC2 上建構中間體 C3bB。隨後，將 FD 以 100 nM 及 5 µl/min 注射到 FC 2 中 300 秒，以建構 C3bBb 複合物。60 秒的穩定期後，開始單循環動力學的樣品注射。將樣品以 30 µl/min 注射到兩個 FC 中 60 秒，並以 3 倍稀釋系列的五個濃度遞增。由於高度穩定的相互作用，最終解離時間設定為以 30 µl/min 之 1200 秒。為了使下一個循環的表面再生，將標準 CAP 晶片再生 8 M Gua-NaOH 注射到兩個 FC 中 120 秒。最後，以 30 µl/min 向兩個 FC 注射運行緩衝液 60 秒，最終穩定期為 60 秒。In the following, the measurement of the human C3bBb complex is described. The running buffer was changed to HBS-P+ supplemented with 5 mM NiSO₄ to obtain a stabilization of the C3bBb complex, which was built de novo on the chip surface in each cycle. Flow cells (FC) 1 and 2 served as active FCs. The sample chamber temperature was set to 12°C, while the analysis temperature was defined at 25°C and 37°C, respectively, depending on the assay step. Each analysis cycle started with the injection of undiluted CAP reagent (part of the Biotin CAPture KIT - Cytiva 28920233) flowing through both FCs at 5 µl/min for 300 sec. Biotinylated C3b was injected into FC 1 and 2 at 9 nM and 10 µl/min for 30 sec (IgG analysis) and 60 sec (Fab analysis), respectively. Separate injections were performed for each FC to obtain equivalent levels on both FCs. D-Biotin (Invitrogen B20656) was injected into both FCs at 50 µM and 10 µl/min for 60 sec to block the remaining biotin binding sites. The FB triple mutant was injected into FC 2 at 100 nM and 5 µl/min for 300 sec to construct the intermediate C3bB on FC2. Subsequently, FD was injected into FC 2 at 100 nM and 5 µl/min for 300 sec to construct the C3bBb complex. After a 60 s stabilization period, sample injection for a single cycle kinetics was started. Samples were injected into both FCs at 30 µl/min for 60 s in a 3-fold dilution series of five concentration increments. Due to the highly stable interaction, the final dissociation time was set to 1200 s at 30 µl/min. To regenerate the surface for the next cycle, standard CAP chip regeneration 8 M Gua-NaOH was injected into both FCs for 120 s. Finally, buffer injection was run into both FCs at 30 µl/min for 60 s with a final stabilization period of 60 s.

為了進行分析，執行了雙重參考，減去參考流通池 (FC1) 訊號及僅注射緩衝液的包圍參考空白循環。使用 Fab 的 1:1 擬合模型及 IgG 的異質配體模型在 BIAevaluation 軟體中擬合曲線，以分別分離 affin 及 avid 結合。For analysis, double referencing, subtraction of the reference flow cell (FC1) signal and a surround reference blank cycle with buffer injection only were performed. Curves were fit in BIAevaluation software using a 1:1 fit model for Fab and a heterogeneous ligand model for IgG to separate affin and avid binding, respectively.

與人類 C3bBb 相互作用之結果顯示於表E6。表E6：實例 3 的臨床候選抗體的人類 C3bBb 結合。#標識符KD 37℃KD 25℃1P1AG9426 (Mab)14 pM＜ 1 pM2P1AG9376 (Mab)＜ 1 pM＜ 1 pM3P1AG9372 (Mab)11.6 pM＜ 1 pM4P1AG9420 (Mab)11 pM＜ 1 pM5P1AG9391 (Mab)1.6 pM＜ 1 pM6P1AH1205 (Fab)95 pM16 pM7P1AH1199 (Fab)200 pM30 pM食蟹獼猴C3bBb結合特性The results of the interaction with human C3bBb are shown inTableE6 .TableE6: Human C3bBb binding of the clinical candidate antibodies of Example 3.#IdentifierKD 37℃KD 25℃ 1 P1AG9426 (Mab) 14 pM ＜ 1 pM 2 P1AG9376 (Mab) ＜ 1 pM ＜ 1 pM 3 P1AG9372 (Mab) 11.6 pM ＜ 1 pM 4 P1AG9420 (Mab) 11 pM ＜ 1 pM 5 P1AG9391 (Mab) 1.6 pM ＜ 1 pM 6 P1AH1205 (Fab) 95 pM 16 pM 7 P1AH1199 (Fab) 200 pM 30 pMCynomolgus macaqueC3bBbbinding properties

為了測量食蟹獼猴 C3bBb 之動力學，採用了上述設定。為了建構食蟹猴 C3bBb，使用了各自的食蟹獼猴組分：生物素化之 cyno C3b (SEQ ID NO: 497)、cyno FB (三突變體，SEQ ID NO: 500) 及 cyno FD (SEQ ID NO: 498)。三種組分之濃度及注射時間變化如下：以 60 nM 及 10 µl/min 注射生物素化之 cyno C3b，分別持續 180 秒 (IgG 分析) 及 300 秒 (Fab 分析)；以 400 nM 及 5µl/min 注射 cyno FB 三突變體，持續 400 秒；以 600 nM 及 5 µl/min 注射 cyno FD，持續 400 秒。每個濃度的分析物注射 75 秒，並且解離時間縮短至 300 秒。所有剩餘參數均保持如關於人類 C3bBb 複合物的測量所述的。To measure the kinetics of cynomolgus macaque C3bBb, the above setup was used. To construct cynomolgus macaque C3bBb, the respective cynomolgus macaque components were used: biotinylated cyno C3b (SEQ ID NO: 497), cyno FB (triple mutant, SEQ ID NO: 500) and cyno FD (SEQ ID NO: 498). The concentration and injection time of the three components were varied as follows: biotinylated cyno C3b was injected at 60 nM and 10 µl/min for 180 sec (IgG analysis) and 300 sec (Fab analysis), respectively; cyno FB triple mutant was injected at 400 nM and 5µl/min for 400 sec; cyno FD was injected at 600 nM and 5 µl/min for 400 sec. Each concentration of analyte was injected for 75 sec, and the dissociation time was shortened to 300 sec. All remaining parameters remained as described for the measurement of human C3bBb complex.

結果係顯示於表E7中。表E7：實例 3 中臨床候選抗體的食蟹獼猴 C3bBb 結合。#標識符KD 37℃KD 25℃1P1AG9426 (Mab)197 nM206 nM2P1AG9376 (Mab)26 nM50 nM3P1AG9372 (Mab)260 nM207 nM4P1AG9420 (Mab)277 nM117 nM5P1AG9391 (Mab)150 nM130 nM6P1AH1205 (Fab)126 nM65 nM7P1AH1199 (Fab)460 nM245 nM實例6：如藉由SPR分析評定對替代途徑的其他組分的交叉反應性The results are shown inTableE7 .TableE7: Cynomolgus macaque C3bBb binding of the clinical candidate antibodies in Example 3.#IdentifierKD 37℃KD 25℃ 1 P1AG9426 (Mab) 197 nM 206 nM 2 P1AG9376 (Mab) 26 nM 50 nM 3 P1AG9372 (Mab) 260 nM 207 nM 4 P1AG9420 (Mab) 277 nM 117 nM 5 P1AG9391 (Mab) 150 nM 130 nM 6 P1AH1205 (Fab) 126 nM 65 nM 7 P1AH1199 (Fab) 460 nM 245 nMExample6:Assessing cross-reactivity to other components of alternative pathwaysbySPR analysis

為了顯示結合劑對 C3bBb 複合物之特異性，在 Biacore 中測試了針對複合物的各個成分以及前驅物及分解產物之結合 (也在 ELISA 及 BLI 中得到證實)。測試的蛋白質為：C3b (複合物的組分)、C3 (C3b 的前驅物)、C3d、iC3b、C3a (C3b 的分解產物) 以及 Bb (複合物的組分)、FB (Bb 的前驅物) 及 Ba (FB 的分解產物)。To show the specificity of the binding agent for the C3bBb complex, binding to individual components of the complex as well as pro- and cleavage products was tested in Biacore (also confirmed in ELISA and BLI). The proteins tested were: C3b (component of the complex), C3 (pro-C3b), C3d, iC3b, C3a (cleavage product of C3b) and Bb (component of the complex), FB (pro-Bb) and Ba (cleavage product of FB).

如下所述設定脫靶 SPR 測定。The off-target SPR assay was set up as described below.

Biacore T200 系統配備有 CM5 晶片，並塗有 1x HBS-N (10 mM HEPES、150 mM NaCl)，由 10x 儲備溶液 (Cytiva BR100670) 製備。將抗人類 Fab 抗體 (Thermo Fisher Scientific 7103082100) 固定在胺偶合中的所有流通池 (FC1-4)，在 10 mM 乙酸鹽 pH 5 中以 10 µl/min 及 30 µg/ml 預設設置及捕獲抗體注射時間為 420 秒。The Biacore T200 system was equipped with a CM5 chip and coated with 1x HBS-N (10 mM HEPES, 150 mM NaCl) prepared from 10x stock solution (Cytiva BR100670). Anti-human Fab antibody (Thermo Fisher Scientific 7103082100) was immobilized in all flow cells (FC1-4) in amine coupling with a default setting of 10 µl/min and 30 µg/ml in 10 mM acetate pH 5 and capture antibody injection time of 420 seconds.

對於以下分析，系統以 HBS-P + 1 mM NiSO₄塗覆。經過至少三個含捕獲及再生的初始調節循環後，每個循環分別在 FC 2、3 及 4 上以 10 µg/ml 捕獲三種抗體，持續 20 秒。以 200 nM 注射脫靶 60 秒，並以 10 µl/min 的流速追蹤解離 60 秒。每個循環使用 10 mM 甘胺酸 pH 2.1 以 30 µl/min 再生 70 秒，並且最終穩定時間為 120 秒。對於每種抗體，不同的脫靶注射循環被緩衝液注射循環括起來，以達到雙重參考之目的。For the following analysis, the system was coated with HBS-P + 1 mM NiSO_4. After at least three initial conditioning cycles with capture and regeneration, the three antibodies were captured at 10 µg/ml on FC 2, 3 and 4 for 20 seconds each. Off-target injections were performed at 200 nM for 60 seconds and dissociation was followed for 60 seconds at a flow rate of 10 µl/min. Regeneration was performed for 70 seconds each using 10 mM glycine pH 2.1 at 30 µl/min and a final stabilization time of 120 seconds. For each antibody, the different off-target injection cycles were bracketed by a buffer injection cycle for double referencing purposes.

為了分析潛在的脫靶結合，分析了預設結合及穩定性報告點。在雙重參考曲線後提取兩個報告點的 RU (活性流通池減去空白流通池 FC1 及相應的空白循環)。使用下列方程式將 RU 值分別歸一化為結合 [%] 及穩定性 [%]： 結合 [%] 或穩定性 [%] =(雙參考結合或穩定性 [RU] /捕獲水平 [RU])*(捕獲分子 [MW]/分析物 [MW])*100To analyze potential off-target binding, preset binding and stability reporting points were analyzed. The RU of both reporting points were extracted after the dual reference curve (active flow cell minus blank flow cell FC1 and the corresponding blank cycle). The RU values were normalized to binding [%] and stability [%], respectively, using the following equations:Binding [%] or stability [%] = (dual reference binding or stability [RU] / capture level [RU])*(capture molecule [MW]/analyte [MW])*100

結果如表E8所示，其報告結合後及達到穩定後的直接反應水平 (以理論 Rmax 計算，以 % 表示)。表E8：實例 3 所示抗體與替代途徑組分之交叉反應性結合P1AG9376P1AG9372P1AG9426P1AG9391P1AH1205P1AH1199#231567C3b0.060.060.320.4900.39C30.140.722.012.610.012.39C3d000000.53iC3b00.040.340.4400.36C3a05.676.1314.531.3318.94Bb000000.29FB00.110.160.2000.53Ba000000.72穩定性P1AG9376P1AG9372P1AG9426P1AG9391P1AH1205P1AH1199#231567C3b0.040.010.080.150.010.18C30.020.241.071.720.011.65C3d000000.48iC3b00.020.210.260.000.25C3a01.450.533.870.657.40Bb000000.27FB00.060.070.1400.46Ba000000.50實例7：本發明之抗體的進一步特徵The results are shown inTableE8 , which reports the level of immediate reactivity after binding and after reaching stability (calculated as % based on the theoretical Rmax).TableE8: Cross-reactivity of the antibodies shown in Example 3 with components of the alternative pathway Combine P1AG9376 P1AG9372 P1AG9426 P1AG9391 P1AH1205 P1AH1199#231567 C3b 0.06 0.06 0.32 0.49 0 0.39 C3 0.14 0.72 2.01 2.61 0.01 2.39 C3d 0 0 0 0 0 0.53 i3 0 0.04 0.34 0.44 0 0.36 C3a 0 5.67 6.13 14.53 1.33 18.94 Bb 0 0 0 0 0 0.29 FB 0 0.11 0.16 0.20 0 0.53 Ba 0 0 0 0 0 0.72 Stability P1AG9376 P1AG9372 P1AG9426 P1AG9391 P1AH1205 P1AH1199#231567 C3b 0.04 0.01 0.08 0.15 0.01 0.18 C3 0.02 0.24 1.07 1.72 0.01 1.65 C3d 0 0 0 0 0 0.48 i3 0 0.02 0.21 0.26 0.00 0.25 C3a 0 1.45 0.53 3.87 0.65 7.40 Bb 0 0 0 0 0 0.27 FB 0 0.06 0.07 0.14 0 0.46 Ba 0 0 0 0 0 0.50Example7:Further characteristics of the antibody of the present invention

藉由將抗體以受控梯度曝露於升高的溫度來評定實例 3 的抗體之熱穩定性，並判定結構解折疊 (藉由固有螢光的T_m) 及/或聚集傾向 (藉由 SLS 的T_agg)。The thermal stability of the antibody of Example 3 was assessed by exposing the antibody to increasing temperatures in a controlled gradient and determining structural unfolding (T_m by intrinsic fluorescence) and/or aggregation tendency (T_agg by SLS).

藉由與已知的高及低疏水性標準分子比較判定疏水性 HPLC 柱上的滯留時間來評估表觀疏水性。Apparent hydrophobicity is assessed by comparing the retention time on a hydrophobic HPLC column with known high and low hydrophobicity standard molecules.

FcRn親和力評定如下：經由 SPR 測量與固定化 FcRn 之相互作用，因為預計不會發生特定相互作用：生物素化之 scFcRn 被固定至 S 系列感測器晶片 SA(500-600 RU)。將抗體以 10 µl/min 在 5 nM 下注射 60 秒。解離追蹤 90 秒。運行在 25°C 的 PBS-P pH 6 中進行，並使用 PBS-P pH 8 以 30 µl/min 再生表面 60 秒。將雙參考訊號的感測圖與 FcRn 結合活性 (赫賽汀，wt FC 部分) 及非活性 (氟西匹單抗，Triple A FC 部分) 之對照進行比較。陽性對照以兩倍稀釋系列稀釋至 5 nM 的 3.125%。使用 Biacore T200 評估軟體 3.0 對結果進行雙重參考 (對照流通池及緩衝液循環)。使用不同濃度之陽性對照的結合反應 (RU) 來建立標準曲線。計算所有候選物在 100% 濃度 (5 nM) 下的剩餘結合百分比 (源自結合 RU)。與陽性對照組相比，所有候選皆顯示出非常低 (＜ 1 或 5 %) 的 FcRn 表面相互作用。陰性對照 (氟西匹單抗 3A) 顯示與 P1AH1205 及 P1AH1199 相似的訊號。FcRnaffinity was assessed as follows: Interaction with immobilized FcRn was measured by SPR, as no specific interaction was expected: Biotinylated scFcRn was immobilized to S-Series Sensor Chip SA (500-600 RU). Antibodies were injected at 5 nM for 60 sec at 10 µl/min. Dissociation was followed for 90 sec. Runs were performed in PBS-P pH 6 at 25°C, and the surface was regenerated for 60 sec with PBS-P pH 8 at 30 µl/min. Sensorgrams of the dual reference signal were compared to FcRn binding active (Herceptin, wt FC portion) and inactive (Fluorapivir, Triple A FC portion) controls. The positive control was diluted in a two-fold dilution series to 3.125% of 5 nM. Results were double referenced (control flow cell and buffer loop) using Biacore T200 Evaluation Software 3.0. Binding responses (RU) of positive controls at different concentrations were used to establish standard curves. The remaining percent bound (derived from bound RU) at 100% concentration (5 nM) was calculated for all candidates. All candidates showed very low (< 1 or 5 %) FcRn surface interactions compared to the positive control. The negative control (Fluorapimab 3A) showed similar signals to P1AH1205 and P1AH1199.

肝素親和層析在特定的 HPLC 親和管柱上進行。將相應的保留時間與基於具有良好及不良 PK 的已知分子建立的閾值進行比較。Heparin affinity chromatography was performed on a specific HPLC affinity column. The corresponding retention times were compared to thresholds established based on known molecules with good and poor PK.

藉由監測保留時間短於主要物種的高分子量物種來測量抗體完整性的品質。這係藉由使用粒徑排阻 HPLC 設定及 UV A280 nm 檢測來完成的。使用自定義基線對獲得的峰值進行積分並計算曲線下面積。顯示總曲線積分的相對面積。此層析法的條件係根據分子大小及製造商對蛋白質分析的建議來選擇的。使用還原且未經處理的毛細管凝膠電泳及固有蛋白質螢光檢測來評估分子之斷裂。監測遷移時間比主要物種短的低分子量物種，並對曲線下的峰面積進行積分。顯示總曲線積分的相對面積。分子的功能完整性藉由對分子標靶特異性之結合測定進行評估 (如實例 5 所述)。在熱應力材料之情況下判定相對活性濃度。假定的天冬醯胺酸及天門冬胺酸降解熱點藉由胰蛋白酶肽圖譜 MS 分析以實驗證實或排除。將野生型及經修飾的肽的萃取離子層析圖 (XIC) 的峰面積進行積分。當評估預測的互補性決定區中的潛在修飾位點時，考慮經修飾的肽 XIC 面積相對於野生型 XIC 面積之比率。The quality of the antibody integrity is measured by monitoring high molecular weight species with shorter retention times than the main species. This is done using a size exclusion HPLC setup with UV A280 nm detection. The peaks obtained are integrated using a custom baseline and the area under the curve is calculated. The relative area to the total curve integration is displayed. The conditions for this chromatographic method were chosen based on molecular size and the manufacturer's recommendations for protein analysis. Molecular fragmentation is assessed using reduced and untreated capillary gel electrophoresis with intrinsic protein fluorescence detection. Low molecular weight species with shorter migration times than the main species are monitored and the peak area under the curve is integrated. The relative area to the total curve integration is displayed. The functional integrity of the molecule was assessed by binding assays specific for the molecule's target (as described in Example 5). Relative activity concentrations were determined in the case of thermally stressed materials. Putative aspartate and aspartate degradation hotspots were experimentally confirmed or excluded by tryptic peptide mapping MS analysis. Peak areas of the extracted ion chromatograms (XICs) of the wild-type and modified peptides were integrated. When evaluating potential modification sites in the predicted complementarity determining regions, the ratio of the modified peptide XIC area relative to the wild-type XIC area was considered.

在無鹽通用緩衝系統中評定不同濃度之目標分子之黏度。這係藉由將不同濃度之目標分子與珠共同孵育並藉由動態光散射檢測來完成的。最大可行濃度由與目標產品概況相關的黏度極限定義，並藉由將可用資料擬合到適當的模型並應用相關閾值來判定。表E9：所示抗體的進一步特徵P1AG9376P1AG9372P1AG9426P1AG9391P1AH1205P1AH1199#231567熱穩定性 (DLS T_agg/ DLS T_m)566263596867表觀疏水性 (HIC)00.10.20.1-0.4-0.2biacore上之 FcRn親和力無交互作用無交互作用無交互作用無交互作用無交互作用無交互作用肝素親和層析0.870.280.230.260.810.12CHO池中之滴度3.4 g/l1.6 g/l6.0 g/l3.3 g/l3.0 g/l2.6 g/l品質＞ 70%＞ 70%＞ 70%＞ 70%＞ 70%＞ 70%低於黏度極限之最大可行濃度 (mg/ml)29.996.581.885.7220.2223.2實例8：本發明之抗體在熱應力下之完整性The viscosity of the target molecule at different concentrations was assessed in a salt-free universal buffer system. This was done by incubating the beads with different concentrations of the target molecule and detecting by dynamic light scattering. The maximum feasible concentration was defined by the viscosity limit associated with the target product profile and determined by fitting the available data to an appropriate model and applying the relevant thresholds.TableE9: Further characterization of the indicated antibodies P1AG9376 P1AG9372 P1AG9426 P1AG9391 P1AH1205 P1AH1199#231567Thermal stability (DLS_Tagg / DLS_Tm ) 56 62 63 59 68 67Apparent hydrophobicity (HIC) 0 0.1 0.2 0.1 -0.4 -0.2 FcRnaffinityonbiacore No interaction No interaction No interaction No interaction No interaction No interactionHeparin affinity chromatography 0.87 0.28 0.23 0.26 0.81 0.12Titer inCHO pool 3.4 g/l 1.6 g/l 6.0 g/l 3.3 g/l 3.0 g/l 2.6 g/lQuality > 70% > 70% > 70% > 70% > 70% > 70%Maximum feasible concentration below viscosity limit (mg/ml) 29.9 96.5 81.8 85.7 220.2 223.2Example8:Integrity of the Antibody of the Present Invention under Thermal Stress

實例 3 之抗體在不同應力條件下的穩定性評定如下：在模擬生理條件 (磷酸鹽緩衝生理食鹽水 pH 7.4) 及保質期指示條件 (組胺酸/HCl、氯化鈉緩衝液 pH 6.0) 之條件下，將分子儲存在具有螺旋蓋的聚丙烯小瓶中的溶液中。分子溶液在相關溫度下保存較長時間段 (生理：37°C 及升高的應力條件：40℃）。隨後的分析集中於與未處理之對照相比，在儲存的樣品中觀察到的變化。The stability of the antibody of Example 3 under different stress conditions was evaluated as follows: The molecules were stored in solution in polypropylene vials with screw caps under conditions simulating physiological conditions (phosphate buffered saline pH 7.4) and shelf-life indicator conditions (histidine/HCl, sodium chloride buffer pH 6.0). The molecule solutions were stored at relevant temperatures for extended periods of time (physiological: 37°C and elevated stress conditions: 40°C). Subsequent analysis focused on changes observed in the stored samples compared to untreated controls.

採用實例 7 中的完整性判定方法來分析變化。表E10：應力條件下處理的抗體的殘餘活性 [%]#標識符40°C HisNaCl 37°C PBS2週40°C HisNaCl 37°C PBS4週3P1AG9372 (Mab)98972P1AG9376 (Mab)100-5P1AG9391 (Mab)99971P1AG9426 (Mab)99986P1AH1205 (Fab)99987P1AH1199 (Fab)9697實例9：本發明之抗體的效力(Wieslab測定及溶血測定)The integrity determination method in Example 7 was used to analyze the changes.TableE10: Residual activity of antibodies treated under stress conditions [%]#Identifier40°C HisNaCl 37°C PBS2weeks40°C HisNaCl 37°C PBS4weeks 3 P1AG9372 (Mab) 98 97 2 P1AG9376 (Mab) 100 - 5 P1AG9391 (Mab) 99 97 1 P1AG9426 (Mab) 99 98 6 P1AH1205 (Fab) 99 98 7 P1AH1199 (Fab) 96 97Example9:Efficacy of the Antibody of the Present Invention(WieslabAssay and Hemolysis Assay)

Wieslab測定：藉由 Wieslab 補體系統替代途徑 (AP) 套組評定實例 3 之抗體的效力。該套組係一種酵素免疫測定法，用於判定人類血清中功能性替代補體途逕。WieslabAssay: The potency of the antibody of Example 3 was assessed by the Wieslab Complement System Alternative Pathway (AP) Kit. This kit is an enzyme immunoassay used to determine the functional alternative complement pathway in human serum.

它將補體活化的溶血測定原理與使用特異性抗體檢測產生的新抗原結合，新抗原與補體途逕的功能活性成正比。簡而言之，在組胺酸緩衝液提供抗體候選及對照化合物 Pegcetacoplan (APL-2，一種 C3 抑制劑，Eur J Clin Invest. 2015 April；45(4): 423–440. doi:10.1111/eci.12419) 及 Iptacopan (LNP023，一種 FB 抑制劑，Proc Natl Acad Sci USA.2019 Apr 16；116(16):7926-7931. doi: 10.1073/pnas.1820892116.Epub 2019 Mar 29) 的 2 倍稀釋系列，然後與人類血清在冰上預孵育 15 分鐘。此時的實際血清濃度為 90%。將此混合物在含有特定阻斷劑的稀釋劑中以 1:18 稀釋 (以便僅可活化 AP)，並於室溫再孵育 15 分鐘。將溶液添加至專門包被有 AP 活化劑的 96 孔板中，並於 37°C 孵育 60 分鐘。依照方案洗滌孔並檢測 C5b-9。30 分鐘後，在 405 nm 處測量吸光度，並使用 Xlfit 計算補體活化量。表E11：Wieslab AP 功能測定中所示抗體之 IC50#標識符IC50 (nM)95conf_i3P1AG9372 (Mab)36.78.82P1AG9376 (Mab)35.79.75P1AG9391 (Mab)39.19.24P1AG9420 (Mab)51.811.21P1AG9426 (Mab)46.47.46P1AH1205 (Fab)71.613.07P1AH1199 (Fab)115.424.3It combines the principle of hemolytic assay of complement activation with the use of specific antibodies to detect generated neoantigens that are proportional to the functional activity of the complement pathway. Briefly, a 2-fold dilution series of antibody candidates and control compounds Pegcetacoplan (APL-2, a C3 inhibitor, Eur J Clin Invest. 2015 April; 45(4): 423–440. doi:10.1111/eci.12419) and Iptacopan (LNP023, a FB inhibitor, Proc Natl Acad Sci USA. 2019 Apr 16; 116(16):7926-7931. doi: 10.1073/pnas.1820892116.Epub 2019 Mar 29) were provided in histidine buffer and then pre-incubated with human serum on ice for 15 min. The actual serum concentration at this time was 90%. This mixture was diluted 1:18 in a diluent containing a specific blocking agent (so that only AP can be activated) and incubated for an additional 15 minutes at room temperature. The solution was added to a 96-well plate specifically coated with an AP activator and incubated at 37°C for 60 minutes. The wells were washed and assayed for C5b-9 according to the protocol. After 30 minutes, the absorbance was measured at 405 nm and the amount of complement activation was calculated using Xlfit.TableE11: IC50 values of the indicated antibodies in the Wieslab AP functional assay#IdentifierIC50 (nM)95conf_i 3 P1AG9372 (Mab) 36.7 8.8 2 P1AG9376 (Mab) 35.7 9.7 5 P1AG9391 (Mab) 39.1 9.2 4 P1AG9420 (Mab) 51.8 11.2 1 P1AG9426 (Mab) 46.4 7.4 6 P1AH1205 (Fab) 71.6 13.0 7 P1AH1199 (Fab) 115.4 24.3

溶血測定：在另一項實驗中，經由替代途徑溶血測定評定抗體之效力。簡而言之，在組胺酸緩衝液中提供了抗體候選及對照化合物 APL-2 (C3 抑制劑) 及 LNP023 (FB 抑制劑) 的 2 倍稀釋系列。將樣品於 4°C 製備或保存在冰上，以免補體級聯反應啟動。將洗滌的兔紅血球 (RBC) 與適合替代途徑的緩衝液中的一系列稀釋抗體一起添加至 V 型 96 孔板中。添加正常人類血清，最終測定濃度為 6.7%。藉由於 37°C 孵育板開始補體活化。每 10 分鐘將板以 800 rpm 振盪 1 分鐘，以防止 RBC 之完全沉澱。60 分鐘後，藉由添加含有 10mM EDTA 之冰冷 NaCl 溶液，終止溶血反應。將板於 4°C 以 1250xg 離心 3 分鐘，以沉澱未裂解之 RBC。小心轉移上清液並在 405 nm 處測量吸光度。計算溶血百分比：(OD 測試樣品 - OD BG 或空白)/(OD 完全裂解 - OD BG 或空白) x 100。使用 Xlfit 計算 IC50 值，表E12：溶血測定中所示抗體之 IC50#標識符IC50 (nM)95conf_i3P1AG9372 (Mab)11.21.82P1AG9376 (Mab)10.42.95P1AG9391 (Mab)13.02.04P1AG9420 (Mab)16.33.51P1AG9426 (Mab)12.81.86P1AH1205 (Fab)23.81.17P1AH1199 (Fab)48.12.8Hemolytic Assay: In another experiment, the potency of the antibodies was assessed via the alternative pathway hemolytic assay. Briefly, a 2-fold dilution series of the antibody candidates and control compounds APL-2 (C3 inhibitor) and LNP023 (FB inhibitor) were provided in histidine buffer. Samples were prepared at 4°C or kept on ice to avoid initiation of the complement cascade. Washed rabbit red blood cells (RBCs) were added to a V-shaped 96-well plate along with a series of antibody dilutions in buffer appropriate for the alternative pathway. Normal human serum was added to a final assay concentration of 6.7%. Complement activation was initiated by incubating the plates at 37°C. The plate was shaken at 800 rpm for 1 min every 10 min to prevent complete sedimentation of RBCs. After 60 min, the hemolysis reaction was stopped by adding ice-cold NaCl solution containing 10 mM EDTA. The plate was centrifuged at 1250xg for 3 min at 4°C to sediment the unlysed RBCs. The supernatant was carefully transferred and the absorbance was measured at 405 nm. The percentage of hemolysis was calculated as: (OD test sample - OD BG or blank)/(OD complete lysis - OD BG or blank) x 100. IC50 values were calculated using Xlfit,TableE12: IC50 values for the antibodies shown in the hemolysis assay#IdentifierIC50 (nM)95conf_i 3 P1AG9372 (Mab) 11.2 1.8 2 P1AG9376 (Mab) 10.4 2.9 5 P1AG9391 (Mab) 13.0 2.0 4 P1AG9420 (Mab) 16.3 3.5 1 P1AG9426 (Mab) 12.8 1.8 6 P1AH1205 (Fab) 23.8 1.1 7 P1AH1199 (Fab) 48.1 2.8

在另一項實驗中，經由基於 BLI 的 C3b 沉積測定評定抗體之效力。In another experiment, the potency of the antibodies was assessed by a BLI-based C3b deposition assay.

基於BLI的C3b沉積測定：藉由 C3 轉化酶裂解 C3 時產生的活化羰基與靠近酵素的親核試劑反應並形成共價加合物。我們利用這一特性，藉由定量沉積在裝載有 C3bBb 並曝露於 C3 的 BLI 感測器上的 C3b 質量來測量轉化酶活性。BLI-basedC3bdeposition assay: The activated carbonyl group generated by C3 convertase cleavage of C3 reacts with nucleophiles in close proximity to the enzyme to form covalent adducts. We took advantage of this property to measure convertase activity by quantifying the mass of C3b deposited on a BLI sensor loaded with C3bBb and exposed to C3.

為此，生物素化之 C3b 以低密度負載在 Octet red 384 裝置中的鏈黴親和素功能化 SAX BLI 感測器 (Sartorius) 上，達到 1 nm 的訊號。藉由於 30°C 將轉化酶曝露於 HBS-T 緩衝液 (150mM NaCl、10mM HEPES、1mM MgCl₂、0.005% Tween20、pH 7.4) 中的 270 nM 血漿純化因子 B 及 27nM 血漿純化因子 D 5 分鐘組裝轉化酶，此時轉化酶組裝與解離之間達到動態平衡。然後，在不同濃度的測試項目存在之情況下，將主動感測器曝露於 C3 (500 nM)，並將對照感測器曝露於單獨的測試項目，持續 15 分鐘，此時轉化酶被認為完全解離。再曝露於緩衝液 5 分鐘以釋放非共價締合材料後，根據活性感測器與對照感測器之間的訊號差異計算沉積的 C3b，並用作活性及 IC50 計算的指數。表E13：BLI 測定中所示抗體之 IC50#標識符IC50 (nM)95conf_i3P1AG9372 (Mab)1.50.112P1AG9376 (Mab)2.20.305P1AG9391 (Mab)1.60.114P1AG9420 (Mab)1.40.231P1AG9426 (Mab)1.60.206P1AH1205 (Fab)4.50.277P1AH1199 (Fab)6.90.38實例10：本發明之抗體相較於靶向替代途徑的現有技術臨床候選的效力To this end, biotinylated C3b was loaded at low density onto a streptavidin-functionalized SAX BLI sensor (Sartorius) in an Octet red 384 device to achieve a signal of 1 nm. The convertase was assembled by exposing it to 270 nM plasma purified factor B and 27 nM plasma purified factor D in HBS-T buffer (150 mM NaCl, 10 mM HEPES, 1 mM MgCl₂ , 0.005% Tween 20, pH 7.4) for 5 min at 30°C, when a dynamic equilibrium between convertase assembly and dissociation was reached. Active sensors were then exposed to C3 (500 nM) in the presence of different concentrations of the test item, and control sensors were exposed to the test item alone for 15 minutes, at which time the convertase was considered to be completely dissociated. After an additional 5-minute exposure to buffer to release non-covalently bound material, the deposited C3b was calculated based on the difference in signal between active and control sensors and used as an index for activity and IC50 calculations.TableE13: IC50 of the indicated antibodies in the BLI assay#IdentifierIC50 (nM)95conf_i 3 P1AG9372 (Mab) 1.5 0.11 2 P1AG9376 (Mab) 2.2 0.30 5 P1AG9391 (Mab) 1.6 0.11 4 P1AG9420 (Mab) 1.4 0.23 1 P1AG9426 (Mab) 1.6 0.20 6 P1AH1205 (Fab) 4.5 0.27 7 P1AH1199 (Fab) 6.9 0.38Example10:Efficacy of the Antibodies of the Invention Compared to Prior Art Clinical Candidates Targeting Alternative Pathways

在對照實驗中，使用先前實例中所述之測定來比較靶向替代途徑的現有技術臨床候選的效力。作為對照，使用 APL-2 肽，其與 C3 (Eur J Clin Invest. 2015 April；45(4): 423–440. Doi:10.1111/eci.12419) 及抑制 FB 之 LNP023 (Proc Natl Acad Sci USA.2019 Apr 16；116(16):7926-7931. doi: 10.1073/pnas.1820892116.Epub 2019 Mar 29) 結合。表E14：所示比較化合物之 IC50Wieslab測定溶血測定BLI測定標識符IC50 (nM)95conf_iIC50 (nM)95conf_iIC50 (nM)95conf_iAPL-2274.210.9274.210.920037.6LNP023161.415.2161.415.2141.17實例11：本發明之抗體與不同猴種之交叉反應性In control experiments, the potency of prior art clinical candidates targeting alternative pathways was compared using the assay described in the previous examples. As controls, the APL-2 peptide, which binds to C3 (Eur J Clin Invest. 2015 April; 45(4): 423–440. Doi:10.1111/eci.12419) and LNP023, which inhibits FB (Proc Natl Acad Sci USA. 2019 Apr 16; 116(16):7926-7931. doi: 10.1073/pnas.1820892116. Epub 2019 Mar 29) were used.TableE14: IC50 values of the compared compounds shownWieslabassayHemolysis assayBLIassayIdentifierIC50 (nM)95conf_iIC50 (nM)95conf_iIC50 (nM)95conf_i APL-2 274.2 10.9 274.2 10.9 200 37.6 LNP023 161.4 15.2 161.4 15.2 14 1.17Example11:Cross-reactivity of the antibodies of the present invention with different monkey species

使用效力測定 (溶血測定) 評定本發明之抗體對來自不同猴種 (亦即石蟹獼猴 (食蟹獼猴) 及綠猴 (非洲綠猴)) 的 C3bBb 之交叉反應性，該效力測定與先前實例中所述者略有不同，這取決於物種。The cross-reactivity of the antibodies of the invention to C3bBb from different monkey species, namely, the stone macaque (Cynodon fascicularis) and the green monkey (Vervet) was assessed using a potency assay (hemolytic assay) that differed slightly from that described in the previous examples, depending on the species.

簡而言之，在組胺酸緩衝液中提供了抗體候選及對照化合物 APL-2 (C3 抑制劑) 及 LNP023 (FB 抑制劑) 的 2 倍稀釋系列。將樣品於 4°C 製備或保存在冰上，以免補體級聯反應啟動。將洗滌的兔紅血球 (RBC) 與適合替代途徑的緩衝液中的一系列稀釋抗體一起添加至 V 型 96 孔板中。Briefly, a 2-fold dilution series of antibody candidates and control compounds APL-2 (C3 inhibitor) and LNP023 (FB inhibitor) were provided in histidine buffer. Samples were prepared at 4°C or kept on ice to avoid initiation of the complement cascade. Washed rabbit red blood cells (RBCs) were added to a V-shaped 96-well plate along with a series of antibody dilutions in buffer appropriate for the alternative pathway.

對於食蟹獼猴，添加正常人類血清，最終測定濃度為 5% (2 個個體的血清池)。補體活化從於 37°C 孵育板開始。每 10 分鐘將板以 800 rpm 振盪 1 分鐘，以防止 RBC 之完全沉澱。20 分鐘後，藉由添加含有 10mM EDTA 之冰冷 NaCl 溶液，終止溶血反應。將板於 4°C 以 1000 xg 離心 3 分鐘，以沉澱未裂解之 RBC。小心轉移上清液並在 405 nm 處測量吸光度。計算溶血百分比：(OD 測試樣品 - OD BG 或空白)/(OD 完全裂解 - OD BG 或空白) x 100。使用 Xlfit 計算 IC50 值。For cynomolgus macaques, normal human serum was added to a final assay concentration of 5% (pool of serum from 2 individuals). Complement activation was initiated by incubating the plates at 37°C. The plates were shaken at 800 rpm for 1 min every 10 min to prevent complete sedimentation of the RBCs. After 20 min, the hemolysis reaction was stopped by the addition of ice-cold NaCl solution containing 10 mM EDTA. The plates were centrifuged at 1000 x g for 3 min at 4°C to sediment the unlysed RBCs. The supernatant was carefully transferred and the absorbance was measured at 405 nm. The percentage of hemolysis was calculated as: (OD test sample - OD BG or blank)/(OD complete lysis - OD BG or blank) x 100. IC50 values were calculated using Xlfit.

對於非洲綠猴 (AGM)，添加正常人類血清，最終測定濃度根據動物個體不同在 4.2% 與 6.7% 之間變化。這些濃度係在先前實驗中以及孵育時間及溫度中判定的，以獲得適當的溶血水平。與「常規」溶血測定之最大區別在於，將板於室溫孵育，20 分鐘後停止活化，並如上所述對板進行進一步處理。表E15：溶血測定中所示化合物之交叉反應性石蟹獼猴綠猴標識符#IC50 (nM)95conf_iIC50 (nM)95conf_iP1AG9372 (Mab)31115176.2111.830.4P1AG9376 (Mab)28021108.927.66.4P1AG9391 (Mab)5981445.574.827.3P1AG9420 (Mab)4＞578＞578P1AG9426 (Mab)1＞2000584.3139.942.2P1AH1205 (Fab)63059600.8445.9149.2P1AH1199 (Fab)7＞60002246.51306.5248.4APL-231630.3147.416.3LNP02373.27.1113.011.3實例12：本發明之抗體對轉化酶解離的影響不同抗 C3bBb 抗體 (抑制劑) 對包含 C3bBb 抑制劑及 C3bBb 之三聯複合物半衰期的影響For African green monkeys (AGM), normal human serum was added and the final assay concentrations varied between 4.2% and 6.7% depending on the individual animal. These concentrations were determined in previous experiments as well as the incubation time and temperature to obtain an appropriate level of hemolysis. The biggest difference from the "conventional" hemolysis assay is that the plates are incubated at room temperature, activation is stopped after 20 minutes and the plates are further processed as described above.TableE15: Cross-reactivity of the indicated compounds in the hemolysis assayStone Crab MascotGreen MonkeyIdentifier#IC50 (nM)95conf_iIC50 (nM)95conf_i P1AG9372 (Mab) 3 1115 176.2 111.8 30.4 P1AG9376 (Mab) 2 802 1108.9 27.6 6.4 P1AG9391 (Mab) 5 981 445.5 74.8 27.3 P1AG9420 (Mab) 4 >578 >578 P1AG9426 (Mab) 1 ＞2000 584.3 139.9 42.2 P1AH1205 (Fab) 6 3059 600.8 445.9 149.2 P1AH1199 (Fab) 7 ＞6000 2246.5 1306.5 248.4 APL-2 316 30.3 147.4 16.3 LNP023 73.2 7.1 113.0 11.3Example12:Effect of the Antibody of the Present Invention on Convertase Dissociation Effect of Different Anti-C3bBb Antibodies (Inhibitors) on the Half-Life of a Triple Complex Comprising a C3bBb Inhibitor and C3bBb

藉由分析組裝在生物層干涉測量感測器上的 C3bBb:Inh 三聯複合物的衰變，研究了 C3bBb 抑制劑 (Inh) 對轉化酶穩定性的影響。The effect of a C3bBb inhibitor (Inh) on the stability of the convertase was studied by analyzing the decay of a C3bBb:Inh triple complex assembled on a biolayer interferometry sensor.

為此，將生物素化之 C3b 以低密度負載到 Octet red384 裝置 (Sartorius) 上的鏈黴親和素功能化 SAX BLI 感測器上，達到 1.5 nm 的訊號。藉由於 30°C 將感測器曝露於 270 nM 血漿緩衝液 (150mM NaCl、10mM HEPES、1mM MgCl₂、0.005% Tween20. pH 7.4 )) 5 分鐘來組裝轉化酶，此時轉化酶組裝與解離之間達到動態平衡。然後，在 FB 及 FD 持續存在之情況下，將負載轉化酶的感測器曝露於 500 nM 測試項目 10 分鐘，使抑制劑與轉化酶達到結合平衡。To this end, biotinylated C3b was loaded at low density onto a streptavidin-functionalized SAX BLI sensor on an Octet red384 device (Sartorius) to achieve a signal of 1.5 nm. The convertase was assembled by exposing the sensor to 270 nM plasma buffer (150 mM NaCl, 10 mM HEPES, 1 mM MgCl₂ , 0.005% Tween 20. pH 7.4) for 5 min at 30°C, where a dynamic equilibrium between convertase assembly and dissociation was reached. Then, the invertase-loaded sensor was exposed to 500 nM of the test compound in the continued presence of FB and FD for 10 min to allow the inhibitor to reach binding equilibrium with the invertase.

在對照感測器上追蹤 C3bBb:Inh 三聯複合物之訊號衰減，並使用 XL fit(IDBS 軟體) 擬合指數函數以計算三聯複合物半衰期。將資料與在沒有抑制劑之情況下進行的平行測定進行比較，揭示了一些探索的 C3bBb 特異性結合物強烈穩定轉化酶，這可能是 C3b–Bb 界面結合的作用，而其他抑制劑則不能穩定轉化酶。表E16a：#標識符濃度 (nM)初始沉積速率抑制 (%)C3b 沉積抑制 (%)C3bBb t1/2 (s)C3bBb:Inh t1/2 (s)增加 (%)8P045.072 (Fab)50087未判定2072453108510P045.225 (Fab)50082未判定20711054349P045.236 (Fab)50058未判定20748413420P046.185 (Fab)50088未判定2072291113P046.127 (Fab)500100未判定2074120189019P055.015 (Fab)50090未判定204628207The signal decay of the C3bBb:Inh triple complex was followed on the control sensor and exponential functions were fitted using XL fit (IDBS software) to calculate the triple complex half-life. Comparison of the data with parallel assays performed in the absence of inhibitors revealed that some of the explored C3bBb-specific binders strongly stabilized the convertase, which may be a function of binding to the C3b–Bb interface, while other inhibitors failed to stabilize the convertase.TableE16a : # Identifier Concentration(nM) Initial deposition rate inhibition (%) C3b deposition inhibition (%) C3bBb t1/2 (s) C3bBb:Inh t1/2 (s) Increase(%)8 P045.072 (Fab) 500 87 Undecided 207 2453 108510 P045.225 (Fab) 500 82 Undecided 207 1105 4349 P045.236 (Fab) 500 58 Undecided 207 484 13420 P046.185 (Fab) 500 88 Undecided 207 229 1113 P046.127 (Fab) 500 100 Undecided 207 4120 189019 P055.015 (Fab) 500 90 Undecided 204 628 207

在另一項實驗中，在確保轉化酶被測試化合物飽和之條件下定量調查所選抑制劑對轉化酶半衰期的影響。實施與先前實驗類似的設計，不同之處在於 C3b 負載僅限於 1 nm BLI 訊號。化合物在 316 倍稀釋範圍內進行測試，與轉化酶的平衡時間延長至 15 分鐘，曝露於 C3 (與對照感測器上的轉化酶衰減平行) 的時間限制為 15 分鐘。In another experiment, the effect of selected inhibitors on the half-life of the convertase was investigated quantitatively under conditions that ensured saturation of the convertase with the test compounds. A similar design to the previous experiment was performed, except that C3b loading was limited to 1 nM BLI signal. Compounds were tested over a 316-fold dilution range, equilibration time with the convertase was extended to 15 minutes, and exposure to C3 (in parallel with convertase decay on a control sensor) was limited to 15 minutes.

在測試的最高濃度 (Mab 及 Fab 分別為 31.6nM、63.2nM、320nM 及 5µM) 下，轉化酶活性基本上完全受到抑制，這表明在實驗條件下，轉化酶佔有率接近 100%。此外，對與 Mab 及 Fab 結合相關的 BLI 訊號偏移的分析證實已達到飽和。因此，報告的半衰期係指三聯複合物，而不是結合/未結合之轉化酶混合物。表E16b：#標識符濃度 (nM)初始沉積速率抑制 (%)C3b 沉積抑制 (%)C3bBb t1/2 (s)C3bBb:Inh t1/2 (s)t1/2 增加 (%)3P1AG9372 (Mab)31.610097229318392P1AG9376 (Mab)31.69999197299525P1AG9391 (Mab)31.610099231313354P1AG9420 (Mab)31.69996188215141P1AG9426 (Mab)31.610099257326276P1AH1205 (Fab)63.29796184207147P1AH1199 (Fab)63.294932042197.3實例13：本發明之抗體係替代途徑的選擇性抑制劑且不抑制典型途徑及凝集素途徑At the highest concentrations tested (31.6nM, 63.2nM, 320nM, and 5µM for Mab and Fab, respectively), convertase activity was essentially completely inhibited, indicating that convertase occupancy was close to 100% under the experimental conditions. In addition, analysis of the BLI signal shift associated with Mab and Fab binding confirmed that saturation was achieved. Therefore, the half-life reported refers to the tripartite complex, not a mixture of bound/unbound convertase.TableE16b: # Identifier Concentration(nM) Initial deposition rate inhibition (%) C3b deposition inhibition (%) C3bBb t1/2 (s) C3bBb:Inh t1/2 (s) t1/2 increase (%)3 P1AG9372 (Mab) 31.6 100 97 229 318 392 P1AG9376 (Mab) 31.6 99 99 197 299 525 P1AG9391 (Mab) 31.6 100 99 231 313 354 P1AG9420 (Mab) 31.6 99 96 188 215 141 P1AG9426 (Mab) 31.6 100 99 257 326 276 P1AH1205 (Fab) 63.2 97 96 184 207 14 7 P1AH1199 (Fab) 63.2 94 93 204 219 7.3Example13:The antibody of the present invention is a selective inhibitor of the alternative pathway and does not inhibit the classical pathway and the lectin pathway

為了證實本發明之抗體係替代途徑的選擇性抑制劑，如下進行典型途徑溶血測定To confirm that the antibody of the present invention is a selective inhibitor of the alternative pathway, a typical pathway hemolysis assay was performed as follows:

簡而言之，在組胺酸緩衝液中提供了抗體候選及對照化合物 APL-2 (C3 抑制劑) 及 LNP023 (FB 抑制劑) 的 2 倍稀釋系列。除了血清外，所有東西均在室溫下製備，血清保存在冰上，以免補體級聯反應啟動。將洗滌的 Ab 致敏的綿羊紅血球 (EA) 與適合典型途逕的緩衝液中的一系列稀釋抗體一起添加至 V 型 96 孔板中。添加正常人類血清，最終測定濃度為 2%，並與其他組分輕輕混合。藉由於 37°C 孵育板開始補體活化，並以 600 rpm 連續振盪，以防止 EA 之完全沉澱。30 分鐘後，藉由添加含有 10mM EDTA 之冰冷 NaCl 溶液，終止溶血反應。將板於 4°C 以 1000 xg 離心 2 分鐘，以沉澱未裂解之 EA。小心轉移上清液並在 405 nm 處測量吸光度。計算溶血百分比：(OD 測試樣品 - OD BG 或 EDTA 對照)/(OD 完全裂解 - OD BG 或 EDTA 對照) x 100。使用 Xlfit 計算 IC50 值。表E17：藉由典型途逕溶血測定評定所示分子之 IC50#標識符IC50 (nM)95conf_i3P1AG9372 (Mab)＞ 20002P1AG9376 (Mab)＞ 20005P1AG9391 (Mab)＞ 20004P1AG9420 (Mab)＞ 5781P1AG9426 (Mab)＞ 20006P1AH1205 (Fab)＞ 60007P1AH1199 (Fab)＞ 6000APL-21022170.7LNP023＞ 20.000Briefly, a 2-fold dilution series of antibody candidates and control compounds APL-2 (C3 inhibitor) and LNP023 (FB inhibitor) were provided in histidine buffer. Everything was prepared at room temperature except for serum, which was kept on ice to prevent activation of the complement cascade. Washed Ab-sensitized sheep erythrocytes (EA) were added to V-shaped 96-well plates along with a series of antibody dilutions in buffer appropriate for the typical route. Normal human serum was added to a final assay concentration of 2% and gently mixed with the other components. Complement activation was initiated by incubating the plates at 37°C with continuous shaking at 600 rpm to prevent complete precipitation of the EA. After 30 minutes, the hemolysis reaction was stopped by adding ice-cold NaCl solution containing 10 mM EDTA. The plate was centrifuged at 1000 x g for 2 minutes at 4°C to precipitate the unlysed EA. The supernatant was carefully transferred and the absorbance was measured at 405 nm. The percentage of hemolysis was calculated as: (OD test sample - OD BG or EDTA control)/(OD complete lysis - OD BG or EDTA control) x 100. IC50 values were calculated using Xlfit.TableE17: IC50 values of the indicated molecules assessed by typical pathway hemolysis assay #IdentifierIC50 (nM)95conf_i3 P1AG9372 (Mab) ＞ 20002 P1AG9376 (Mab) ＞ 20005 P1AG9391 (Mab) ＞ 20004 P1AG9420 (Mab) ＞ 5781 P1AG9426 (Mab) ＞ 20006 P1AH1205 (Fab) ＞ 60007 P1AH1199 (Fab) ＞ 6000 APL-2 1022 170.7 LNP023 ＞ 20,000

正如預期的那樣，LNP023 (一種因子 B 抑制劑) 不會抑制典型途逕。它僅對替代途徑係特異性的。實例14：與野生型人類C3bBb之結合As expected, LNP023 (a factor B inhibitor) does not inhibit the classical pathway. It is specific only for the alternative pathway.Example14:Bindingto wild-type humanC3bBb

經由 SPR 分析來分析本發明之抗體 P1AG9426 (#1) 與野生型人類 C3bBb 複合物特異性 結合。野生型人類C3bBb SPR測定The antibody P1AG9426 (#1) of the present invention specifically binds to the wild-type human C3bBb complex by SPR analysis.Wild-type humanC3bBb SPRassay

Biacore T200 系統配備有 CM5 晶片，並塗有 1x HBS-N (10 mM HEPES、150 mM NaCl)，由 10x 儲備溶液 (Cytiva BR100670) 製備。將抗人類 Fab 抗體 (Thermo Fisher Scientific 7103082100) 固定在胺偶合中的所有流通池 (FC1-4)，在 10 mM 乙酸鹽 pH 5 中以 10 µl/min 及 30 µg/ml 預設設置及捕獲抗體注射時間為 420 秒。The Biacore T200 system was equipped with a CM5 chip and coated with 1x HBS-N (10 mM HEPES, 150 mM NaCl) prepared from 10x stock solution (Cytiva BR100670). Anti-human Fab antibody (Thermo Fisher Scientific 7103082100) was immobilized in all flow cells (FC1-4) in amine coupling with a default setting of 10 µl/min and 30 µg/ml in 10 mM acetate pH 5 and capture antibody injection time of 420 seconds.

以下方法在 HBS-P + 1 mM NiSO₄中運行。如果沒有不同說明，將樣品在電泳緩衝液中稀釋。以 10 µl/min 捕獲抗體 60 秒 (在 HBS-N 中稀釋)。然後，以 10 µl/min 注射預先建構的 C3bBb wt 複合物 120 秒，解離 600 秒。該複合物係藉由於室溫孵育 300 nM 人類 C3b、310 nM 人類 wt 因子 B 及 40 nM 人類因子 D 5 分鐘來預先建構的。藉由在 60 秒內以 30 µl/min 注射 10 mM 甘胺酸 pH 2.1 來再生表面。藉由雙重參考 FC2 至 FC1 上的訊號及緩衝循環，注射電泳緩衝液而不是 C3bBb wt 複合物來分析分析資料。實例15：C5轉化酶抑制The following methods were run in HBS-P + 1 mM NiSO_4. If not stated differently, samples were diluted in electrophoresis buffer. Antibodies were captured at 10 µl/min for 60 sec (diluted in HBS-N). Then, pre-constituted C3bBb wt complex was injected at 10 µl/min for 120 sec and dissociated for 600 sec. The complex was pre-constituted by incubation of 300 nM human C3b, 310 nM human wt factor B and 40 nM human factor D for 5 min at room temperature. The surface was regenerated by injecting 10 mM glycine pH 2.1 at 30 µl/min for 60 sec. The data were analyzed by doubly referencing the signal on FC2 to FC1 and the buffer cycle by injecting electrophoresis buffer instead of the C3bBb wt complex.Example15:C5Convertase Inhibition

溶血測定：標準溶血測定進行了修改，以評定抗體在替代途徑 C5 轉化酶水平上的特異性抑制潛力。將樣品於 4°C 製備或保存在冰上，以免補體級聯反應啟動。將經洗滌的兔紅血球 (RBC) 添加至 V 型 96 孔板中，其含有適合替代途徑的低鹽 (60 mM NaCl) 緩衝液，但也含有 200 nM C5 抑制劑 (克羅伐單抗 (Crovalimab)) 以防止 MAC 形成。將細胞於 37°C 預熱 10 分鐘，然後添加冰冷的正常人類血清，最終測定濃度為 6.7%，並持續振盪再孵育 10 分鐘，以形成 C3 和 C5 轉化酶，但沒有 C5 裂解。藉由添加含有 40 mM EDTA 的緩衝液來停止進一步轉化酶的形成，將細胞離心，並在兩個連續步驟中重懸沉澱：首先使用含有最終 1.25% 豚鼠血清 (作為 MAC 形成所需的補體蛋白 C5-9 的來源) 、EDTA 及抗體 (濃度請參考表 E18) 的緩衝液，然後用含有 Mg-EGTA 的緩衝液。在這些條件下，沒有從頭形成轉化酶，且溶血的抑制係先前形成的 C5 轉化酶的抑制的直接結果。 將細胞於 37°C 持續振盪孵育 1 小時後測量溶血。表E18：所示抗體之 C5 轉化酶抑制#標識符濃度 (nM)抑制水平 [%]3P1AG9372 (Mab)21682P1AG9376 (Mab)58705P1AG9391 (Mab)52734P1AG9420 (Mab)165631P1AG9426 (Mab)276636P1AH1205 (Fab)5207420P1AF8499100070153PT5629.F09_30.A20_183973LNP0232000070Hemolysis assay: The standard hemolysis assay was modified to assess the specific inhibitory potential of antibodies at the level of the alternative pathway C5 convertase. Samples were prepared at 4°C or kept on ice to avoid initiation of the complement cascade. Washed rabbit red blood cells (RBCs) were added to V-shaped 96-well plates containing low-salt (60 mM NaCl) buffer appropriate for the alternative pathway, but also containing 200 nM C5 inhibitor (Crovalimab) to prevent MAC formation. Cells were prewarmed at 37°C for 10 min, then ice-cold normal human serum was added to a final measured concentration of 6.7% and incubated for another 10 min with constant shaking to allow for the formation of C3 and C5 convertases, but without C5 cleavage. Further convertase formation was stopped by the addition of a buffer containing 40 mM EDTA, the cells were centrifuged, and the pellet was resuspended in two consecutive steps: first with a buffer containing a final 1.25% guinea pig serum (as a source of complement protein C5-9 required for MAC formation), EDTA, and antibodies (concentrations see Table E18), and then with a buffer containing Mg-EGTA. Under these conditions, there is no de novo formation of the convertase and the inhibition of hemolysis is a direct result of the inhibition of the previously formed C5 convertase. Hemolysis was measured after incubation of the cells at 37°C with constant shaking for 1 hour.TableE18 : C5 Convertase Inhibition by the Indicated Antibodies #IdentifierConcentration(nM)Inhibition level [%]3 P1AG9372 (Mab) twenty one 682 P1AG9376 (Mab) 58 705 P1AG9391 (Mab) 52 734 P1AG9420 (Mab) 165 631 P1AG9426 (Mab) 276 636 P1AH1205 (Fab) 520 7420 P1AF8499 1000 70153 PT5629.F09_30.A20_1 839 73 LNP023 20000 70

圖1：左側影像顯示 P1AF8499 Fab 片段與 C3bBb 之間形成的三聚體複合物。P1AF8499 Fab 片段所結合之抗原決定基包含來自兩種組分 C3b 及 Bb 之胺基酸 (右側影像)。圖2：抗體 P1AG9426 (#1) 與野生型人類 C3bBb 複合物之結合。如實例 14 所述產生的傳感圖。Figure1: The left image shows the trimeric complex formed between the P1AF8499 Fab fragment and C3bBb. The antigenic determinant bound by the P1AF8499 Fab fragment contains amino acids from both components, C3b and Bb (right image).Figure2: Binding of antibody P1AG9426 (#1) to the wild-type human C3bBb complex. Sensorgram generated as described in Example 14.

TW202517673A_113136082_SEQL.xmlTW202517673A_113136082_SEQL.xml

Claims (15)

Translated fromChinese

一種與人類 C3bBb 結合之抗體。An antibody that binds to human C3bBb.一種與人類 C3bBb 結合之抗體，其中該抗體： 與野生型人類 C3bBb 結合；及/或 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:491 之因子 B (FB) 之 Bb 次單元； 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:492 之因子 B (FB) 之 Bb 次單元；及/或 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含根據 SEQ ID NO:493 之因子 B (FB) 之 Bb 次單元；及/或 與重組人類 C3bBb 結合，該重組人類 C3bBb 包含重組因子 B (FB) 蛋白之 Bb 次單元，該重組因子 B (FB) 蛋白包含 D279G 突變及視情況的突變 K350N 及/或 M458I； 抑制替代途徑；及/或 為 C3bBb 活性之促效劑或拮抗劑；及/或 與食蟹獼猴 C3bBb 及人類 C3bBb 特異性結合， 與非洲綠猴 C3bBb 及人類 C3bBb 特異性結合， 藉由 SPR 所測量，在 37°C 以 ≤ 300 pM 之親和力結合，及/或 不能穩定 C3 轉化酶。An antibody that binds to human C3bBb, wherein the antibody: binds to wild-type human C3bBb; and/or binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:491; binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:492; and/or binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of factor B (FB) according to SEQ ID NO:493; and/or binds to recombinant human C3bBb, the recombinant human C3bBb comprising the Bb subunit of recombinant factor B (FB) protein Bb subunit, the recombinant factor B (FB) protein comprises the D279G mutation and, as appropriate, the mutations K350N and/or M458I;inhibits the alternative pathway; and/oris an agonist or antagonist of C3bBb activity; and/orbinds specifically to cynomolgus macaque C3bBb and human C3bBb,binds specifically to African green monkey C3bBb and human C3bBb,binds with an affinity of ≤ 300 pM at 37°C as measured by SPR, and/ordoes not stabilize C3 convertase.一種與人類 C3bBb 結合之抗體，其與人類 C3bBb 之抗原決定基結合，該抗原決定基包括 C3b 次單元之胺基酸殘基及人類 FB 之 Bb 次單元之胺基酸殘基。An antibody that binds to human C3bBb binds to an antigenic determinant of human C3bBb, wherein the antigenic determinant includes an amino acid residue of a C3b subunit and an amino acid residue of a Bb subunit of human FB.一種與人類 C3bBb 結合之抗體，其與藉由低溫電子顯微鏡術所檢測的在 C3bBb 上包含下列胺基酸殘基之抗原決定基結合： C3b 次單元：Arg444、Lys534、Gly539、Ser540、Val524、Lys544、Gly546、Gln547、Ser548、Arg551、Gln557、Gln558、Thr560、Lys562、Glu564、Glu758、Pro759、Lys761、Asn762、Ile764、Leu768、Asn770、Asp797，以及 Bb 次單元：Tyr465、Lys473、Ile474、Ser475、Ile477、Gly482、His483、Lys513、Val514、Ser515、Lys520、Arg521、Asp522、Glu610、Lys613。An antibody that binds to human C3bBb, which binds to an antigenic determinant comprising the following amino acid residues on C3bBb as detected by cryogenic electron microscopy:C3b subunit: Arg444, Lys534, Gly539, Ser540, Val524, Lys544, Gly546, Gln547, Ser548, Arg551, Gln557, Gln558, Thr560, Lys562, Glu564, Glu758, Pro759, Lys761, Asn762, Ile764, Leu768, Asn770, Asp797, andBb Subunits: Tyr465, Lys473, Ile474, Ser475, Ile477, Gly482, His483, Lys513, Val514, Ser515, Lys520, Arg521, Asp522, Glu610, Lys613.一種與具有 SEQ ID NO: 39 之 VH 域及 SEQ ID NO: 40 之 VL 域之抗體 (P1AF8499) 結合相同或重疊抗原決定基之抗體。An antibody that binds to the same or overlapping antigenic determinant as an antibody (P1AF8499) having a VH domain of SEQ ID NO: 39 and a VL domain of SEQ ID NO: 40.一種與人類 C3bBb 結合之抗體，其中該抗體包含選自表 D1 之抗體之重鏈及輕鏈 CDR。An antibody that binds to human C3bBb, wherein the antibody comprises heavy chain and light chain CDRs of an antibody selected from Table D1.如前述請求項中任一項之抗體，其包含 i)  重鏈可變域 (VH) (a) 包含 SEQ ID NO:449 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:450 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:451 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:452 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:453 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:454 之胺基酸序列的 CDR-L3 (對應於抗體 #1，P1AG9426)； ii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:455 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:456 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:457 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:458 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:459 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:460 之胺基酸序列的 CDR-L3 (對應於抗體 #2，P1AG9376)； iii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:461 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:462 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:463 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:464 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:465 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:466 之胺基酸序列的 CDR-L3 (對應於抗體 #3，P1AG9372)； iv)  重鏈可變域 (VH) (a) 包含 SEQ ID NO:467 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:468 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:469 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:470 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:471 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:472 之胺基酸序列的 CDR-L3 (對應於抗體 #4，P1AG9420)； v) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:473 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:474 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:475 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:476 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:477 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:478 之胺基酸序列的 CDR-L3 (對應於抗體 #5，P1AG9391)； vi)  重鏈可變域 (VH) (a) 包含 SEQ ID NO:479 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:480 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:481 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:482 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:483 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:484 之胺基酸序列的 CDR-L3 (對應於抗體 #6，P1AH1205)；或 vii) 重鏈可變域 (VH) (a) 包含 SEQ ID NO:485 之胺基酸序列的 CDR-H1；(b) 包含 SEQ ID NO:486 之胺基酸序列的 CDR-H2；及 (c) 包含 SEQ ID NO:487 之胺基酸序列的 CDR-H3；以及輕鏈可變域 (VL)，其包含：(d) 包含 SEQ ID NO:488 之胺基酸序列的 CDR-L1；(e) 包含 SEQ ID NO:489 之胺基酸序列的 CDR-L2；及 (f) 包含 SEQ ID NO:490 之胺基酸序列的 CDR-L3 (對應於抗體 #7，P1AH1199)。An antibody as claimed in any of the preceding claims, comprisingi) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:449; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:450; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:451; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:452; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:453; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:454 (corresponding to antibody #1, P1AG9426);ii) a heavy chain variable domain (VH) (a) comprising SEQ ID NO:455; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:456; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:457; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:458; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:459; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:460 (corresponding to antibody #2, P1AG9376);iii) heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:461; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:462 CDR-H2; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:463; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:464; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:465; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:466 (corresponding to antibody #3, P1AG9372);iv)  Heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:467; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:468; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO:469 CDR-H3; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:470; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:471; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:472 (corresponding to antibody #4, P1AG9420);v) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:473; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:474; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:475; and a light chain variable domain (VL) comprising: (d) CDR-L2 comprising the amino acid sequence of SEQ ID NO:476 (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:477; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:478 (corresponding to antibody #5, P1AG9391); vi)  A heavy chain variable domain (VH) (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:479; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:480; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:481; and a light chain variable domain (VL) comprising: (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:482; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:483 CDR-L2; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:484 (corresponding to antibody #6, P1AH1205); orvii) a heavy chain variable domain (VH) (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:485; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:486; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:487; and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:488; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:489; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:490 (Corresponding to antibody #7, P1AH1199).如前述請求項中任一項之抗體，其中該抗體包含具有 VH3 骨架之 VH 域及具有 Vκ1 骨架之 VL 域。The antibody of any of the preceding claims, wherein the antibody comprises a VH domain having a VH3 framework and a VL domain having a Vκ1 framework.如前述請求項中任一項之抗體，其包含選自由以下所組成之群組的序列： i)   包含 SEQ ID NO:1 之 VH 域及包含 SEQ ID NO:2 之 VL 域 (對應於抗體 #1，P1AG9426)； ii)  包含 SEQ ID NO:3 之 VH 域及包含 SEQ ID NO:4 之 VL 域 (對應於抗體 #2，P1AG9376)； iii) 包含 SEQ ID NO:5 之 VH 域及包含 SEQ ID NO:6 之 VL 域 (對應於抗體 #3，P1AG9372)； iv)  包含 SEQ ID NO:7 之 VH 域及包含 SEQ ID NO:8 之 VL 域 (對應於抗體 #4，P1AG9420)； v)   包含 SEQ ID NO:9 之 VH 域及包含 SEQ ID NO:10 之 VL 域 (對應於抗體 #5，P1AG9391)； vi)  包含 SEQ ID NO:11 之 VH 域及包含 SEQ ID NO:12 之 VL 域 (對應於抗體 #6，P1AH1205)；或 vii) 包含 SEQ ID NO:13 之 VH 域及包含 SEQ ID NO:14 之 VL 域 (對應於抗體 #7，P1AH1199)。An antibody as claimed in any of the preceding claims, comprising a sequence selected from the group consisting of: i)   comprising a VH domain of SEQ ID NO:1 and a VL domain of SEQ ID NO:2 (corresponding to antibody #1, P1AG9426); ii)  comprising a VH domain of SEQ ID NO:3 and a VL domain of SEQ ID NO:4 (corresponding to antibody #2, P1AG9376); iii)  comprising a VH domain of SEQ ID NO:5 and a VL domain of SEQ ID NO:6 (corresponding to antibody #3, P1AG9372); iv)  comprising a VH domain of SEQ ID NO:7 and a VL domain of SEQ ID NO:8 (corresponding to antibody #4, P1AG9420); v)   comprising a VH domain of SEQ ID NO:9 domain and a VL domain comprising SEQ ID NO:10 (corresponding to antibody #5, P1AG9391);vi) a VH domain comprising SEQ ID NO:11 and a VL domain comprising SEQ ID NO:12 (corresponding to antibody #6, P1AH1205); orvii) a VH domain comprising SEQ ID NO:13 and a VL domain comprising SEQ ID NO:14 (corresponding to antibody #7, P1AH1199).一種經分離之核酸，其編碼如請求項 1 至 8 中任一項之抗體。An isolated nucleic acid encoding the antibody of any one of claims 1 to 8.一種宿主細胞，其包含如請求項 9 之核酸。A host cell comprising the nucleic acid of claim 9.一種生產與人類 C3bBb 結合的抗體之方法，其包含在適合於該抗體之表現的條件下培養如請求項 10 之宿主細胞。A method for producing an antibody that binds to human C3bBb, comprising culturing the host cell of claim 10 under conditions suitable for the expression of the antibody.一種醫藥組成物，其包含如請求項 1 至 8 中任一項之抗體以及醫藥上可接受之載劑。A pharmaceutical composition comprising the antibody of any one of claims 1 to 8 and a pharmaceutically acceptable carrier.如請求項 1 至 8 中任一項之抗體或如請求項 12 之醫藥組成物，其用為藥物。The antibody of any one of claims 1 to 8 or the pharmaceutical composition of claim 12, which is used as a drug.如請求項 1 至 8 中任一項之抗體或如請求項 12 中任一項之醫藥組成物在製造用於治療眼部疾病之藥物中之用途。Use of an antibody as claimed in any one of claims 1 to 8 or a pharmaceutical composition as claimed in any one of claim 12 in the manufacture of a medicament for treating an eye disease.