TW202426048A - Supplemental dosage and administration of anti-c5 antibodies for treating hematopoietic stem cell transplant-associated thrombotic microangiopathy (hsct-tma) - Google Patents

Abstract

Provided herein are methods for treating HSCT-TMA in a particular patient sub-population (e.g., HSCT-TMA patients with body weight ≥30 kg who received a transfusion (e.g., platelet or red blood cell (RBC) transfusion) in the 4 weeks following a maintenance dose), comprising administering to the patient an anti‑C5 antibody, or antigen binding fragment thereof, wherein the anti‑C5 antibody, or antigen binding fragment thereof, is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at particular loading, maintenance, and supplemental dose amounts, and according to a specific schedule).

Description

Translated fromChinese

用於治療造血幹細胞移植相關血栓性微血管病（HSCT-TMA）的抗C5抗體的補充劑量和投與Supplemental dose and administration of anti-C5 antibodies for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)

相關申請的交叉引用Cross-references to related applications

本申請要求美國臨時申請案號63/404061（於2022年9月6日提交）和美國臨時申請案號63/440984（於2023年1月25日提交）的優先權和權益。上述申請的全部內容藉由引用併入本文。This application claims priority to and the benefit of U.S. Provisional Application No. 63/404061 (filed on September 6, 2022) and U.S. Provisional Application No. 63/440984 (filed on January 25, 2023), the entire contents of which are incorporated herein by reference.

血栓性微血管病（Thrombotic microangiopathy，TMA）係造血幹細胞移植（hematopoietic stem cell transplant，HSCT）的移植後併發症，可影響10%至35%的HSCT受者（Dvorak等人,Front Pediatr. [兒科前沿] 2019;7:133）；Jodele等人,Blood Rev. [血液評論] 2015; 29(3):191-204；Seaby等人,Pediatr Nephrol. [兒科腎臟病學] 2018;33(9):1489-1500）。其經由內皮損傷出現並影響腎臟和其他器官。據估計，30%的患有HSCT TMA患者將表現出重度疾病（Rosenthal等人,J. Blood Med. [血醫學雜誌] 2016;7:181-186），並且在該等情況下，患有HSCT-TMA的患者發生全身性血管損傷，表現為腎損害、漿膜炎、肺性高血壓和多系統器官衰竭。據報導，患有HSCT-TMA的患者在1年時的生存率為18%至40%（Wanchoo等人,Am. J. Kidney Dis. [美國腎臟病雜誌] 2018;72(6):857-865）。重度HSCT-TMA與大約80%的長期發病率和死亡率相關。研究表明，大多數患者在6個月內死亡（Cho等人,Bone Marrow Transplant. [骨髓移植] 2008;41(9):813-820；Cho等人,Transplantation. [移植] 2010;90(8):918-926; Oran, 2007）。另一項研究顯示了未接受TMA靶向療法的重度HSCT-TMA患者9%的總生存率，其中所有死亡均發生在TMA診斷10個月內（Jodele等人,Blood. [血液] 2014b;124(4):645-653）。Thrombotic microangiopathy (TMA) is a post-transplant complication of hematopoietic stem cell transplant (HSCT) that affects 10% to 35% of HSCT recipients (Dvorak et al.,Front Pediatr . 2019;7:133); Jodele et al.,Blood Rev. 2015;29(3):191-204; Seaby et al.,Pediatr Nephrol . 2018;33(9):1489-1500). It occurs via endothelial damage and affects the kidney and other organs. It is estimated that 30% of patients with HSCT TMA will present with severe disease (Rosenthal et al.,J. Blood Med . 2016;7:181-186), and in these settings, patients with HSCT-TMA develop systemic vascular damage manifested by renal damage, serous inflammation, pulmonary hypertension, and multisystem organ failure. Survival rates at 1 year for patients with HSCT-TMA have been reported to be 18% to 40% (Wanchoo et al.,Am. J. Kidney Dis . 2018;72(6):857-865). Severe HSCT-TMA is associated with approximately 80% long-term morbidity and mortality. Studies have shown that most patients die within 6 months (Cho et al.,Bone Marrow Transplant . 2008;41(9):813-820; Cho et al.,Transplantation . 2010;90(8):918-926; Oran, 2007). Another study showed an overall survival rate of 9% in patients with severe HSCT-TMA who did not receive TMA-targeted therapy, with all deaths occurring within 10 months of TMA diagnosis (Jodele et al.,Blood . 2014b;124(4):645-653).

在兒童患者中，HSCT-TMA通常發生在同種異體HSCT後早期，其中中位診斷在HSCT後35至47天，並且88%至92%發生在第+100天之前。然而，在HSCT後長達2年仍有病例報導。自體受者可甚至更早發生HSCT TMA，其中中位數為在HSCT後18天（Dvorak等人,Front Pediatr. [兒科前沿] 2019;7:133）。In pediatric patients, HSCT-TMA typically develops early after allogeneic HSCT, with a median diagnosis of 35 to 47 days after HSCT and 88% to 92% occurring before day +100. However, cases have been reported up to 2 years after HSCT. Autologous recipients may develop HSCT TMA even earlier, with a median of 18 days after HSCT (Dvorak et al.,Front Pediatr . 2019;7:133).

內皮損傷係HSCT-TMA發病機理的基礎，其中補體激活失調可能是內皮損傷的結果。與HSCT-TMA發生相關並引發內皮損傷的風險因素包括鈣調磷酸酶抑制劑（CNI）、感染和預處理方案（高劑量化學治療或全身放射治療）（Khosla等人,Bone Marrow Transplant.[骨髓移植] 2018;53(2):129-137；Masias等人,Blo od. [血液] 2017;129(21):2857-2863）。Endothelial injury underlies the pathogenesis of HSCT-TMA, and dysregulated complement activation may be a consequence of endothelial injury. Risk factors associated with the development of HSCT-TMA and causing endothelial injury include calcineurin inhibitors (CNIs), infection, and conditioning regimen (high-dose chemotherapy or whole-body radiation therapy) (Khosla et al.,Bone Marrow Transplant. 2018;53(2):129-137; Masias et al.,Blood . 2017;129(21):2857-2863).

目前，還沒有經批准的用於治療HSCT-TMA的療法。HSCT-TMA的主要干預涉及停用觸犯劑（例如CNI）和/或治療任何觸發條件（例如感染的治療）（Dvorak, 等人,Front Pediatr. [兒科前沿] 2019;7:133）；Seaby等人，Pediatr. Nephrol.[兒科腎臟病學] 2018;33(9):1489-1500）。在一些患者中，停用觸犯劑和/或治療任何相關的觸發條件並不能逆轉HSCT-TMA。因此，本揭露之目的係提供用於治療HSCT-TMA患者之改進方法。Currently, there are no approved therapies for the treatment of HSCT-TMA. The primary intervention for HSCT-TMA involves discontinuation of triggering agents (e.g., CNIs) and/or treatment of any triggering conditions (e.g., treatment of infection) (Dvorak, et al.,Front Pediatr . 2019;7:133); Seaby et al.,Pediatr. Nephrol. 2018;33(9):1489-1500). In some patients, discontinuation of triggering agents and/or treatment of any associated triggering conditions does not reverse HSCT-TMA. Therefore, an object of the present disclosure is to provide improved methods for the treatment of patients with HSCT-TMA.

藉由本發明，發現根據特定的臨床劑量方案（例如，以特定的負荷和維持劑量，和根據特定的給藥時間表）用瑞利珠單抗（ravulizumab）治療的HSCT-TMA患者（接受了一次或多次輸注（例如血小板或紅血球（RBC）輸注））經歷了更快的抗體清除（例如，與未輸注的患者相比），因此用補充劑量的瑞利珠單抗治療HSCT-TMA患者的輸注隊列提供了有意義的臨床益處。特別地，使用補充給藥模擬模型，發明人確定了遞送補充劑量的瑞利珠單抗以在給藥間隔期間分別獲得474（200）µg/mL與1350（430）µg/mL之間的平均（標準差）最小和最大瑞利珠單抗血漿濃度，為在治療期間接受輸注（例如RBC輸注）的HSCT-TMA患者提供了更有效的治療。特別地，如非限制性實例所例示的，在維持劑量後4週向在該維持劑量後4週內接受了任何（例如，一次、兩次、三次或更多次）RBC輸注的體重 ≥ 30 kg的HSCT患者投與補充劑量的瑞利珠單抗。補充瑞利珠單抗劑量方案實現了立即、完全和持續的末端補體抑制。補充給藥方案也應用於有效治療較低體重（例如，＜ 30 kg）和特別地超低體重（例如，＜ 20 kg，特別地 ＜ 10 kg）隊列中的HSCT-TMA患者。According to the present invention, it was found that HSCT-TMA patients (who received one or more transfusions (e.g., platelet or red blood cell (RBC) transfusions)) treated with ravulizumab according to a specific clinical dosing regimen (e.g., at specific loading and maintenance doses, and according to a specific dosing schedule) experienced faster antibody clearance (e.g., compared to patients who were not transfused), and thus treating the transfusion queue of HSCT-TMA patients with supplemental doses of ravulizumab provides significant clinical benefit. In particular, using the supplemental dosing simulation model, the inventors determined that delivering a supplemental dose of reslizumab to achieve a mean (standard deviation) minimum and maximum reslizumab plasma concentration between 474 (200) µg/mL and 1350 (430) µg/mL, respectively, during the dosing interval provided more effective treatment for HSCT-TMA patients who received transfusions (e.g., RBC transfusions) during treatment. In particular, as illustrated by non-limiting example, a supplemental dose of reslizumab was administered 4 weeks after a maintenance dose to HSCT patients weighing ≥ 30 kg who received any (e.g., one, two, three or more) RBC transfusions within 4 weeks after the maintenance dose. The supplemental reslizumab dosing regimen achieved immediate, complete, and sustained terminal complement suppression. The supplemental dosing regimen also has applications in effectively treating HSCT-TMA patients in the lower-weight (e.g., < 30 kg) and particularly ultra-low-weight (e.g., < 20 kg, particularly < 10 kg) cohort.

在其他實施方式中，如非限制性實例所例示的，在維持劑量後的指定時間範圍，向在該維持劑量後的指定時間範圍（例如，對於 ＜ 20 kg的患者為2週，對於 ≥ 20 kg（例如，20 kg ＜ 30 kg；30 kg ＜ 40 kg；40 kg ＜ 60 kg；60 kg ＜ 100 kg；或 ≥ 100 kg）的患者為4週）內接受任何（例如，一次、兩次、三次或更多次）RBC輸注的體重 ＜ 30 kg的HSCT患者投與補充劑量的瑞利珠單抗。補充瑞利珠單抗劑量方案實現了立即、完全和持續的末端補體抑制。In other embodiments, as illustrated by non-limiting example, a supplemental dose of reslizumab is administered to HSCT patients weighing < 30 kg who receive any (e.g., one, two, three, or more) RBC transfusions within a specified time range after a maintenance dose (e.g., 2 weeks for patients < 20 kg, 4 weeks for patients ≥ 20 kg (e.g., 20 kg < 30 kg; 30 kg < 40 kg; 40 kg < 60 kg; 60 kg < 100 kg; or ≥ 100 kg)). The supplemental reslizumab dosing regimen achieves immediate, complete, and sustained terminal complement suppression.

因此，本文提供了用於治療 特定患者亞群（例如，在維持劑量後4週內接受輸注（例如，血小板或RBC輸注）的體重 ≥ 30 kg的HSCT-TMA患者）的HSCT-TMA之方法，該方法包括向患者投與抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段根據特定的臨床劑量方案（例如，以特定的負荷、維持和一或多個補充劑量，和根據特定的時間表）投與（或用於投與）。本文還提供了用於治療 特定患者亞群（例如，在維持劑量後2週（＜ 20 kg）或4週（≥ 20 kg至30 kg）內接受輸注（例如，血小板或RBC輸注）的體重 ＜ 30 kg的HSCT-TMA患者）的HSCT-TMA之方法，該方法包括向患者投與抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段根據特定的臨床劑量方案（例如，以特定的負荷、維持和一或多個補充劑量，和根據特定的時間表）投與（或用於投與）。Thus, provided herein are methods for treating HSCT-TMA in a specific patient subpopulation (e.g., HSCT-TMA patients weighing ≥ 30 kg who receive a transfusion (e.g., a platelet or RBC transfusion) within 4 weeks after a maintenance dose), the method comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (e.g., with a specific loading, maintenance and one or more supplemental doses, and according to a specific schedule). Also provided herein are methods for treating HSCT-TMA in specific patient subpopulations (e.g., HSCT-TMA patients weighing <30 kg who receive transfusions (e.g., platelet or RBC transfusions) within 2 weeks (<20 kg) or 4 weeks (≥20 kg to 30 kg) after a maintenance dose), the method comprising administering an anti-C5 antibody or an antigen-binding fragment thereof to the patient, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (e.g., with specific loading, maintenance and one or more supplemental doses, and according to a specific schedule).

示例性抗C5抗體係包含分別具有SEQ ID NO:14和11所示序列的重鏈和輕鏈的瑞利珠單抗（ULTOMIRIS®）或其抗原結合片段和變體。在其他實施方式中，抗體包含瑞利珠單抗的重鏈和輕鏈互補決定區（CDR）或可變區（VR）。因此，在一個實施方式中，抗體包含具有SEQ ID NO:12所示序列的瑞利珠單抗重鏈可變（VH）區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的瑞利珠單抗輕鏈可變（VL）區的CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列。在另一個實施方式中，抗體包含分別具有SEQ ID NO:12和SEQ ID NO:8所示胺基酸序列的VH和VL區。在另一個實施方式中，抗體包含如SEQ ID NO:13所示的重鏈恒定區。Exemplary anti-C5 antibodies are reslizumab (ULTOMIRIS®) or antigen-binding fragments and variants thereof comprising heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively. In other embodiments, the antibody comprises the heavy and light chain complementation determining regions (CDRs) or variable regions (VRs) of reslizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the reslizumab heavy chain variable (VH) region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the reslizumab light chain variable (VL) region having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having amino acid sequences as shown in SEQ ID NOs: 12 and 8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as shown in SEQ ID NO: 13.

在另一個實施方式中，抗體包含與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中變體人Fc CH3恒定區在對應於天然人IgG Fc恒定區的甲硫胺酸428和天冬醯胺434的殘基處包含Met429Leu和Asn435Ser取代，各自根據EU編號規定編號。In another embodiment, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each numbered according to the EU numbering convention.

在另一個實施方式中，抗體包含分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，和分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列；以及與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中該變體人Fc CH3恒定區在對應於天然人IgG Fc恒定區的甲硫胺酸428和天冬醯胺434的殘基處包含Met429Leu和Asn435Ser取代，各自根據EU編號規定編號。In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively; and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each numbered according to the EU numbering convention.

在另一個實施方式中，抗C5抗體包含BNJ421抗體的重鏈和輕鏈CDR或可變區（WO 2015134894和美國專利案號9,079,949所述）。在另一個實施方式中，抗C5抗體包含7086抗體的重鏈和輕鏈CDR或可變區（參見美國專利案號8,241,628和8,883,158）。在另一個實施方式中，抗C5抗體包含8110抗體的重鏈和輕鏈CDR或可變區（參見美國專利案號8,241,628和8,883,158）。在另一個實施方式中，抗C5抗體包含305LO5抗體的重鏈和輕鏈CDR或可變區（參見美國專利案號9,765,135）。在另一個實施方式中，抗C5抗體包含SKY59抗體的重鏈和輕鏈CDR或可變區。在另一個實施方式中，抗C5抗體包含REGN3918抗體的重鏈和輕鏈CDR或可變區。In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the BNJ421 antibody (described in WO 2015134894 and U.S. Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the 8110 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the 305LO5 antibody (see U.S. Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy chain and light chain CDRs or variable regions of the REGN3918 antibody.

在另一個實施方式中，抗C5抗體係依庫珠單抗（eculizumab）（SOLIRIS®）的生物類似物。例如，在一個實施方式中，抗C5抗體係例如ABP 959抗體（由美國安進公司（Amgen Inc.，USA）製造）、ELIZARIA®（由俄羅斯Generium JNC公司（Generium JNC，Russia）製造）、SB12（由韓國仁川三星Bioepis公司（Samsung Bioepis，Incheon，South Korea）製造）、ISU305（來自韓國ISU Abxis公司（ISU Abxis, South Korea）的依庫珠單抗生物類似物）、ABLYZE®（來自伊朗CinnaGen公司（CinnaGen，Iran）的依庫珠單抗生物類似物）、BCD 148（來自加拿大魁北克省Biocad醫療公司（Biocad Medical，Quebec，Canada）的依庫珠單抗生物類似物）、特度魯單抗（tesidolumab）（由諾華股份有限公司（Novartis）製造）、可伐利單抗（Crovalimab）（由羅氏公司（Roche）製造）、CAN106（由中國北海康成製藥有限公司（CanBridge Pharmaceuticals，China）製造）或帕澤利單抗（Pozelimab）（由再生元製藥公司（Regeneron）製造）。In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP 959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), SB12 (manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD 148 (manufactured by Biocad Medical, Quebec, Canada), Medical, Quebec, Canada), tesidolumab (made by Novartis), crovalimab (made by Roche), CAN106 (made by CanBridge Pharmaceuticals, China), or pozelimab (made by Regeneron).

在另一個實施方式中，抗體與上述抗體中任意一個競爭結合C5上的相同表位和/或與C5上相同的表位結合。在另一個實施方式中，抗體與上述抗體中任意一個具有至少約90%的可變區胺基酸序列同一性（例如，與SEQ ID NO:12或SEQ ID NO:8具有至少約90%、95%或99%的可變區同一性）。In another embodiment, the antibody competes for binding to the same epitope on C5 and/or binds to the same epitope on C5 as any of the above antibodies. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with any of the above antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

在另一個實施方式中，抗體在pH 7.4和25°C下以在0.1 nM ≤ K_D≤ 1 nM範圍內的親和解離常數（K_D）結合人C5。在另一個實施方式中，抗體在pH 7.4和25°C下以約0.5 nM的親和解離常數（K_D）結合人C5。在另一個實施方式中，抗體在pH 6.0和25°C下以K_D≥ 10 nM結合人C5。在另一個實施方式中，抗體在pH 6.0和25°C下以約22 nM的K_D結合人C5。在又一個實施方式中，抗體的[（抗體或其抗原結合片段在pH 6.0和25°C下對人C5的K_D）/（抗體或其抗原結合片段在pH 7.4和25°C對人C5的K_D）]大於25。In another embodiment, the antibody binds human C5 at pH 7.4 and 25°C with an affinity dissociation constant (_KD ) in the range of 0.1 nM ≤_KD ≤ 1 nM. In another embodiment, the antibody binds human C5 at pH 7.4 and 25°C with an affinity dissociation constant (_KD ) of about 0.5 nM. In another embodiment, the antibody binds human C5 at pH 6.0 and 25°C with a_KD ≥ 10 nM. In another embodiment, the antibody binds human C5 at pH 6.0 and 25°C with a_KD of about 22 nM. In yet another embodiment, the antibody has [(_KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and 25°C)/(_KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and 25°C)] greater than 25.

在某些實施方式中，本文所述之劑量方案提供最佳期望響應（例如，有效治療）。在一些實施方式中，有效治療包括在HSCT-TMA患者中獲得立即、完全和持續的末端補體抑制。In certain embodiments, the dosage regimens described herein provide the best desired response (e.g., effective treatment). In some embodiments, effective treatment includes obtaining immediate, complete, and sustained terminal complement suppression in HSCT-TMA patients.

根據本揭露，提供了用於治療經歷了輸注（例如，血小板或RBC輸注）的患者中HSCT-TMA之方法，其中本揭露的抗C5抗體（或抗原結合片段）以包含分階段給藥、隨後維持給藥和補充給藥的給藥週期投與。在實施方式中，抗C5抗體或其抗原結合片段在（例如，投與週期的）第1天以負荷劑量投與一次，在（例如，投與週期的）第5天以負荷劑量投與一次，在（例如，投與週期的）第10天以負荷劑量投與一次，並且此後從第15天開始每八週投與維持劑量。在另一個實施方式中，維持劑量的抗C5抗體或其抗原結合片段在治療（例如，投與週期）之後每八週投與，持續長達兩年的延長期。According to the present disclosure, a method for treating HSCT-TMA in patients who have undergone transfusions (e.g., platelet or RBC transfusions) is provided, wherein the anti-C5 antibody (or antigen-binding fragment) of the present disclosure is administered in a dosing cycle comprising a phased administration, followed by a maintenance administration, and a supplemental administration. In an embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once in a loading dose on day 1 (e.g., of the administration cycle), once in a loading dose on day 5 (e.g., of the administration cycle), once in a loading dose on day 10 (e.g., of the administration cycle), and thereafter a maintenance dose is administered every eight weeks starting from day 15. In another embodiment, a maintenance dose of an anti-C5 antibody or antigen-binding fragment thereof is administered every eight weeks following treatment (e.g., administration cycle) for an extension period of up to two years.

在實施方式中，抗C5抗體或其抗原結合片段在（例如，投與週期的）第1天以負荷劑量投與一次，在（例如，投與週期的）第5天以負荷劑量投與一次，在（例如，投與週期的）第10天以負荷劑量投與一次，此後從第15天開始每八週投與維持劑量，並投與補充劑量。在實施方式中，向在維持劑量的四週內接受紅血球（RBC）輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。在另一個實施方式中，向在維持劑量的四週內接受RBC輸注的體重≥ 30 kg的患者投與補充劑量，其中該補充劑量在該維持劑量後四週按以下劑量投與：體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg。In embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered once as a loading dose on day 1 (e.g., of a dosing cycle), once as a loading dose on day 5 (e.g., of a dosing cycle), once as a loading dose on day 10 (e.g., of a dosing cycle), and thereafter a maintenance dose and a supplemental dose every eight weeks starting on day 15. In embodiments, a supplemental dose is administered to a patient who receives a red blood cell (RBC) transfusion within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose. In another embodiment, a supplemental dose is administered to patients weighing ≥ 30 kg who receive RBC transfusions within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses: 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or the antigen-binding fragment thereof is administered as follows: (a) Once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 1200 mg for patients weighing ≥ 40 to < 60 kg kg, 2400 mg for patients weighing ≥ 60 to < 100 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, mg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on Day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, and 900 mg for patients weighing ≥ 3300 mg for patients weighing 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and wherein the supplemental dose is administered to:(i)     a patient weighing < 30 kg who receives a red blood cell (RBC) transfusion within a specified time frame of the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose as follows:a. 300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b. 600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, orc. 2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or(ii)  Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of a maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向患者投與有效量的包含以下的抗C5抗體：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，和分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，以及與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中變體人Fc CH3恒定區在對應於天然人IgG Fc恒定區的甲硫胺酸428和天冬醯胺434的殘基處包含Met429Leu和Asn435Ser取代，各自根據EU編號規定編號，其中該抗C5抗體按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, and a variant human Fc constant region that binds to a human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each numbered according to EU numbering regulations, wherein the anti-C5 antibody is administered as follows:(a) Once on day 1, as a loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg mg for patients weighing ≥ 60 to < 100 kg, 900 mg for patients weighing ≥ 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10 as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter as a maintenance dose: 300 or 400 mg for patients weighing 5 to < 10 kg or 10 to < 20 kg kg, or(ii)    every eight weeks thereafter, at a maintenance dose of: 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and wherein the supplemental dose is administered to:(i)     a patient weighing < 30 kg who receives a red blood cell (RBC) transfusion within the specified time frame of the maintenance dose, wherein the supplemental dose is administered within the specified time frame after the maintenance dose at the following doses:a.  300 or 400 mg for patients weighing 5 to < 10 kg mg, where the specified time frame is two weeks, b. 600 or 800 mg for patients weighing 10 to < 20 kg, where the specified time frame is two weeks, or c. 2100 mg for patients weighing 20 to < 30 kg, where the specified time frame is four weeks, or (ii)    patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose as follows: a. 2700 mg for patients weighing ≥ 30 to < 40 kg, b. 3000 mg for patients weighing ≥ 40 to < 60 kg, c. 3300 mg for patients weighing ≥ 60 to < 100 kg, or d. 3600 mg for a 100 kg patient.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的瑞利珠單抗，其中瑞利珠單抗按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of reslizumab, wherein reslizumab is administered as follows:(a) once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, at the following loading dose: 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and(i)     every 30 weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; andkg who receive red blood cell (RBC) transfusions within a specified time frame of the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose at the following doses: a. 300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks, b. 600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, or c. 2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or (ii)    patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a.  2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c.  3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

並且其中該治療使得LDH水平降低至正常水平內或降低至低於視為的ULN水平（例如，在105-333 IU/L（國際單位/升）以內）50%以內，抗C5抗體或其抗原結合片段的血清谷濃度為至少175 µg/mL或更高，和/或游離C5濃度為0.5 µg/mL或更低（例如，0.4 µg/mL、0.3 µg/mL、0.2 µg/mL、或0.1 µg/mL或更低）。and wherein the treatment results in a reduction in LDH levels to within normal levels or to within 50% below levels considered to be ULN (e.g., within 105-333 IU/L (International Units/L)), a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of at least 175 µg/mL or greater, and/or a free C5 concentration of 0.5 µg/mL or less (e.g., 0.4 µg/mL, 0.3 µg/mL, 0.2 µg/mL, or 0.1 µg/mL or less).

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按300 mg的維持劑量；以及 (e) 向在維持劑量的指定時間範圍內接受RBC輸注的患者投與300 mg的補充劑量，其中該補充劑量在該維持劑量後的指定時間範圍投與，其中該指定時間範圍係兩週。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 5 to <10 kg as follows: (a) once on day 1, at a loading dose of 600 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; (d) On day 15 and every four weeks thereafter, at a maintenance dose of 300 mg; and(e) administering a supplemental dose of 300 mg to patients who receive RBC transfusions within a specified time frame of the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose, wherein the specified time frame is two weeks.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按400 mg的維持劑量；以及 (e) 向在維持劑量的指定時間範圍內接受RBC輸注的患者投與400 mg的補充劑量，其中該補充劑量在該維持劑量後的指定時間範圍投與，其中該指定時間範圍係兩週。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 5 to <10 kg as follows: (a) once on day 1, at a loading dose of 600 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; (d) On day 15 and every four weeks thereafter, at a maintenance dose of 400 mg; and(e) administering a supplemental dose of 400 mg to patients who receive RBC transfusions within a specified time frame of the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose, wherein the specified time frame is two weeks.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按600 mg的維持劑量，以及 (e) 向在維持劑量的指定時間範圍內接受RBC輸注的患者投與600 mg的補充劑量，其中該補充劑量在該維持劑量後的指定時間範圍投與，其中該指定時間範圍係兩週。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients transfused with RBCs, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 10 to < 20 kg as follows:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) a maintenance dose of 600 mg on day 15 and every four weeks thereafter, and(e) a supplemental dose of 600 mg to patients who receive RBC transfusions within a specified time frame of the maintenance dose, where the supplemental dose is administered within a specified time frame after the maintenance dose, where the specified time frame is two weeks.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按800 mg的維持劑量，以及 (e) 向在維持劑量的指定時間範圍內接受RBC輸注的患者投與800 mg的補充劑量，其中該補充劑量在該維持劑量後的指定時間範圍投與，其中該指定時間範圍係兩週。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients transfused with RBCs, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 10 to < 20 kg as follows:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 800 mg, and(e) to patients who receive RBC transfusions within a specified time frame of the maintenance dose, a supplemental dose of 800 mg is administered within a specified time frame after the maintenance dose, wherein the specified time frame is two weeks.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者 投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體 或其抗原結合片段（例如，瑞利珠單抗）按以下投與至 體重為20至＜ 30 kg的患者： (a) 在第1天一次，按900 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2100 mg的維持劑量；以及 (e) 向在維持劑量的指定時間範圍內接受RBC輸注的患者投與2100 mg的補充劑量，其中該補充劑量在該維持劑量後的指定時間範圍投與，其中該指定時間範圍係四週。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 20 to <30 kg as follows: (a) once on day 1, at a loading dose of 900 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; mg loading dose;(d) on day 15 and every eight weeks thereafter, a maintenance dose of 2100 mg; and(e) to patients who receive RBC transfusions within a specified time frame of the maintenance dose, a supplemental dose of 2100 mg is administered within a specified time frame after the maintenance dose, wherein the specified time frame is four weeks.

在一些實施方式中，如有必要，根據如圖3所示的臨床演算法投與補充劑量。在一些實施方式中，如有必要，根據如表7所示的臨床演算法投與補充劑量。In some embodiments, if necessary, supplemental doses are administered according to the clinical algorithm shown in Figure 3. In some embodiments, if necessary, supplemental doses are administered according to the clinical algorithm shown in Table 7.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 30至＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按2700 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與2700 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 30 to < 40 kg as follows: (a) once on day 1, at a loading dose of 1200 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 2700 mg,and wherein the patient receives RBC transfusions within four weeks of the maintenance dose and then a supplemental dose of 2700 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 30至＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按2700 mg的維持劑量， 其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與2700 mg的補充劑量，並且其中該治療實現立即、完全和持續的末端補體抑制。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 30 to < 40 kg as follows: (a) once on day 1, at a loading dose of 1200 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 2700 mg,wherein the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 2700 mg four weeks after the maintenance dose, and wherein the treatment achieves immediate, complete, and sustained terminal complement suppression.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 40至＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3000 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3000 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 40 to < 60 kg as follows: (a) once on day 1, at a loading dose of 2400 mg; (b) once on day 5, at a loading dose of 600 mg; (c) once on day 10, at a loading dose of 600 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 3000 mg,and wherein the patient receives RBC transfusions within four weeks of the maintenance dose and then a supplemental dose of 3000 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 40至＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3000 mg的維持劑量， 其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3000 mg的補充劑量，並且其中該治療實現立即、完全和持續的末端補體抑制。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 40 to < 60 kg as follows: (a) once on day 1, at a loading dose of 2400 mg; (b) once on day 5, at a loading dose of 600 mg; (c) once on day 10, at a loading dose of 600 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 3000 mg,wherein the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3000 mg four weeks after the maintenance dose, and wherein the treatment achieves immediate, complete, and sustained terminal complement suppression.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 60至＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3300 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3300 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising the following: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 60 to < 100 kg as follows: (a) once on day 1, at a loading dose of 2700 mg; (b) once on day 5, at a loading dose of 900 mg; (c) once on day 10, at a loading dose of 900 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 3300 mg,and wherein the patient receives RBC transfusions within four weeks of the maintenance dose and then a supplemental dose of 3300 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 60至＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3300 mg的維持劑量， 其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3300 mg的補充劑量，並且其中該治療實現立即、完全和持續的末端補體抑制。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising the following: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to patients weighing ≥ 60 to < 100 kg as follows: (a) once on day 1, at a loading dose of 2700 mg; (b) once on day 5, at a loading dose of 900 mg; (c) once on day 10, at a loading dose of 900 mg. mg loading dose; and(d) on day 15 and every eight weeks thereafter, a maintenance dose of 3300 mg,wherein the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3300 mg four weeks after the maintenance dose, and wherein the treatment achieves immediate, complete, and sustained terminal complement suppression.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3600 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3600 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing ≥ 100 kg as follows: (a) once on day 1 at a loading dose of 3000 mg; (b) once on day 5 at a loading dose of 900 mg; (c) once on day 10 at a loading dose of 900 mg; and (d) On day 15 and every eight weeks thereafter, a maintenance dose of 3600 mg is administered, and the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3600 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者、較佳的是輸注了RBC的HSCT-TMA患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3600 mg的維持劑量， 其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3600 mg的補充劑量，並且其中該治療實現立即、完全和持續的末端補體抑制。In another embodiment, a method for treating HSCT-TMA human patients, preferably HSCT-TMA patients who have received RBC transfusions, is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing ≥ 100 kg as follows: (a) once on day 1 at a loading dose of 3000 mg; (b) once on day 5 at a loading dose of 900 mg; (c) once on day 10 at a loading dose of 900 mg; and (d) On day 15 and every eight weeks thereafter, at a maintenance dose of 3600 mg,wherein the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3600 mg four weeks after the maintenance dose, and wherein the treatment achieves immediate, complete, and sustained terminal complement suppression.

在一些實施方式中，其中患者在第一維持劑量後的2週內經歷RBC輸注，該患者僅在2次維持劑量之間的中間點接受一次輸注後補充劑量的抗C5抗體（例如，瑞利珠單抗）。由於對於某些較低體重的隊列（例如，＜ 20 kg；參見表8），每四週（Q4W）投與維持劑量，因此第2週之後（例如，維持劑量後14天）投與補充劑量的抗C5抗體（例如，瑞利珠單抗）。In some embodiments, where the patient undergoes an RBC transfusion within 2 weeks after the first maintenance dose, the patient receives a supplemental dose of anti-C5 antibody (e.g., reslizumab) after only one infusion at the midpoint between the 2 maintenance doses. Since the maintenance dose is administered every four weeks (Q4W) for certain lower weight cohorts (e.g., <20 kg; see Table 8), the supplemental dose of anti-C5 antibody (e.g., reslizumab) is administered after Week 2 (e.g., 14 days after the maintenance dose).

在一些實施方式中，其中患者在第一維持劑量後的4週內經歷RBC輸注，該患者僅在2次維持劑量之間的中間點接受一次輸注後補充劑量的抗C5抗體（例如，瑞利珠單抗）。由於每八週（Q8W）投與維持劑量，因此第4週之後（例如，維持劑量後28天）投與補充劑量的抗C5抗體（例如，瑞利珠單抗）。在這樣的實施方式中，如果患者在第二維持給藥期期間沒有經歷任何輸注，則在該維持給藥週期期間不需要補充劑量。同樣，如果患者在第二維持給藥期的後半段期間經歷RBC輸注，則在該維持給藥週期期間不需要補充給藥。換句話說，如果第一次RBC輸注發生在前一次維持劑量後超過4週，則不需要輸注後補充劑量。此外，如果患者在負荷劑量期期間接受輸注，則不投與補充給藥。In some embodiments, where the patient undergoes an RBC transfusion within 4 weeks after the first maintenance dose, the patient receives only one post-transfusion supplemental dose of an anti-C5 antibody (e.g., reslizumab) at the midpoint between the 2 maintenance doses. Since the maintenance dose is administered every eight weeks (Q8W), the supplemental dose of the anti-C5 antibody (e.g., reslizumab) is administered after the 4th week (e.g., 28 days after the maintenance dose). In such embodiments, if the patient does not experience any transfusions during the second maintenance dosing period, no supplemental dose is required during that maintenance dosing cycle. Similarly, if the patient undergoes an RBC transfusion during the second half of the second maintenance dosing period, no supplemental dosing is required during that maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than 4 weeks after the previous maintenance dose, no post-transfusion booster dose is required. In addition, if the patient receives a transfusion during the loading dose period, no booster dose is administered.

在本揭露的一或多種治療方法的一些實施方式中，在給定維持劑量後2週期間（對於體重 ＜ 20 kg的參與者，）或4週期間（對於體重 ≥ 20 kg的參與者），持續補充給藥方案，直至不投與輸注。In some embodiments of one or more treatment methods disclosed herein, the supplemental dosing regimen is continued until no infusion is administered for a 2-week period (for participants weighing < 20 kg) or a 4-week period (for participants weighing ≥ 20 kg) after a maintenance dose is given.

根據本文所述之治療方法，如果在最後維持劑量後2週或4週內向患者提供任何量的RBC輸注，則在例如該最後維持劑量後僅2週（＜ 20 kg的患者）或僅4週（≥ 20 kg的患者）向HSCT-TMA患者投與一次輸注後補充劑量的抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）。According to the treatment methods described herein, if any amount of RBC transfusion is provided to the patient within 2 weeks or 4 weeks after the last maintenance dose, a post-infusion supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to the HSCT-TMA patient, for example, only 2 weeks (for patients < 20 kg) or only 4 weeks (for patients ≥ 20 kg) after the last maintenance dose.

在另一個實施方式中，投與抗C5抗體或其抗原結合片段持續一或多個投與週期。在一個實施方式中，治療（例如，投與週期）為至少26週、至少52週、至少1.5年、至少2年。In another embodiment, administration of the anti-C5 antibody or antigen-binding fragment thereof continues for one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is at least 26 weeks, at least 52 weeks, at least 1.5 years, at least 2 years.

在另一個實施方式中，在投與補充劑量的抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）後，實現了立即、完全和持續的末端補體抑制。In another embodiment, immediate, complete, and sustained terminal complement inhibition is achieved following administration of a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab).

在一個實施方式中，本文揭露的治療方法還包括投與最佳支持治療（BSC）措施。BSC措施包括但不限於輸血支持、皮質類固醇、透析和抗高血壓藥物。In one embodiment, the treatment methods disclosed herein further include administering best supportive care (BSC) measures. BSC measures include but are not limited to transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

在一個實施方式中，患者以前沒有用依庫珠單抗治療過。在另一個實施方式中，患者以前已用依庫珠單抗治療過。在另一個實施方式中，患者以前已用依庫珠單抗治療，並且（例如，投與週期的）第1天距患者最後一次劑量的依庫珠單抗兩週或更長時間。In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab, and Day 1 (e.g., of an administration cycle) is two weeks or more from the patient's last dose of eculizumab.

在另一個方面，所描述的治療方案足以維持抗C5抗體或其抗原結合片段的特定血清谷濃度。在一個實施方式中，例如，治療方案維持抗C5抗體或其抗原結合片段的血清谷濃度為50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200、205、210、215、220、225、230、240、245、250、255、260、265、270、280、290、300、305、310、315、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500、505、510、515、520、525、530、535、540、545、550、555、560、565、570、575、580、585、590、595、600、605、610、615、620、625、630、635、640、645、650、655、660、665、670、675、680、685、690、695、700 µg/mL或更高。在一個實施方式中，治療方案維持抗C5抗體或其抗原結合片段的血清谷濃度為100 µg/mL或更高、150 µg/mL或更高、200 µg/mL或更高、250 µg/mL或更高、300 µg/mL或更高、350 µg/mL或更高、400 µg/mL或更高、或450 µg/mL或更高。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清谷濃度在100 µg/mL和700 µg/mL之間；較佳的是在300 µg/mL和600 µg/mL之間。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清谷濃度為約475 µg/mL。在一個實施方式中，治療方案維持抗C5抗體或其抗原結合片段的血清峰濃度為小於約1800、1780、1760、1740、1720、1700、1680、1660、1640、1620、1600、1580、1560、1540、1520、1500、1480、1460、1440、1420、1400、1380、1360、1340、1320、1300、1280、1260、1240、1220、1200、1180、1160、1140、1120、1100、1080、1060、1040、1020、1000、980、960、940、920、或900 µg/mL或更小。在實施方式中，治療維持抗C5抗體或其抗原結合片段的血清峰濃度在900 µg/mL和1800 µg/mL之間；較佳的是在1050 µg/mL和1550 µg/mL之間。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清峰濃度為約1350 µg/mL。In another aspect, the treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 3 55, 360, 365, 3 70, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 52 0, 525, 530, 53 5, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 µg/mL or higher. In one embodiment, the treatment regimen maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of 100 µg/mL or more, 150 µg/mL or more, 200 µg/mL or more, 250 µg/mL or more, 300 µg/mL or more, 350 µg/mL or more, 400 µg/mL or more, or 450 µg/mL or more. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof between 100 µg/mL and 700 µg/mL; preferably between 300 µg/mL and 600 µg/mL. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof at about 475 µg/mL. In one embodiment, the treatment regimen maintains a peak serum concentration of anti-C5 antibody or antigen-binding fragment thereof of less than about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440 0, 1420, 1400, 1380, 1360, 1340, 1320, 1300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 μg/mL or less. In embodiments, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof between 900 μg/mL and 1800 μg/mL; preferably between 1050 μg/mL and 1550 μg/mL. In another embodiment, the treatment maintains a peak serum concentration of anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg/mL.

在另一個實施方式中，為了獲得有效響應，以一定的量和頻率向患者投與抗C5抗體，以維持至少50 µg、55 µg、60 µg、65 µg、70 µg、75 µg、80 µg、85 µg、90 µg、95 µg、100 µg、105 µg、110 µg、115 µg、120 µg、125 µg、130 µg、135 µg、140 µg、145 µg、150 µg、155 µg、160 µg、165 µg、170 µg、175 µg、180 µg、185 µg、190 µg、195 µg、200 µg、205 µg、210 µg、215 µg、220 µg、225 µg、230 µg、235 µg、240 µg、245 µg、250 µg、255 µg、260 µg、270 µg、280 µg、290 µg、300 µg、320 µg、340 µg、360 µg、380 µg、400 µg、420 µg、440 µg、460 µg、480 µg、500 µg、550 µg、600 µg、650 µg、700 µg、750 µg、800 µg、850 µg、900 µg、950 µg、1000 µg、1050 µg、1100 µg、1150 µg、1200 µg、1250 µg、1300 µg、1350 µg、1400 µg、1450 µg、1500 µg、1550 µg、1600 µg、1650 µg、1700 µg、1750 µg或更多，例如1800 µg抗體/毫升患者血液。In another embodiment, in order to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain at least 50 µg, 55 µg, 60 µg, 65 µg, 70 µg, 75 µg, 80 µg, 85 µg, 90 µg, 95 µg, 100 µg, 105 µg, 110 µg, 115 µg, 120 µg, 125 µg, 130 µg, 135 µg, 140 µg, 145 µg, 150 µg, 155 µg, 160 µg, 165 µg, 170 µg, 175 µg, 180 µg, 185 µg, 190 µg, 195 µg, 200 µg, 205 µg, 210 µg, 215 µg, 220 µg, 225 µg, 230 µg, 235 µg, 240 µg, 245 µg, 250 µg, 255 µg, 260 µg, 270 µg, 280 µg, 290 µg, 300 µg, 320 µg, 340 µg, 360 µg, 380 µg, 400 µg, 420 µg, 440 µg, 460 µg, 480 µg, 500 µg, 550 µg, 600 µg, 650 µg, 700 µg, 750 µg, 800 µg, 850 µg, 900 µg, 950 µg, 1000 µg, 1050 µg, 1100 µg, 1150 µg, 1 200 µg, 1250 µg, 1300 µg, 1350 µg, 1400 µg, 1450 µg, 1500 µg, 1550 µg, 1600 µg, 1650 µg, 1700 µg, 1750 µg or more, for example, 1800 µg antibody/mL patient blood.

在實施方式中，為了獲得有效響應，以一定的量和頻率向患者投與抗C5抗體（例如，瑞利珠單抗），以維持抗C5抗體（例如，瑞利珠單抗）的最小和最大血漿濃度（±標準差）在給藥間隔內較佳的是分別在474（± 200）µg/mL和1350（± 430）µg/mL之間。In an embodiment, in order to obtain an effective response, an anti-C5 antibody (e.g., reslizumab) is administered to a patient in an amount and frequency to maintain the minimum and maximum plasma concentrations (± standard deviation) of the anti-C5 antibody (e.g., reslizumab) within the dosing interval preferably between 474 (± 200) µg/mL and 1350 (± 430) µg/mL, respectively.

在另一個實施方式中，為了獲得有效響應，以一定的量和頻率向患者投與抗C5抗體，以維持最小游離C5濃度。在一個實施方式中，例如，以一定的量和頻率向患者投與抗C5抗體，以維持0.5 μg/mL或更低（例如，0.4 µg/mL、0.3 µg/mL、0.2 µg/mL、或0.1 µg/mL或更低）的游離C5濃度。In another embodiment, in order to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain a free C5 concentration of 0.5 μg/mL or less (e.g., 0.4 μg/mL, 0.3 μg/mL, 0.2 μg/mL, or 0.1 μg/mL or less).

可以將抗C5抗體或其抗原結合片段藉由任何合適的方法投與於患者。在一個實施方式中，抗體經配製用於靜脈內投與。The anti-C5 antibody or antigen-binding fragment thereof can be administered to a patient by any suitable method. In one embodiment, the antibody is formulated for intravenous administration.

本文所提供的治療方法的療效可使用任何適合的方式評估。在一個實施方式中，對於HSCT-TMA患者，治療產生選自由以下組成之群組的至少一種治療效果：與基線相比，微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭減少或停止。The efficacy of the treatment methods provided herein can be assessed using any suitable means. In one embodiment, for HSCT-TMA patients, the treatment produces at least one therapeutic effect selected from the group consisting of: microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous membrane inflammation, pulmonary hypertension, and multisystem organ failure are reduced or stopped compared to baseline.

在另一個實施方式中，治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數 ≥ 50,000/mm³，(b) LDH ＜ 1.5 × ULN，和 (c) 不存在血球裂片（如果在基線時存在血球裂片）。In another embodiment, treatment results in (a) a platelet count ≥ 50,000/mm³ in the absence of transfusion support in the prior 7 days, (b) LDH < 1.5 x ULN, and (c) the absence of schistocytes (if schistocytes were present at baseline).

在另一個實施方式中，治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數 ≥ 50,000/mm³，(b) LDH ＜ 1.5 × ULN，(c) 不存在血球裂片（如果在基線時存在血球裂片），和 (d) 蛋白尿相對於基線減少至少50%。在一個實施方式中，蛋白尿係指蛋白質/肌酸酐比率 ≥ 0.5 mg/mg。In another embodiment, treatment results in (a) platelet count ≥ 50,000/mm³ in the absence of transfusion support in the prior 7 days, (b) LDH < 1.5 × ULN, (c) absence of blood cell fragments (if blood cell fragments were present at baseline), and (d) a reduction in proteinuria of at least 50% relative to baseline. In one embodiment, proteinuria refers to a protein/creatinine ratio ≥ 0.5 mg/mg.

在另一個實施方式中，治療使得產生有利的血液學響應。In another embodiment, treatment results in a favorable hematologic response.

在另一個實施方式中，治療使得LDH正常化、紅血球和血小板輸注需求得以解決、且血球裂片消失。In another embodiment, treatment results in normalization of LDH, resolution of red blood cell and platelet transfusion requirements, and disappearance of blood cell fragmentation.

在另一個實施方式中，治療使得患者能夠在沒有輸血支持的情況下維持血紅素 ≥ 8 g/dL。在另一個實施方式中，在沒有輸血支持的情況下，治療使得血紅素 ≥ 8 g/dL。In another embodiment, the treatment enables the patient to maintain a hemoglobin ≥ 8 g/dL without transfusion support. In another embodiment, the treatment enables a hemoglobin ≥ 8 g/dL without transfusion support.

在另一個實施方式中，與基線相比，治療使得LDH降低、血小板增加和/或血紅素增加。In another embodiment, treatment results in a decrease in LDH, an increase in platelets and/or an increase in hemoglobin compared to baseline.

在另一個實施方式中，與基線相比，治療產生正常水平的血清肌酸酐。In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

在另一個實施方式中，與基線相比，治療使得腎、心血管、肺、CNS和/或GI系統中TMA相關器官功能障礙有改善。In another embodiment, treatment results in improvement in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS and/or GI systems compared to baseline.

在另一個實施方式中，治療實現末端補體抑制。In another embodiment, the treatment achieves terminal complement inhibition.

在另一個實施方式中，治療使不良事件減少。In another embodiment, treatment results in a reduction in adverse events.

在另一個實施方式中，治療促使與血管炎症（例如，脫落腫瘤壞死因子受體1 [TNF-R1]）、內皮損傷和/或激活（例如，凝血酶調節蛋白和脫落血管細胞黏附分子1 [VCAM-1]）、腎損傷（例如，胱蛋白C）和/或補體蛋白和補體激活途徑產物相關的生物標誌物向正常水平轉變。在另一個實施方式中，治療促使凝血酶調節蛋白（TM）和/或黏結蛋白聚糖-1（SYND1）向正常水平轉變。在另一個實施方式中，治療促使補體因子Ba向正常水平轉變。In another embodiment, treatment results in a change toward normal levels of biomarkers associated with vascular inflammation (e.g., abscessed tumor necrosis factor receptor 1 [TNF-R1]), endothelial damage and/or activation (e.g., thrombomodulin and sloughed vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystin C), and/or complement proteins and complement activation pathway products. In another embodiment, treatment results in a change toward normal levels of thrombomodulin (TM) and/or syndecan-1 (SYND1). In another embodiment, treatment results in a change toward normal levels of complement factor Ba.

在另一個實施方式中，治療使得如經由生活品質評估（例如，生活品質評定問卷（PedsQL）量表或EQ-5D-5L問卷）所評估的生活品質相對於基線有所變化。In another embodiment, treatment results in a change from baseline in quality of life as assessed by a quality of life assessment (e.g., the Parenteral Quality of Life Questionnaire (PedsQL) scale or the EQ-5D-5L questionnaire).

在另一個實施方式中，與基線相比，如藉由乳酸脫氫酶（LDH）水平評估，治療使得溶血減少。在一個實施方式中，根據所揭露的方法治療的患者的LDH水平降低至接近正常水平或降低至高於視為的正常水平（例如，在105-333 IU/L（國際單位/升）以內）10%以內或20%以內。在另一個實施方式中，在整個治療維持期間，患者的LDH水平正常化。在另一個實施方式中，所治療患者的LDH水平在治療維持期間的至少95%的時間裡正常化。在另一個實施方式中，所治療患者的LDH水平在治療維持期間的至少90%、85%或80%的時間裡正常化。在一個實施方式中，在起始治療之前，患者的LDH水平高於正常上限 ≥ 1.5倍（LDH ≥ 1.5 × ULN）。In another embodiment, treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels compared to baseline. In one embodiment, LDH levels in patients treated according to the disclosed methods are reduced to near normal levels or to within 10% or 20% above levels considered normal (e.g., within 105-333 IU/L (International Units/L)). In another embodiment, the patient's LDH level is normalized throughout the treatment maintenance period. In another embodiment, the LDH level of the treated patient is normalized for at least 95% of the time during the treatment maintenance period. In another embodiment, the LDH level of the treated patient is normalized for at least 90%, 85%, or 80% of the time during the treatment maintenance period. In one embodiment, prior to initiating treatment, the patient's LDH level is ≥ 1.5 times above the upper limit of normal (LDH ≥ 1.5 × ULN).

在一個實施方式中，根據所揭露的方法治療的患者的LDH水平降低至正常水平內或降低至低於視為的ULN水平（例如，在105-333 IU/L（國際單位/升）以內）10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%或50%以內。在一個實施方式中，在起始治療之前，患者的LDH水平高於ULN ≥ 1.5倍（LDH ≥ 1.5 × ULN）。In one embodiment, LDH levels in a patient treated according to the disclosed methods are reduced to within normal levels or to within 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% below levels considered ULN (e.g., within 105-333 IU/L (International Units/L)). In one embodiment, the patient's LDH level is greater than 1.5 times ULN (LDH ≥ 1.5 x ULN) prior to initiating treatment.

在一個實施方式中，與基線相比，根據所揭露的方法治療的患者經歷10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%或60%的LDH百分比變化。In one embodiment, patients treated according to the disclosed methods experience a 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% change in percent LDH compared to baseline.

還提供了包含藥物組成物的套組（kit），該藥物組成物含有適用於在本文所述之方法（例如用於有效治療經歷了至少一種輸注（例如，血小板或RBC輸注）的HSCT-TMA患者之方法）中使用的治療有效量的抗C5抗體或其抗原結合片段（如瑞利珠單抗）和藥學上可接受的載體。在一個實施方式中，套組包含：(a) 一定劑量的抗C5抗體或其抗原結合片段，其包含具有SEQ ID NO:12所示序列的重鏈可變區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的輕鏈可變區的CDR1、CDR2和CDR3結構域；以及(b) 用於在本文所述方法中使用該抗C5抗體或其抗原結合片段的說明書。Also provided are kits comprising a pharmaceutical composition containing a therapeutically effective amount of an anti-C5 antibody or an antigen-binding fragment thereof (such as reslizumab) and a pharmaceutically acceptable carrier suitable for use in the methods described herein (e.g., a method for effectively treating HSCT-TMA patients who have undergone at least one transfusion (e.g., platelet or RBC transfusion)). In one embodiment, the kit comprises: (a) a dose of an anti-C5 antibody or an antigen-binding fragment thereof, which comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or an antigen-binding fragment thereof in the methods described herein.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按300 mg的維持劑量；以及 (e) 300 mg的補充劑量，按以下說明：向在維持劑量的2週內接受紅血球（RBC）輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 to <10 kg as follows:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 300 mg; and(e) 300 mg supplement as follows: Administer the supplement to patients who receive red blood cell (RBC) transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按400 mg的維持劑量；以及 (e) 400 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 to <10 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 400 mg; and(e) 400 mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按600 mg的維持劑量，以及 (e) 600 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 to <20 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 600 mg, and(e) 600 mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按800 mg的維持劑量，以及 (e) 800 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 to <20 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 800 mg, and(e) 800 mg mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為20至＜ 30 kg的患者： (a) 在第1天一次，按900 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2100 mg的維持劑量；以及 (e) 2100 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 20 to <30 kg as follows:(a) once on day 1 at a loading dose of 900 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 2100 mg; and(e) 2100 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 30至＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2700 mg的維持劑量， 以及 (e) 2700 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 to < 40 kg as follows:(a) once on day 1 at a loading dose of 1200 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 2700 mg,and (e) 2700 mg. mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 40至＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量； (d) 在第15天和此後每八週，按3000 mg的維持劑量， 以及 (e) 3000 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg as follows:(a) once on day 1 at a loading dose of 2400 mg;(b) once on day 5 at a loading dose of 600 mg;(c) once on day 10 at a loading dose of 600 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3000 mg,and (e) 3000 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 60至＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量； (d) 在第15天和此後每八週，按3300 mg的維持劑量， 以及 (e) 3300 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg as follows:(a) once on day 1 at a loading dose of 2700 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3300 mg,and (e) 3300 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量； (d) 在第15天和此後每八週，按3600 mg的維持劑量， 以及 (e) 3600 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg as follows:(a) once on day 1 at a loading dose of 3000 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3600 mg,and (e) 3600 mg. mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個方面，提供了抗C5抗體或其抗原結合片段（例如，瑞利珠單抗（ULTOMIRIS®）），用於在治療在治療的維持期的前半段期間經歷了RBC輸注的HSCT-TMA患者中使用，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another aspect, an anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab (ULTOMIRIS®)) is provided for use in treating HSCT-TMA patients who have undergone RBC transfusions during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows:(a) once on day 1 at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) Once on day 5, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) Once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg mg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg;and wherein the supplemental dose is administered to:(i)     Patients weighing < 30 kg who receive RBC transfusions within a specified time frame of a maintenance dose, where the supplemental dose is administered within a specified time frame after the maintenance dose at the following doses: a. 300 or 400 mg for patients weighing 5 to < 10 kg, where the specified time frame is two weeks, b. 600 or 800 mg for patients weighing 10 to < 20 kg, where the specified time frame is two weeks, or c. 2100 mg for patients weighing 20 to < 30 kg, where the specified time frame is four weeks, or (ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a.  2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c.  3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

本文進一步提供了抗C5抗體或其抗原結合片段（例如，瑞利珠單抗（ULTOMIRIS®））用於治療在治療的維持期的前半段期間經歷了RBC輸注的HSCT-TMA患者之用途，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  在維持劑量後兩週，體重為5至＜ 10 kg的患者300或400 mg， b. 在維持劑量後兩週，體重為10至＜ 20 kg的患者600或800 mg，或 c.  在維持劑量後四週，體重為20至＜ 30 kg的患者2100 mg，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。Further provided herein is the use of an anti-C5 antibody or an antigen-binding fragment thereof (e.g., reslizumab (ULTOMIRIS®)) for treating HSCT-TMA patients who have undergone RBC transfusions during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows:(a) once on day 1 at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) Once on day 5, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) Once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg mg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg;and wherein the supplemental dose is administered to:(i)     Patients weighing < 30 kg who receive RBC transfusions within the specified time frame of a maintenance dose, where the supplemental dose is administered within the specified time frame after the maintenance dose at the following doses: a.  300 or 400 mg for patients weighing 5 to < 10 kg two weeks after the maintenance dose, b.  600 or 800 mg for patients weighing 10 to < 20 kg two weeks after the maintenance dose, or c.  2100 mg for patients weighing 20 to < 30 kg four weeks after the maintenance dose, or (ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a.  2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c.  3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

I.定義I. Definition

如本文所用，術語「受試者」或「患者」係人患者（例如，患有造血幹細胞移植相關血栓性微血管病（HSCT-TMA）的患者）。As used herein, the term "subject" or "patient" refers to a human patient (eg, a patient with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)).

如本文所用，術語「兒童」患者係被醫生或護理人員分類為屬於非成人類別的人患者，並且可以包括例如新生兒（早產兒和足月兒二者）、嬰兒、兒童和青少年。通常，兒童患者係18歲以下（＜ 18歲）的患者。As used herein, the term "pediatric" patient is a human patient classified by a physician or nurse as belonging to a non-adult category, and can include, for example, newborns (both premature and full-term), infants, children, and adolescents. Typically, a pediatric patient is a patient under 18 years of age (<18 years old).

如本文所用，術語「成人」患者係已經被醫生或護理人員分類為人患者，例如，基於年齡、發育狀態、生理特徵等的例如不是新生兒、嬰兒、兒童或青少年的患者。通常，成年患者係18歲或以上（≥ 18歲）的患者。As used herein, the term "adult" patient is a patient who has been classified as a human patient by a physician or caregiver, e.g., a patient who is not a newborn, infant, child, or adolescent, e.g., based on age, developmental status, physiological characteristics, etc. Typically, an adult patient is a patient 18 years of age or older (≥ 18 years of age).

HSCT-TMA係由可由移植過程中的數種機制觸發的系統性血管內皮損傷引起的多因素障礙。其經由內皮損傷出現並影響腎臟和其他器官。據估計，30%的患有HSCT TMA患者將表現出重度疾病（Rosenthal等人,J. Blood Med. [血醫學雜誌] 2016;7:181-186），並且在該等情況下，患有HSCT-TMA的患者發生全身性血管損傷，表現為腎損害、漿膜炎、肺性高血壓和多系統器官衰竭。在一個實施方式中，TMA診斷基於同時出現的所有以下標準：(a) 新生血小板減少或血小板輸注無效，其中：新生血小板減少定義為血小板計數新下降至 ≤ 50,000/mm³，輸注無效定義為輸注後10-60分鐘血小板增量未能超過輸注觸發值，或在至少2次血小板輸注之後的輸注後20-24小時升高低於10 × 10⁹/L，(b) 新生貧血（定義為血紅素新下降至 ≤ 8 g/dL）或輸注需求增加（定義為需要實施更頻繁的輸注以便維持血紅素 ≥ 8 g/dL），(c) 下列溶血標誌物中的任一者：LDH ＞ 1.5 × ULN或在周邊血塗片中出現血球裂片 ≥ 2高倍視野（HPF），(d) 現場尿分析中的蛋白尿，其中蛋白尿定義為蛋白質/肌酸酐比率 ≥ 0.5 mg/mg。蛋白尿的存在應藉由第二次測量（其中兩次測量至少相隔4小時）來確認；(e) 存在高血壓，高血壓定義為存在以下3種情況中的任何一種：在至少間隔1小時的連續2次測量中，收縮壓 ≥ 139 mm Hg或舒張壓大於80 mm Hg。HSCT-TMA is a multifactorial disorder caused by systemic vascular endothelial damage that can be triggered by several mechanisms during the transplant process. It manifests via endothelial damage and affects the kidney and other organs. It is estimated that 30% of patients with HSCT TMA will present with severe disease (Rosenthal et al.,J. Blood Med . 2016;7:181-186), and in these cases, patients with HSCT-TMA develop systemic vascular damage manifested by kidney damage, serous membrane inflammation, pulmonary hypertension, and multisystem organ failure. In one embodiment, the TMA diagnosis is based on the presence of all of the following criteria simultaneously: (a) new thrombocytopenia or platelet transfusion refractoriness, where: new thrombocytopenia is defined as a new decrease in platelet count to ≤ 50,000/^mm3 , transfusion refractoriness is defined as failure to increase platelets above the transfusion trigger value 10-60 minutes after transfusion, or an increase below 10 ×¹⁰⁹ /L 20-24 hours after transfusion following at least 2 platelet transfusions, (b) new anemia (defined as a new decrease in hemoglobin to ≤ 8 g/dL) or increased transfusion requirements (defined as the need for more frequent transfusions to maintain hemoglobin ≥ 8 g/dL), (c) any of the following hemolytic markers: LDH > 1.5 × ULN or presence of blood cell fragments ≥ 2 high-power fields (HPF) in peripheral blood smears, (d) proteinuria on field urinalysis, where proteinuria is defined as a protein/creatinine ratio ≥ 0.5 mg/mg. The presence of proteinuria should be confirmed by a second measurement (where the two measurements are at least 4 hours apart); (e) the presence of hypertension, where hypertension is defined as the presence of any of the following 3 conditions: systolic blood pressure ≥ 139 mm Hg or diastolic blood pressure greater than 80 mm Hg in 2 consecutive measurements at least 1 hour apart.

如本文所用，「有效治療」係指產生有益效果的治療，例如，改善疾病或障礙的至少一種症狀。有益效果可以採取相對於基線改善的形式，例如，相對於根據該方法開始療法之前進行的測量或觀察的改善。有效治療可指緩解HSCT-TMA的至少一種症狀（例如，微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭）。As used herein, "effective treatment" refers to treatment that produces a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement relative to baseline, e.g., an improvement relative to a measurement or observation made prior to initiating treatment according to the method. Effective treatment can refer to relief of at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous inflammation, pulmonary hypertension, and multisystem organ failure).

術語「有效量」係指提供所需生物學、治療和/或預防結果的藥劑的量。該結果可為減少、改善、緩和、減輕、延遲和/或緩解疾病的一或多種體征、症狀或原因，或任何其他期望的生物學系統改變。在一個實例中，「有效量」係抗C5抗體或其抗原結合片段的量，其被臨床證明緩解HSCT-TMA的至少一種症狀（例如，微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭）。有效量可以一次或多次投與。The term "effective amount" refers to the amount of an agent that provides the desired biological, therapeutic and/or preventive result. The result may be reduction, improvement, alleviation, reduction, delay and/or relief of one or more signs, symptoms or causes of a disease, or any other desired change in a biological system. In one example, an "effective amount" is an amount of an anti-C5 antibody or an antigen-binding fragment thereof that is clinically shown to relieve at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous inflammation, pulmonary hypertension, and multisystem organ failure). An effective amount may be administered once or multiple times.

如本文所用，術語「負荷劑量」係指在投與週期（例如，在第1、5和10天）期間投與的初始劑量。As used herein, the term "loading dose" refers to the initial dose administered during a dosing cycle (eg, on days 1, 5, and 10).

如本文所用，術語「維持」和「維持期」可互換使用，並且係指治療的第二階段（例如，從第15天開始每八週投與的劑量）。在某些實施方式中，只要觀察到臨床益處就繼續治療或繼續治療直到發生無法控制的毒性或疾病進展。As used herein, the terms "maintenance" and "maintenance period" are used interchangeably and refer to the second phase of treatment (e.g., dosing administered every eight weeks starting on day 15). In certain embodiments, treatment is continued for as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs.

如本文所用，術語「補充劑量」係指投與至在維持劑量後4週內接受了RBC輸注的HSCT-TMA患者（例如，體重 ≥ 30 kg）的額外劑量。As used herein, the term "supplement dose" refers to an additional dose administered to HSCT-TMA patients (e.g., weighing ≥ 30 kg) who received an RBC transfusion within 4 weeks after a maintenance dose.

如本文所用，術語「血液輸注」係指將全血或部分血液例如經由靜脈注入患者血流的過程。血液可能是由另一個人捐獻的，也可能是從患者身上抽取並儲存起來備用的。As used herein, the term "blood transfusion" refers to the process of injecting whole or partial blood into a patient's bloodstream, such as via a vein. The blood may be donated by another person, or it may be drawn from the patient and stored for future use.

如本文所用，術語「紅血球（RBC）輸注」係指將紅血球（即從捐獻的全血或藉由供體單採獲得的濃縮紅血球）例如經由靜脈輸注到患者的血流中。大多數RBC輸注係輸注濃縮RBC，該等濃縮RBC藉由從全血採集中去除血漿或藉由單採製備，隨後與添加劑一起儲存以增強細胞生存力和儲存期。As used herein, the term "red blood cell (RBC) transfusion" refers to the transfusion of red blood cells (i.e., concentrated red blood cells obtained from donated whole blood or by donor apheresis) into a patient's bloodstream, for example, via a vein. Most RBC transfusions are transfusions of concentrated RBCs, which are prepared by removing plasma from a whole blood collection or by apheresis and then stored with additives to enhance cell viability and shelf life.

如本文所用，術語「血清谷水平」係指血清中存在的藥劑（例如，抗C5抗體或其抗原結合片段）或藥物的最低水平。相比之下，「血清峰水平」係指血清中藥劑的最高水平。「平均血清水平」係指血清中藥劑隨時間的平均水平。As used herein, the term "serum trough level" refers to the lowest level of an agent (e.g., an anti-C5 antibody or antigen-binding fragment thereof) or drug present in the serum. In contrast, "serum peak level" refers to the highest level of an agent in the serum. "Average serum level" refers to the average level of an agent in the serum over time.

術語「抗體」描述了包含至少一個抗體來源的抗原結合位點（例如，VH/VL區或Fv、或CDR）的多肽。抗體包括已知形式的抗體，例如，抗體可為人抗體、人源化抗體、雙特異性抗體或嵌合抗體。抗體也可為Fab、Fab'2、ScFv、SMIP、Affibody^®、奈米抗體或單結構域抗體。抗體也可為以下任何同種型：IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgD、IgE或其組合。抗體可為天然存在的抗體或已經藉由蛋白質工程技術改變的抗體（例如，藉由突變、缺失、取代、與非抗體部分軛合）。抗體可以包括例如一或多個變體胺基酸（與天然存在的抗體相比），其改變抗體的特性（例如，功能特性）。許多這樣的改變在本領域中係已知的，它們影響例如半衰期、效應功能和/或患者對抗體的免疫響應。術語抗體還包括包含至少一個抗體衍生的抗原結合位點的人工或工程化的多肽構建體。 II. 抗C5抗體The term "antibody" describes a polypeptide comprising at least one antigen binding site (e.g., VH/VL region or Fv, or CDR) of antibody origin. Antibodies include known forms of antibodies, for example, antibodies may be human antibodies, humanized antibodies, bispecific antibodies, or chimeric antibodies. Antibodies may also be Fab, Fab'2, ScFv, SMIP,^Affibody® , nanobodies, or single domain antibodies. Antibodies may also be any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE, or a combination thereof. Antibodies may be naturally occurring antibodies or antibodies that have been altered by protein engineering techniques (e.g., by mutation, deletion, substitution, or conjugation to a non-antibody portion). Antibodies can include, for example, one or more variant amino acids (compared to naturally occurring antibodies) that alter a property (e.g., a functional property) of the antibody. Many such alterations are known in the art that affect, for example, half-life, effector function, and/or the patient's immune response to the antibody. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen binding site. II. Anti-C5 Antibodies

本文所述之抗C5抗體與補體成分C5（例如，人C5）結合並抑制C5裂解成片段C5a和C5b。如上所述，相對於用於治療目的的其他抗C5抗體（例如，依庫珠單抗），這樣的抗體還具有例如改善的藥物動力學特性。The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have, for example, improved pharmacokinetic properties relative to other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

適用於本文所述方法的抗C5抗體（或衍生自該抗體的VH/VL結構域）可以使用本領域已知的方法產生。可替代地，可以使用本領域公認的抗C5抗體。也可以使用與任何該等本領域公認的抗體或本文所述之抗體競爭結合C5的抗體。Anti-C5 antibodies (or VH/VL domains derived therefrom) suitable for use in the methods described herein can be produced using methods known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete for binding to C5 with any of these art-recognized antibodies or antibodies described herein can also be used.

示例性抗C5抗體係包含分別具有SEQ ID NO:14和11中所示序列的重鏈和輕鏈的瑞利珠單抗或其抗原結合片段和變體。瑞利珠單抗（也稱為ULTOMIRIS®、BNJ441和ALXN1210）描述於WO 2015134894和美國專利案號9,079,949中，它們的全部教導內容藉由引用特此併入。在本文件通篇，術語瑞利珠單抗、BNJ441和ALXN1210可互換使用，但都係指同一抗體。瑞利珠單抗選擇性地結合人補體蛋白C5，在補體激活過程中抑制其裂解為C5a和C5b。這種抑制防止促炎介質C5a的釋放和溶細胞孔形成性攻膜複合物（MAC）C5b-9的形成，同時保留對微生物的調理作用和免疫複合物的清除至關重要的補體激活的近端或早期成分（例如，C3和C3b）。Exemplary anti-C5 antibody systems include reslizumab, or antigen-binding fragments and variants thereof, having the heavy and light chains of the sequences set forth in SEQ ID NO: 14 and 11, respectively. Reslizumab (also known as ULTOMIRIS®, BNJ441 and ALXN1210) is described in WO 2015134894 and US Patent No. 9,079,949, the entire teachings of which are hereby incorporated by reference. Throughout this document, the terms reslizumab, BNJ441, and ALXN1210 are used interchangeably but refer to the same antibody. Reslizumab selectively binds to human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the lytic pore-forming membrane attack complex (MAC) C5b-9, while preserving complement activation crucial for the opsonization of microorganisms and clearance of immune complexes. terminal or early components (e.g., C3 and C3b).

在KEGG藥物數據庫（https://www.kegg.jp/entry/D11054）中登記的瑞利珠單抗的多肽序列顯示可變重鏈的N-末端胺基酸係「X」，但是該數據庫沒有說明X係什麼。瑞利珠單抗的化學文摘（CAS）（CAS 1803171-55-2）也顯示N-末端X係焦麩胺酸（在CAS報告中指定為「鏈1焦麩胺酸-1」）。儘管該資訊可能看起來不同於瑞利珠單抗的VH序列，例如，包含SEQ ID NO: 12所示胺基酸序列的重鏈可變區多肽和/或包含SEQ ID NO:14所示胺基酸序列的重鏈多肽，但是在專利序列和藥物數據庫/CAS序列之間存在比對，因為本領域中認識到多肽和/或抗體序列中的N-末端Q在製程開發過程中環化，以產生接近100%的藥物產物轉化為焦麩胺酸鹽（Pryo-Q），如以下中揭露：Liu等人（J Pharm Sci. [藥物科學雜誌] 2019年10月;108(10):3194-3200）https://pubmed.ncbi.nlm.nih.gov/ 31145921/和Nguyen等人（Int. J. Mol. Sci.[國際分子科學雜誌] 2017年7月20日;18(7):1575）https://www.researchgate.net/figure/Cyclization-reactions-of-N-terminal-glutamine-and-glutamate-residues-in-a-polypeptide_fig4_318926365。以下文獻中提供了額外資訊：Xu等人（MAbs[單株抗體], 2019年2月/3月;11(2):239-264）的第7頁和表4以及以下參考出版物：(1) Yu等人, 「Investigation of N-terminal glutamatecyclization of recombinant monoclonal antibody in formulation development [配製物開發中重組單株抗體N-末端麩胺酸環化的研究]」,J. Pharm.Biomed. Anal. [藥學和生物醫學分析雜誌], 2006, 42, 455-463和Dick等人, 「Determination of the origin of the N-terminal pyro-glutamatevariation in monoclonal antibodies using model peptides [使用模型肽確定單株抗體中N-末端焦麩胺酸鹽轉化的來源]」,Biotechnol.Bioeng. [生物技術與生物工程], 2007, 97, 544-553，其揭露內容藉由引用以其全文併入。The peptide sequence of reslizumab registered in the KEGG drug database (https://www.kegg.jp/entry/D11054) shows that the N-terminal amino acid of the variable heavy chain is "X", but the database does not specify what X is. The Chemical Abstracts (CAS) of reslizumab (CAS 1803171-55-2) also shows that the N-terminal X is pyroglutamine (specified as "Chain 1 pyroglutamine-1" in the CAS report). Although the information may appear different from the VH sequence of reslizumab, for example, a heavy chain variable region polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 12 and/or a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14, there is an alignment between the patent sequence and the drug database/CAS sequence because it is recognized in the art that the N-terminal Q in the polypeptide and/or antibody sequence is cyclized during process development to produce nearly 100% conversion of the drug product to pyroglutamate (Pryo-Q), as disclosed in: Liu et al. (J Pharm Sci. 2019 Oct;108(10):3194-3200) https://pubmed.ncbi.nlm.nih.gov/31145921/ and Nguyen et al. (Int. J. Mol. Sci. 2017 Jul 20;18(7):1575) https://www.researchgate.net/figure/Cyclization-reactions-of-N-terminal-glutamine-and-glutamate-residues-in-a-polypeptide_fig4_318926365. Additional information is provided in the following references: page 7 and Table 4 of Xu et al. (MAbs , 2019 Feb/Mar;11(2):239–264) and the following references: (1) Yu et al., “Investigation of N-terminal glutamate cyclization of recombinant monoclonal antibody in formulation development,”J. Pharm.Biomed. Anal . , 2006, 42, 455–463 and Dick et al., “Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides,”Biotechnol .Bioeng . [Biotechnology and Bioengineering], 2007, 97, 544-553, the disclosure of which is incorporated by reference in its entirety.

在其他實施方式中，抗體包含瑞利珠單抗的重鏈和輕鏈CDR或可變區。因此，在一個實施方式中，抗體包含具有SEQ ID NO:12所示序列的瑞利珠單抗VH區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的瑞利珠單抗VL區的CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含分別具有SEQ ID NO:19、18和3所示序列的重鏈CDR1、CDR2和CDR3結構域，以及分別具有SEQ ID NO:4、5和6所示序列的輕鏈CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含分別具有SEQ ID NO:12和SEQ ID NO:8所示胺基酸序列的VH和VL區。In other embodiments, the antibody comprises the heavy chain and light chain CDRs or variable regions of reslizumab. Therefore, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the reslizumab VH region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the reslizumab VL region having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NO: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NO: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

另一種示例性抗C5抗體係包含分別具有SEQ ID NO:20和11所示序列的重鏈和輕鏈的抗體BNJ421或其抗原結合片段和變體。BNJ421（也稱為ALXN1211）描述於WO 2015134894和美國專利案號9,079,949中，其全部教導內容藉由引用特此併入。Another exemplary anti-C5 antibody is antibody BNJ421 or an antigen-binding fragment and variant thereof comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in WO 2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are hereby incorporated by reference.

在其他實施方式中，抗體包含BNJ421的重鏈和輕鏈CDR或可變區。因此，在一個實施方式中，抗體包含具有SEQ ID NO:12所示序列的BNJ421 VH區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的BNJ421 VL區的CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含分別具有SEQ ID NO:19、18和3所示序列的重鏈CDR1、CDR2和CDR3結構域，以及分別具有SEQ ID NO:4、5和6所示序列的輕鏈CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含分別具有SEQ ID NO:12和SEQ ID NO:8所示胺基酸序列的VH和VL區。In other embodiments, the antibody comprises the heavy chain and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the BNJ421 VH region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the BNJ421 VL region having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NO: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NO: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

CDR的確切邊界根據不同的方法進行了不同的定義。在一些實施方式中，輕鏈或重鏈可變結構域內的CDR或框架區的位置如以下所定義：Kabat等人[(1991)「Sequences of Proteins of Immunological Interest [具有免疫學意義的蛋白質序列].」NIH出版號91-3242, U.S. Department of Health and Human Services [美國衛生與公眾服務部], 貝塞斯達, 馬里蘭州]。在這種情況下，CDR可以稱為「Kabat CDR」（例如，「Kabat LCDR2」或「Kabat HCDR1」）。在一些實施方式中，輕鏈或重鏈可變區的CDR的位置如以下所定義：Chothia等人 （Nature[自然], 342:877-83, 1989）。因此，該等區域可以稱為「Chothia CDR」（例如，「Chothia LCDR2」或「Chothia HCDR3」）。在一些實施方式中，輕鏈和重鏈可變區的CDR的位置可以如Kabat-Chothia組合定義所定義。在這樣的實施方式中，該等區域可稱為「組合的Kabat-Chothia CDR。」 Thomas, C.等人（Mol. Immunol.[分子免疫學], 33:1389-401, 1996）舉例說明了根據Kabat和Chothia編號方案鑒定CDR邊界。The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the positions of CDRs or framework regions within a light or heavy chain variable domain are defined as follows: Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91-3242, US Department of Health and Human Services, Bethesda, Maryland]. In this case, the CDR may be referred to as a "Kabat CDR" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the positions of CDRs of a light or heavy chain variable region are defined as follows: Chothia et al. (Nature , 342:877-83, 1989). Thus, such regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions may be defined as in the Kabat-Chothia combined definition. In such embodiments, such regions may be referred to as "combined Kabat-Chothia CDRs." Thomas, C. et al. (Mol. Immunol. , 33:1389-401, 1996) exemplify the identification of CDR boundaries according to the Kabat and Chothia numbering schemes.

另一種示例性抗C5抗體係美國專利案號8,241,628和8,883,158中描述的7086抗體。在一個實施方式中，抗體包含7086抗體的重鏈和輕鏈CDR或可變區（參見美國專利案號8,241,628和8,883,158）。在另一個實施方式中，抗體或其抗原結合片段包含分別具有SEQ ID NO:21、22和23所示序列的重鏈CDR1、CDR2和CDR3結構域，以及分別具有SEQ ID NO:24、25和26所示序列的輕鏈CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體或其抗原結合片段包含具有SEQ ID NO:27所示序列的7086抗體VH區，以及具有SEQ ID NO:28所示序列的7086抗體VL區。Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy chain and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 24, 25 and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises the 7086 antibody VH region having the sequence shown in SEQ ID NO:27, and the 7086 antibody VL region having the sequence shown in SEQ ID NO:28.

另一種示例性抗C5抗體係美國專利案號8,241,628和8,883,158中也描述的8110抗體。在一個實施方式中，抗體包含8110抗體的重鏈和輕鏈CDR或可變區。在另一個實施方式中，抗體或其抗原結合片段包含分別具有SEQ ID NO:29、30和31所示序列的重鏈CDR1、CDR2和CDR3結構域，以及分別具有SEQ ID NO:32、33和34所示序列的輕鏈CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含具有SEQ ID NO:35所示序列的8110抗體VH區和具有SEQ ID NO:36所示序列的8110抗體VL區。Another exemplary anti-C5 antibody is the 8110 antibody also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy chain and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 32, 33 and 34, respectively. In another embodiment, the antibody comprises a 8110 antibody VH region having a sequence shown in SEQ ID NO: 35 and a 8110 antibody VL region having a sequence shown in SEQ ID NO: 36.

另一種示例性抗C5抗體係美國專利案號9,765,135中描述的305LO5抗體。在一個實施方式中，抗體包含305LO5抗體的重鏈和輕鏈CDR或可變區。在另一個實施方式中，抗體或其抗原結合片段包含分別具有SEQ ID NO:37、38和39所示序列的重鏈CDR1、CDR2和CDR3結構域，以及分別具有SEQ ID NO:40、41和42所示序列的輕鏈CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗體包含具有SEQ ID NO:43所示序列的305LO5抗體VH區和具有SEQ ID NO:44所示序列的305LO5抗體VL區。Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy chain and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having sequences shown in SEQ ID NOs: 40, 41 and 42, respectively. In another embodiment, the antibody comprises a 305LO5 antibody VH region having a sequence shown in SEQ ID NO: 43 and a 305LO5 antibody VL region having a sequence shown in SEQ ID NO: 44.

另一種示例性抗C5抗體係SKY59抗體（Fukuzawa, T.等人，Sci. Rep.[科學報導], 7:1080, 2017）。在一個實施方式中，抗體包含SKY59抗體的重鏈和輕鏈CDR或可變區。在另一個實施方式中，抗體或其抗原結合片段包含含有SEQ ID NO:45的重鏈和含有SEQ ID NO:46的輕鏈。Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et al.,Sci. Rep. , 7:1080, 2017). In one embodiment, the antibody comprises the heavy chain and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody or its antigen-binding fragment comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.

在一些實施方式中，抗C5抗體包含REGN3918抗體的重鏈和輕鏈可變區或重鏈和輕鏈（參見美國專利案號10,633,434）。在一些實施方式中，抗C5抗體或其抗原結合片段包含重鏈可變區和輕鏈可變區，該重鏈可變區包含SEQ ID NO:47所示的序列，該輕鏈可變區包含SEQ ID NO:48所示的序列。在一些實施方式中，抗C5抗體或其抗原結合片段包含SEQ ID NO: 49所示的重鏈序列，以及SEQ ID NO: 50所示的輕鏈序列。In some embodiments, the anti-C5 antibody comprises the heavy chain and light chain variable regions or the heavy chain and light chain of the REGN3918 antibody (see U.S. Patent No. 10,633,434). In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the sequence shown in SEQ ID NO: 47, and the light chain variable region comprises the sequence shown in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody or its antigen-binding fragment comprises the heavy chain sequence shown in SEQ ID NO: 49, and the light chain sequence shown in SEQ ID NO: 50.

在另一個實施方式中，抗C5抗體係依庫珠單抗（SOLIRIS®）的生物類似物。例如，在一個實施方式中，抗C5抗體係例如ABP 959抗體（由美國安進公司製造的依庫珠單抗生物類似物）、ELIZARIA®（由俄羅斯Generium JNC公司製造的依庫珠單抗生物類似物）、SB12（由韓國仁川三星Bioepis公司製造的依庫珠單抗生物類似物）、ISU305（來自韓國ISU Abxis公司（ISU Abxis, South Korea）的依庫珠單抗生物類似物）、ABLYZE®（來自伊朗CinnaGen公司的依庫珠單抗生物類似物）、BCD 148（來自加拿大魁北克省Biocad醫療公司的依庫珠單抗生物類似物）、特度魯單抗（由諾華股份有限公司製造）、可伐利單抗（由羅氏公司製造）、CAN106（由中國北海康成製藥有限公司製造）或帕澤利單抗（由再生元製藥公司製造）。In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP 959 antibody (an eculizumab biosimilar manufactured by Amgen, USA), ELIZARIA® (an eculizumab biosimilar manufactured by Generium JNC, Russia), SB12 (an eculizumab biosimilar manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (an eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (an eculizumab biosimilar from CinnaGen, Iran), BCD 148 (a biosimilar of eculizumab from Biocad Medical in Quebec, Canada), tertulumab (made by Novartis AG), kovalizumab (made by Roche), CAN106 (made by Beihai Kangcheng Pharmaceutical Co., Ltd. in China), or pazelimumab (made by Regeneron Pharmaceuticals).

在一些實施方式中，本文所述之抗C5抗體包含重鏈CDR1，該重鏈CDR1包含以下胺基酸序列或由以下胺基酸序列組成：GHIFSNYWIQ（SEQ ID NO:19）。在一些實施方式中，本文所述之抗C5抗體包含重鏈CDR2，該重鏈CDR2包含以下胺基酸序列或由以下胺基酸序列組成：EILPGSGHTEYTENFKD（SEQ ID NO:18）。在一些實施方式中，本文所述之抗C5抗體包含重鏈可變區，該重鏈可變區包含以下胺基酸序列： QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS（SEQ ID NO:12）。In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibody described herein comprises a heavy chain variable region comprising the following amino acid sequence:QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS (SEQ ID NO: 12).

在一些實施方式中，本文所述之抗C5抗體包含輕鏈可變區，該輕鏈可變區包含以下胺基酸序列： DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK（SEQ ID NO:8）。In some embodiments, the anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK (SEQ ID NO: 8).

在一些實施方式中，本文所述之抗C5抗體可以包含與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中結合的親和力大於與作為變體人Fc恒定區來源的天然人Fc恒定區結合的親和力。該Fc恒定區相對於作為變體人Fc恒定區來源的天然人Fc恒定區可以包含例如一或多個（例如，兩個、三個、四個、五個、六個、七個或八個或更多個）胺基酸取代。取代可以增加含有變體Fc恒定區的IgG抗體在pH 6.0下對FcRn的結合親和力，同時維持相互作用的pH依賴性。用於測試抗體Fc恒定區中的一或多個取代是否增加在pH 6.0下Fc恒定區對FcRn的親和力（同時維持相互作用的pH依賴性）之方法在本領域中係已知的並且在工作實例中舉例說明。參見例如WO 2015134894和美國專利案號9,079949，其中每一個的揭露內容藉由引用以其全文併入本文。In some embodiments, the anti-C5 antibodies described herein may comprise a variant human Fc constant region that binds to a human neonatal Fc receptor (FcRn) with an affinity greater than that of a natural human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region may comprise, for example, one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions relative to the natural human Fc constant region from which the variant human Fc constant region is derived. The substitutions may increase the binding affinity of an IgG antibody containing a variant Fc constant region to FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in an antibody Fc constant region increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and exemplified in the working examples. See, for example, WO 2015134894 and U.S. Patent No. 9,079949, the disclosures of each of which are incorporated herein by reference in their entirety.

增強抗體Fc恒定區對FcRn的結合親和力的取代係本領域已知的，包括，例如，(1) M252Y/S254T/T256E三重取代（Dall’Acqua, W.等人, J. Biol. Chem. [生物化學雜誌], 281:23514-24, 2006）；(2) M428L或T250Q/M428L取代（Hinton, P.等人,J. Biol. Chem.[生物化學雜誌], 279:6213-6, 2004；Hinton, P.等人,J. Immunol.[免疫學雜誌], 176:346-56, 2006）；和 (3) N434A或T307/E380A/N434A取代（Petkova, S.等人,Int. Immunol.[國際免疫學], 18:1759 -69, 2006）。另外的取代配對：P257I/Q311I、P257I/N434H和D376V/N434H（Datta-Mannan, A.等人,J. Biol.Chem.[生物化學雜誌], 282:1709-17, 2007），其中每一個的揭露內容藉由引用以其全文併入本文。Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, for example, (1) a triple substitution of M252Y/S254T/T256E (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) a M428L or T250Q/M428L substitution (Hinton, P. et al.,J. Biol. Chem. , 279:6213-6, 2004; Hinton, P. et al.,J. Immunol. , 176:346-56, 2006); and (3) a N434A or T307/E380A/N434A substitution (Petkova, S. et al.,Int. Immunol. , 18:1759-69, 2006). Additional substitution pairs: P257I/Q311I, P257I/N434H, and D376V/N434H (Datta-Mannan, A. et al.,J. Biol.Chem. , 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

在一些實施方式中，變體恒定區在EU胺基酸第255位處具有對纈胺酸的取代。在一些實施方式中，變體恒定區在EU胺基酸位置309處具有對天冬醯胺的取代。在一些實施方式中，變體恒定區在EU胺基酸位置312處具有對異白胺酸的取代。在一些實施方式中，變體恒定區在EU胺基酸位置386處具有取代。In some embodiments, the variant constant region has a substitution for valine at EU amino acid position 255. In some embodiments, the variant constant region has a substitution for asparagine at EU amino acid position 309. In some embodiments, the variant constant region has a substitution for isoleucine at EU amino acid position 312. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

在一些實施方式中，變體Fc恒定區相對於作為其來源的天然恒定區包含不超過30個（例如，不超過29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3或2個）胺基酸取代、插入或缺失。在一些實施方式中，變體Fc恒定區包含一或多個選自由以下組成之群組的胺基酸取代：M252Y、S254T、T256E、N434S、M428L、V259I、T250I和V308F。在一些實施方式中，變體人Fc恒定區在天然人IgG Fc恒定區的位置428處包含甲硫胺酸，在位置434處包含天冬醯胺，各自採用EU編號。在一些實施方式中，變體Fc恒定區包含428L/434S雙取代，如美國專利案號8,088,376中描述。In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it is derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region comprises methionine at position 428 and asparagine at position 434 of a native human IgG Fc constant region, each using EU numbering. In some embodiments, the variant Fc constant region comprises a 428L/434S double substitution as described in U.S. Patent No. 8,088,376.

在一些實施方式中，該等突變的精確位置可能由於抗體工程而從天然人Fc恒定區位置偏移。例如，當在IgG2/4嵌合Fc中使用時，428L/434S雙取代可對應於在瑞利珠單抗中發現並描述於美國專利案號9,079,949（其揭露內容藉由引用以其全文併入本文）中的M429L和N435S變體中的429L和435S。In some embodiments, the exact positions of the mutations may be shifted from the natural human Fc constant region positions due to antibody engineering. For example, when used in an IgG2/4 chimeric Fc, the 428L/434S double substitution may correspond to 429L and 435S in the M429L and N435S variants found in reslizumab and described in U.S. Patent No. 9,079,949 (the disclosure of which is incorporated herein by reference in its entirety).

在一些實施方式中，變體恒定區相對於天然人Fc恒定區在胺基酸位置237、238、239、248、250、252、254、255、256、257、258、265、270、286、289、297、298、303、305、307、308、309、311、312、314、315、317、325、332、334、360、376、380、382、384、385、386、387、389、424、428、433、434或436（EU編號）處包含取代。在一些實施方式中，取代選自由以下組成之群組：位置237處甲硫胺酸取代甘胺酸；位置238處丙胺酸取代脯胺酸；位置239處離胺酸取代絲胺酸；位置248處異白胺酸取代離胺酸；位置250處丙胺酸、苯丙胺酸、異白胺酸、甲硫胺酸、麩醯胺酸、絲胺酸、纈胺酸、色胺酸或酪胺酸取代蘇胺酸；位置252處苯丙胺酸、色胺酸或酪胺酸取代甲硫胺酸；位置254處蘇胺酸取代絲胺酸；位置255處麩胺酸取代精胺酸；位置256處天冬胺酸、麩胺酸或麩醯胺酸取代蘇胺酸；位置257處丙胺酸、甘胺酸、異白胺酸、白胺酸、甲硫胺酸、天冬醯胺、絲胺酸、蘇胺酸或纈胺酸取代脯胺酸；位置258處組胺酸取代麩胺酸；位置265處丙胺酸取代天冬胺酸；位置270處苯丙胺酸取代天冬胺酸；位置286處丙胺酸或麩胺酸取代天冬醯胺；位置289處組胺酸取代蘇胺酸；位置297處丙胺酸取代天冬醯胺；位置298處甘胺酸取代絲胺酸；位置303處丙胺酸取代纈胺酸；位置305處丙胺酸取代纈胺酸；位置307處丙胺酸、天冬胺酸、苯丙胺酸、甘胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、天冬醯胺、脯胺酸、麩醯胺酸、精胺酸、絲胺酸、纈胺酸、色胺酸或酪胺酸取代蘇胺酸；位置308處丙胺酸、苯丙胺酸、異白胺酸、白胺酸、甲硫胺酸、脯胺酸、麩醯胺酸或蘇胺酸取代纈胺酸；位置309處丙胺酸、天冬胺酸、麩胺酸、脯胺酸或精胺酸取代白胺酸或纈胺酸；位置311處丙胺酸、組胺酸或異白胺酸取代麩醯胺酸；位置312處丙胺酸或組胺酸取代天冬胺酸；位置314處離胺酸或精胺酸取代白胺酸；位置315處丙胺酸或組胺酸取代天冬醯胺；位置317處丙胺酸取代離胺酸；位置325處甘胺酸取代天冬醯胺；位置332處纈胺酸取代異白胺酸；位置334處白胺酸取代離胺酸；位置360處組胺酸取代離胺酸；位置376處丙胺酸取代天冬胺酸；位置380處丙胺酸取代麩胺酸；位置382處丙胺酸取代麩胺酸；位置384處丙胺酸取代天冬醯胺或絲胺酸；位置385處天冬胺酸或組胺酸取代甘胺酸；位置386處脯胺酸取代麩醯胺酸；位置387處麩胺酸取代脯胺酸；位置389處丙胺酸或絲胺酸取代天冬醯胺；位置424處丙胺酸取代絲胺酸；位置428處丙胺酸、天冬胺酸、苯丙胺酸、甘胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、天冬醯胺、脯胺酸、麩醯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸取代甲硫胺酸；位置433處離胺酸取代組胺酸；位置434處丙胺酸、苯丙胺酸、組胺酸、絲胺酸、色胺酸或酪胺酸取代天冬醯胺；以及位置436處組胺酸取代酪胺酸或苯丙胺酸，均採用EU編號。In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 (EU numbering) relative to a native human Fc constant region. In some embodiments, the substitution is selected from the group consisting of: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine at position 250. threonine; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamine for arginine at position 255; aspartic acid, glutamine, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine for proline at position 257 ; histidine substituted for glutamine at position 258; alanine substituted for aspartic acid at position 265; phenylalanine substituted for aspartic acid at position 270; alanine or glutamine substituted for asparagine at position 286; histidine substituted for threonine at position 289; alanine substituted for asparagine at position 297; glycine substituted for serine at position 298; alanine substituted for valine at position 303; Alanine is substituted for valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine is substituted for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline at position 308 , glutamine, glutamic acid, or threonine for valine; alanine, aspartic acid, glutamine, proline, or arginine for leucine or valine at position 309; alanine, histidine, or isoleucine for glutamic acid at position 311; alanine or histidine for aspartic acid at position 312; lysine or arginine for leucine at position 314; alanine or histidine for isoleucine at position 315; asparagine; alanine substituted for lysine at position 317; glycine substituted for asparagine at position 325; valine substituted for isoleucine at position 332; leucine substituted for lysine at position 334; histidine substituted for lysine at position 360; alanine substituted for aspartic acid at position 376; alanine substituted for glutamine at position 380; alanine substituted for glutamine at position 382; alanine substituted for asparagine or serine at position 385; aspartic acid or histidine substituted for glycine at position 386; proline substituted for glutamine at position 387; glutamine substituted for proline at position 389; alanine or serine substituted for asparagine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine at position 428 434; and a substitution of alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine for asparagine at position 436, all using the EU numbering.

在一些實施方式中，用於在本文所述之方法中使用的合適的抗C5抗體包含含有SEQ ID NO:14所示的胺基酸序列的重鏈多肽和/或含有SEQ ID NO:11所示的胺基酸序列的輕鏈多肽。可替代地，在一些實施方式中，用於在本文所述之方法中使用的抗C5抗體包含含有SEQ ID NO:20所示的胺基酸序列的重鏈多肽和/或含有SEQ ID NO:11所示的胺基酸序列的輕鏈多肽。In some embodiments, suitable anti-C5 antibodies for use in the methods described herein comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and/or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. Alternatively, in some embodiments, anti-C5 antibodies for use in the methods described herein comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 20 and/or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

在一個實施方式中，抗體在pH 7.4和25°C（以及，否則，在生理條件下）以至少0.1（例如至少0.15、0.175、0.2、0.25、0.275、0.3、0.325、0.35、0.375、0.4、0.425、0.45、0.475、0.5、0.525、0.55、0.575、0.6、0.625、0.65、0.675、0.7、0.725、0.75、0.775、0.8、0.825、0.85、0.875、0.9、0.925、0.95或0.975）nM的親和解離常數（K_D）與C5結合。在一個實施方式中，抗體在pH 7.4和25°C下（以及，否則，在生理條件下）以約0.5 nM的親和解離常數（K_D）與C5結合。在一些實施方式中，抗C5抗體或其抗原結合片段的K_D不大於1（例如，不大於0.9、0.8、0.7、0.6、0.5、0.4、0.3或0.2）nM。在一些實施方式中，抗體在pH 6.0和25°C下（以及，否則，在生理條件下）以約22 nM的K_D與C5結合。In one embodiment, the antibody binds to C5 with an affinity dissociation constant (_KD ) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM at pH 7.4 and 25°C (and, otherwise under physiological conditions). In one embodiment, the antibody binds to C5 with an affinity dissociation constant (_KD ) of about 0.5 nM at pH 7.4 and 25°C (and, otherwise, under physiological conditions). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a_KD of no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2) nM. In some embodiments, the antibody binds to C5 with a_KD of about 22 nM at pH 6.0 and 25°C (and, otherwise, under physiological conditions).

在其他實施方式中，[(在pH 6.0和25°C時抗體對C5的K_D)/(在pH 7.4和25°C時抗體對C5的K_D)]大於21（例如，大於22、23、24、25、26、27、28、29、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、350、400、450、500、600、700、800、900、1000、1500、2000、2500、3000、3500、4000、4500、5000、5500、6000、6500、7000、7500或8000）。In other embodiments, [(_KD of the antibody for C5 at pH 6.0 and 25°C)/(_KD of the antibody for C5 at pH 7.4 and 25°C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 261, 271, 272, 283, 284, 285, 290, 300, 310, 311, 312, 313, 314, 315 40, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or 8000).

用於確定抗體是否與蛋白質抗原結合和/或抗體對蛋白質抗原的親和力的方法係本領域已知的。例如，可以使用多種技術檢測和/或定量抗體與蛋白質抗原的結合，例如但不限於西方墨點法、斑點印跡、表面電漿共振（SPR）檢測（例如，BIAcore系統；Pharmacia Biosensor AB公司，瑞典烏普薩拉和新澤西州皮斯卡塔韋）或酶聯免疫吸附測定（ELISA；Benny K. C. Lo (2004) 「Antibody Engineering: Methods and Protocols [抗體工程：方法和方案],」 Humana出版社 (ISBN: 1588290921)；Johne, B.等人,J. Immunol.Meth.[免疫學方法雜誌], 160:191-8, 1993；Jönsson, U.等人,Ann.Biol. Clin.[臨床生物學年鑒], 51:19-26, 1993；和Jönsson, U.等人,Biotechniques[生物技術], 11:620-7, 1991）。此外，用於測量親和力（例如，解離和締合常數）之方法在工作實例中進行了闡述。Methods for determining whether an antibody binds to a protein antigen and/or the affinity of an antibody for a protein antigen are known in the art. For example, the binding of an antibody to a protein antigen can be detected and/or quantified using a variety of techniques, such as, but not limited to, Western blotting, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, New Jersey), or enzyme-linked immunosorbent assay (ELISA; Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne, B.et al .,J. Immunol.Meth. , 160:191-8, 1993; Jönsson, U. et al.,Ann. Biol. Clin. , 51:19-26, 1993). 1993; and Jönsson, U. et al.,Biotechniques , 11:620-7, 1991). In addition, methods for measuring affinities (e.g., dissociation and association constants) are described in the working examples.

如本文所用，術語「k_a」係指抗體與抗原締合的速率常數。術語「k_d」係指抗體從抗體/抗原複合物中解離的速率常數。並且術語「K_D」係指抗體-抗原相互作用的平衡解離常數。平衡解離常數由動力學速率常數的比率推導出，K_D= k_a/k_d。這樣的確定可以在例如25°C或37°C下進行（參見工作實例）。例如，抗體與人C5結合的動力學可以在pH 8.0、7.4、7.0、6.5和6.0通過BIAcore 3000儀器上的SPR使用抗Fc捕獲方法固定抗體來確定。As used herein, the term "_ka " refers to the rate constant for the association of an antibody with an antigen. The term "_k " refers to the rate constant for the dissociation of an antibody from an antibody/antigen complex. And the term "_K " refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is derived from the ratio of the kinetic rate constants,_K =_ka /_k . Such determinations can be made, for example, at 25°C or 37°C (see working examples). For example, the kinetics of binding of an antibody to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5, and 6.0 by SPR on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.

在一個實施方式中，抗C5抗體或其抗原結合片段阻斷C5裂解成C5a和C5b。通過這種阻斷作用，例如，C5a的促炎作用和細胞表面的C5b-9攻膜複合物（MAC）的產生被抑制。In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the cleavage of C5 into C5a and C5b. Through this blocking effect, for example, the pro-inflammatory effect of C5a and the generation of C5b-9 membrane attack complex (MAC) on the cell surface are inhibited.

用於確定本文所述之特定抗體是否抑制C5裂解之方法係本領域已知的。抑制人補體成分C5可降低受試者體液中補體的細胞裂解能力。一或多種體液中存在的補體的細胞裂解能力的這樣的降低可以藉由本領域已知的方法來測量，例如藉由常規溶血測定，例如溶血測定（Kabat和Mayer (編輯), 「Experimental Immunochemistry [實驗免疫化學], 第2版,」 135-240, 斯普林菲爾德（Springfield）, 伊利諾州, CC Thomas (1961), 第135-139頁），或該測定的其他常規形式，例如雞紅血球溶血法（Hillmen, P.等人,N. Engl. J. Med.[新英格蘭醫學雜誌], 350:552-9, 2004）。確定候選化合物是否抑制人C5裂解成C5a和C5b形式之方法係本領域已知的（Evans, M.等人,Mol. Immunol.[分子免疫學], 32:1183-95, 1995）。可以例如藉由本領域已知的方法測量體液中C5a和C5b的濃度和/或生理活性。對於C5b，可以使用如本文討論的針對可溶性C5b-9的一或多種溶血測定。也可以使用本領域已知的其他測定。使用該等或其他合適類型的測定，可以篩選能夠抑制人補體成分C5的候選藥劑。Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cell lytic ability of complement in the subject's body fluids. Such a reduction in the cell lytic ability of a complement present in one or more body fluids can be measured by methods known in the art, for example, by a conventional hemolytic assay, such as the hemolytic assay (Kabat and Mayer (eds.), "Experimental Immunochemistry, 2nd ed.," 135-240, Springfield, IL, CC Thomas (1961), pp. 135-139), or other conventional forms of the assay, such as the chicken erythrocyte hemolysis assay (Hillmen, P. et al.,N. Engl. J. Med. , 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into C5a and C5b forms are known in the art (Evans, M. et al.,Mol. Immunol. , 32: 1183-95, 1995). The concentration and/or physiological activity of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, one or more hemolytic assays for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using these or other suitable types of assays, candidate agents that can inhibit human complement component C5 can be screened.

免疫學技術如但不限於ELISA可用於測量C5和/或其分裂產物的蛋白質濃度以確定抗C5抗體或其抗原結合片段抑制C5轉化為生物活性產物的能力。在一些實施方式中，測量C5a的產生。在一些實施方式中，C5b-9新表位特異性抗體用於檢測MAC形成。Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and/or its cleavage products to determine the ability of anti-C5 antibodies or antigen-binding fragments thereof to inhibit the conversion of C5 into biologically active products. In some embodiments, the production of C5a is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect MAC formation.

溶血測定可用於確定抗C5抗體或其抗原結合片段對補體激活的抑制活性。為了確定抗C5抗體或其抗原結合片段對體外血清測試溶液中經典補體途徑介導的溶血的影響，例如，用溶血素包被的綿羊紅血球或用抗雞紅血球抗體敏化的雞紅血球用作靶細胞。藉由將100%裂解視為等於在不存在抑制劑的情況下發生的裂解來對裂解百分比進行歸一化。在一些實施方式中，經典補體途徑由人IgM抗體激活，例如Wieslab^®經典途徑補體套組（Classical Pathway Complement Kit）（Wieslab^®COMPL CP310，Euro-Diagnostica公司，瑞典）中所使用。簡而言之，在存在人IgM抗體的情況下，將測試血清與抗C5抗體或其抗原結合片段一起孵育。藉由使混合物與酶軛合的抗C5b-9抗體和螢光底物接觸，並且在適當波長下測量吸光度，來測量所產生的C5b-9的量。作為對照，在不存在抗C5抗體或其抗原結合片段的情況下孵育測試血清。在一些實施方式中，測試血清係用C5多肽重構的C5缺陷血清。Hemolysis assays can be used to determine the inhibitory activity of anti-C5 antibodies or antigen-binding fragments thereof on complement activation. In order to determine the effect of anti-C5 antibodies or antigen-binding fragments thereof on hemolysis mediated by the classical complement pathway in anin vitro serum test solution, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibodies are used as target cells. The percentage of lysis is normalized by considering 100% lysis to be equal to the lysis that occurs in the absence of an inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, such as that used in the^Wieslab® Classical Pathway Complement Kit (^Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or an antigen-binding fragment thereof in the presence of human IgM antibodies. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescent substrate and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of an anti-C5 antibody or an antigen-binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.

為了確定抗C5抗體或其抗原結合片段對替代途徑介導的溶血的影響，可將未敏化的兔或豚鼠紅血球用作靶細胞。在一些實施方式中，血清測試溶液係用C5多肽重構的C5缺陷血清。藉由將100%裂解視為等於在不存在抑制劑的情況下發生的裂解來對裂解百分比進行歸一化。在一些實施方式中，替代補體途徑由脂多糖分子激活，例如Wieslab^®替代途徑補體套組（Alternative Pathway Complement Kit）（Wieslab^®COMPL AP330，Euro-Diagnostica公司，瑞典）中所使用。簡而言之，在存在脂多糖的情況下，將測試血清與抗C5抗體或其抗原結合片段一起孵育。藉由使混合物與酶軛合的抗C5b-9抗體和螢光底物接觸，並在適當波長下測量螢光度，來測量所產生的C5b-9的量。作為對照，在不存在抗C5抗體或其抗原結合片段的情況下孵育測試血清。To determine the effect of anti-C5 antibodies or antigen-binding fragments thereof on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis to be equivalent to the lysis that occurs in the absence of an inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, such as used in the^Wieslab® Alternative Pathway Complement Kit (^Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or antigen-binding fragment thereof in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescent substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of anti-C5 antibody or its antigen-binding fragment.

在一些實施方式中，C5活性或其抑制使用CH50eq測定來定量。CH50eq測定係用於測量血清中總經典補體活性之方法。該測試係裂解測定，它使用抗體敏化的紅血球作為經典補體途徑的激活劑和測試血清的各種稀釋以確定提供50%裂解所需的量（CH50）。例如，可以使用分光光度計確定溶血百分比。CH50eq測定提供了末端補體複合物（TCC）形成的間接測量，因為TCC本身直接負責所測量的溶血。該測定係熟悉該項技術者所已知的並且通常實踐的。簡而言之，為了激活經典補體途徑，將未稀釋的血清樣本（例如，重構的人血清樣本）添加到含有抗體敏化的紅血球的微量測定孔中，由此產生TCC。接下來，將激活的血清在微量測定孔中稀釋，該等微量測定孔塗有捕獲試劑（例如，與TCC的一或多種成分結合的抗體）。激活的樣本中存在的TCC與塗布微量測定孔表面的單株抗體結合。洗滌各孔，並將可檢測地標記並識別結合的TCC的檢測試劑添加到每個孔中。可檢測標記可為例如螢光標記或酶標記。測定結果以每毫升CH50單位當量（CH50 U Eq/mL）表示。In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. The test is a lysis assay that uses antibody-sensitized erythrocytes as activators of the classical complement pathway and various dilutions of the test serum to determine the amount (CH50) required to provide 50% lysis. For example, the percentage of hemolysis can be determined using a spectrophotometer. The CH50eq assay provides an indirect measurement of the formation of the terminal complement complex (TCC) because the TCC itself is directly responsible for the measured hemolysis. The assay is known and commonly practiced by those familiar with the art. In brief, in order to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized erythrocytes, thereby generating a TCC. Next, the activated serum is diluted in microassay wells coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). TCC present in the activated sample binds to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed, and a detection reagent that detectably labels and recognizes bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. The assay results are expressed as CH50 unit equivalents per milliliter (CH50 U Eq/mL).

例如，與末端補體活性有關的抑制包括與在相似條件和等莫耳濃度下的對照抗體（或其抗原結合片段）的作用相比降低至少5%（例如，至少6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%或60%）的例如溶血測定或CH50eq測定中的末端補體活性。如本文所用，顯著抑制係指給定活性（例如，末端補體活性）被抑制至少40%（例如，至少45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%或更高）。在一些實施方式中，本文所述之抗C5抗體相對於依庫珠單抗的CDR（即，SEQ ID NO:1-6）含有一或多個胺基酸取代，但仍保留溶血測定或CH50eq測定中的依庫珠單抗的補體抑制活性的至少30%（例如，至少31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%）。For example, inhibition related to terminal complement activity includes a decrease of at least 5% (e.g., at least 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60%) in, for example, a hemolytic assay or a CH50eq assay of terminal complement activity compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at equal molar concentrations. As used herein, significant inhibition means that a given activity (e.g., terminal complement activity) is inhibited by at least 40% (e.g., at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or more). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6), but still retain at least 30% (e.g., at least 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the complement inhibitory activity of eculizumab in a hemolytic assay or a CH50eq assay.

本文所述之抗C5抗體在人中具有至少20（例如，至少21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54或55）天的血清半衰期。在另一個實施方式中，本文所述之抗C5抗體在人中具有至少40天的血清半衰期。在另一個實施方式中，本文所述之抗C5抗體在人中具有大約43天的血清半衰期。在另一個實施方式中，本文所述之抗C5抗體在人中具有在39天至48天之間的血清半衰期。用於測量抗體的血清半衰期的方法係本領域已知的。在一些實施方式中，本文所述之抗C5抗體或其抗原結合片段的血清半衰期比依庫珠單抗的血清半衰期大至少20%（例如，至少30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、100%、125%、150%、175%、200%、250%、300%、400%或500%），例如，如在工作實例中描述的小鼠模型系統之一（例如，C5缺陷/NOD/scid小鼠或hFcRn轉基因小鼠模型系統）中測量的。The anti-C5 antibodies described herein have a serum half-life in humans of at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of about 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of between 39 and 48 days. Methods for measuring the serum half-life of antibodies are known in the art. In some embodiments, the serum half-life of an anti-C5 antibody or antigen-binding fragment thereof described herein is at least 20% greater (e.g., at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, or 500%) than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., a C5-deficient/NOD/scid mouse or a hFcRn transgenic mouse model system).

在一個實施方式中，抗體與本文所述之抗體競爭結合C5上的相同表位和/或與C5上相同的表位結合。關於兩種或更多種抗體的術語「結合相同的表位」意指抗體結合相同的胺基酸殘基區段，如藉由給定方法所確定的。用於確定抗體是否與本文所描述的抗體結合C5上的相同的表位的技術包括例如表位作圖法，例如抗原:抗體複合物的晶體的x射線分析，以及氫/氘交換質譜法（HDX-MS）。具有相同VH和VL或相同CDR1、CDR2和CDR3序列的抗體預計會與相同的表位結合。In one embodiment, the antibody competes for binding to the same epitope on C5 and/or binds to the same epitope on C5 as an antibody described herein. The term "binds to the same epitope" with respect to two or more antibodies means that the antibodies bind to the same segment of amino acid residues as determined by a given method. Techniques for determining whether an antibody binds to the same epitope on C5 as an antibody described herein include, for example, epitope mapping, such as x-ray analysis of crystals of antigen:antibody complexes, and hydrogen/deuterium exchange mass spectrometry (HDX-MS). Antibodies with identical VH and VL or identical CDR1, CDR2, and CDR3 sequences are expected to bind to the same epitope.

「與另一種抗體競爭結合靶標」的抗體係指抑制（部分或完全抑制）另一種抗體與靶標結合的抗體。兩種抗體是否相互競爭結合靶標，即，一種抗體是否抑制另一種抗體與靶標的結合以及抑制到何種程度，可以使用已知的競爭實驗來確定。在某些實施方式中，抗體與另一種抗體競爭並將另一種抗體與靶標的結合抑制至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%。抑制或競爭的水平可能會有所不同，這具體取決於哪種抗體係「阻斷性抗體」（即，首先與靶標一起孵育的抗體）。競爭性抗體可以結合例如相同的表位、重疊的表位或相鄰的表位（例如，如立體阻礙所示）。An antibody that "competes with another antibody for binding to a target" is one that inhibits (partially or completely) the binding of another antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition assays. In certain embodiments, an antibody competes with another antibody and inhibits the binding of the other antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition may vary, depending on which antibody is the "blocking antibody" (i.e., the antibody that is incubated with the target first). Competing antibodies can bind, for example, to the same epitope, to overlapping epitopes, or to adjacent epitopes (e.g., as indicated by steric hindrance).

用於本文所述之方法的本文所述抗C5抗體或其抗原結合片段可使用多種本領域公認的技術產生。單株抗體可以藉由熟悉該項技術者熟悉的各種技術獲得。簡而言之，將來自用所需抗原免疫的動物的脾細胞通常藉由與骨髓瘤細胞融合來永生化（Köhler, G.和Milstein, C.,Eur. J. Immunol.[歐洲免疫學雜誌], 6:511-9, 1976））。永生化方法包括用Epstein-Barr二氏病毒（Epstein Barr Virus）、癌基因或反轉錄病毒進行轉化或本領域已知的其他方法。針對對抗原具有所需特異性和親和力的抗體的產生，篩選來自單個永生化細胞的集落，並且由該等細胞產生的單株抗體的產率可以藉由各種技術提高，包括注射到脊椎動物宿主的腹膜腔中。可替代地，可以藉由篩選來自人B細胞的DNA文庫來分離編碼單株抗體或其結合片段的DNA序列（Huse, W.等人,Science[科學], 246:1275-81, 1989）。 III. 組成物The anti-C5 antibodies or antigen-binding fragments thereof described herein for use in the methods described herein can be produced using a variety of techniques recognized in the art. Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from animals immunized with the desired antigen are usually immortalized by fusion with myeloma cells (Köhler, G. and Milstein, C.,Eur. J. Immunol. [European Journal of Immunology], 6:511-9, 1976). Immortalization methods include transformation with Epstein-Barr Virus, oncogenes or retroviruses or other methods known in the art. Colonies from single immortalized cells are screened for the production of antibodies with the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be increased by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening DNA libraries from human B cells (Huse, W. et al.,Science , 246:1275-81, 1989). III. Composition

本文還提供了包含抗C5抗體或其抗原結合片段的組成物。在一個實施方式中，組成物包含抗C5抗體，該抗體包含在具有SEQ ID NO:12所示序列的重鏈可變區中的CDR1、CDR2和CDR3結構域，以及在具有SEQ ID NO:8所示序列的輕鏈可變區中的CDR1、CDR2和CDR3結構域。在另一個實施方式中，抗C5抗體包含分別具有SEQ ID NO:14和11所示序列的重鏈和輕鏈。在另一個實施方式中，抗C5抗體包含分別具有SEQ ID NO:20和11所示序列的重鏈和輕鏈。Also provided herein are compositions comprising anti-C5 antibodies or antigen-binding fragments thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2, and CDR3 domains in a heavy chain variable region having a sequence as shown in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains in a light chain variable region having a sequence as shown in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having sequences as shown in SEQ ID NO: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having sequences as shown in SEQ ID NO: 20 and 11, respectively.

組成物可以配製成藥物溶液，例如，用於向受試者投與以治療HSCT-TMA。藥物組成物通常包含藥學上可接受的載體。如本文所用，「藥學上可接受的載體」係指並且包括在生理上相容的任何和所有溶劑、分散介質、包衣、抗細菌劑和抗真菌劑、等滲劑和吸收延遲劑等。組成物可以包含藥學上可接受的鹽，例如酸加成鹽或鹼加成鹽、糖、碳水化合物、多元醇和/或張度調節劑。The composition can be formulated as a pharmaceutical solution, for example, for administration to a subject to treat HSCT-TMA. The pharmaceutical composition typically comprises a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. that are physiologically compatible. The composition may comprise a pharmaceutically acceptable salt, such as an acid addition salt or a base addition salt, a sugar, a carbohydrate, a polyol and/or a tonicity modifier.

可以根據標準方法配製組成物。藥物配製物係已建立的領域（參見，例如，Gennaro (2000) 「Remington: The Science and Practice of Pharmacy [雷明頓：藥物科學與實踐]」, 第20版, Lippincott, Williams & Wilkins [利平科特威廉姆斯和威爾金斯出版公司] (ISBN: 0683306472)；Ansel等人 (1999) 「Pharmaceutical Dosage Forms and Drug Delivery Systems [藥物劑型和藥物遞送系統]」, 第7版, Lippincott Williams & Wilkins Publishers [利平科特威廉姆斯和威爾金斯出版公司] (ISBN: 0683305727)；以及Kibbe (2000) 「Handbook of Pharmaceutical Excipients American Pharmaceutical Association [美國醫藥協會藥物賦形劑手冊]」第3版 (ISBN: 091733096X)）。在一些實施方式中，組成物可以例如配製為合適濃度並且適合於在2°C-8°C（例如，4°C）儲存的緩衝溶液。在一些實施方式中，組成物可以配製用於在低於0°C的溫度（例如，-20°C或-80°C）儲存。在一些實施方式中，組成物可以配製用於在2°C-8°C（例如，4°C）儲存長達2年（例如，1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月、1年、1½年或2年）。因此，在一些實施方式中，本文所述之組成物在2°C-8°C（例如，4°C）儲存至少1年係穩定的。The compositions may be formulated according to standard methods. Pharmaceutical formulation is an established field (see, e.g., Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) Handbook of Pharmaceutical Excipients American Pharmaceutical Association [American Medical Association Handbook of Drug Formulations]" 3rd Edition (ISBN: 091733096X)). In some embodiments, the composition can be formulated, for example, as a buffer solution of suitable concentration and suitable for storage at 2°C-8°C (e.g., 4°C). In some embodiments, the composition can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage at 2°C-8°C (e.g., 4°C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1½ years, or 2 years). Thus, in some embodiments, the compositions described herein are stable when stored at 2°C-8°C (e.g., 4°C) for at least 1 year.

藥物組成物可以呈各種形式。該等形式包括例如液體、半固體和固體劑型，如液體溶液（例如可注射和可輸注溶液）、分散劑或混懸劑、片劑、丸劑、粉末、脂質體和栓劑。較佳的形式部分取決於預期的投與方式和治療應用。例如，含有預期用於全身或局部遞送的組成物的組成物可以呈可注射或可輸注溶液的形式。因此，組成物可以配製用於藉由腸胃外方式投與（例如靜脈內、皮下、腹膜內或肌肉內注射）。如本文所用，「腸胃外投與（Parenteral administration或administered parenterally）」和其他語法上等同的短語係指除腸內和局部投與以外的投與方式，通常藉由注射，並且包括但不限於靜脈內、鼻內、眼內、肺部、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、肺內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛網膜下、脊髓內、硬膜外、腦內、顱內、頸動脈內和胸骨內注射和輸注。 IV. 方法Pharmaceutical compositions can be in various forms. Such forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends in part on the intended mode of administration and therapeutic application. For example, a composition containing a composition intended for systemic or local delivery can be in the form of an injectable or infusible solution. Thus, the composition can be formulated for administration by parenteral means (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, "parenteral administration" or "administered parenterally" and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.IV. METHODS

本文提供了用於治療 特定患者亞群（例如，在維持劑量後4週內接受輸注（例如，血小板或RBC輸注）的體重＜ 30 kg或體重 ≥30 kg的HSCT-TMA患者）的HSCT-TMA之方法，該方法包括向患者投與抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段根據特定的臨床劑量方案（例如，以特定的負荷、維持和一或多個補充劑量，和根據特定的時間表）投與（或用於投與）。Provided herein are methods for treating HSCT-TMA in specific patient subpopulations (e.g., HSCT-TMA patients weighing <30 kg or weighing ≥30 kg who receive a transfusion (e.g., a platelet or RBC transfusion) within 4 weeks after a maintenance dose), the method comprising administering an anti-C5 antibody or an antigen-binding fragment thereof to the patient, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or used for administration) according to a specific clinical dosing regimen (e.g., with a specific loading, maintenance, and one or more supplemental doses, and according to a specific schedule).

在一個實施方式中，抗C5抗體或其抗原結合片段的劑量基於患者的體重。例如，在一個實施方式中，將300 mg或600 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 5至＜ 10 kg的患者。在另一個實施方式中，將400 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 5至＜ 10 kg的患者。在另一個實施方式中，將400 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 5至＜ 10 kg的患者。在一些實施方式中，將300 mg或600 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 10至＜ 20 kg的患者。在另一個實施方式中，將800 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 10至＜ 20 kg的患者。在另一個實施方式中，將800 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 10至＜ 20 kg的患者。在一些實施方式中，將300 mg或900 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 20至＜ 30 kg的患者。在另一個實施方式中，將2100 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 20至＜ 30 kg的患者。在另一個實施方式中，將2100 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 20至＜ 30 kg的患者。In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. For example, in one embodiment, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 to < 10 kg. In another embodiment, a maintenance dose of 400 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 to < 10 kg. In another embodiment, a supplemental dose of 400 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 to < 10 kg. In some embodiments, a loading dose of 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 10 to < 20 kg. In another embodiment, a maintenance dose of 800 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 10 to < 20 kg. In another embodiment, a supplemental dose of 800 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 10 to < 20 kg. In some embodiments, a loading dose of 300 mg or 900 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 20 to < 30 kg. In another embodiment, a maintenance dose of 2100 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 20 to < 30 kg. In another embodiment, a supplemental dose of 2100 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 20 to < 30 kg.

例如，在一個實施方式中，將300 mg或1200 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 30至＜ 40 kg的患者。在另一個實施方式中，將2700 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 30至＜ 40 kg的患者。在另一個實施方式中，將2700 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 30至＜ 40 kg的患者。For example, in one embodiment, a loading dose of 300 mg or 1200 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 to < 40 kg. In another embodiment, a maintenance dose of 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 to < 40 kg. In another embodiment, a supplemental dose of 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 to < 40 kg.

在另一個實施方式中，將600 mg或2400 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 40至＜ 60 kg的患者。在另一個實施方式中，將3000 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 40至＜ 60 kg的患者。在另一個實施方式中，將3000 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 40至＜ 60 kg的患者。In another embodiment, a loading dose of 600 mg or 2400 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg. In another embodiment, a maintenance dose of 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg. In another embodiment, a supplemental dose of 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg.

在另一個實施方式中，將900 mg或2700 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 60至＜ 100 kg的患者。在另一個實施方式中，將3300 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 60至＜ 100 kg的患者。在另一個實施方式中，將3300 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 60至＜ 100 kg的患者。In another embodiment, a loading dose of 900 mg or 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg. In another embodiment, a maintenance dose of 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg. In another embodiment, a supplemental dose of 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg.

在另一個實施方式中，將900 mg或3000 mg負荷劑量的抗C5抗體或其抗原結合片段投與於體重≥ 100 kg的患者。在另一個實施方式中，將3600 mg維持劑量的抗C5抗體或其抗原結合片段投與於體重≥ 100 kg的患者。在另一個實施方式中，將3600 mg補充劑量的抗C5抗體或其抗原結合片段投與於體重≥ 100 kg的患者。In another embodiment, a loading dose of 900 mg or 3000 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg. In another embodiment, a maintenance dose of 3600 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg. In another embodiment, a supplemental dose of 3600 mg of an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg.

在某些實施方式中，調整劑量方案以提供最佳期望響應（例如，有效響應）。In certain embodiments, the dosage regimen is adjusted to provide the optimal desired response (e.g., an effective response).

在一些實施方式中，其中患者在第一維持劑量後的4週內經歷RBC輸注，該患者僅在2次維持劑量之間的中間點接受一次輸注後補充劑量的抗C5抗體（例如，瑞利珠單抗）。由於維持劑量對於較低（例如＜ 20 kg）體重級別每四週（Q4W）投與，對於較高（例如≥ 20 kg）體重級別每八週（Q8W）投與，因此第2週（＜ 20 kg的患者）和第4週（≥ 20 kg的患者）之後（例如，維持劑量後14天或28天）投與補充劑量的抗C5抗體（例如，瑞利珠單抗）。在這樣的實施方式中，如果患者在第二維持給藥期期間沒有經歷任何輸注，則在該維持給藥週期期間不需要補充劑量。同樣，如果患者在第二維持給藥期的後半段期間經歷RBC輸注，則在該維持給藥週期期間不需要補充給藥。換句話說，如果第一次RBC輸注發生在前一次維持劑量後超過4週，則不需要輸注後補充劑量。此外，如果患者在負荷劑量期期間接受輸注，則不投與補充給藥。In some embodiments, where the patient undergoes an RBC transfusion within 4 weeks after the first maintenance dose, the patient receives a post-transfusion supplemental dose of the anti-C5 antibody (e.g., reslizumab) only at the midpoint between the 2 maintenance doses. Since the maintenance dose is administered every four weeks (Q4W) for lower (e.g., <20 kg) weight classes and every eight weeks (Q8W) for higher (e.g., ≥20 kg) weight classes, the supplemental dose of the anti-C5 antibody (e.g., reslizumab) is administered after Week 2 (for patients <20 kg) and Week 4 (for patients ≥20 kg) (e.g., 14 days or 28 days after the maintenance dose). In such an embodiment, if the patient does not experience any transfusions during the second maintenance dosing period, no supplemental dose is required during that maintenance dosing cycle. Likewise, if the patient experiences an RBC transfusion during the second half of the second maintenance dosing period, no supplemental dose is required during that maintenance dosing cycle. In other words, if the first RBC transfusion occurs more than 4 weeks after the previous maintenance dose, no post-transfusion supplemental dose is required. Furthermore, if the patient receives a transfusion during the loading dose period, no supplemental dose is administered.

根據本文所述之治療方法，如果在最後維持劑量後4週內向患者提供任何量的RBC輸注，則在例如該最後維持劑量後僅4週向HSCT-TMA患者投與一次輸注後補充劑量的抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）。According to the treatment methods described herein, if any amount of RBC transfusion is provided to the patient within 4 weeks after the last maintenance dose, a post-infusion supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to the HSCT-TMA patient, for example, only 4 weeks after the last maintenance dose.

在另一個實施方式中，投與抗C5抗體或其抗原結合片段持續一或多個投與週期。在一個實施方式中，治療（例如，投與週期）係26週。在一個實施方式中，抗C5抗體或其抗原結合片段以負荷劑量在（例如，投與週期的）第1天投與一次，在（例如，投與週期的）第5天投與一次，在（例如，投與週期的）第10天投與一次。在另一個實施方式中，抗C5抗體或其抗原結合片段在（例如，投與週期的）第1天以負荷劑量投與一次，在（例如，投與週期的）第5天以負荷劑量投與一次，在（例如，投與週期的）第10天以負荷劑量投與一次，並且此後從第15天開始每八週投與維持劑量。在另一個實施方式中，抗C5抗體或其抗原結合片段在治療（例如，投與週期）後每八週投與長達兩年的延長期（例如，劑量為300 mg、600 mg、900 mg、1200 mg、2100 mg、2400 mg、2700 mg、3000 mg、3300 mg或3600 mg）。In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered for one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), and once on day 10 (e.g., of the administration cycle) as a loading dose. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once as a loading dose on day 1 (e.g., of a dosing cycle), once as a loading dose on day 5 (e.g., of a dosing cycle), once as a loading dose on day 10 (e.g., of a dosing cycle), and a maintenance dose is administered every eight weeks thereafter starting on day 15. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every eight weeks for an extension period of up to two years after treatment (e.g., dosing cycle) (e.g., at a dose of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg).

在另一個實施方式中，向在維持劑量的兩週或四週內接受輸注（例如，血小板或RBC輸注）的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週或四週投與。在實施方式中，向在維持劑量的兩週內接受RBC輸注的體重＜ 20 kg的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週按以下劑量投與：體重≥ 5至＜ 10 kg的患者400 mg，體重≥ 10至＜ 20 kg的患者800 mg。在實施方式中，向在維持劑量的四週內接受RBC輸注的體重≥ 20 ＜ 30 kg的患者投與補充劑量，其中該補充劑量在該維持劑量後四週按以下劑量投與：體重≥ 20 ＜ 30 kg的患者2100 mg。In another embodiment, a supplement is administered to a patient who receives a transfusion (e.g., a platelet or RBC transfusion) within two or four weeks of a maintenance dose, wherein the supplement is administered two or four weeks after the maintenance dose. In an embodiment, a supplement is administered to a patient weighing < 20 kg who receives an RBC transfusion within two weeks of a maintenance dose, wherein the supplement is administered two weeks after the maintenance dose at the following doses: 400 mg for patients weighing ≥ 5 to < 10 kg, 800 mg for patients weighing ≥ 10 to < 20 kg. In an embodiment, a supplemental dose is administered to patients weighing ≥ 20 < 30 kg who receive RBC transfusions within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following dose: 2100 mg for patients weighing ≥ 20 < 30 kg.

在另一個實施方式中，向在維持劑量的四週內接受RBC輸注的體重≥ 30 kg的患者投與補充劑量，其中該補充劑量在該維持劑量後四週按以下劑量投與：體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg。In another embodiment, a supplemental dose is administered to patients weighing ≥ 30 kg who receive RBC transfusions within four weeks of a maintenance dose, wherein the supplemental dose is administered four weeks after the maintenance dose at the following doses: 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg.

在一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In one embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or the antigen-binding fragment thereof is administered as follows: (a) Once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2400 mg for patients weighing ≥ 60 to < 2700 mg for patients weighing 5 to < 10 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 900 mg for patients weighing ≥ 300 mg for patients weighing 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on Day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 100 kg; 3600 mg; and wherein the supplemental dose is administered to:(i)     a patient weighing < 30 kg who receives RBC transfusions within a specified time frame of a maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose as follows:a. 300 or 400 mg for a patient weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b. 600 or 800 mg for a patient weighing 10 to < 20 kg, wherein the specified time frame is two weeks, orc. 2100 mg for a patient weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or(ii)    a patient weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a.  2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c.  3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向患者投與 有效量的包含以下的抗C5抗體：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，和分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，以及與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中變體人Fc CH3恒定區在對應於天然人IgG Fc恒定區的甲硫胺酸428和天冬醯胺434的殘基處包含Met429Leu和Asn435Ser取代，各自根據EU編號規定編號，其中該 抗C5抗體按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, and a variant human Fc constant region that binds to a human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each numbered according to EU numbering regulations, wherein the anti-C5 antibody is administered as follows: (a) once on day 1, at the following loading dose: 5 to < 600 mg for patients weighing 10 kg or less, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) once on day 5, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg mg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10 as a loading dose of 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter as a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)  Every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and wherein the supplemental dose is administered to:(i)     patients weighing < 30 kg who receive RBC transfusions within a specified time frame for the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose at the following doses:a. 300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b. 600 or 800 mg for patients weighing 20 kg, where the specified time frame is two weeks, orc. 2100 mg for patients weighing 20 to < 30 kg, where the specified time frame is four weeks, or(ii)    patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose as follows:a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的瑞利珠單抗，其中瑞利珠單抗按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。In another embodiment, a method for treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of reslizumab, wherein reslizumab is administered as follows:(a) once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, at the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg;and wherein the supplemental dose is administered to:(i)     patients weighing < 30 kg who receives RBC transfusions within a specified time frame of the maintenance dose, wherein the supplement is administered at a specified time frame after the maintenance dose as follows:a.  300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b.  600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, orc.  2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or(ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplement is administered four weeks after the maintenance dose as follows:a.  2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c.  3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的瑞利珠單抗，其中瑞利珠單抗按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受RBC輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。 以及In another embodiment, a method for treating a human patient with HSCT-TMA is provided, the method comprising administering to the patient an effective amount of reslizumab, wherein reslizumab is administered as follows:(a) once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, at the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg;and wherein the supplemental dose is administered to:(i)     patients weighing < 30 kg who receives RBC transfusions within a specified time frame of the maintenance dose, wherein the supplement is administered at a specified time frame after the maintenance dose as follows:a.  300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b.  600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, orc.  2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or(ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplement is administered four weeks after the maintenance dose as follows:a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.and

其中治療使得LDH水平降低至正常水平內或降低至低於視為的ULN水平（例如，在105-333 IU/L（國際單位/升）以內）50%以內，抗C5抗體或其抗原結合片段的血清谷濃度為至少175 µg/mL或更高，和/或游離C5濃度為0.5 µg/mL或更低（例如，0.4 µg/mL、0.3 µg/mL、0.2 µg/mL、或0.1 µg/mL或更低）。wherein treatment results in a reduction in LDH levels to within normal levels or to within 50% below a level considered ULN (e.g., within 105-333 IU/L (International Units/L)), a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of at least 175 µg/mL or greater, and/or a free C5 concentration of 0.5 µg/mL or less (e.g., 0.4 µg/mL, 0.3 µg/mL, 0.2 µg/mL, or 0.1 µg/mL or less).

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按300 mg的維持劑量；以及 (e) 向在維持劑量的兩週內接受RBC輸注的患者投與300 mg的補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 5 to <10 kg as follows: (a) once on day 1 at a loading dose of 600 mg; (b) once on day 5 at a loading dose of 300 mg; (c) once on day 10 at a loading dose of 300 mg; (d) once on day 15 and every four weeks thereafter at a loading dose of 300 mg. mg maintenance dose; and(e) administering a supplemental dose of 300 mg to a patient who receives RBC transfusions within two weeks of the maintenance dose, wherein the supplemental dose is administered two weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按400 mg的維持劑量；以及 (e) 向在維持劑量的兩週內接受RBC輸注的患者投與400 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 5 to <10 kg as follows: (a) once on day 1 at a loading dose of 600 mg; (b) once on day 5 at a loading dose of 300 mg; (c) once on day 10 at a loading dose of 300 mg; (d) on day 15 and every four weeks thereafter at a loading dose of 400 mg. mg maintenance dose; and(e) administering a supplemental dose of 400 mg to a patient who receives RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按600 mg的維持劑量，以及 (e) 向在維持劑量的兩週內接受RBC輸注的患者投與600 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 10 to < 20 kg as follows: (a) once on day 1, at a loading dose of 600 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; (d) On day 15 and every four weeks thereafter, a maintenance dose of 600 mg, and(e) a supplemental dose of 600 mg to patients who receive RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按800 mg的維持劑量，以及 (e) 向在維持劑量的兩週內接受RBC輸注的患者投與800 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 10 to < 20 kg as follows: (a) once on day 1, at a loading dose of 600 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; (d) On day 15 and every four weeks thereafter, at a maintenance dose of 800 mg, and(e) to patients who receive RBC transfusions within two weeks of the maintenance dose, administer a supplemental dose of 800 mg, and wherein the supplemental dose is administered two weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重為20至＜ 30 kg的患者： (a) 在第1天一次，按900 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2100 mg的維持劑量；以及 (e) 向在維持劑量的兩週內接受RBC輸注的患者投與2100 mg的補充劑量，並且其中該補充劑量在該維持劑量後四週投與。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing 20 to <30 kg as follows: (a) once on day 1, at a loading dose of 900 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; (d) On day 15 and every eight weeks thereafter, at a maintenance dose of 2100 mg; and(e) administering a supplemental dose of 2100 mg to patients who receive RBC transfusions within two weeks of the maintenance dose, and wherein the supplemental dose is administered four weeks after the maintenance dose.

在一些實施方式中，如有必要，根據如圖3所示的臨床演算法投與補充劑量。在一些實施方式中，如有必要，根據如表7所示的臨床演算法投與補充劑量。In some embodiments, if necessary, supplemental doses are administered according to the clinical algorithm shown in Figure 3. In some embodiments, if necessary, supplemental doses are administered according to the clinical algorithm shown in Table 7.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）按以下投與至體重≥ 30至＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按2700 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與2700 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing ≥ 30 to < 40 kg as follows: (a) once on day 1, at a loading dose of 1200 mg; (b) once on day 5, at a loading dose of 300 mg; (c) once on day 10, at a loading dose of 300 mg; and (d) On day 15 and every eight weeks thereafter, a maintenance dose of 2700 mg is administered, and the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 2700 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體 或其抗原結合片段（例如，瑞利珠單抗）按以下投與 至體重 ≥ 40至＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3000 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3000 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibodyor its antigen-binding fragment (e.g., reslizumab) is administered to a patient weighing ≥ 40 to < 60 kg as follows:(a) once on day 1, at a loading dose of 2400 mg;(b) once on day 5, at a loading dose of 600 mg;(c) once on day 10, at a loading dose of 600 mg; and(d) On day 15 and every eight weeks thereafter, a maintenance dose of 3000 mg is administered, and the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3000 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與 有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體 或其抗原結合片段（例如，瑞利珠單抗）按以下投與 至體重 ≥ 60至＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3300 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3300 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing ≥ 60 to < 100 kg as follows: (a) once on day 1 at a loading dose of 2700 mg; (b) once on day 5 at a loading dose of 900 mg; (c) once on day 10 at a loading dose of 900 mg; and (d) On day 15 and every eight weeks thereafter, a maintenance dose of 3300 mg is administered, and the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3300 mg four weeks after the maintenance dose.

在另一個實施方式中，提供了治療HSCT-TMA人患者之方法，該方法包括向該患者投與 有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中該抗C5抗體 或其抗原結合片段（例如，瑞利珠單抗）按以下投與 至體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3600 mg的維持劑量， 並且其中該患者在維持劑量的四週內接受RBC輸注，然後在該維持劑量後四週投與3600 mg的補充劑量。In another embodiment, a method for treating HSCT-TMA human patients is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab) is administered to a patient weighing ≥ 100 kg as follows: (a) once on day 1 at a loading dose of 3000 mg; (b) once on day 5 at a loading dose of 900 mg; (c) once on day 10 at a loading dose of 900 mg; and (d) On day 15 and every eight weeks thereafter, a maintenance dose of 3600 mg is administered, and the patient receives RBC transfusions within four weeks of the maintenance dose, followed by a supplemental dose of 3600 mg four weeks after the maintenance dose.

在另一個實施方式中，在投與補充劑量的抗C5抗體或其抗原結合片段（例如，瑞利珠單抗）後，實現了立即、完全和持續的末端補體抑制。In another embodiment, immediate, complete, and sustained terminal complement inhibition is achieved following administration of a supplemental dose of an anti-C5 antibody or antigen-binding fragment thereof (e.g., reslizumab).

在一個實施方式中，本文揭露的治療方法還包括投與最佳支持治療（BSC）措施。BSC措施包括但不限於輸血支持、皮質類固醇、透析和抗高血壓藥物。In one embodiment, the treatment methods disclosed herein further include administering best supportive care (BSC) measures. BSC measures include but are not limited to transfusion support, corticosteroids, dialysis, and antihypertensive drugs.

在一個實施方式中，患者以前沒有用依庫珠單抗治療過。在另一個實施方式中，患者以前已用依庫珠單抗治療過。在另一個實施方式中，患者以前已用依庫珠單抗治療，並且（例如，投與週期的）第1天距患者最後一次劑量的依庫珠單抗兩週或更長時間。 V. 結果In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab and Day 1 (e.g., of a dosing cycle) is two weeks or more from the patient's last dose of eculizumab.V. Results

本文提供了用於治療患者的HSCT-TMA之方法，該方法包括向該患者投與抗C5抗體。HSCT-TMA的症狀包括但不限於例如微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭。Provided herein is a method for treating HSCT-TMA in a patient, the method comprising administering an anti-C5 antibody to the patient. Symptoms of HSCT-TMA include, but are not limited to, microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous membrane inflammation, pulmonary hypertension, and multisystem organ failure.

根據本文所揭露的方法治療的患者經歷至少一種HSCT-TMA體征的改善。與基線相比，治療可產生選自由以下組成之群組的至少一種治療效果：例如微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭的減少或停止。Patients treated according to the methods disclosed herein experience improvement in at least one HSCT-TMA sign. Treatment may produce at least one therapeutic effect selected from the group consisting of, for example, reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous membrane inflammation, pulmonary hypertension, and multisystem organ failure, as compared to baseline.

在另一個實施方式中，治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數 ≥ 50,000/mm³，(b) LDH ＜1.5 × ULN，和 (c) 不存在血球裂片（如果在基線時存在血球裂片）。In another embodiment, treatment results in (a) a platelet count ≥ 50,000/mm³ without transfusion support in the prior 7 days, (b) LDH <1.5 x ULN, and (c) the absence of schizonts (if schizonts were present at baseline).

在另一個實施方式中，治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數 ≥ 50,000/mm³，(b) LDH ＜ 1.5 × ULN，(c) 不存在血球裂片（如果在基線時存在血球裂片），和 (d) 蛋白尿相對於基線減少至少50%。在一個實施方式中，蛋白尿係指蛋白質/肌酸酐比率 ≥ 0.5 mg/mg。In another embodiment, treatment results in (a) platelet count ≥ 50,000/mm³ in the absence of transfusion support in the prior 7 days, (b) LDH < 1.5 × ULN, (c) absence of blood cell fragments (if blood cell fragments were present at baseline), and (d) a reduction in proteinuria of at least 50% relative to baseline. In one embodiment, proteinuria refers to a protein/creatinine ratio ≥ 0.5 mg/mg.

在另一個實施方式中，治療使得產生有利的血液學響應。In another embodiment, treatment results in a favorable hematologic response.

在另一個實施方式中，治療使得LDH正常化、紅血球和血小板輸注需求得以解決、且血球裂片消失。In another embodiment, treatment results in normalization of LDH, resolution of red blood cell and platelet transfusion requirements, and disappearance of blood cell fragmentation.

在另一個實施方式中，治療使得患者能夠在沒有輸血支持的情況下維持血紅素≥ 8 g/dL。在另一個實施方式中，在沒有輸血支持的情況下，治療使得血紅素≥ 8 g/dL。In another embodiment, the treatment enables the patient to maintain a hemoglobin ≥ 8 g/dL without transfusion support. In another embodiment, the treatment enables a hemoglobin ≥ 8 g/dL without transfusion support.

在另一個實施方式中，與基線相比，治療使得LDH降低、血小板增加和/或血紅素增加。In another embodiment, treatment results in a decrease in LDH, an increase in platelets and/or an increase in hemoglobin compared to baseline.

在另一個實施方式中，與基線相比，治療產生正常水平的血清肌酸酐。In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

在另一個實施方式中，與基線相比，治療使得腎、心血管、肺、CNS和/或GI系統中TMA相關器官功能障礙有改善。In another embodiment, treatment results in improvement in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS and/or GI systems compared to baseline.

在另一個實施方式中，治療實現末端補體抑制。In another embodiment, the treatment achieves terminal complement inhibition.

在另一個實施方式中，治療使不良事件減少。In another embodiment, treatment results in a reduction in adverse events.

在另一個實施方式中，治療促使與血管炎症（例如，脫落腫瘤壞死因子受體1 [TNF-R1]）、內皮損傷和/或激活（例如，凝血酶調節蛋白和脫落血管細胞黏附分子1 [VCAM-1]）、腎損傷（例如，胱蛋白C）和/或補體蛋白和補體激活途徑產物相關的生物標誌物向正常水平轉變。在另一個實施方式中，治療促使凝血酶調節蛋白（TM）和/或黏結蛋白聚糖-1（SYND1）向正常水平轉變。在另一個實施方式中，治療促使補體因子Ba向正常水平轉變。In another embodiment, treatment results in a change toward normal levels of biomarkers associated with vascular inflammation (e.g., abscessed tumor necrosis factor receptor 1 [TNF-R1]), endothelial damage and/or activation (e.g., thrombomodulin and sloughed vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystin C), and/or complement proteins and complement activation pathway products. In another embodiment, treatment results in a change toward normal levels of thrombomodulin (TM) and/or syndecan-1 (SYND1). In another embodiment, treatment results in a change toward normal levels of complement factor Ba.

在另一個實施方式中，治療使得如經由生活品質評估（例如，生活品質評定問卷（PedsQL）量表或EQ-5D-5L問卷）所評估的生活品質相對於基線有所變化。PedsQL 4.0普適性核心量表係多維兒童自我報告和父母代理報告標準化工具，用於測量2-18歲兒童和青少年的健康相關的生活品質（QoL）。In another embodiment, treatment results in a change from baseline in quality of life as assessed by a quality of life assessment, such as the PedsQL scale or the EQ-5D-5L questionnaire. The PedsQL 4.0 Universal Core Scale is a multidimensional child self-report and parent proxy-report standardized instrument used to measure health-related quality of life (QoL) in children and adolescents aged 2-18 years.

在另一個實施方式中，乳酸脫氫酶（LDH）水平可用於評價對療法的響應性。LDH係血管內溶血的標誌物（Hill, A.等人,Br. J. Haematol.[英國血液學雜誌], 149:414-25, 2010；Hillmen, P.等人,N. Engl. J. Med.[新英格蘭醫學雜誌], 350:552-9, 2004；Parker, C.等人,Blood[血液], 106:3699-709, 2005）。紅血球含有大量的LDH，並且在體外（Van Lente, F.等人，Clin.Chem.[臨床化學], 27:1453-5, 1981）和體內（Kato, G.等人,Blood[血液],107:2279-85, 2006）無細胞血紅素與LDH濃度之間的相關性已有報導。溶血的後果與貧血無關（Hill, A.等人,Haematologica[血液學], 93(s1):359 Abs.0903, 2008；Kanakura, Y.等人,Int. J. Hematol.[國際血液學雜誌], 93:36-46, 2011）。在基線時以及隨後在整個治療期中連續獲得的LDH濃度係溶血的重要量度。正常LDH值範圍係105-333 IU/L（國際單位/升）。In another embodiment, lactate dehydrogenase (LDH) levels can be used to assess responsiveness to therapy. LDH is a marker for intravascular hemolysis (Hill, A. et al.,Br. J. Haematol. , 149:414-25, 2010; Hillmen, P. et al.,N. Engl. J. Med. , 350:552-9, 2004; Parker, C. et al.,Blood , 106:3699-709, 2005). Red blood cells contain large amounts of LDH, and a correlation between acellular hemoglobin and LDH concentrations has been reported in vitro (Van Lente, F. et al.,Clin. Chem. , 27:1453-5, 1981) and in vivo (Kato, G. et al.,Blood , 107:2279-85, 2006). The consequences of hemolysis are not related to anemia (Hill, A. et al.,Haematologica , 93(s1):359 Abs.0903, 2008; Kanakura, Y. et al.,Int. J. Hematol. , 93:36-46, 2011). LDH concentrations obtained at baseline and then continuously throughout treatment are an important measure of hemolysis. Normal LDH values range from 105-333 IU/L (International Units per Liter).

LDH水平可以使用任何合適的測試或測定來測量，如以下中描述的那些：Ferri FF編輯Ferri's Clinical Advisor[Ferri臨床診療指南]2014.費城: 賓夕法尼亞州: Elsevier Mosby [Elsevier Mosby出版社]; 2014: Section IV- Laboratory tests and interpretation of results [第四節-實驗室測試和結果解讀]。LDH濃度可以在從患者獲得的各種樣本中、特別是在血清樣本中測量。如本文所用，術語「樣本」係指來自受試者的生物材料。儘管血清LDH濃度很值得關注，但是樣本可以來自其他來源，包括例如單個細胞、多個細胞、組織、腫瘤、生物流體、生物分子或前述任一種的上清液或提取物。實例包括為進行生檢而取出的組織、在切除過程中取出的組織、血液、尿液、淋巴組織、淋巴液、腦脊髓液、黏液和糞便樣本。所使用的樣本可以根據測定法的形式、檢測方法以及要測定的腫瘤、組織、細胞或提取物的性質而有所不同。用於製備樣本之方法係本領域已知的，並且可以容易地進行調整以獲得與所用方法相容的樣本。LDH levels can be measured using any suitable test or assay, such as those described in Ferri FF, ed., Ferri's Clinical Advisor2014. Philadelphia: Pennsylvania: Elsevier Mosby; 2014: Section IV- Laboratory tests and interpretation of results. LDH concentrations can be measured in a variety of samples obtained from patients, particularly serum samples. As used herein, the term "sample" refers to biological material from a subject. Although serum LDH concentrations are of particular interest, samples can be from other sources, including, for example, a single cell, a plurality of cells, a tissue, a tumor, a biological fluid, a biomolecule, or a supernatant or extract of any of the foregoing. Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymphatic tissue, lymph fluid, cerebrospinal fluid, mucus, and fecal samples. The sample used may vary depending on the format of the assay, the detection method, and the nature of the tumor, tissue, cell, or extract to be assayed. Methods for preparing samples are known in the art and can be readily adapted to obtain samples that are compatible with the method being used.

在一個實施方式中，根據所揭露的方法治療的患者的LDH水平降低至正常水平或降低至高於視為的正常水平（例如，在105-333 IU/L以內）10%或20%以內。例如，根據所揭露的方法治療的患者LDH水平降低至正常水平以內或降低至低於視為的ULN水平（例如，在105-333 IU/L（國際單位/升）以內）10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%或50%以內。在一個實施方式中，在起始治療之前，患者的LDH水平高於ULN ≥ 1.5倍（LDH ≥ 1.5 × ULN）。In one embodiment, LDH levels in a patient treated according to the disclosed methods are reduced to normal levels or reduced to within 10% or 20% above levels considered normal (e.g., within 105-333 IU/L). For example, a patient treated according to the disclosed methods has LDH levels reduced to within normal levels or to within 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% below a level considered ULN (e.g., within 105-333 IU/L (International Units/L)). In one embodiment, the patient's LDH level is greater than 1.5 times ULN (LDH ≥ 1.5 x ULN) prior to initiating treatment.

在一個實施方式中，與基線相比，根據所揭露的方法治療的患者經歷10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%或60%的LDH百分比變化。In one embodiment, patients treated according to the disclosed methods experience a 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% change in percent LDH compared to baseline.

在另一個方面，所描述的治療方案足以維持抗C5抗體或其抗原結合片段的特定血清谷濃度。在一個實施方式中，例如，治療方案維持抗C5抗體或其抗原結合片段的血清谷濃度為50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、200、205、210、215、220、225、230、240、245、250、255、260、265、270、280、290、300、305、310、315、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500、505、510、515、520、525、530、535、540、545、550、555、560、565、570、575、580、585、590、595、600、605、610、615、620、625、630、635、640、645、650、655、660、665、670、675、680、685、690、695、700 µg/mL或更高。在一個實施方式中，治療方案維持抗C5抗體或其抗原結合片段的血清谷濃度為100 µg/mL或更高、150 µg/mL或更高、200 µg/mL或更高、250 µg/mL或更高、300 µg/mL或更高、350 µg/mL或更高、400 µg/mL或更高、或450 µg/mL或更高。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清谷濃度在100 µg/mL和700 µg/mL之間；較佳的是在300 µg/mL和600 µg/mL之間。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清谷濃度為約475 µg/mL。在一個實施方式中，治療方案維持抗C5抗體或其抗原結合片段的血清峰濃度為小於約1800、1780、1760、1740、1720、1700、1680、1660、1640、1620、1600、1580、1560、1540、1520、1500、1480、1460、1440、1420、1400、1380、1360、1340、1320、1300、1280、1260、1240、1220、1200、1180、1160、1140、1120、1100、1080、1060、1040、1020、1000、980、960、940、920、或900 µg/mL或更小。在實施方式中，治療維持抗C5抗體或其抗原結合片段的血清峰濃度在900 µg/mL和1800 µg/mL之間；較佳的是在1050 µg/mL和1550 µg/mL之間。在另一個實施方式中，治療維持抗C5抗體或其抗原結合片段的血清峰濃度為約1350 µg/mL。In another aspect, the treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 3 55, 360, 365, 3 70, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 52 0, 525, 530, 53 5, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 µg/mL or higher. In one embodiment, the treatment regimen maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of 100 µg/mL or more, 150 µg/mL or more, 200 µg/mL or more, 250 µg/mL or more, 300 µg/mL or more, 350 µg/mL or more, 400 µg/mL or more, or 450 µg/mL or more. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof between 100 µg/mL and 700 µg/mL; preferably between 300 µg/mL and 600 µg/mL. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof at about 475 µg/mL. In one embodiment, the treatment regimen maintains a peak serum concentration of anti-C5 antibody or antigen-binding fragment thereof of less than about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440 0, 1420, 1400, 1380, 1360, 1340, 1320, 1300, 1280, 1260, 1240, 1220, 1200, 1180, 1160, 1140, 1120, 1100, 1080, 1060, 1040, 1020, 1000, 980, 960, 940, 920, or 900 μg/mL or less. In embodiments, treatment maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof between 900 μg/mL and 1800 μg/mL; preferably between 1050 μg/mL and 1550 μg/mL. In another embodiment, the treatment maintains a peak serum concentration of anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg/mL.

在另一個實施方式中，為了獲得有效響應，以一定的量和頻率向患者投與抗C5抗體，以維持至少50 µg、55 µg、60 µg、65 µg、70 µg、75 µg、80 µg、85 µg、90 µg、95 µg、100 µg、105 µg、110 µg、115 µg、120 µg、125 µg、130 µg、135 µg、140 µg、145 µg、150 µg、155 µg、160 µg、165 µg、170 µg、175 µg、180 µg、185 µg、190 µg、195 µg、200 µg、205 µg、210 µg、215 µg、220 µg、225 µg、230 µg、235 µg、240 µg、245 µg、250 µg、255 µg、260 µg、270 µg、280 µg、290 µg、300 µg、320 µg、340 µg、360 µg、380 µg、400 µg、420 µg、440 µg、460 µg、480 µg、500 µg、550 µg、600 µg、650 µg、700 µg、750 µg、800 µg、850 µg、900 µg、950 µg、1000 µg、1050 µg、1100 µg、1150 µg、1200 µg、1250 µg、1300 µg、1350 µg、1400 µg、1450 µg、1500 µg、1550 µg、1600 µg、1650 µg、1700 µg、1750 µg或更多，例如1800 µg抗體/毫升患者血液。In another embodiment, in order to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain at least 50 µg, 55 µg, 60 µg, 65 µg, 70 µg, 75 µg, 80 µg, 85 µg, 90 µg, 95 µg, 100 µg, 105 µg, 110 µg, 115 µg, 120 µg, 125 µg, 130 µg, 135 µg, 140 µg, 145 µg, 150 µg, 155 µg, 160 µg, 165 µg, 170 µg, 175 µg, 180 µg, 185 µg, 190 µg, 195 µg, 200 µg, 205 µg, 210 µg, 215 µg, 220 µg, 225 µg, 230 µg, 235 µg, 240 µg, 245 µg, 250 µg, 255 µg, 260 µg, 270 µg, 280 µg, 290 µg, 300 µg, 320 µg, 340 µg, 360 µg, 380 µg, 400 µg, 420 µg, 440 µg, 460 µg, 480 µg, 500 µg, 550 µg, 600 µg, 650 µg, 700 µg, 750 µg, 800 µg, 850 µg, 900 µg, 950 µg, 1000 µg, 1050 µg, 1100 µg, 1150 µg, 1 200 µg, 1250 µg, 1300 µg, 1350 µg, 1400 µg, 1450 µg, 1500 µg, 1550 µg, 1600 µg, 1650 µg, 1700 µg, 1750 µg or more, for example, 1800 µg antibody/mL patient blood.

在實施方式中，為了獲得有效響應，以一定的量和頻率向患者投與抗C5抗體（例如，瑞利珠單抗），以維持抗C5抗體（例如，瑞利珠單抗）的最小和最大血漿濃度（±標準差）在給藥間隔內較佳的是分別在474（± 200）µg/mL和1350（± 430）µg/mL之間。In an embodiment, in order to obtain an effective response, an anti-C5 antibody (e.g., reslizumab) is administered to a patient in an amount and frequency to maintain the minimum and maximum plasma concentrations (± standard deviation) of the anti-C5 antibody (e.g., reslizumab) within the dosing interval preferably between 474 (± 200) µg/mL and 1350 (± 430) µg/mL, respectively.

在一個實施方式中，根據所揭露的方法治療的患者具有0.5 µg/mL或更低（例如，0.4 µg/mL、0.3 µg/mL、0.2 µg/mL、或0.1 µg/mL或更低）的游離C5濃度。In one embodiment, a patient treated according to the disclosed methods has a free C5 concentration of 0.5 µg/mL or less (e.g., 0.4 µg/mL, 0.3 µg/mL, 0.2 µg/mL, or 0.1 µg/mL or less).

在另一個實施方式中，根據所揭露的方法治療的患者實現了立即、完全和持續的末端補體抑制。 VI. 套組和單位劑型In another embodiment, a patient treated according to the disclosed methods achieves immediate, complete and sustained terminal complement suppression.VI.Kits and Unit Dosage Formulations

本文還提供了包含藥物組成物的套組，該藥物組成物含有適用於在前述方法中使用的治療有效量的抗C5抗體或其抗原結合片段（如瑞利珠單抗），以及藥學上可接受的載體。套組視需要還可以包含說明書，該說明書例如包含投與時間表，以允許從業者（例如，醫師、護士或患者）投與其中包含的組成物，由此將該組成物投與於患有HSCT-TMA的患者。套組還可以包含注射器。Also provided herein is a kit comprising a pharmaceutical composition containing a therapeutically effective amount of an anti-C5 antibody or an antigen-binding fragment thereof (such as reslizumab) suitable for use in the aforementioned method, and a pharmaceutically acceptable carrier. The kit may also include instructions as needed, which may include, for example, a dosing schedule to allow a practitioner (e.g., a physician, a nurse, or a patient) to administer the composition contained therein, thereby administering the composition to a patient with HSCT-TMA. The kit may also include a syringe.

視需要，套組包含單劑量藥物組成物的多個包裝，每個包裝含有用於根據上文提供的方法單次投與的有效量的抗C5抗體或其抗原結合片段。投與一或多種藥物組成物所需的儀器或設備也可以包含在套組中。例如，套組可以提供含有一定量的抗C5抗體或其抗原結合片段的一或多個預填充注射器。Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each package containing an effective amount of anti-C5 antibody or antigen-binding fragment thereof for single administration according to the methods provided above. Instruments or equipment required for administering one or more pharmaceutical compositions may also be included in the kit. For example, the kit may provide one or more pre-filled syringes containing a certain amount of anti-C5 antibody or antigen-binding fragment thereof.

在一個實施方式中，用於治療人類兒童患者的HSCT-TMA的套組包含：(a) 一定劑量的抗C5抗體或其抗原結合片段，其包含具有SEQ ID NO:12所示序列的重鏈可變區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的輕鏈可變區的CDR1、CDR2和CDR3結構域；以及 (b) 根據本文描述的任何方法使用抗C5抗體或其抗原結合片段的說明書。In one embodiment, a kit for treating HSCT-TMA in human pediatric patients comprises: (a) a dose of an anti-C5 antibody or an antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having a sequence shown in SEQ ID NO:12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having a sequence shown in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody or an antigen-binding fragment thereof according to any of the methods described herein.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按300 mg的維持劑量；以及 (e) 300 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 to <10 kg as follows:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 300 mg; and(e) 300 mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按400 mg的維持劑量；以及 (e) 400 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 5 to <10 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 400 mg; and(e) 400 mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按600 mg的維持劑量，以及 (e) 600 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 to <20 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 600 mg, and(e) 600 mg supplement, as follows: Administer the supplement to patients who receive RBC transfusions within 2 weeks of the maintenance dose, where the supplement is administered 2 weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按800 mg的維持劑量，以及 (e) 800 mg的補充劑量，按以下說明：向在維持劑量的2週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在維持劑量後兩週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 10 to <20 kg as follows:(a) once on day 1 at a loading dose of 600 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter at a maintenance dose of 800 mg, and(e) 800 mg mg supplements are given as follows: Patients who receive RBC transfusions within 2 weeks of the maintenance dose are given a supplement two weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重為20至＜ 30 kg的患者： (a) 在第1天一次，按900 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2100 mg的維持劑量；以及 (e) 2100 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing 20 to <30 kg as follows:(a) once on day 1 at a loading dose of 900 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 2100 mg; and(e) 2100 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 30至＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2700 mg的維持劑量， 以及 (e) 2700 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 to < 40 kg as follows:(a) once on day 1 at a loading dose of 1200 mg;(b) once on day 5 at a loading dose of 300 mg;(c) once on day 10 at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 2700 mg,and (e) 2700 mg. mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 40至＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量； (d) 在第15天和此後每八週，按3000 mg的維持劑量， 以及 (e) 3000 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg as follows:(a) once on day 1 at a loading dose of 2400 mg;(b) once on day 5 at a loading dose of 600 mg;(c) once on day 10 at a loading dose of 600 mg;(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3000 mg,and (e) 3000 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 60至＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3300 mg的維持劑量， 以及 (e) 3300 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg as follows:(a) once on day 1 at a loading dose of 2700 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg; and(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3300 mg,and (e) 3300 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

在另一個實施方式中，套組包含負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段按以下投與至體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3600 mg的維持劑量， 以及 (e) 3600 mg的補充劑量，按以下說明：向在維持劑量的4週內接受RBC輸注的患者投與補充劑量，其中該補充劑量在該維持劑量後四週投與。In another embodiment, the kit comprises loading, maintenance, and supplemental doses of an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg as follows:(a) once on day 1 at a loading dose of 3000 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg; and(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3600 mg,and (e) 3600 mg mg supplement as follows: Administer the supplement to patients who receive RBC transfusions within 4 weeks of the maintenance dose, where the supplement is administered four weeks after the maintenance dose.

以下實例僅是示例性的，並且不應以任何方式解釋為限制本揭露的範圍，因為在閱讀了本揭露之後，許多變化和等效內容對於熟悉該項技術者來說將是顯而易見的。本申請通篇所引用的所有參考文獻、GENBANK條目、專利以及公佈的專利申請的內容均清楚地藉由引用併入本文。實例實例1：瑞利珠單抗在全球3期研究中的劑量確認分析，以評估造血幹細胞移植後發生血栓性微血管病的成人和青少年的藥物動力學/藥效學The following examples are illustrative only and should not be construed in any way as limiting the scope of the present disclosure, as many variations and equivalents will be apparent to those skilled in the art after reading the present disclosure. The contents of all references, GENBANK entries, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.ExamplesExample1: Dose Confirmation Analysis of Reslizumab in a Global Phase3 Study to Evaluate the Pharmacokinetics/Pharmacodynamicsof Adults and Adolescents with Thrombotic Microangiopathy Following Hematopoietic Stem Cell Transplantation

進行了藥物動力學-藥效學（PK-PD）分析，以確認在3期研究中用於治療HSCT-TMA患者的瑞利珠單抗劑量方案，該研究描述於WO/2022/036151中，其內容藉由引用明確併入本文。此外，在本研究中，針對在治療期間接受血小板或RBC輸注的患者實施了新的補充給藥方案。A pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed to confirm the reslizumab dosing regimen for the treatment of HSCT-TMA patients in the Phase 3 study described in WO/2022/036151, the contents of which are expressly incorporated herein by reference. In addition, in this study, a new supplemental dosing regimen was implemented for patients who received platelet or RBC transfusions during treatment.

用於治療患有HSCT-TMA（NCT04543591）的成人和青少年（年齡 ≥ 12歲）的瑞利珠單抗3期研究的第1階段係開放標籤、單組期，旨在確認瑞利珠單抗劑量方案。參與者在第1、5和10天接受基於體重的負荷劑量，隨後在第15天接受維持劑量，並且此後每8週接受維持劑量。在任何血小板或紅血球（RBC）輸注後24小時內給予補充劑量。補充劑量的數量沒有限制。在治療期期間採集血液樣本進行分析。一旦至少前10名入組患者完成第21天，就進行劑量確認分析（DCA）。Phase 1 of the Phase 3 study of reslizumab for the treatment of adults and adolescents (aged ≥ 12 years) with HSCT-TMA (NCT04543591) was an open-label, single-arm phase designed to confirm the reslizumab dosing regimen. Participants received a weight-based loading dose on Days 1, 5, and 10, followed by a maintenance dose on Day 15, and every 8 weeks thereafter. Supplemental doses were given within 24 hours of any platelet or red blood cell (RBC) transfusion. There was no limit to the number of supplemental doses. Blood samples were collected for analysis during the treatment period. Dose confirmation analysis (DCA) was performed once at least the first 10 enrolled patients completed Day 21.

DCA涉及三個步驟。步驟1：PK和游離C5（主要PD）數據視覺化。先前建立的指示完全C5抑制的閾值用於憑經驗確認劑量方案產生適當的瑞利珠單抗濃度，並提供對游離C5的立即、完全和持續抑制。步驟2：瑞利珠單抗濃度-時間數據的群體藥物動力學（popPK）建模。將體重和輸注應用於先前開發的aHUS popPK模型，以個性化每個HSCT-TMA患者的預測暴露量，並從患者群體水平評估該等因素的影響。標準評估用於模型鑒定。步驟3：使用合格的popPK模型進行模擬，以確認/調整瑞利珠單抗劑量方案（包括輸注相關的補充劑量）。進行濃度-時間曲線的蒙特卡洛（Monte Carlo）模擬，以評估隨機產生的暴露（基於PK參數的群體可變性）是否會保持在PK閾值以上，從而確保完全的末端補體抑制。DCA involves three steps. Step 1: Visualization of PK and free C5 (primary PD) data. Previously established thresholds indicative of complete C5 inhibition were used to empirically confirm that the dosing regimen produced appropriate reslizumab concentrations and provided immediate, complete, and sustained inhibition of free C5. Step 2: Population pharmacokinetic (popPK) modeling of reslizumab concentration-time data. Body weight and infusion were applied to the previously developed aHUS popPK model to personalize the predicted exposure for each HSCT-TMA patient and to assess the impact of these factors at the patient population level. Standard assessments were used for model qualification. Step 3: Perform simulations using the qualified popPK model to confirm/adjust the reslizumab dosing regimen (including infusion-related supplements). Monte Carlo simulations of concentration-time curves were performed to assess whether randomly generated exposures (based on population variability of PK parameters) would remain above PK thresholds, thereby ensuring complete terminal complement inhibition.

在經驗評估中納入了來自14名患者的總共361個PK觀察（圖1和2），揭示了使用本研究方案的劑量方案可同時滿足PK和PD閾值。此外，圖2顯示，第5天和第10天的負荷劑量適當地控制了補體複合物的高基線水平，其中瑞利珠單抗濃度維持在 ＞ 175 µg/mL。合格的popPK模型很好地表徵了劑量-濃度關係。此外，還確定了RBC輸注後清除更快。考慮到這一點，模擬的重點係調整/優化瑞利珠單抗的輸注相關補充給藥。A total of 361 PK observations from 14 patients were included in the empirical evaluation (Figures1and2 ), revealing that the dosing regimen using the study protocol could meet both PK and PD thresholds. In addition, Figure 2 shows that the loading doses on days 5 and 10 appropriately controlled the high baseline levels of the tocopherol complex, with reslizumab concentrations maintained at >175 µg/mL. The qualified popPK model well characterized the dose-concentration relationship. In addition, it was determined that RBCs were cleared more quickly after transfusion. With this in mind, the simulation focused on adjusting/optimizing the infusion-related supplemental dosing of reslizumab.

模擬證實，補充劑量方案可以更新，以便在維持劑量後4週向在該維持劑量後4週內接受RBC輸注的體重 ≥ 30 kg的患者投與補充劑量的瑞利珠單抗。劑量模擬預測給藥間隔期間的平均（標準差）最小和最大濃度分別為474（200）µg/mL和1350（430）µg/mL。更新的劑量方案總結於表1中。輸注後補充給藥時間表如表2所示。發生一次或多次RBC輸注時應採取的措施的總結如表3所示。 [表1]：更新的瑞利珠單抗基於體重的劑量方案體重^a負荷期劑量維持劑量（第15天開始）補充劑量^b第1天第5天第10天30至＜ 40 kg1200 mg300 mg300 mg2700 mg Q8W2700 mg40至＜ 60 kg2400 mg600 mg600 mg3000 mg Q8W3000 mg60至＜ 100 kg2700 mg900 mg900 mg3300 mg Q8W3300 mg≥ 100 kg3000 mg900 mg900 mg3600 mg Q8W3600 mg^a基於體重的給藥係基於輸注訪視當天記錄的患者體重。如果無法獲得輸注當天的體重，則使用先前研究訪視期間記錄的體重。^b在維持劑量後4週，向在該維持劑量後4週內接受了任何紅血球輸注的體重≥ 30 kg的參與者投與補充劑量的瑞利珠單抗。負荷期期間不需要補充給藥，血小板輸注後也不需要補充給藥。Q8W，每8週。 [表2]：輸注後補充給藥時間表常規方案訪視V1V2V3V4V5V6V7V8V9V10V11V12V13V14天D1D5D10D15D21D29D43D57D71D85D99D127D155D183瑞利珠單抗/安慰劑常規給藥方案（負荷 + 維持）XXXX        X    X    根據患者接受RBC輸注的時間，需要輸注後補充給藥。            X      X  X  [表3]：發生一次或多次RBC輸注時應採取的措施如果發生一次或多次RBC輸注：應採取的措施：D15（維持劑量後）和D43之間在D43給予輸注後補充劑量D44和D71之間在下一個維持劑量（D71）之前，不需要輸注後補充劑量D71（維持劑量後）和D99之間在D99給予輸注後補充劑量D100和D127之間在下一個維持劑量（D127）之前，不需要輸注後補充劑量D127（維持劑量後）和D155之間在D155給予輸注後補充劑量D155後在治療期結束之前，不需要輸注後補充劑量Simulations confirmed that the supplemental dosing regimen could be updated to allow administration of a supplemental dose of reslizumab 4 weeks after a maintenance dose to patients weighing ≥ 30 kg who received an RBC transfusion within 4 weeks of the maintenance dose. The dose simulation predicted mean (standard deviation) minimum and maximum concentrations during the dosing interval to be 474 (200) µg/mL and 1350 (430) µg/mL, respectively. The updated dosing regimen is summarized in Table 1. The post-transfusion supplemental dosing schedule is shown in Table 2. A summary of actions to be taken if one or more RBC transfusions occur is shown in Table 3. [Table1 ]: Updated weight-based dosing regimen of reslizumabWeight^​Loading doseMaintenance dose( starting on day15)Supplementary^dosebDay1​Day5​Day10​ 30 to < 40 kg 1200 mg 300 mg 300 mg 2700 mg q8W 2700 mg 40 to < 60 kg 2400 mg 600 mg 600 mg 3000 mg q8W 3000 mg 60 to < 100 kg 2700 mg 900 mg 900 mg 3300 mg q8W 3300 mg ≥ 100 kg 3000 mg 900 mg 900 mg 3600 mg q8W 3600 mg^aWeight -based dosing is based on the patient's weight recorded on the day of the infusion visit. If the weight on the day of the infusion was not available, the weight recorded during the previous study visit was used.^bFour weeks after the maintenance dose, a supplemental dose of reslizumab was administered to participants weighing ≥ 30 kg who received any red blood cell transfusion within 4 weeks of the maintenance dose. No supplemental dosing is required during the loading phase or after platelet transfusions. Q8W, every 8 weeks. [Table2 ]: Post-infusion supplemental dosing schedule Regular program visits V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 sky D1 D5 D10 D15 D21 D29 D43 D57 D71 D85 D99 D127 D155 D183 Reslizumab/placebo conventional dosing regimen (loading + maintenance) X X X X X X Depending on when the patient received the RBC transfusion, supplemental medication may be needed after the transfusion. X X X [Table3 ]:Actions to be taken whenone or moreRBC transfusions occurIf one or moreRBCtransfusions occur:Measures to be taken: Between D15 (after maintenance dose) and D43 Give a supplemental dose after the infusion at D43 Between D44 and D71 No post-infusion boost dose is required before the next maintenance dose (D71) Between D71 (after maintenance dose) and D99 Give a supplemental dose after the infusion at D99 Between D100 and D127 No post-infusion boost dose is required until the next maintenance dose (D127) Between D127 (after maintenance dose) and D155 Give a supplemental dose after the infusion at D155 After D155 No post-infusion replenishment doses are required until the end of the treatment period

這一徹底的DCA證實，更新的補充瑞利珠單抗劑量方案實現了立即、完全和持續的末端補體抑制。因此，劑量方案已優化用於瑞利珠單抗對HSCT-TMA的療效和安全性的3期研究的第2階段（雙盲、隨機、安慰劑對照期）。實例2：體重低於30 kg的患者的給藥方案This thorough DCA confirmed that the updated dosing regimen of supplemental reslizumab achieved immediate, complete, and sustained terminal complement suppression. Therefore, the dosing regimen has been optimized for use in the second phase (double-blind, randomized, placebo-controlled period) of a Phase 3 study of the efficacy and safety of reslizumab in HSCT-TMA.Example2:Dosing regimen for patients weighing less than30 kg

進行了PK-PD分析，以確認在3期研究中用於治療HSCT-TMA患者的瑞利珠單抗劑量方案，基本上如以上實例1和WO/2022/036151中所述。在本研究中，針對在治療期間接受血小板或RBC輸注的體重低於30 kg的患者實施了補充給藥方案。輸注後補充給藥時間表如表4所示。 [表4]：體重低於30 kg的患者的輸注後補充給藥時間表體重負荷期劑量維持劑量補充劑量  第1天第5天第10天第15天開始5至＜ 10 kg600 mg300 mg300 mg300 mg q4wMD後兩週，300 mg10至＜ 20 kg600 mg300 mg300 mg600 mg q4wMD後兩週，600 mg20至＜ 30 kg900 mg300 mg300 mg2100 mg q8wMD後四週，2100 mgA PK-PD analysis was performed to confirm the reslizumab dosing regimen for the treatment of HSCT-TMA patients in the Phase 3 study, essentially as described in Example 1 above and WO/2022/036151. In this study, a supplemental dosing regimen was implemented for patients weighing less than 30 kg who received platelet or RBC transfusions during treatment. The post-transfusion supplemental dosing schedule is shown in Table 4. [Table4 ]:Post-transfusion supplemental dosing schedule for patients weighing less than30 kgWeightLoading doseMaintenance doseSupplemental dosageDay1​Day5​Day10​Day15starts 5 to < 10 kg 600 mg 300 mg 300 mg 300 mg every 4 weeks 2 weeks after MD, 300 mg 10 to < 20 kg 600 mg 300 mg 300 mg 600 mg every 4 weeks 2 weeks after MD, 600 mg 20 to < 30 kg 900 mg 300 mg 300 mg 2100 mg every 8 weeks 4 weeks after MD, 2100 mg

對十名患者進行了可能的劑量確認分析（DCA）評估。十名患者中有一名無法評估。其中兩名患者接受了高頻RBC輸注（稱為「高瑞利珠單抗清除」）。七名患者在治療期間PK ＞ 175 mcg/mL（稱為「低頻RBC輸注」）。Ten patients were evaluated for potential dose confirmation analysis (DCA). One of the ten patients was not evaluable. Two of these patients received high-frequency RBC transfusions (termed “gorelizumab clearance”). Seven patients had PK > 175 mcg/mL during treatment (termed “low-frequency RBC transfusions”).

9/9的患者的初始DCA失敗（＜ 175 mcg/mL）。然而，在進一步研究後，確定「高瑞利珠單抗清除」患者係DCA失敗的原因。除去這兩名劑量未確認的患者（22%）後，DCA確認了其餘7/9的患者的劑量。然而，＜ 30 kg的患者可以從修訂的劑量方案中進一步受益，因為不可能知道患者何時可能成為「高瑞利珠單抗清除」患者。實例3：體重低於30 kg的患者的修訂給藥方案9/9 patients failed the initial DCA (< 175 mcg/mL). However, upon further investigation, it was determined that the “gorelizumab cleared” patient was the cause of the DCA failure. After removing these two patients with unconfirmed doses (22%), the DCA confirmed the dose for the remaining 7/9 patients. However, patients < 30 kg may further benefit from a revised dosing regimen, as it is impossible to know when a patient may become a “gorelizumab cleared” patient.Example3 :Revised Dosing Regimen for PatientsWeighing Less Than30 kg

在實例2中，表4所述之劑量方案被確認用於7/9的患者（22%）。然而，已經確定，某些體重＜ 30 kg且頻繁輸注RBC的患者（例如，體重＜ 30 kg的「高瑞利珠單抗清除」患者）可能無法維持目標谷水平（175 mcg/mL），因此無法實現完全的C5抑制。因此，這一特定患者組可以從修訂的劑量方案中進一步受益。因此，基本上根據實例1-2和WO/2022/036151中描述的方法（有指出的修改），在該患者組中評估表5所述之修訂的給藥方案。 [表5]：體重低於30 kg的患者的修訂給藥時間表體重負荷期劑量維持劑量補充劑量第1天第5天第10天第15天開始5至＜ 10 kg600 mg300 mg300 mg400 mg q4wMD後兩週，400 mg10至＜ 20 kg600 mg300 mg300 mg800 mg q4wMD後兩週，800 mg20至＜ 30 kg900 mg300 mg300 mg2100 mg q8w （與實例2的劑量相比沒有變化）MD後四週，2100 mg （與實例2的劑量相比沒有變化）In Example 2, the dosing regimen described in Table 4 was confirmed for 7/9 patients (22%). However, it has been determined that some patients weighing < 30 kg and receiving frequent RBC transfusions (e.g., "gorelizumab cleared" patients weighing < 30 kg) may not be able to maintain target trough levels (175 mcg/mL) and therefore may not achieve complete C5 inhibition. Therefore, this particular patient group may further benefit from a revised dosing regimen. Therefore, the revised dosing regimen described in Table 5 was evaluated in this patient group, essentially according to the methods described in Examples 1-2 and WO/2022/036151 (with the modifications indicated). [Table5 ]:Revised dosing schedule for patients weighing less than30 kgWeightLoading doseMaintenance doseSupplemental dosageDay1​Day5​Day10​Day15starts 5 to < 10 kg 600 mg 300 mg 300 mg400 mg every 4 weeks2 weeks afterMD ,400 mg 10 to < 20 kg 600 mg 300 mg 300 mg800 mg every 4 weeks2 weeks afterMD ,800 mg 20 to < 30 kg 900 mg 300 mg 300 mg 2100 mg q8w (No change from Example 2) Four weeks after MD, 2100 mg (no change from Example 2)

對於所有患者，當患者達到表6所述維持劑量之間的中間點時，評估是否需要RBC輸注後補充劑量的瑞利珠單抗。對於體重 ≥ 30 kg的參與者，如果參與者自最後維持劑量以來接受了至少1次RBC輸注，則投與RBC輸注後補充劑量。對於體重 ＜ 20 kg或體重 ≥ 20至 ＜ 30 kg的參與者，遵循臨床演算法來評估是否需要RBC輸注後補充給藥。 [表6]：RBC輸注後補充給藥的時機體重RBC輸注後補充劑量的評估時機＜ 20 kg每次維持劑量後2週（±3天）（即第29、57、85、113、141和169天）。^*≥ 20至 ＜ 30 kg每次維持劑量後4週（±3天）（即第43、99和155天）。^*≥ 30 kg每次維持劑量後4週（±3天）（即第43、99和155天）。^**對於每個體重類別，補充劑量在相同的視窗內投與。如果在預定研究訪視的同時需要補充給藥，則可以在該訪視時給藥。For all patients, the need for a post-RBC transfusion supplemental dose of reslizumab was assessed when the patient reached the midpoint between the maintenance doses described in Table 6. For participants weighing ≥ 30 kg, a post-RBC transfusion supplemental dose was administered if the participant had received at least 1 RBC transfusion since the last maintenance dose. For participants weighing < 20 kg or weighing ≥ 20 to < 30 kg, a clinical algorithm was followed to assess the need for a post-RBC transfusion supplemental dose. [Table6 ]:Timing of Post-RBC Transfusion Supplemental DosingWeightTiming of supplemental dose assessment afterRBC transfusion ＜ 20 kg 2 weeks (±3 days) after each maintenance dose (i.e., Days 29, 57, 85, 113, 141, and 169).^* ≥ 20 to < 30 kg 4 weeks (±3 days) after each maintenance dose (i.e., Days 43, 99, and 155).^* ≥ 30 kg 4 weeks (±3 days) after each maintenance dose (i.e., Days 43, 99, and 155).^* *For each weight category, supplemental doses are administered within the same window. If a supplemental dose is needed at a scheduled study visit, it may be administered at that visit.

當RBC輸注日頻率超過 ＞ 3.5天/週時（即，當 ＞ 10%的患者谷水平 ＜ 175 mcg/mL時的閾值），修訂的給藥方案觸發臨床演算法。特別地，臨床演算法監測RBC輸注天數（至少1次RBC輸注的天數）和臨床惡化。此前，研究者僅評估參與者自最後維持劑量以來是否接受了至少一次RBC輸注。修訂的給藥方案旨在同時增加維持劑量和補充劑量，以緩解問題。臨床演算法在圖3中示出，並在表7中總結。 [表7]：RBC輸注後補充給藥的必要性評估體重用於評估RBC輸注後補充給藥的臨床演算法＜ 20 kg1.     自最後維持劑量以來，參與者是否接受過任何RBC輸注? •       如果是，請繼續問題#2 •       如果否，則等待下一次預定的維持劑量 2.     自最後維持劑量以來，參與者是否在 ＞ 7天接受過RBC輸注? •       如果是，請繼續問題#3 •       如果否，則投與補充劑量 3.     參與者是否符合臨床惡化的標準? •       如果是，研究者必須與醫學監查員聯繫，以確定參與者是否應繼續研究治療並接受補充劑量 •       如果否，請繼續問題#4 4.     根據研究者的臨床判斷，參與者是否從研究治療中獲益? •       如果是，則投與補充劑量 •       如果否，研究者必須確定是否需要停止研究治療≥ 20至 ＜ 30 kg1.     自最後維持劑量以來，參與者是否接受過任何RBC輸注? •       如果是，請繼續問題#2 •       如果否，則等待下一次預定的維持劑量 2.     自最後維持劑量以來，參與者是否在＞14天接受過RBC輸注? •       如果是，請繼續問題#3 •       如果否，則投與補充劑量 3.     參與者是否符合臨床惡化的標準? •       如果是，與醫學監查員聯繫，以確定參與者是否應繼續研究治療並接受補充劑量 •       如果否，請繼續問題#4 4.     根據研究者的臨床判斷，參與者是否從研究治療中獲益? •       如果是，則投與補充劑量 •       如果否，研究者必須確定是否需要停止研究治療≥30 kg1.     自最後維持劑量以來，參與者是否接受過任何RBC輸注? •       如果是，則投與補充劑量 •       如果否，則等待下一次預定的維持劑量  A revised dosing regimen triggers a clinical algorithm when the daily frequency of RBC transfusions exceeds >3.5 days/week (i.e., a threshold when >10% of patients have trough levels <175 mcg/mL). Specifically, the clinical algorithm monitors the number of RBC transfusion days (days with at least 1 RBC transfusion) and clinical worsening. Previously, investigators only assessed whether participants had received at least one RBC transfusion since the last maintenance dose. The revised dosing regimen aims to alleviate the problem by increasing both the maintenance dose and the supplemental dose. The clinical algorithm is shown inFigure3 and summarized in Table 7. [Table7 ]:Assessment of the need for supplemental dosing afterRBC transfusionWeight Clinical Algorithmfor EvaluatingSupplemental Medication Administration FollowingRBC Transfusion ＜ 20 kg 1. Has the participant received any RBC transfusions since the last maintenance dose? • If yes, proceed to question #2 • If no, wait for the next scheduled maintenance dose 2. Has the participant received an RBC transfusion > 7 days since the last maintenance dose? • If yes, proceed to question #3 • If no, administer a supplemental dose 3. Does the participant meet the criteria for clinical worsening? • If yes, the investigator must contact the Medical Monitor to determine if the participant should continue study treatment and receive a supplemental dose • If no, proceed to question #4 4. In the investigator’s clinical judgment, is the participant receiving benefit from study treatment? • If yes, give supplemental dose • If no, investigator must determine if study treatment needs to be stopped ≥ 20 to < 30 kg 1. Has the participant received any RBC transfusions since the last maintenance dose? • If yes, proceed to question #2 • If no, wait for the next scheduled maintenance dose 2. Has the participant received an RBC transfusion >14 days since the last maintenance dose? • If yes, proceed to question #3 • If no, administer a supplemental dose 3. Does the participant meet the criteria for clinical worsening? • If yes, contact the Medical Monitor to determine if the participant should continue study treatment and receive a supplemental dose • If no, proceed to question #4 4. In the investigator’s clinical judgment, is the participant receiving benefit from study treatment? • If yes, give supplemental dose • If no, investigator must determine if study treatment needs to be stopped ≥30 kg 1. Has the participant received any RBC transfusions since the last maintenance dose? • If yes, give a supplemental dose • If no, wait for the next scheduled maintenance dose

對於所有參與者，如果沒有進行RBC輸注，則不需要補充給藥。For all participants, no supplemental medication was required if no RBC transfusion was given.

對於表現出臨床惡化的患者，在第15天投與第一維持劑量後的治療期期間，允許補充劑量的瑞利珠單抗。臨床惡化定義為符合以下2個或更多個標準： 1.   血清肌酸酐較基線翻倍或新的透析需求； 2.   與基線相比，LDH增加 ＞ 25%； 3.   與基線相比，血小板減少 ＞ 25%； 4.   與基線相比，血紅素減少 ＞ 10%；和/或 5.   隨時增加對血小板或RBC的需求。For patients who demonstrated clinical worsening, supplemental doses of reslizumab were permitted during the treatment period after the first maintenance dose was administered on Day 15. Clinical worsening was defined as meeting 2 or more of the following criteria:1.   Doubling of serum creatinine from baseline or new dialysis requirement;2.   Increase in LDH > 25% from baseline;3.   Decrease in platelets > 25% from baseline;4.   Decrease in hemoglobin > 10% from baseline; and/or5.   Increased need for platelets or RBCs at any time.

臨床惡化的標準藉由至少間隔8小時（理想間隔24小時）收集的兩個獨立樣本確認。The criterion for clinical deterioration was confirmed by two independent samples collected at least 8 hours apart (ideally 24 hours apart).

根據本揭露的補充給藥方案總結在下表8中： [表8]：補充給藥方案體重負荷期劑量第15天的維持劑量補充劑量第1天第5天第10天5至＜ 10 kg600 mg300 mg300 mg400 mg q4wMD後2週，400 mg10 ＜ 20 kg600 mg300 mg300 mg800 mg q4wMD後2週，800 mg20 ＜ 30 kg900 mg300 mg300 mg2100 mg q8wMD後4週，2100 mg30 ＜ 40 kg1200 mg300 mg300 mg2700 mg q8wMD後4週，2700 mg40 ＜ 60 kg2400 mg600 mg600 mg3000 mg q8wMD後4週，3000 mg60 ＜ 100 kg2700 mg900 mg900 mg3300 mg q8wMD後4週，3300 mg≥ 100 kg3000 mg900 mg900 mg3600 mg q8wMD後4週，3600 mgThe supplemental dosing regimen according to the present disclosure is summarized in Table 8 below: [Table8 ]: Supplemental dosing regimenWeightLoading doseMaintenance dose onday15Supplemental dosageDay1​Day5​Day10​5to< 10 kg 600 mg 300 mg 300 mg 400 mg every 4 weeks 2 weeks after MD, 400 mg10 ＜ 20 kg 600 mg 300 mg 300 mg 800 mg every 4 weeks 2 weeks after MD, 800 mg20 ＜ 30 kg 900 mg 300 mg 300 mg 2100 mg every 8 weeks 4 weeks after MD, 2100 mg30 ＜ 40 kg 1200 mg 300 mg 300 mg 2700 mg every 8 weeks 4 weeks after MD, 2700 mg40 ＜ 60 kg 2400 mg 600 mg 600 mg 3000 mg every 8 weeks 4 weeks after MD, 3000 mg60 ＜ 100 kg 2700 mg 900 mg 900 mg 3300 mg every 8 weeks 4 weeks after MD, 3300 mg≥ 100 kg 3000 mg 900 mg 900 mg 3600 mg every 8 weeks 4 weeks after MD, 3600 mg

在投與瑞利珠單抗的任何補充給藥訪視期間進行的最低評估包括尿液懷孕試驗、給藥前PK/PD血液樣本採集和生命徵象。序列總結SEQ ID NO:1GYIFSNYWIQSEQ ID NO:2EILPGSGSTEYTENFKDSEQ ID NO:3YFFGSSPNWYFDVSEQ ID NO:4GASENIYGALNSEQ ID NO:5GATNLADSEQ ID NO:6QNVLNTPLTSEQ ID NO:7QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSSEQ ID NO:8DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIKSEQ ID NO:9ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGKSEQ ID NO:10QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGKSEQ ID NO:11DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGECSEQ ID NO:12QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSSEQ ID NO:13ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVLHEA LHSHYTQKSL SLSLGKSEQ ID NO:14QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVLH EALHSHYTQK SLSLSLGKSEQ ID NO:15ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VTSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL YITREPEVTC VVVDVSHEDP EVQFNWYVDG MEVHNAKTKP REEQFNSTFR VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGKSEQ ID NO:16QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVTSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLYITREPEV TCVVVDVSHE DPEVQFNWYV DGMEVHNAKT KPREEQFNST FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP APIEKTISKT KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGKSEQ ID NO:17GASENIYHALNSEQ ID NO:18EILPGSGHTEYTENFKDSEQ ID NO:19GHIFSNYWIQSEQ ID NO:20QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGKSEQ ID NO:21SYAISSEQ ID NO:22GIGPFFGTANYAQKFQGSEQ ID NO:23DTPYFDYSEQ ID NO:24SGDSIPNYYVYSEQ ID NO:25DDSNRPSSEQ ID NO:26QSFDSSLNAEVSEQ ID NO:27QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISVWRQA PGQGLEWMGG IGPFFGTANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARDT PYFDYWGQGT LVTVSSSEQ ID NO:28DIELTQPPSV SVAPGQTARI SCSGDSIPNY YVYWYQQKPG QAPVLVIYDD SNRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCQSF DSSLNAEVFG GGTKLTVLSEQ ID NO:29NYISSEQ ID NO:30IIDPDDSYTEYSPSFQGSEQ ID NO:31YEYGGFDISEQ ID NO:32SGDNIGNSYVHSEQ ID NO:33KDNDRPSSEQ ID NO:34GTYDIESYVSEQ ID NO:35EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYISWVRQMP GKGLEWMGII DPDDSYTEYS PSFQGQVTIS ADKSISTAYL QWSSLKASDT AMYYCARYEY GGFDIWGQGT LVTVSSSEQ ID NO:36SYELTQPPSV SVAPGQTARI SCSGDNIGNS YVHWYQQKPG QAPVLVIYKD NDRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCGTY DIESYVFGGG TKLTVLSEQ ID NO:37SSYYVASEQ ID NO:38AIYTGSGATYKASWAKGSEQ ID NO:39DGGYDYPTHAMHYSEQ ID NO:40QASQNIGSSLASEQ ID NO:41GASKTHSSEQ ID NO:42QSTKVGSSYGNHSEQ ID NO:43QVQLVESGGG LVQPGGSLRL SCAASGFTSH SSYYVAWVRQ APGKGLEWVG AIYTGSGATY KASWAKGRFT ISKDTSKNQV VLTMTNMDPV DTATYYCASD GGYDYPTHAM HYWGQGTLVT VSSSEQ ID NO:44DVVMTQSPSS LSASVGDRVT ITCQASQNIG SSLAWYQQKP GQAPRLLIYG ASKTHSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQS TKVGSSYGNH FGGGTKVEIKSEQ ID NO:45QVQLVESGGG LVQPGRSLRL SCAASGFTVH SSYYMAWVRQ APGKGLEWVG AIFTGSGAEY KAEWAKGRVT ISKDTSKNQV VLTMTNMDPV DTATYYCASD AGYDYPTHAM HYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL RRGPKVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVLHEALHA HYTRKELSLS PSEQ ID NO:46DIQMTQSPSS LSASVGDRVT ITCRASQGIS SSLAWYQQKP GKAPKLLIYG ASETESGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN TKVGSSYGNT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGECSEQ ID NO:47QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSN YNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLV TVSSSEQ ID NO:48AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKSEQ ID NO:49QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNY NPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKSEQ ID NO:50AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECMinimum assessments performed during any supplemental dosing visit for reslizumab includeda urine pregnancy test, predose PK/PD blood sample collection, and vital signs.SEQ ID NO:1 GYIFSNYWIQSEQ ID NO:2 EILPGSGSTEYTENFKDSEQ ID NO:3 YFFGSSPNWYFDVSEQ ID NO:4 GASENIYGALNSEQ ID NO:5 GATNLADSEQ ID NO:6 QNVLNTPLTSEQ ID NO:7 QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSSEQ ID NO:8 DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIKSEQ ID NO:9 ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSV LTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGKSEQ ID NO:10 QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLS SV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGKSEQ ID NO:11 DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSST LT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGECSEQ ID NO:12 QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSSEQ ID NO:13 ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VV SLSLGKSEQ ID NO:14 QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVLH EALHSHYTQK SLSLSLGKSEQ ID NO:15 ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VTSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL YITREPEVTC VVVDVSHEDP EVQFNWYVDG MEVHNAKTKP REEQFNSTFR VV SLSPGKSEQ ID NO:16 QVQLVQSGAE VKKPGASVKV SCKASGYIFS NYWIQWVRQA PGQGLEWMGE ILPGSGSTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLS SV VTVTSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLYITREPEV TCVVVDVSHE DPEVQFNWYV DGMEVHNAKT KPREEQFNST FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP APIEKTISKT KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGKSEQ ID NO:17 GASENIYHALNSEQ ID NO:18 EILPGSGHTEYTENFKDSEQ ID NO:19 GHIFSNYWIQSEQ ID NO:20 QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGKSEQ ID NO:21 SYAISSEQ ID NO:22 GIGPFFGTANYAQKFQGSEQ ID NO:23 DTPYFDYSEQ ID NO:24 SGDSIPNYYVYSEQ ID NO:25 DDSNRPSSEQ ID NO:26 QSFDSSLNAEVSEQ ID NO:27 QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISVWRQA PGQGLEWMGG IGPFFGTANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARDT PYFDYWGQGT LVTVSSSEQ ID NO:28 DIELTQPPSV SVAPGQTARI SCSGDSIPNY YVYWYQQKPG QAPVLVIYDD SNRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCQSF DSSLNAEVFG GGTKLTVLSEQ ID NO:29 NYISSEQ ID NO:30 IIDPDDSYTEYSPSFQGSEQ ID NO:31 YEYGGFDISEQ ID NO:32 SGDNIGNSYVHSEQ ID NO:33 KDNDRPSSEQ ID NO:34 GTYDIESYVSEQ ID NO:35 EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYISWVRQMP GKGLEWMGII DPDDSYTEYS PSFQGQVTIS ADKSISTAYL QWSSLKASDT AMYYCARYEY GGFDIWGQGT LVTVSSSEQ ID NO:36 SYELTQPPSV SVAPGQTARI SCSGDNIGNS YVHWYQQKPG QAPVLVIYKD NDRPSGIPER FSGSNSGNTA TLTISGTQAE DEADYYCGTY DIESYVFGGG TKLTVLSEQ ID NO:37 SSYYVASEQ ID NO:38 AIYTGSGATYKASWAKGSEQ ID NO:39 DGGYDYPTHAMHYSEQ ID NO:40 QASQNIGSSLASEQ ID NO:41 GASKTHSSEQ ID NO:42 QSTKVGSSYGNHSEQ ID NO:43 QVQLVESGGG LVQPGGSLRL SCAASGFTSH SSYYVAWVRQ APGKGLEWVG AIYTGSGATY KASWAKGRFT ISKDTSKNQV VLTMTNMDPV DTATYYCASD GGYDYPTHAM HYWGQGTLVT VSSSEQ ID NO:44 DVVMTQSPSS LSASVGDRVT ITCQASQNIG SSLAWYQQKP GQAPRLLIYG ASKTHSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQS TKVGSSYGNH FGGGTKVEIKSEQ ID NO:45 QVQLVESGGG LVQPGRSLRL SCAASGFTVH SSYYMAWVRQ APGKGLEWVG AIFTGSGAEY KAEWAKGRVT ISKDTSKNQV VLTMTNMDPV DTATYYCASD AGYDYPTHAM HYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL Q SSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL RRGPKVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVLHEALHA HYTRKELSLS PSEQ ID NO:46 DIQMTQSPSS LSASVGDRVT ITCRASQGIS SSLAWYQQKP GKAPKLLIYG ASETESGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN TKVGSSYGNT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSL SS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGECSEQ ID NO:47 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSN YNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLV TVSSSEQ ID NO:48 AIQMTQSPSSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKSEQ ID NO:49 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNY NPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKSEQ ID NO:50 AIQMTQSPSSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC

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[圖1]係示出了每個患者的瑞利珠單抗藥物動力學（PK）曲線之圖。在第5天和第10天，瑞利珠單抗濃度維持在175 µg/mL閾值（虛線）以上。[Figure1 ] is a graph showing the pharmacokinetic (PK) curve of reslizumab for each patient. On days 5 and 10, the reslizumab concentration was maintained above the 175 µg/mL threshold (dashed line).

[圖2]係示出了每個患者的游離C5濃度-時間曲線（即，藥效學（PD）曲線）之圖。所有患者的游離C5濃度均低於0.5 µg/mL閾值（虛線）。[Figure2 ] is a graph showing the free C5 concentration-time curve (i.e., pharmacodynamic (PD) curve) for each patient. The free C5 concentration of all patients was below the 0.5 µg/mL threshold (dashed line).

[圖3]係描繪用於評估RBC後補充給藥的臨床演算法之示意圖。[Figure3 ] is a schematic diagram depicting the clinical algorithm used to evaluate RBC post-replenishment dosing.

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TW202426048A_112132717_SEQL.xmlTW202426048A_112132717_SEQL.xml

Claims (51)

Translated fromChinese

一種治療患有造血幹細胞移植相關血栓性微血管病（HSCT-TMA）的人患者之方法，該方法包括向該患者投與有效量的包含以下的抗C5抗體或其抗原結合片段：分別如SEQ ID NO:19、18和3所示的CDR1、CDR2和CDR3重鏈序列，以及分別如SEQ ID NO:4、5和6所示的CDR1、CDR2和CDR3輕鏈序列，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後的指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。A method for treating a human patient with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), the method comprising administering to the patient an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or the antigen-binding fragment thereof is administered as follows: (a) Once on day 1, at the following loading dose: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 1200 mg for patients weighing ≥ 40 to < 60 kg kg, 2400 mg for patients weighing ≥ 60 to < 100 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, with the following loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, mg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; and(d) on Day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, and 900 mg for patients weighing ≥ 3300 mg for patients weighing 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and wherein the supplemental dose is administered to:(i)     a patient weighing < 30 kg who receives a red blood cell (RBC) transfusion within a specified time frame of the maintenance dose, wherein the supplemental dose is administered within a specified time frame after the maintenance dose as follows:a. 300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks,b. 600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, orc. 2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or(ii)  Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of a maintenance dose, where the supplement is administered four weeks after the maintenance dose at the following doses:a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.如請求項1所述之方法，其中該抗C5抗體或其抗原結合片段進一步包含與人新生兒Fc受體（FcRn）結合的變體人Fc恒定區，其中該變體人Fc恒定區在對應於天然人IgG Fc恒定區的甲硫胺酸428和天冬醯胺434的殘基處包含Met429Leu和Asn435Ser取代，各自採用EU編號。The method as described in claim 1, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the native human IgG Fc constant region, each using the EU numbering.如請求項1或2所述之方法，其中該抗C5抗體包含SEQ ID NO:12所示的重鏈可變區和SEQ ID NO:8所示的輕鏈可變區。The method as described in claim 1 or 2, wherein the anti-C5 antibody comprises the heavy chain variable region shown in SEQ ID NO:12 and the light chain variable region shown in SEQ ID NO:8.如前述請求項中任一項所述之方法，其中該抗C5抗體進一步包含SEQ ID NO:13所示的重鏈恒定區。The method of any of the preceding claims, wherein the anti-C5 antibody further comprises a heavy chain constant region as shown in SEQ ID NO:13.如前述請求項中任一項所述之方法，其中該抗體包含含有SEQ ID NO:14所示的胺基酸序列的重鏈多肽和含有SEQ ID NO:11所示的胺基酸序列的輕鏈多肽。The method of any of the preceding claims, wherein the antibody comprises a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:14 and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:11.如前述請求項中任一項所述之方法，其中該抗C5抗體在pH 7.4和25°C下以0.1 nM ≤ K_D≤ 1 nM（例如，約0.5 nM）範圍內的親和解離常數（K_D）結合人C5。The method of any of the preceding claims, wherein the anti-C5 antibody binds human C5 with an affinity dissociation constant (K_D ) in the range of 0.1 nM ≤ K_D ≤ 1 nM (e.g., about 0.5 nM) at pH 7.4 and 25°C.如前述請求項中任一項所述之方法，其中該抗C5抗體在pH 6.0和25°C下以K_D≥ 10 nM（例如，約22 nM）結合人C5。The method of any of the preceding claims, wherein the anti-C5 antibody binds human C5 with a_KD ≥ 10 nM (e.g., about 22 nM) at pH 6.0 and 25°C.如前述請求項中任一項所述之方法，其中該抗C5抗體投與於體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按300 mg的維持劑量；以及 (e) 向在維持劑量的2週內接受RBC輸注的患者投與300 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。A method as described in any of the preceding claims, wherein the anti-C5 antibody is administered to a patient weighing 5 to < 10 kg:(a) once on day 1 as a loading dose of 600 mg;(b) once on day 5 as a loading dose of 300 mg;(c) once on day 10 as a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter as a maintenance dose of 300 mg; and(e) a supplemental dose of 300 mg is administered to a patient who receives an RBC transfusion within 2 weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重為5至＜ 10 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按400 mg的維持劑量；以及 (e) 向在維持劑量的2週內接受RBC輸注的患者投與400 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing 5 to <10 kg:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 400 mg; and(e) a supplemental dose of 400 mg is administered to a patient who receives an RBC transfusion within 2 weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按600 mg的維持劑量，以及 (e) 向在維持劑量的2週內接受RBC輸注的患者投與600 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing 10 to < 20 kg:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 600 mg, and(e) a supplemental dose of 600 mg is administered to a patient who receives an RBC transfusion within 2 weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重為10至＜ 20 kg的患者： (a) 在第1天一次，按600 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每四週，按800 mg的維持劑量，以及 (e) 向在維持劑量的2週內接受RBC輸注的患者投與800 mg的補充劑量，並且其中該補充劑量在該維持劑量後兩週投與。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing 10 to < 20 kg:(a) once on day 1, at a loading dose of 600 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every four weeks thereafter, at a maintenance dose of 800 mg, and(e) a supplemental dose of 800 mg is administered to a patient who receives an RBC transfusion within 2 weeks of the maintenance dose, and wherein the supplemental dose is administered two weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重為20至＜ 30 kg的患者： (a) 在第1天一次，按900 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2100 mg的維持劑量；以及 (e) 向在維持劑量的4週內接受RBC輸注的患者投與2100 mg的補充劑量，並且其中該補充劑量在該維持劑量後四週投與。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing 20 to < 30 kg:(a) once on day 1, at a loading dose of 900 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter, at a maintenance dose of 2100 mg; and(e) a supplemental dose of 2100 mg is administered to a patient who receives an RBC transfusion within 4 weeks of the maintenance dose, and wherein the supplemental dose is administered four weeks after the maintenance dose.如請求項8-12中任一項所述之方法，其中如有必要，根據如圖3所示的臨床演算法投與該補充劑量。The method of any one of claims 8-12, wherein the supplemental dose is administered, if necessary, according to the clinical algorithm shown in FIG3.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重≥ 30至 ＜ 40 kg的患者： (a) 在第1天一次，按1200 mg的負荷劑量； (b) 在第5天一次，按300 mg的負荷劑量； (c) 在第10天一次，按300 mg的負荷劑量； (d) 在第15天和此後每八週，按2700 mg的維持劑量。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing ≥ 30 to < 40 kg:(a) once on day 1, at a loading dose of 1200 mg;(b) once on day 5, at a loading dose of 300 mg;(c) once on day 10, at a loading dose of 300 mg;(d) on day 15 and every eight weeks thereafter, at a maintenance dose of 2700 mg.如請求項14所述之方法，其中該患者在維持劑量的四週內接受紅血球（RBC）輸注，然後在該維持劑量後四週投與2700 mg的補充劑量。The method of claim 14, wherein the patient receives a red blood cell (RBC) transfusion within four weeks of the maintenance dose and then is administered a supplemental dose of 2700 mg four weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重≥ 40至 ＜ 60 kg的患者： (a) 在第1天一次，按2400 mg的負荷劑量； (b) 在第5天一次，按600 mg的負荷劑量； (c) 在第10天一次，按600 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3000 mg的維持劑量。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing ≥ 40 to < 60 kg:(a) once on day 1, at a loading dose of 2400 mg;(b) once on day 5, at a loading dose of 600 mg;(c) once on day 10, at a loading dose of 600 mg; and(d) on day 15 and every eight weeks thereafter, at a maintenance dose of 3000 mg.如請求項16所述之方法，其中該患者在維持劑量的四週內接受紅血球（RBC）輸注，然後在該維持劑量後四週投與3000 mg的補充劑量。The method of claim 16, wherein the patient receives a red blood cell (RBC) transfusion within four weeks of the maintenance dose and then is administered a supplemental dose of 3000 mg four weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重≥ 60至 ＜ 100 kg的患者： (a) 在第1天一次，按2700 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3300 mg的維持劑量。The method of any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing ≥ 60 to < 100 kg:(a) once on day 1 at a loading dose of 2700 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg; and(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3300 mg.如請求項18所述之方法，其中該患者在維持劑量的四週內接受紅血球（RBC）輸注，然後在該維持劑量後四週投與3300 mg的補充劑量。The method of claim 18, wherein the patient receives a red blood cell (RBC) transfusion within four weeks of the maintenance dose and then is administered a supplemental dose of 3300 mg four weeks after the maintenance dose.如請求項1-7中任一項所述之方法，其中該抗C5抗體投與於體重≥ 100 kg的患者： (a) 在第1天一次，按3000 mg的負荷劑量； (b) 在第5天一次，按900 mg的負荷劑量； (c) 在第10天一次，按900 mg的負荷劑量；以及 (d) 在第15天和此後每八週，按3600 mg的維持劑量。A method as described in any of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing ≥ 100 kg:(a) once on day 1 at a loading dose of 3000 mg;(b) once on day 5 at a loading dose of 900 mg;(c) once on day 10 at a loading dose of 900 mg; and(d) on day 15 and every eight weeks thereafter at a maintenance dose of 3600 mg.如請求項20所述之方法，其中該患者在維持劑量的四週內接受紅血球（RBC）輸注，然後在該維持劑量後四週投與3600 mg的補充劑量。The method of claim 20, wherein the patient receives a red blood cell (RBC) transfusion within four weeks of the maintenance dose and then is administered a supplemental dose of 3600 mg four weeks after the maintenance dose.如前述請求項中任一項所述之方法，其中該治療維持該抗C5抗體 的血清谷濃度為175 μg/mL或更高。The method of any of the preceding claims, wherein the treatment maintains the serum trough concentration of the anti-C5 antibody at 175 μg/mL or greater.如前述請求項中任一項所述之方法，其中該治療維持該抗C5抗體 的血清谷濃度為200 μg/mL或更高。The method of any of the preceding claims, wherein the treatment maintains the serum trough concentration of the anti-C5 antibody at 200 μg/mL or greater.如前述請求項中任一項所述之方法，其中該抗C5抗體經配製用於靜脈內投與。The method of any preceding claim, wherein the anti-C5 antibody is formulated for intravenous administration.如前述請求項中任一項所述之方法，其中該治療為包含總共26週治療的投與週期。The method of any of the preceding claims, wherein the treatment is an administration cycle comprising a total of 26 weeks of treatment.如前述請求項中任一項所述之方法，其中與基線相比，該治療使得微血管病性溶血性貧血、血小板減少、內皮損傷、腎損害、腎衰竭、漿膜炎、肺性高血壓和多系統器官衰竭減少或停止。The method of any preceding claim, wherein the treatment reduces or stops microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serous membrane inflammation, pulmonary hypertension, and multisystem organ failure compared to baseline.如前述請求項中任一項所述之方法，其中該治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數≥ 50,000/mm³，(b) LDH ＜ 1.5 × ULN，和 (c) 不存在血球裂片（如果在基線時存在血球裂片）。The method of any of the preceding claims, wherein the treatment results in (a) a platelet count ≥ 50,000/mm³ without transfusion support in the prior 7 days, (b) LDH < 1.5 x ULN, and (c) the absence of schisis (if schisis was present at baseline).如前述請求項中任一項所述之方法，其中該治療使得 (a) 在前7天沒有輸血支持的情況下，血小板計數≥ 50,000/mm³，(b) LDH ＜ 1.5 × ULN，(c) 不存在血球裂片（如果在基線時存在血球裂片），和 (d) 蛋白尿相對於基線減少至少50%。The method of any of the preceding claims, wherein the treatment results in (a) a platelet count ≥ 50,000/mm³ without transfusion support in the prior 7 days, (b) LDH < 1.5 × ULN, (c) absence of schizonts (if schizonts were present at baseline), and (d) a reduction in proteinuria of at least 50% relative to baseline.如前述請求項中任一項所述之方法，其中該治療使得產生有利的血液學響應。The method of any preceding claim, wherein the treatment results in a favorable hematological response.如前述請求項中任一項所述之方法，其中該治療使得LDH正常化、紅血球和血小板輸注需求得以解決、且血球裂片消失。The method of any of the preceding claims, wherein the treatment results in normalization of LDH, resolution of red blood cell and platelet transfusion requirements, and disappearance of blood cell fragmentation.如前述請求項中任一項所述之方法，其中該治療使得 在沒有輸血支持的情況下，血紅素 ≥ 8 g/dL。The method of any preceding claim, wherein the treatment results in a hemoglobin ≥ 8 g/dL without transfusion support.如前述請求項中任一項所述之方法，其中與基線相比，該治療使得LDH降低、血小板增加和/或血紅素增加。The method of any of the preceding claims, wherein the treatment results in a decrease in LDH, an increase in platelets and/or an increase in hemoglobin compared to baseline.如前述請求項中任一項所述之方法，其中與基線相比，該治療產生正常水平的血清肌酸酐。The method of any preceding claim, wherein the treatment produces normal levels of serum creatinine compared to baseline.如前述請求項中任一項所述之方法，其中與基線相比，該治療使得腎、心血管、肺、CNS和/或GI系統中TMA相關器官功能障礙有改善。The method of any of the preceding claims, wherein the treatment results in an improvement in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS and/or GI system compared to baseline.如前述請求項中任一項所述之方法，其中該治療實現末端補體抑制。The method of any preceding claim, wherein the treatment achieves terminal complement inhibition.如前述請求項中任一項所述之方法，其中該治療使得不良事件減少。The method of any preceding claim, wherein the treatment results in a reduction in adverse events.如前述請求項中任一項所述之方法，其中該治療促使與血管炎症（例如，脫落腫瘤壞死因子受體1 [TNF-R1]）、內皮損傷和/或激活（例如，凝血酶調節蛋白和脫落血管細胞黏附分子1 [VCAM-1]）、腎損傷（例如，胱蛋白C）和/或補體蛋白和補體激活途徑產物相關的生物標誌物向正常水平轉變。The method of any of the preceding claims, wherein the treatment results in a shift toward normal levels of biomarkers associated with vascular inflammation (e.g., TNF-R1), endothelial damage and/or activation (e.g., thrombomodulin and VCAM-1), renal damage (e.g., cystin C), and/or complement proteins and complement activation pathway products.如前述請求項中任一項所述之方法，其中該治療促使凝血酶調節蛋白（TM）和/或黏結蛋白聚糖-1（SYND1）以及視需要補體因子Ba向正常水平轉變。A method as claimed in any preceding claim, wherein the treatment results in a shift towards normal levels of thrombomodulin (TM) and/or syndecan-1 (SYND1) and optionally complement factor Ba.如前述請求項中任一項所述之方法，其中該治療使得如通過生活品質評估所評估的生活品質相對於基線有所變化。The method of any preceding claim, wherein the treatment results in a change from baseline in quality of life as assessed by a quality of life assessment.如前述請求項中任一項所述之方法，其中該生活品質評估係生活品質評定問卷（PedsQL）量表或EQ-5D-5L問卷）。The method of any of the preceding claims, wherein the quality of life assessment is the Parent Quality of Life Questionnaire (PedsQL) or the EQ-5D-5L questionnaire).如前述請求項中任一項所述之方法，其中與基線相比，該治療使得乳酸脫氫酶（LDH）水平降低。The method of any preceding claim, wherein the treatment results in a decrease in lactate dehydrogenase (LDH) levels compared to baseline.如前述請求項中任一項所述之方法，其中該治療使得該患者中游離C5濃度降低或紅血球（RBC）溶血降低；特別地其中與未經治療的患者相比，該治療產生0.5 µg/mL或更低的游離C5濃度和/或20%或更低的RBC溶血。The method of any of the preceding claims, wherein the treatment results in a reduction in free C5 concentration or a reduction in red blood cell (RBC) hemolysis in the patient; particularly wherein the treatment results in a free C5 concentration of 0.5 µg/mL or less and/or RBC hemolysis of 20% or less compared to an untreated patient.如前述請求項中任一項所述之方法，其中該人患者係兒童患者或成人患者，較佳的是兒童患者。The method of any of the preceding claims, wherein the human patient is a pediatric patient or an adult patient, preferably a pediatric patient.如前述請求項中任一項所述之方法，其中該人患者係輸注了RBC的患者，較佳的是在用該抗C5抗體治療的維持給藥期期間接受了RBC輸注的患者。The method of any of the preceding claims, wherein the human patient is a patient who has received an RBC transfusion, preferably a patient who has received an RBC transfusion during a maintenance dosing period of treatment with the anti-C5 antibody.如前述請求項中任一項所述之方法，該方法進一步包括投與一或多種最佳支持治療（BSC）措施。The method of any of the preceding claims, further comprising administering one or more best supportive care (BSC) measures.如請求項45所述之方法，其中該一或多種BSC措施選自由以下組成之群組：輸血支持、皮質類固醇、透析和抗高血壓藥物。The method of claim 45, wherein the one or more BSC measures are selected from the group consisting of: transfusion support, corticosteroids, dialysis, and antihypertensive medications.一種用於治療人患者的造血幹細胞移植相關血栓性微血管病（HSCT-TMA）的套組，該人患者在用抗C5抗體或其抗原結合片段治療的維持期的前半段期間經歷了RBC移植，該套組包含： (a) 負荷、維持和補充劑量的抗C5抗體或其抗原結合片段，該抗C5抗體或其抗原結合片段包含具有SEQ ID NO:12所示序列的重鏈可變區的CDR1、CDR2和CDR3結構域，以及具有SEQ ID NO:8所示序列的輕鏈可變區的CDR1、CDR2和CDR3結構域；以及 (b) 用於在前述請求項中任一項所述之方法中使用該抗C5抗體或其抗原結合片段的說明書。A kit for treating hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) in a human patient who has undergone an RBC transplant during the first half of a maintenance period of treatment with an anti-C5 antibody or an antigen-binding fragment thereof, the kit comprising:(a) loading, maintenance, and replenishing doses of an anti-C5 antibody or an antigen-binding fragment thereof, the anti-C5 antibody or an antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:8; and(b) instructions for using the anti-C5 antibody or an antigen-binding fragment thereof in the method described in any of the preceding claims.一種抗C5抗體或其抗原結合片段，用於在治療在治療的維持期的前半段期間經歷了RBC輸注的HSCT-TMA患者中使用，其中按以下投與該抗C5抗體或其抗原結合片段： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。An anti-C5 antibody or antigen-binding fragment thereof for use in treating HSCT-TMA patients who have undergone RBC transfusions during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered as follows:(a) once on day 1, at a loading dose of: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, at a loading dose of: 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; kg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; and(i)     every 30 weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; andkg who receives red blood cell (RBC) transfusions within a specified time frame of the maintenance dose, wherein the supplement is administered at the following doses within the specified time frame: a.  300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks, b.  600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, or c.  2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or (ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplement is administered four weeks after the maintenance dose at the following doses: a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.抗C5抗體或其抗原結合片段用於治療在治療的維持期的前半段期間經歷了RBC輸注的HSCT-TMA患者之用途，其中該抗C5抗體或其抗原結合片段按以下投與： (a) 在第1天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者600 mg，體重為10至＜ 20 kg的患者600 mg，體重為20至＜ 30 kg的患者900 mg，體重≥ 30至＜ 40 kg的患者1200 mg，體重≥ 40至＜ 60 kg的患者2400 mg，體重≥ 60至＜ 100 kg的患者2700 mg，或體重≥ 100 kg的患者3000 mg； (b) 在第5天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg； (c) 在第10天一次，按以下負荷劑量：體重為5至＜ 10 kg的患者300 mg，體重為10至＜ 20 kg的患者300 mg，體重為20至＜ 30 kg的患者300 mg，體重≥ 30至＜ 40 kg的患者300 mg，體重≥ 40至＜ 60 kg的患者600 mg，體重≥ 60至＜ 100 kg的患者900 mg，或體重≥ 100 kg的患者900 mg；以及 (d) 在第15天和 (i)     此後每四週，按以下維持劑量：體重為5至＜ 10 kg的患者300或400 mg或體重為10至＜ 20 kg的患者600或800 mg，或者 (ii)    此後每八週，按以下維持劑量：體重為20至＜ 30 kg的患者2100 mg，體重≥ 30至＜ 40 kg的患者2700 mg，體重≥ 40至＜ 60 kg的患者3000 mg，體重≥ 60至＜ 100 kg的患者3300 mg，或體重≥ 100 kg的患者3600 mg； 並且其中將補充劑量投與於： (i)     體重＜ 30 kg的患者，該患者在維持劑量的指定時間範圍內接受紅血球（RBC）輸注，其中該補充劑量在該指定時間範圍按以下劑量投與： a.  體重為5至＜ 10 kg的患者300或400 mg，其中該指定時間範圍係兩週， b. 體重為10至＜ 20 kg的患者600或800 mg，其中該指定時間範圍係兩週，或 c.  體重為20至＜ 30 kg的患者2100 mg，其中該指定時間範圍係四週，或者 (ii)    體重≥ 30 kg的患者，該患者在維持劑量的四週內接受紅血球（RBC）輸注，其中該補充劑量在該維持劑量後四週按以下劑量投與： a.  體重≥ 30至＜ 40 kg的患者2700 mg， b. 體重≥ 40至＜ 60 kg的患者3000 mg， c.  體重≥ 60至＜ 100 kg的患者3300 mg，或 d. 體重 ≥ 100 kg的患者3600 mg。Use of an anti-C5 antibody or an antigen-binding fragment thereof for treating HSCT-TMA patients who have undergone RBC transfusions during the first half of the maintenance phase of treatment, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered as follows:(a) once on day 1, at a loading dose of: 600 mg for patients weighing 5 to < 10 kg, 600 mg for patients weighing 10 to < 20 kg, 900 mg for patients weighing 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg;(b) once on day 5, at a loading dose of: 300 mg for patients weighing 5 to < 10 kg, mg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg;(c) once on day 10, as a loading dose: 300 mg for patients weighing 5 to < 10 kg, 300 mg for patients weighing 10 to < 20 kg, 300 mg for patients weighing 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg mg; and(d) on day 15 and(i)     every four weeks thereafter, at a maintenance dose of 300 or 400 mg for patients weighing 5 to < 10 kg or 600 or 800 mg for patients weighing 10 to < 20 kg, or(ii)    every eight weeks thereafter, at a maintenance dose of 2100 mg for patients weighing 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg;and wherein the supplemental dose is administered to:(i)     patients weighing < 30 kg who receives red blood cell (RBC) transfusions within a specified time frame of the maintenance dose, wherein the supplement is administered at the following doses within the specified time frame: a.  300 or 400 mg for patients weighing 5 to < 10 kg, wherein the specified time frame is two weeks, b.  600 or 800 mg for patients weighing 10 to < 20 kg, wherein the specified time frame is two weeks, or c.  2100 mg for patients weighing 20 to < 30 kg, wherein the specified time frame is four weeks, or (ii)    Patients weighing ≥ 30 kg who receive red blood cell (RBC) transfusions within four weeks of the maintenance dose, wherein the supplement is administered four weeks after the maintenance dose at the following doses: a. 2700 mg for patients weighing ≥ 30 to < 40 kg,b. 3000 mg for patients weighing ≥ 40 to < 60 kg,c. 3300 mg for patients weighing ≥ 60 to < 100 kg, ord. 3600 mg for patients weighing ≥ 100 kg.如請求項48所述之抗C5抗體或其抗原結合片段，其中該抗C5抗體或其抗原結合片段係瑞利珠單抗（ULTOMIRIS®）。The anti-C5 antibody or antigen-binding fragment thereof as described in claim 48, wherein the anti-C5 antibody or antigen-binding fragment thereof is reslizumab (ULTOMIRIS®).如請求項49所述之用途，其中該抗C5抗體或其抗原結合片段係瑞利珠單抗（ULTOMIRIS®）。The use as described in claim 49, wherein the anti-C5 antibody or antigen-binding fragment thereof is reslizumab (ULTOMIRIS®).