发明背景Background of the Invention
年龄相关性黄斑变性(AMD)影响全世界约14-24％的65-74岁人群和全世界约35％的75岁以上人群，并且因为视网膜受损而导致视野中心(黄斑)视力受损或丧失。它是50岁以上人群视力丧失和潜在失明的主要原因。AMD的两种主要形式是萎缩性(非渗出性或“干性”)AMD和新生血管性(渗出性或“湿性”)AMD。萎缩性AMD的特征在于AMD晚期黄斑中央的地图样萎缩(GA)，并且由于光感受器的丧失和GA的发展，视力可以缓慢恶化多年。新生血管性AMD是更严重的AMD形式，并且其特征在于AMD晚期的新生血管形成(例如，脉络膜新生血管形成)，其可迅速导致失明。新生血管性AMD影响全球超过3000万患者，并且是60岁或以上人群视力丧失的主要原因-如果不治疗，患者可能在疾病发作后24个月内在受影响的眼睛中失去中心视力。大约90％的AMD患者是干性形式的，并且约10％的患者发展为新生血管性AMD。在美国，没有批准的萎缩性AMD治疗，而新生血管性AMD的批准的治疗(主要是抗血管生成剂)在约50％的新生血管性AMD患者中显示出疗效。Age-related macular degeneration (AMD) affects approximately 14-24% of the world's population aged 65-74 and approximately 35% of the world's population over the age of 75 and results in impaired vision in the center of the visual field (macular) due to damage to the retina or lost. It is the leading cause of vision loss and potential blindness in people over the age of 50. The two main forms of AMD are atrophic (non-exudative or "dry") AMD and neovascular (exudative or "wet") AMD. Atrophic AMD is characterized by geographic atrophy (GA) in the center of the macula in advanced stages of AMD, and vision can slowly deteriorate over many years due to loss of photoreceptors and development of GA. Neovascular AMD is a more severe form of AMD and is characterized by neovascularization (eg, choroidal neovascularization) in the advanced stages of AMD, which can rapidly lead to blindness. Neovascular AMD affects more than 30 million patients worldwide and is the leading cause of vision loss in people 60 years of age or older - if untreated, patients can lose central vision in the affected eye within 24 months of disease onset. About 90% of AMD patients are in the dry form, and about 10% of patients develop neovascular AMD. In the United States, there are no approved treatments for atrophic AMD, whereas approved treatments for neovascular AMD (primarily anti-angiogenic agents) show efficacy in approximately 50% of neovascular AMD patients.
发明内容SUMMARY OF THE INVENTION
本公开内容提供了用于治疗AMD和其他眼部疾病和病症的载脂蛋白(apo)模拟物。在一些实施方案中，施用apoA-I模拟物和/或apoE模拟物以治疗AMD或另一种眼部病症。在某些实施方案中，所述apoA-I模拟物包含L-4F或D-4F，或是L-4F或D-4F。在一些实施方案中，所述apoE模拟物包含AEM-28-14，或是AEM-28-14。一种或多种其他治疗剂可以与apo模拟物组合施用以治疗AMD或另一种眼部病症。可以选择一种或多种其他治疗剂以靶向AMD或其他眼部病症的不同潜在因素。可以施用apo模拟物，任选地与另一种治疗剂联合，以在例如AMD的不同阶段(包括早期、中期和晚期阶段)和AMD的不同表型(包括地图样萎缩和新生血管性AMD)中治疗AMD，以及预防或减缓AMD进展到下一阶段。The present disclosure provides apolipoprotein (apo) mimetics for the treatment of AMD and other ocular diseases and disorders. In some embodiments, the apoA-I mimetic and/or the apoE mimetic are administered to treat AMD or another ocular disorder. In certain embodiments, the apoA-I mimetic comprises L-4F or D-4F, or is L-4F or D-4F. In some embodiments, the apoE mimetic comprises AEM-28-14, or is AEM-28-14. One or more other therapeutic agents can be administered in combination with the apo mimetic to treat AMD or another ocular disorder. One or more other therapeutic agents may be selected to target different underlying factors in AMD or other ocular disorders. Apo mimetics can be administered, optionally in combination with another therapeutic agent, to, for example, treat different stages of AMD (including early, intermediate, and advanced stages) and different phenotypes of AMD (including geographic atrophy and neovascular AMD) treatment of AMD, as well as preventing or slowing AMD progression to the next stage.
除了载脂蛋白模拟物之外，可用于治疗AMD和其他眼部疾病和病症的其他治疗剂包括但不限于：In addition to apolipoprotein mimetics, other therapeutic agents that can be used to treat AMD and other ocular diseases and disorders include, but are not limited to:
1)抗血脂异常剂；1) Anti-dyslipidemic agents;
2)PPAR-α激动剂、PPAR-δ激动剂和PPAR-γ激动剂；2) PPAR-α agonists, PPAR-δ agonists and PPAR-γ agonists;
3)抗淀粉样蛋白剂；3) anti-amyloid agents;
4)脂褐素或其组分的抑制剂；4) inhibitors of lipofuscin or components thereof;
5)视觉/光周期调节剂和暗适应剂；5) Vision/photoperiod regulators and dark adaptors;
6)抗氧化剂；6) Antioxidants;
7)神经保护剂(神经保护试剂)；7) Neuroprotective agents (neuroprotective agents);
8)凋亡抑制剂和坏死抑制剂；8) Apoptosis inhibitors and necrosis inhibitors;
9)C-反应蛋白抑制剂；9) C-reactive protein inhibitor;
10)补体系统或其组分(例如蛋白质)的抑制剂；10) Inhibitors of the complement system or its components (eg proteins);
11)炎性体抑制剂；11) Inflammasome inhibitors;
12)抗炎剂；12) Anti-inflammatory agents;
13)免疫抑制剂；13) Immunosuppressants;
14)基质金属蛋白酶的调节剂；和14) Modulators of matrix metalloproteinases; and
15)抗血管生成剂。15) Anti-angiogenic agents.
除了AMD之外，可以用载脂蛋白模拟物(任选地与一种或多种其他治疗剂联合)治疗的其他眼部疾病和病症包括但不限于黄斑病变(例如，与年龄相关的黄斑病变和糖尿病性黄斑病变)、黄斑水肿(例如，糖尿病性黄斑水肿[DME]和视网膜静脉阻塞[RVO]后的黄斑水肿)、视网膜病变(例如糖尿病视网膜病变[包括DME患者])、RVO(例如，中央RVO和分支RVO)、Coats病(渗出性视网膜炎)、葡萄膜炎、视网膜色素上皮细胞脱离、以及AMD之外的与细胞内或细胞外脂质储存或积聚增加相关的疾病。In addition to AMD, other ocular diseases and disorders that can be treated with apolipoprotein mimetics (optionally in combination with one or more other therapeutic agents) include, but are not limited to, macular degeneration (eg, age-related macular degeneration) and diabetic macular degeneration), macular edema (eg, diabetic macular edema [DME] and macular edema following retinal vein occlusion [RVO]), retinopathy (eg, diabetic retinopathy [including patients with DME]), RVO (eg, Central RVO and branch RVO), Coats disease (exudative retinitis), uveitis, retinal pigment epithelial cell detachment, and diseases other than AMD associated with increased intracellular or extracellular lipid storage or accumulation.
附图简述Brief Description of Drawings
通过参考以下详细描述和附图将获得对本公开的特征和优点的更好理解，所述详细描述阐述了本公开的说明性实施例。A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description, which sets forth illustrative embodiments of the present disclosure, and the accompanying drawings.
图1示出了涉及AMD病理学的组织层和脂质积累在AMD发病机理中的作用。OS：光感受器的外段；RPE：视网膜色素上皮；RPE-BL：RPE基底层；ICL：内胶原层，EL：弹性层，OCL：外胶原层；ChC-BL：ChC基底层；ChC：脉络膜毛细血管内皮；BLamD：基底层状沉积物；BLinD：基底线性沉积物；前BLinD：前基底线性沉积物；L：脂褐素；M：黑素体；ML：黑脂褐素(melanolipofuscin)；Mt：线粒体；圆圈：脂蛋白颗粒。布鲁赫膜(Bruch’s membrane，BrM)由ICL、EL和OCL组成。BlamD是加厚的RPE-BL。基底丘(Basal mound)是BLamD内的软玻璃疣(soft druse)材质。RPE细胞含有黑素体、脂褐素和黑脂褐素，其为例如彩色眼底照相术、眼底自发荧光和光学相干断层照相术提供信号。Figure 1 shows the role of tissue layers involved in AMD pathology and lipid accumulation in AMD pathogenesis. OS: outer segment of photoreceptors; RPE: retinal pigment epithelium; RPE-BL: RPE basal layer; ICL: inner collagen layer, EL: elastic layer, OCL: outer collagen layer; ChC-BL: ChC basal layer; ChC: choroid capillary endothelium; BLamD: basal lamellar deposits; BLinD: basal linear deposits; anterior BLinD: anterior basal linear deposits; L: lipofuscin; M: melanosomes; ML: melanolipofuscin; Mt: mitochondria; circles: lipoprotein particles. Bruch's membrane (BrM) consists of ICL, EL and OCL. BlamD is thickened RPE-BL. Basal mounds are soft druses within BLamD. RPE cells contain melanosomes, lipofuscin, and melano-lipofuscin, which provide signals for, for example, color fundus photography, fundus autofluorescence, and optical coherence tomography.
图2显示在注射的猕猴的眼中以及对应未注射的猕猴的眼中的布鲁赫膜中和布鲁赫膜上的中性脂质以油红O(ORO)染色的评分，所述注射的猕猴的眼以及对应未注射的猕猴的眼接受6个月的玻璃体内注射L-4F或安慰剂(乱序的L-4F)。统计学分析：1)同一组注射的眼与非注射的眼之间的配对t检验；2)治疗(L-4F)组和对照(安慰剂)组中注射的眼睛之间的非配对t检验。Figure 2 shows the scoring of oil red O (ORO) staining of neutral lipids in Bruch's membrane and on Bruch's membrane in the eyes of injected rhesus monkeys and in the eyes of corresponding uninjected rhesus monkeys. Eyes and those of corresponding uninjected rhesus monkeys received 6 months of intravitreal injections of L-4F or placebo (scrambled L-4F). Statistical analysis: 1) Paired t-test between injected eyes and non-injected eyes in the same group; 2) Unpaired t-test between injected eyes in treatment (L-4F) and control (placebo) groups .
图3显示在注射的猕猴的眼中以及对应未注射的猕猴的眼中的布鲁赫膜中的酯化胆固醇以非律平(filipin)染色的强度，所述注射的猕猴的眼以及对应未注射的猕猴的眼接受6个月的玻璃体内注射L-4F或安慰剂(乱序的L-4F)。统计学分析：1)同一组注射的眼与非注射的眼之间的配对t检验；2)治疗(L-4F)组和对照(安慰剂)组中注射的眼睛之间的非配对t检验。Figure 3 shows the intensity of filipin staining of esterified cholesterol in Bruch's membrane in the eyes of injected rhesus monkeys and in eyes of corresponding uninjected rhesus monkeys Eyes of macaques received 6 months of intravitreal injections of L-4F or placebo (scrambled L-4F). Statistical analysis: 1) Paired t-test between injected eyes and non-injected eyes in the same group; 2) Unpaired t-test between injected eyes in treatment (L-4F) and control (placebo) groups .
图4显示在注射的猕猴的眼中以及对应未注射的猕猴的眼中布鲁赫膜中的膜攻击复合物(MAC，C5b-9)和脉络膜毛细血管的染色强度，所述注射的猕猴的眼以及对应未注射的猕猴的眼接受6个月的玻璃体内注射L-4F或安慰剂(乱序的L-4F)。统计学分析：1)同一组注射的眼与非注射的眼之间的配对t检验；2)治疗(L-4F)组和对照(安慰剂)组中注射的眼睛之间的非配对t检验。Figure 4 shows the staining intensity of membrane attack complex (MAC, C5b-9) and choriocapillaris in Bruch's membrane in the eyes of injected rhesus monkeys and corresponding uninjected eyes of rhesus monkeys, and Eyes of corresponding uninjected macaques received intravitreal injections of L-4F or placebo (scrambled L-4F) for 6 months. Statistical analysis: 1) Paired t-test between injected eyes and non-injected eyes in the same group; 2) Unpaired t-test between injected eyes in treatment (L-4F) and control (placebo) groups .
图5显示在注射的猕猴的眼中以及对应未注射的猕猴的眼中的补体因子D的染色强度，所述注射的猕猴的眼以及对应未注射的猕猴的眼接受6个月的玻璃体内注射L-4F或安慰剂(乱序的L-4F)。统计学分析：1)同一组注射的眼与非注射的眼之间的配对t检验；2)治疗(L-4F)组和对照(安慰剂)组中注射的眼睛之间的非配对t检验。Figure 5 shows the staining intensity of complement factor D in the eyes of injected and corresponding uninjected macaques receiving 6 months of intravitreal injection of L- 4F or placebo (scrambled L-4F). Statistical analysis: 1) Paired t-test between injected eyes and non-injected eyes in the same group; 2) Unpaired t-test between injected eyes in treatment (L-4F) and control (placebo) groups .
图6显示了在注射的猕猴的眼中以及对应未注射的猕猴的眼中的颞外黄斑处测量的布鲁赫膜的厚度，所述注射的猕猴的眼以及对应未注射的猕猴的眼接受6个月的玻璃体内注射L-4F或安慰剂(乱序的L-4F)。统计学分析：1)同一组注射的眼与非注射的眼之间的配对t检验；2)治疗(L-4F)组和对照(安慰剂)组中注射的眼睛之间的非配对t检验。Figure 6 shows the thickness of Bruch's membrane measured at the extratemporal macula in the eyes of injected rhesus monkeys and corresponding uninjected rhesus monkey eyes that received 6 Monthly intravitreal injection of L-4F or placebo (scrambled L-4F). Statistical analysis: 1) Paired t-test between injected eyes and non-injected eyes in the same group; 2) Unpaired t-test between injected eyes in treatment (L-4F) and control (placebo) groups .
发明详述Detailed description of the invention
虽然本文描述了本公开的各种实施方案，但是对于本领域技术人员显而易见的是，这些实施方案仅以举例的方式提供。在不脱离本公开的情况下，对本文描述的实施方案的许多修改和改变以及对本文描述的实施例的变化和替换对于本领域技术人员将是显而易见的。应理解，本文所述实施方案的各种替代方案可用于实践本公开。还应理解，本公开的每个实施方案可以可选地与本文描述的与该实施例一致的任何一个或多个其他实施方案组合。While various embodiments of the present disclosure are described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous modifications and changes to the embodiments described herein, and variations and substitutions to the embodiments described herein will be apparent to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the present disclosure. It should also be understood that each embodiment of the present disclosure may optionally be combined with any one or more of the other embodiments described herein consistent with that embodiment.
在以列表格式(例如，在马库什组中)呈现元素的情况下，应当理解，还公开了元素的每个可能子组，并且可以从列表或组中移除任何一个或多个元素。Where elements are presented in a list format (eg, in a Markush group), it should be understood that every possible subgroup of elements is also disclosed, and any one or more elements may be removed from the list or group.
还应理解，除非明确相反地指出，否则在本文描述或请求保护的包括一个以上步骤的任何方法中，该方法的动作的顺序不一定限于所述的方法中的动作的顺序，但是本公开涵盖了具有如此限定的顺序的实施方案。It should also be understood that, in any method described or claimed herein that includes more than one step, the order of the actions of the method is not necessarily limited to the order of the actions of the method described, unless explicitly stated to the contrary, but the disclosure covers Embodiments with the order thus defined are presented.
还应理解，通常，在说明书或权利要求书中的实施方案被称为包括一个或多个特征的情况下，本公开还包括由这样的特征组成或基本上由这些特征组成的实施方案。It is also to be understood that generally where embodiments in the specification or claims are referred to as comprising one or more features, the disclosure also includes embodiments which consist of, or consist essentially of, such features.
还应当理解，本公开的任何实施方案，例如，可以明确地从权利要求中排除现有技术中发现的任何实施方案，而不管说明书中是否叙述了该特定排除。It should also be understood that any embodiment of the present disclosure, eg, any embodiment found in the prior art, may expressly be excluded from the claims, regardless of whether such specific exclusion is recited in the specification.
还应理解，适当地，本公开涵盖本文公开的化合物/物质的所有的类似物、衍生物、前药、片段、盐、溶剂化物、水合物、包合物和多晶型物。关于在本公开的特定情况下的化合物/物质或一组化合物/物质的“类似物”、“衍生物”、“前药”、“片段”、“盐”、“溶剂化物”、“水合物”、“包合物”或“多晶型物”的具体叙述不应被解释为故意在本公开的其他情况下遗漏任何这些形式，其中所述化合物/物质或一组化合物/物质在没有列举任何这些形式的情况下而被提及。It is also to be understood that this disclosure encompasses all analogs, derivatives, prodrugs, fragments, salts, solvates, hydrates, clathrates and polymorphs of the compounds/substances disclosed herein, as appropriate. "Analogs", "derivatives", "prodrugs", "fragments", "salts", "solvates", "hydrates" of a compound/substance or a group of compounds/substances in the specific context of the present disclosure The specific recitation of "inclusion compounds" or "polymorphs" should not be construed as intentional omission of any of these forms in other instances of this disclosure in which the compound/substance or group of compounds/substances are not recited. are mentioned in the context of any of these forms.
本文包括标题以供参考并有助于定位某些部分。标题不旨在限制在那些标题下的部分中描述的实施方案和概念的范围，并且那些实施方案和概念可以在完整公开内容的其他部分中具有适用性。This article includes headings for reference and to help locate certain sections. Headings are not intended to limit the scope of the embodiments and concepts described in the sections under those headings, and those embodiments and concepts may have applicability in other sections of the complete disclosure.
本文引用的所有专利文献和所有非专利文献均以引用的方式整体并入本文，其程度如同每个专利文献或非专利文献具体和单独地指出通过整体引用并入本文。All patent documents and all non-patent documents cited herein are incorporated by reference in their entirety to the same extent as if each patent document or non-patent document was specifically and individually indicated to be incorporated by reference in its entirety.
I.定义I.Definitions
如说明书和所附权利要求中所使用的，除非另外特别说明，否则不定冠词“一”(a)和“一”(an)以及定冠词“该”(the)可包括复数指代以及单数指代。As used in the specification and the appended claims, the indefinite articles "a" (a) and "an" (an) and the definite article "the" (the) may include plural referents as well as unless specifically stated otherwise. Singular designation.
这里使用的术语“示例性”意味着“用作示例、实例或说明”。本文中表征为“示例性”的任何实施方案不必被解释为比其他实施方案优选或有利。The term "exemplary" as used herein means "serving as an example, instance, or illustration." Any embodiment characterized herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
术语“约”或“近似”是指本领域普通技术人员确定的特定值的可接受误差，其部分取决于如何测量或确定该值。在某些实施方案中，术语“约”或“近似”意指在一个标准偏差内。在一些实施方案中，当没有列举特定的误差范围(例如，图表或数据表中给出的平均值的标准偏差)时，术语“约”或“近似”意指将包含所述值的范围以及通过向上或向下舍入到所述值而包括的范围，同时考虑显著性数值。在某些实施方案中，术语“约”或“近似”意指在指定值的20％、15％、10％或5％内。只要术语“约”或“近似”在一系列两个或更多个数值中的第一个数值之前或在一系列两个或更多个数值范围中的第一个数值之前，术语“约”或“近似”适用于该系列数值或该系列数值范围内的数值的每个数值。The terms "about" or "approximately" refer to an acceptable error within a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms "about" or "approximately" mean within one standard deviation. In some embodiments, the term "about" or "approximately" is intended to encompass the range of the stated value when no specific error range is recited (eg, the standard deviation of the mean given in a graph or data table) as well as Ranges are included by rounding up or down to the stated value, taking into account significant values. In certain embodiments, the term "about" or "approximately" means within 20%, 15%, 10%, or 5% of the specified value. The term "about" is used whenever the term "about" or "approximately" precedes the first value in a series of two or more values or precedes the first value in a series of two or more values Or "approximately" applies to each value in the series of values or values within the series of values.
只要术语“至少”或“大于”在一系列两个或更多个数值中的第一数值之前，则该术语“至少”或“大于”适用于该系列数值的每个数值。As long as the term "at least" or "greater than" precedes the first value of the series of two or more values, the term "at least" or "greater than" applies to each value of the series of values.
只要术语“不超过”或“大于”在一系列两个或更多个数值中的第一个数值之前，则术语“不超过”或“小于”适用于该系列数值中的每个数值。As long as the term "not more than" or "greater than" precedes the first value in a series of two or more values, the term "not more than" or "less than" applies to each value in the series of values.
术语“抗氧化剂”包括但不限于抑制其他物质氧化的物质，通过氧化阻止其他物质变质的物质，以及自由基物质、活性氧物质、羟基自由基物质、和氧化的脂质和脂质过氧化产物的清除剂。The term "antioxidant" includes, but is not limited to, substances that inhibit the oxidation of other substances, substances that prevent the deterioration of other substances by oxidation, and free radical substances, reactive oxygen species, hydroxyl radical substances, and oxidized lipids and lipid peroxidation products scavenger.
术语“载脂蛋白模拟物”涵盖载脂蛋白肽模拟物和载脂蛋白模拟肽。The term "apolipoprotein mimetic" encompasses both apolipoprotein peptidomimetics and apolipoprotein peptidomimetics.
术语“保守取代”是指用功能上、结构上或化学上相似的天然或非天然氨基酸取代多肽中的氨基酸。在某些实施方案中，以下各组包含彼此为保守取代的天然氨基酸：The term "conservative substitution" refers to the replacement of amino acids in a polypeptide with functionally, structurally, or chemically similar natural or non-natural amino acids. In certain embodiments, the following groups comprise natural amino acids that are conservatively substituted for each other:
1)甘氨酸(G)，丙氨酸(A)；1) Glycine (G), Alanine (A);
2)天冬氨酸(D)，谷氨酸(E)；2) Aspartic acid (D), glutamic acid (E);
3)天冬酰胺(N)，谷氨酰胺(Q)；3) Asparagine (N), Glutamine (Q);
4)精氨酸(R)，赖氨酸(K)；4) Arginine (R), Lysine (K);
5)异亮氨酸(I)，亮氨酸(L)，甲硫氨酸(M)，缬氨酸(V)，丙氨酸(A)；5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V), Alanine (A);
6)苯丙氨酸(F)，酪氨酸(Y)，色氨酸(W)；和6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); and
7)丝氨酸(S)，苏氨酸(T)，半胱氨酸(C)。7) Serine (S), Threonine (T), Cysteine (C).
在其他实施方案中，氨基酸可以分组如下：In other embodiments, amino acids can be grouped as follows:
1)疏水性：Met(M)，Ala(A)，Val(V)，Leu(L)，lie(I)，Phe(F)，Trp(W)；1) Hydrophobicity: Met(M), Ala(A), Val(V), Leu(L), lie(I), Phe(F), Trp(W);
2)中性亲水：Cys(C)，Ser(S)，Thr(T)，Asn(N)，Gln(Q)；2) Neutral hydrophilic: Cys(C), Ser(S), Thr(T), Asn(N), Gln(Q);
3)酸性：Asp(D)，Glu(E)；3) Acidic: Asp(D), Glu(E);
4)碱性：His(H)，Lys(K)，Arg(R)；4) Alkaline: His(H), Lys(K), Arg(R);
5)影响骨架方向的残基：Gly(G)，Pro(P)；和5) Residues affecting backbone orientation: Gly(G), Pro(P); and
6)芳香族：Trp(W)，Tyr(Y)，Phe(F)，His(H)。6) Aromatic: Trp(W), Tyr(Y), Phe(F), His(H).
在进一步的实施方案中，以下各组包含彼此为保守取代的天然氨基酸：In further embodiments, the following groups comprise natural amino acids that are conservatively substituted for each other:
1)酸性：Asp，Glu；1) Acidic: Asp, Glu;
2)碱性：Lys，Arg，His；2) Alkaline: Lys, Arg, His;
3)不带电的极性：Gly，Ser，Thr，Cys，Tyr，Asn，Gin；3) Uncharged polarity: Gly, Ser, Thr, Cys, Tyr, Asn, Gin;
4)含脂肪族羟基或巯基：Ser，Thr，Cys；4) Containing aliphatic hydroxyl or sulfhydryl: Ser, Thr, Cys;
5)含酰胺：Asn，Gin；5) Amide-containing: Asn, Gin;
6)非极性：Ala，Val，Leu，lie，Met，Pro，Phe，Trp；6) Non-polar: Ala, Val, Leu, lie, Met, Pro, Phe, Trp;
7)疏水性：Val，Leu，lie，Phe；7) Hydrophobicity: Val, Leu, lie, Phe;
8)脂肪族：Ala，Val，Leu，IIe；8) Aliphatic: Ala, Val, Leu, IIe;
9)芳香族：Phe，Trp，Tyr，His；和9) Aromatic: Phe, Trp, Tyr, His; and
10)小的：Gly，Ala，Ser，Cys。10) Small: Gly, Ala, Ser, Cys.
术语“药学上可接受的”是指物质(例如，活性成分或赋形剂)适合用于与对象的组织和器官接触而没有过度刺激、过敏反应、免疫原性和毒性，所述物质具有与之相当的合理的利益/风险比，并且对其预期用途有效。药学组合物的“药学上可接受的”载体或赋形剂也与组合物的其他成分相容。The term "pharmaceutically acceptable" refers to a substance (eg, an active ingredient or excipient) suitable for use in contact with the tissues and organs of a subject without undue irritation, allergic reaction, immunogenicity, and toxicity, said substance having a a reasonable benefit/risk ratio and is valid for its intended use. A "pharmaceutically acceptable" carrier or excipient of a pharmaceutical composition is also compatible with the other ingredients of the composition.
术语“治疗有效量”是指当施用于对象时足以预防待治疗的医学病况(例如，年龄相关性黄斑变性[AMD])、降低待治疗的医学病况(例如，年龄相关性黄斑变性[AMD])的发展风险、延迟待治疗的医学病况(例如，年龄相关性黄斑变性[AMD])的发作或减缓待治疗的医学病况(例如，年龄相关性黄斑变性[AMD])的进展的物质的量，或在某种程度上缓解该病况的一种或多种症状或并发症。术语“治疗有效量”还指足以引起细胞、组织、器官、系统、动物或人的生物或医学反应的物质的量，所述细胞、组织、器官、系统、动物或人由研究人员、兽医、医生或临床医生寻找。The term "therapeutically effective amount" means, when administered to a subject, sufficient to prevent the medical condition to be treated (eg, age-related macular degeneration [AMD]), reduce the medical condition to be treated (eg, age-related macular degeneration [AMD]) ), delay the onset of the medical condition to be treated (eg, age-related macular degeneration [AMD]), or slow the progression of the medical condition to be treated (eg, age-related macular degeneration [AMD] ) amount of substances , or relieve to some extent one or more symptoms or complications of the condition. The term "therapeutically effective amount" also refers to an amount of a substance sufficient to elicit a biological or medical response in a cell, tissue, organ, system, animal, or human being administered by a researcher, veterinarian, Doctor or clinician looking for.
术语“治疗”(treat)、“治疗”(treating)和“治疗”(treatment)包括减轻或消除医学病况或与该病况相关的一种或多种症状或并发症，以及减轻或消除该病况的一种或多种原因。医学病况(例如AMD)的“治疗”的参照包括预防(排除)该病况或一种或多种与该病况相关的症状或并发症、降低该病况或一种或多种与该病况相关的症状或并发症的发展风险、延迟该病况或一种或多种与该病况相关的症状或并发症的发作和减缓该病况或一种或多种与该病况相关的症状或并发症的进展。The terms "treat," "treating," and "treatment" include alleviating or eliminating a medical condition or one or more symptoms or complications associated with the condition, as well as reducing or eliminating the condition. one or more reasons. Reference to "treatment" of a medical condition (eg AMD) includes preventing (excluding) the condition or one or more symptoms or complications associated with the condition, reducing the condition or one or more symptoms associated with the condition or risk of developing complications, delaying the onset of the condition or one or more symptoms or complications associated with the condition, and slowing the progression of the condition or one or more symptoms or complications associated with the condition.
术语“对象”是指动物，包括哺乳动物，例如灵长类动物(例如，人、黑猩猩或猴子)，啮齿动物(例如，大鼠、小鼠、沙鼠、或仓鼠)，兔类(例如，兔子)，猪类(例如，猪)，马类(例如，马)，犬类(例如，狗)和猫类(例如，猫)。对于例如哺乳动物对象(例如人对象)，术语“对象”和“患者”在本文中可互换使用。The term "subject" refers to animals, including mammals, such as primates (eg, humans, chimpanzees, or monkeys), rodents (eg, rats, mice, gerbils, or hamsters), lagomorphs (eg, rabbits), porcine (eg, pigs), equine (eg, horses), canines (eg, dogs), and felines (eg, cats). For, eg, mammalian subjects (eg, human subjects), the terms "subject" and "patient" are used interchangeably herein.
II.AMD的发病机制和病理生理学II.Pathogenesis and Pathophysiology of AMD
年龄相关的视网膜和脉络膜的变化使年龄相关性黄斑变性(AMD)发展，所述年龄相关性黄斑变性(AMD)包括视杆光感受器的损失、脉络膜的变薄、以及以下的累积：视网膜色素上皮细胞(RPE)中的脂褐素以及据报道为其组分(例如，A2E[N-亚视黄基-N-视黄基-乙醇胺])，以及RPE基底层下(亚RPE-BL)空间和布鲁赫膜(BrM，这是脉络膜的一部分)中的脂质。脂蛋白颗粒和据报道的β-淀粉样蛋白(Aβ)聚集在BrM上形成基底线性沉积物(BLinD)。BLinD和玻璃疣被认为是从在BrM上形成的脂质壁发展而来的。脂质壁和异常沉积物的积累刺激慢性炎症，所述脂质壁和异常沉积物的积累部分地导致调节BrM的蛋白水解过程中的异常。材质的异常聚集伴随着正常细胞外基质(ECM)维持功能的丧失(部分由基质金属蛋白酶[MMP]和MMP组织抑制剂[TIMP]的比例改变而介导)，导致BrM的改变，随之而来形成BLinD和玻璃疣。玻璃疣是富含脂质(例如，酯化的胆固醇[EC]和磷脂)和脂蛋白组分(例如，载脂蛋白B[apoB]和/或apoE)的细胞外沉积物并且在RPE-BL和BrM的内部胶原层之间的亚RPE-BL空间中形成，可能是由于RPE在基底外侧分泌富含EC的极低密度脂蛋白(VLDL)。酯化的胆固醇和磷脂(以60-80nm直径的脂蛋白颗粒的形式)在整个成年期在BrM中累积并且最终在BrM上聚集为BLinD或在较老的眼睛的亚RPE-BL空间中聚集为软玻璃疣。软玻璃疣和BLinD分别是含有脂蛋白衍生残骸的相同病变的两种形式(分别为肿块和薄层)。BrM保留了由RPE细胞分泌的富含EC、含有apoB/apoE的脂蛋白(例如，VLDL)，所述BrM随着年龄的增长逐渐变厚，直到在BrM上形成油性层，伴随着脂质氧化或其他修饰随后个别脂蛋白的融合随着时间的推移形成BLinD。炎症发生，并且通过随后的钙化和破裂使得BrM改变，含脂质材质的积累导致亚RPE-BL空间中的新生血管形成并突破到视网膜下空间，即光感受器和RPE之间的潜在空间。此外，亚RPE-BL空间中富含脂质的玻璃疣和覆盖BrM的BLinD阻断营养物(包括维生素A)到达视网膜中的光感受器(视杆细胞和视锥细胞)，导致所述光感受器萎缩/退化并最终死亡。与AMD相关的其他细胞外病变包括视网膜下玻璃疣沉积物(SDD)，其在组成上不同于玻璃疣，含有未酯化(游离)胆固醇(UC)并在RPE和光感受器之间形成，可能是由于RPE在顶部分泌的富含UC的脂蛋白。视网膜下空间中形成的SDD也可能导致后遗症，例如炎症和新生血管形成(例如，2型或3型)。Age-related changes in the retina and choroid contribute to the development of age-related macular degeneration (AMD), which includes loss of rod photoreceptors, thinning of the choroid, and accumulation of the retinal pigment epithelium. Lipofuscin in cells (RPE) and its reported components (eg, A2E [N-retinylidene-N-retinyl-ethanolamine]), as well as in the RPE subbasal (sub-RPE-BL) space and cloth Lipids in Luch's membrane (BrM, which is part of the choroid). Lipoprotein granules and reported β-amyloid (Aβ) aggregate on BrM to form basal linear deposits (BLinD). BLinD and drusen are thought to develop from lipid walls formed on BrM. Chronic inflammation is stimulated by the accumulation of lipid walls and abnormal deposits, which in part lead to abnormalities in the proteolytic processes that regulate BrM. Abnormal aggregation of material is accompanied by loss of normal extracellular matrix (ECM) maintenance function (mediated in part by altered ratios of matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]), resulting in changes in BrM, followed by to form BLinD and drusen. Drusen are extracellular deposits rich in lipids (eg, esterified cholesterol [EC] and phospholipids) and lipoprotein components (eg, apolipoprotein B [apoB] and/or apoE) and in RPE-BL and BrM in the sub-RPE-BL space between the inner collagen layer, probably due to the basolateral secretion of EC-rich very low-density lipoprotein (VLDL) by the RPE. Esterified cholesterol and phospholipids (in the form of 60-80 nm diameter lipoprotein particles) accumulate in BrM throughout adulthood and eventually aggregate on BrM as BLinD or in the sub-RPE-BL space of older eyes as Soft drusen. Soft drusen and BLinD are two forms of the same lesion (mass and lamella, respectively) containing lipoprotein-derived debris. BrM retains EC-rich, apoB/apoE-containing lipoproteins (eg, VLDL) secreted by RPE cells that thicken with age until an oily layer forms on BrM with lipid oxidation or other modifications followed by fusion of individual lipoproteins over time to form BLinD. Inflammation occurs, and BrM is altered by subsequent calcification and rupture, and accumulation of lipid-containing material leads to neovascularization in the sub-RPE-BL space and breakthrough into the subretinal space, the potential space between photoreceptors and RPE. In addition, lipid-rich drusen and BrM-covered BLinD in the sub-RPE-BL space block nutrients (including vitamin A) from reaching photoreceptors (rods and cones) in the retina, causing the photoreceptors Shrinks/degenerates and eventually dies. Other extracellular lesions associated with AMD include subretinal drusen deposits (SDD), which are different in composition from drusen, contain unesterified (free) cholesterol (UC) and form between the RPE and photoreceptors, possibly UC-rich lipoprotein secreted at the top due to RPE. SDD that develops in the subretinal space may also lead to sequelae such as inflammation and neovascularization (eg, type 2 or 3).
图1说明了涉及AMD病理学的组织层和脂质积累在AMD发病机理中的作用。BrM由三层组成：内胶原层(ICL)、弹性层(EL)和外胶原层(OCL)。在健康的眼睛中，RPE基底层(RPE-BL)附着在BrM的ICL上，并且RPE-BL和ICL之间没有空间(亚RPE-BL空间是“潜在的”空间)。在整个成年期，RPE细胞以基底水平分泌脂蛋白颗粒(图1中的圆圈)，其分散在BrM的ICL和OCL中(图1中的最左侧的图)。随着在多年内分泌和积累了更多的脂蛋白颗粒，它们在BrM的紧密堆积的ICL上形成前BLinD(图1中的左起第二个图)。多年来更多脂蛋白颗粒的分泌和积累导致脂蛋白颗粒聚集而在BrM ICL上形成BLinD(层状)和软玻璃疣(肿块)(图1中的两个中间图)。前BLinD的形成使得在RPE-BL和BrM ICL之间产生空间(亚RPE-BL空间)，其随着BLinD和软玻璃疣的形成以及更大量的形成而增加。脂质沉积物(BLinD和软玻璃疣)的积聚使RPE从BrM ICL升高(图1中的右起第二个图)，并且如果升高(亚RPE-BL空间)得足够多，RPE-BL可以从BrM ICL脱离。例如，由于形成直径约350微米或更大的软玻璃疣，可发生玻璃疣样色素上皮脱离(PED)。随着玻璃疣的长大，RPE细胞越来越多地远离脉络膜毛细血管中的营养物和氧气。玻璃疣顶部的一些RPE细胞向前迁移到感觉神经视网膜中以寻找视网膜脉管系统，并且当RPE细胞死亡时RPE层破裂，导致RPE层萎缩。此外，由BLinD和软玻璃疣产生的脂质屏障阻断了脉络膜毛细血管和RPE细胞之间营养物(包括维生素A)进入和废物排出的交换，这导致RPE细胞萎缩并然后死亡。RPE细胞萎缩和死亡也导致光感受器的萎缩和死亡，因为RPE细胞不再能够将营养物传递给光感受器。此外，BrM上的BLinD和亚RPE-BL空间中的软玻璃疣是富含脂质的来源，其可以被氧化以形成高度抗炎的，并因此促血管生成的氧化的脂质(例如氧化的磷脂)。由BLinD和软玻璃疣产生的生物力学脆弱的解理面很容易受到新生血管的分枝的影响，所述新血管从脉络膜发出，穿过BrM，并渗入1型新生血管形成(NV)中的亚RPE-BL空间并突破到2型NV中的视网膜下空间，如下所述。从1型和2型NV中的新生血管到亚RPE-BL空间的流体渗出进一步造成亚RPE-BL空间的体积和RPE从BrM的升高，并且从而可导致PED。Figure 1 illustrates the role of tissue layers involved in AMD pathology and lipid accumulation in AMD pathogenesis. BrM consists of three layers: the inner collagen layer (ICL), the elastic layer (EL) and the outer collagen layer (OCL). In healthy eyes, the RPE basal layer (RPE-BL) is attached to the ICL of BrM, and there is no space between the RPE-BL and the ICL (the sub-RPE-BL space is the "latent" space). Throughout adulthood, RPE cells secrete lipoprotein particles (circles in Figure 1) at a basal level, which are dispersed in the ICL and OCL of BrM (leftmost panel in Figure 1). As more lipoprotein particles are endocrine and accumulated over the years, they form pre-BLinD on the tightly packed ICL of BrM (second panel from left in Figure 1). The secretion and accumulation of more lipoprotein particles over the years leads to aggregation of lipoprotein particles to form BLinD (lamellar) and soft drusen (mass) on BrM ICLs (two middle panels in Figure 1). The formation of pre-BLinD resulted in the creation of spaces between RPE-BL and BrM ICLs (sub-RPE-BL spaces), which increased with the formation of BLinD and soft drusen and in greater amounts. The accumulation of lipid deposits (BLinD and soft drusen) elevates the RPE from the BrM ICL (second panel from the right in Figure 1), and if the elevation (sub-RPE-BL space) is sufficiently high, the RPE- BL can be detached from BrM ICL. For example, drusen-like pigmented epithelial detachment (PED) can occur due to the formation of soft drusen that are about 350 microns in diameter or larger. As the drusen grows, the RPE cells increasingly move away from nutrients and oxygen in the choriocapillaries. Some RPE cells on top of the drusen migrate forward into the sensory neural retina to find retinal vasculature, and the RPE layer ruptures when the RPE cells die, causing the RPE layer to atrophy. Furthermore, the lipid barrier created by BLinD and soft drusen blocks the exchange of nutrients (including vitamin A) in and waste out between choriocapillaries and RPE cells, which causes RPE cells to shrink and then die. RPE cell shrinkage and death also leads to photoreceptor shrinkage and death because RPE cells are no longer able to deliver nutrients to the photoreceptors. Furthermore, BLinD on BrM and soft drusen in the sub-RPE-BL space are lipid-rich sources that can be oxidized to form highly anti-inflammatory, and thus pro-angiogenic, oxidized lipids (e.g., oxidized phospholipids). The biomechanically fragile cleavage surfaces created by BLinD and soft drusen are susceptible to branching of neovascularization that emanates from the choroid, traverses BrM, and infiltrates in type 1 neovascularization (NV). sub-RPE-BL space and breakthrough into the subretinal space in type 2 NV, as described below. The extravasation of fluid from neovascularization in type 1 and 2 NV into the sub-RPE-BL space further contributes to an increase in the volume of the sub-RPE-BL space and the RPE from BrM, and thereby can lead to PED.
针对上述变化的慢性炎症反应包括补体介导的途径、通过循环巨噬细胞而浸润、以及炎性体和小胶质细胞的激活。补体级联的激活导致中心组分3(C3)的活化和末端途径的起始，其中组分5(C5)分解成C5a和C5b。末端途径导致膜攻击复合物(MAC)的组装，例如，在基底RPE膜、BrM或脉络膜内皮细胞膜中，通过C5b、C6、C7、C8和聚合的C9的逐步结合在膜的脂质双层中形成孔。MAC可导致RPE、BrM和/或脉络膜毛细血管内皮功能障碍和死亡，随后出现外层视网膜萎缩。此外，C5a引起促血管生成作用，并且与BrM的钙化和破裂相结合，可以造成NV(包括脉络膜NV(CNV))。Chronic inflammatory responses to these changes include complement-mediated pathways, infiltration by circulating macrophages, and activation of inflammasomes and microglia. Activation of the complement cascade leads to activation of central component 3 (C3) and initiation of the terminal pathway, with component 5 (C5) dissociating into C5a and C5b. The terminal pathway leads to the assembly of membrane attack complexes (MACs), e.g., in basal RPE membranes, BrM or choroidal endothelial cell membranes, in the lipid bilayer of the membrane through the stepwise incorporation of C5b, C6, C7, C8, and polymerized C9 form holes. MAC can lead to RPE, BrM, and/or choriocapillary endothelial dysfunction and death, followed by atrophy of the outer retina. In addition, C5a causes pro-angiogenic effects and, in combination with calcification and disruption of BrM, can cause NV (including choroidal NV (CNV)).
AMD的早期阶段(其为萎缩性AMD)的特征在于存在少量中等大小玻璃疣和色素异常(例如RPE的色素沉着过度或色素减退)。AMD的中期阶段(其为萎缩性AMD)的特征在于存在至少一种大的晶状体、多种中等大小玻璃疣、RPE的色素沉着过度或色素减退，以及不延伸至黄斑中央的地图样萎缩(GA)(非中央[或旁中央]GA)。GA代表着不存在连续的着色层并且至少一部分RPE细胞死亡。非中央GA不伤害中央凹，并且从而保留中心视力。然而，具有非中央GA的患者可能经历视觉障碍(例如旁中央暗点)，其可以损害在昏暗的光线下的视力、降低对比敏感度并损害阅读能力。亚RPE-BL玻璃疣使RPE从BrM升高，并从而可以通过干扰重叠的光感受器和减慢视杆细胞介导的暗适应引起轻度视力丧失(包括视物变形症(视觉缺陷，其中物体看起来是变形的))。The early stages of AMD, which are atrophic AMD, are characterized by the presence of a small number of medium-sized drusen and pigment abnormalities (eg, hyperpigmentation or hypopigmentation of RPE). Intermediate stages of AMD, which are atrophic AMD, are characterized by the presence of at least one large lens, multiple medium-sized drusen, hyperpigmentation or hypopigmentation of the RPE, and geographic atrophy (GA) that does not extend to the center of the macula ) (noncentral [or paracentral] GA). GA represents the absence of a continuous pigmented layer and at least a portion of the RPE cells died. Noncentral GA does not damage the fovea and thus preserves central vision. However, patients with noncentral GA may experience visual disturbances (eg, paracentral scotoma) that can impair vision in dim light, reduce contrast sensitivity, and impair reading ability. Sub-RPE-BL drusen elevates RPE from BrM and can thereby cause mild vision loss (including dystropia (visual deficits in which objects) by interfering with overlapping photoreceptors and slowing rod-mediated dark adaptation. It looks deformed )).
仍然是萎缩性AMD的AMD的晚期(后期)阶段的特征在于存在玻璃疣和延伸至黄斑中央的GA(中央GA)。中央GA包括黄斑萎缩。中央GA涉及中央凹，并因此导致中心视力和视敏度的显著丧失。视网膜萎缩下RPE，通过光感受器的死亡导致视力丧失。当玻璃疣变厚并且RPE远离脉络膜毛细血管时，RPE萎缩可由大量积累的玻璃疣和/或BLinD引起，所述大量积累的玻璃疣和/或BLinD导致重叠的RPE的死亡。玻璃疣可以包括羟基磷灰石形式的钙化，并且可以进展至完全钙化，在此阶段RPE细胞已经死亡。RPE-BL以定型的方式变厚，以形成基底层状沉积物(BLamD)；因此RPE细胞位于厚的BLamD层上。正常六边形RPE细胞之间的连接可能被扰动，并且各个RPE细胞可以聚拢、堆叠并向前迁移到感觉神经视网膜中，其中RPE细胞远离其在脉络膜毛细血管上的营养供应和氧气供应。一旦RPE细胞开始前移，则整个RPE层开始萎缩。Advanced (late) stages of AMD, which are still atrophic AMD, are characterized by the presence of drusen and GA extending to the center of the macula (central GA). Central GA includes macular atrophy. Central GA involves the fovea and thus results in a significant loss of central vision and visual acuity. RPE under retinal atrophy, leading to vision loss through photoreceptor death. When the drusen thickens and the RPE moves away from the choriocapillary, RPE atrophy can be caused by a massive accumulation of drusen and/or BLinD that leads to the death of the overlapping RPE. Drusen can include calcification in the form of hydroxyapatite and can progress to full calcification, at which stage the RPE cells have died. RPE-BL thickened in a definitive manner to form basal lamellar deposits (BLamD); thus RPE cells were located on the thick BLamD layer. Connections between normal hexagonal RPE cells can be perturbed, and individual RPE cells can aggregate, pack, and migrate forward into the sensory neural retina, where RPE cells move away from their nutrient and oxygen supply on the choriocapillaris. Once the RPE cells start to move forward, the entire RPE layer begins to shrink.
成为新生血管性AMD的晚期阶段的AMD的特征在于新生血管形成及其任何潜在的后遗症，包括渗漏(例如血浆)、血浆脂质和脂蛋白沉积、亚RPE-BL、视网膜下和视网膜内液、出血、纤维蛋白、纤维血管瘢痕和RPE脱离。在CNV中，新血管从脉络膜毛细血管层并通过BrM长出，这通过上述后遗症导致视力丧失。有三种类型的新生血管形成(NV)。1型NV发生在亚RPE-BL空间中，并且新血管从黄斑区域下的脉络膜发出。2型NV发生在RPE上方的视网膜下空间中，并且新血管从脉络膜发出并突破到视网膜下空间。在1型和2型NV中，新血管穿过BrM并且可以在由软玻璃疣和BLinD产生的促血管发生的解理面中分枝。3型NV(视网膜血管瘤增生)主要发生在视网膜以内(视网膜内)，但也可发生在视网膜下空间，并且可能与脉络膜循环吻合的新血管从视网膜发出。3型NV是最难诊断的NV亚型，并且在光感受器损伤方面具有最具破坏性的后果，但是3型NV对用抗VEGF剂治疗反应良好。新生血管性AMD患者也可以具有混合的NV亚型，包括1型加2型、1型加3型和2型加3型。新出现的新生血管性AMD患者中NV的不同亚型大致出现为：40％为1型、9％为2型、34％为3型和17％为混合型(对于混合型，80％为1型加2型、16％为1型加3型和4％为2型加3型)。另一种形式的NV是息肉样血管病变，其起源自脉络膜并且是亚洲人中最常见的NV形式，其眼睛通常几乎没有玻璃疣但可能具有BLinD。在NV的每个亚型中，RPE可以与BrM分离。例如，流体从新生血管渗漏到1型NV中的亚RPE-BL空间中可导致色素上皮脱离。由NV产生的新血管是脆弱的，导致黄斑下方的液体、血液和蛋白质渗漏。血液渗漏至视网膜下空间对光感受器特别有害，而视网膜内的液体意味着视力预后不良。新血管出血和渗漏，随后出现纤维化，如果不及时治疗可能会对视网膜造成不可逆的损伤并导致视力快速下降。Advanced stages of AMD that become neovascular AMD are characterized by neovascularization and any potential sequelae, including leakage (eg, plasma), plasma lipid and lipoprotein deposition, sub-RPE-BL, subretinal and intraretinal fluid , bleeding, fibrin, fibrovascular scarring, and RPE detachment. In CNV, new blood vessels grow from the choriocapillary layer and through BrM, which leads to vision loss through the aforementioned sequelae. There are three types of neovascularization (NV). Type 1 NV occurs in the sub-RPE-BL space and new blood vessels emanate from the choroid below the macular area. Type 2 NV occurs in the subretinal space above the RPE, and new blood vessels emerge from the choroid and break through into the subretinal space. In both type 1 and type 2 NV, new blood vessels traverse BrM and can branch in pro-angiogenic cleavage planes produced by soft drusen and BLinD. Type 3 NV (retinal hemangioma hyperplasia) occurs primarily within the retina (intraretinal), but can also occur in the subretinal space, and new blood vessels that may be anastomosed to the choroidal circulation emanate from the retina. Type 3 NV is the most difficult to diagnose NV subtype and has the most devastating consequences in terms of photoreceptor damage, but type 3 NV responds well to treatment with anti-VEGF agents. Patients with neovascular AMD can also have mixed NV subtypes, including type 1 plus type 2, type 1 plus type 3, and type 2 plus type 3. The different subtypes of NV in newly emerging neovascular AMD patients were roughly as follows: 40% were type 1, 9% were type 2, 34% were type 3, and 17% were mixed (for mixed, 80% were type 1). Type 2 plus Type 2, 16% Type 1 plus Type 3 and 4% Type 2 plus Type 3). Another form of NV is polypoid vasculopathy, which originates from the choroid and is the most common form of NV in Asians, whose eyes are often virtually free of drusen but may have BLinD. In each subtype of NV, RPE can be separated from BrM. For example, leakage of fluid from neovascularization into the sub-RPE-BL space in type 1 NV can lead to detachment of the pigment epithelium. The new blood vessels created by NV are fragile, causing leakage of fluid, blood, and proteins beneath the macula. Leakage of blood into the subretinal space is particularly harmful to photoreceptors, and fluid within the retina means poor vision outcomes. Bleeding and leakage of new blood vessels, followed by fibrosis, can cause irreversible damage to the retina and rapid vision loss if left untreated.
修饰的脂质(包括过氧化脂质)，可以是强烈促炎的，并因此可以是促血管生成的。因此，脂质的修饰(包括氧化)可以是导致NV(包括1型NV)发展的重要步骤。例如，修饰的脂质，亚油酸氢过氧化物和7-酮胆固醇，可以存在于BrM中和BrM上并且可以刺激NV。NV可被视为炎症后的伤口愈合过程。Modified lipids, including lipid peroxides, can be strongly pro-inflammatory and thus can be pro-angiogenic. Thus, modification of lipids, including oxidation, can be an important step leading to the development of NV, including type 1 NV. For example, modified lipids, linoleic acid hydroperoxide and 7-ketocholesterol, can be present in and on BrM and can stimulate NV. NV can be viewed as a post-inflammatory wound healing process.
患有AMD的患者的两只眼，无论是萎缩性的还是新生血管性的，通常都处于患病状态。然而，其中一只眼睛通常比另一只眼睛处于更重的疾病状态。Both eyes of patients with AMD, whether atrophic or neovascular, are usually diseased. However, one eye is usually in a more severe disease state than the other eye.
关于AMD的不同阶段的描述，参见例如R.Jager et al.,N.Engl.J.Med.,358:2606-2617(2008)。年龄相关性眼病研究(AREDS)研究小组还为AMD开发了眼底照相术严重程度量表。例如，参见M.Davis et al.,Arch.Ophthalmol.,123:1484-1498(2005)。For a description of the different stages of AMD, see, eg, R. Jager et al., N. Engl. J. Med., 358:2606-2617 (2008). The Age-Related Eye Disease Study (AREDS) research group also developed the Fundus Photography Severity Scale for AMD. See, eg, M. Davis et al., Arch. Ophthalmol., 123:1484-1498 (2005).
关于AMD的发病机理和病理生理学的讨论，参见例如C.A.Curcio et al.,The oilspill in ageing Bruch membrane,Br.J.Ophthalmol.,95(12):1638-1645(2011)；J.W.Miller,Age-Related Macular Degeneration Revisited-Piecing the Puzzle,Am.J.Ophthalmol.,155(1):1-35(2013)；R.Spaide et al.,Choroidalneovascularization in age-related macular degeneration-what is the cause？,Retina,23:595-614(2003)；以及S.Bressler et al.,Age-Related MacularDegeneration:Non-neovascular Early AMD,Intermediate AMD,and GeographicAtrophy,in Retina,S.Ryan et al.,Eds.,pp.1150-1182,Elsevier(London 2013)。For a discussion of the pathogenesis and pathophysiology of AMD, see, eg, C.A. Curcio et al., The oilspill in ageing Bruch membrane, Br. J. Ophthalmol., 95(12):1638-1645 (2011); J.W. Miller, Age- Related Macular Degeneration Revisited-Piecing the Puzzle, Am. J. Ophthalmol., 155(1):1-35 (2013); R. Spaide et al., Choroidalneovascularization in age-related macular degeneration-what is the cause? , Retina, 23:595-614 (2003); and S. Bressler et al., Age-Related MacularDegeneration: Non-neovascular Early AMD, Intermediate AMD, and Geographic Atrophy, in Retina, S. Ryan et al., Eds., pp. 1150-1182, Elsevier (London 2013).
III.载脂蛋白模拟物III.Apolipoprotein Mimics
如上所述，年龄相关性黄斑变性(AMD)是具有多种潜在因素的疾病或病症。AMD的三个主要因素是在视网膜、视网膜下空间、亚RPE-BL空间和BrM中形成富含脂质的沉积物、炎症和新生血管形成。含脂沉积物的形成是导致后遗症的最初主要因素之一，所述后遗症例如慢性炎症、视网膜的非中央和/或中央地图样萎缩(GA)、新生血管形成(包括CNV)以及最终中心视力丧失或形成法定盲。脂质清除载脂蛋白模拟物可用于治疗AMD及其并发症，所述模拟物还具有其他有益特性，例如抗炎、抗氧化和抗血管生成特性。As mentioned above, age-related macular degeneration (AMD) is a disease or disorder with multiple underlying factors. The three major contributors to AMD are the formation of lipid-rich deposits, inflammation, and neovascularization in the retina, subretinal space, sub-RPE-BL space, and BrM. The formation of lipid-containing deposits is one of the first major contributors to sequelae such as chronic inflammation, non-central and/or central geographic atrophy (GA) of the retina, neovascularization (including CNV), and ultimately loss of central vision or form legal blindness. Lipid-scavenging apolipoprotein mimetics are useful in the treatment of AMD and its complications, which also have other beneficial properties, such as anti-inflammatory, antioxidant, and antiangiogenic properties.
载脂蛋白肽模拟物可以有效地减少眼中富含脂质的沉积物的积累。载脂蛋白(apo)模拟物可以调节(例如，抑制)脂蛋白(例如，VLDL)的产生、调节(例如，抑制)血浆脂质(例如，胆固醇)和脂蛋白(例如，VLDL)的细胞摄取、介导清理或清除脂质(例如，胆固醇和氧化的脂质，例如羟固醇)和脂蛋白(例如，VLDL)及其残余物(例如，低密度脂蛋白[LDL]和乳糜微粒残余物)，并抑制含脂质病变的形成。例如，apoE模拟物增加脂质(例如胆固醇)流出、介导脂质(例如胆固醇)和脂蛋白(例如VLDL和乳糜微粒)的清理、降低胆固醇和甘油三酯水平、减少含脂质病变的形成、以及具有抗氧化和抗炎特性。作为另一个例子，apoA-I模拟物促进脂质(例如胆固醇)流出、减少含脂质病变(在眼睛和动脉内膜中)的形成、并表现出抗氧化和抗炎特性。作为另一个实例，apoA-V模拟物降低VLDL-甘油三酯(TG)产生并刺激脂蛋白脂酶介导的VLDL-TG脂解。作为另外的实例，apoC-II模拟物增加脂质(例如，胆固醇)流出并激活脂蛋白脂酶介导的脂蛋白脂解。增加的脂蛋白脂酶介导的脂蛋白脂解的有益效果可以是，例如，降低膳食来源的脂质的组织可用性，这可能影响分泌到BrM、亚RPE-BL空间和视网膜下空间中的源自RPE的脂蛋白的上游来源。Apolipoprotein peptide mimetics can effectively reduce the accumulation of lipid-rich deposits in the eye. Apolipoprotein (apo) mimetics can modulate (eg, inhibit) production of lipoproteins (eg, VLDL), modulate (eg, inhibit) cellular uptake of plasma lipids (eg, cholesterol) and lipoproteins (eg, VLDL) , mediates clearance or clearance of lipids (eg, cholesterol and oxidized lipids such as oxysterols) and lipoproteins (eg, VLDL) and their remnants (eg, low density lipoprotein [LDL] and chylomicron residues) ), and inhibited the formation of lipid-containing lesions. For example, apoE mimetics increase lipid (eg, cholesterol) efflux, mediate clearance of lipids (eg, cholesterol) and lipoproteins (eg, VLDL and chylomicrons), lower cholesterol and triglyceride levels, and reduce the formation of lipid-containing lesions , as well as having antioxidant and anti-inflammatory properties. As another example, apoA-I mimetics promote lipid (eg, cholesterol) efflux, reduce the formation of lipid-containing lesions (in the eye and arterial intima), and exhibit antioxidant and anti-inflammatory properties. As another example, apoA-V mimetics reduce VLDL-triglyceride (TG) production and stimulate lipoprotein lipase-mediated lipolysis of VLDL-TG. As an additional example, apoC-II mimetics increase lipid (eg, cholesterol) efflux and activate lipoprotein lipase-mediated lipolysis of lipoproteins. Beneficial effects of increased lipoprotein lipase-mediated lipolysis of lipoproteins may be, for example, reduced tissue availability of dietary-derived lipids, which may affect sources secreted into BrM, the sub-RPE-BL space, and the subretinal space. Upstream source of lipoproteins from RPE.
作为说明性实例，apoA-I模拟物(例如本文所述的那些)(例如，L-4F和D-4F)可以溶解、动员和去除眼中积累的细胞外和潜在细胞内脂质沉积物。例如，L-4F和D-4F可能能够通过形成前βHDL颗粒通过LDL-受体去除细胞内脂质。BrM上的脂质沉积物形成脂质壁，其充当RPE和脉络膜毛细血管之间的扩散屏障，促进基底线性沉积物(BLinD)和软玻璃疣的形成，并且牵连到局部炎症和氧化应激。As an illustrative example, apoA-I mimetics such as those described herein (eg, L-4F and D-4F) can solubilize, mobilize, and remove accumulated extracellular and potentially intracellular lipid deposits in the eye. For example, L-4F and D-4F may be able to remove intracellular lipids through the LDL-receptor by forming pre-βHDL particles. Lipid deposits on BrM form lipid walls that act as a diffusion barrier between the RPE and choriocapillaries, promote the formation of basal linear deposits (BLinD) and soft drusen, and are implicated in local inflammation and oxidative stress.
ApoA-I模拟物(例如，L-4F)可以清理BrM中的脂质沉积物，从而将BrM结构重塑为正常或更健康的状态并恢复BrM功能，包括降低水力阻率(hydraulic resistivity)和增加代谢物和微量营养物在脉络膜毛细血管和RPE之间的交换，来改善RPE的健康状况。此外，apoA-I模拟物(例如L-4F)可以促进脂质、脂蛋白和脂蛋白组分通过BrM清理到脉络膜毛细血管和全身循环中，并最终导致到肝脏进行其代谢并排泄到胆汁中。此外，apoA-I模拟物(例如，L-4F)可以通过例如从BrM、BLinD和软玻璃疣中清理脂质沉积物来减少局部炎症和氧化应激。此外，apoA-I模拟物(例如，L-4F)可以通过例如结合接种分子来保护磷脂免于氧化，所述接种分子为形成促炎的氧化的磷脂所需的，所述氧化的磷脂例如Ox-PAPC(PAPC是L-α-1-棕榈酰-2-花生四烯酰-sn-甘油-3-磷酸胆碱)、POVPC(1-棕榈酰-2-[5-氧化戊酰]-sn-甘油-3-磷酸胆碱)、PGPC(1-棕榈酰基-2-戊二酰基-sn-甘油-3-磷酸胆碱)和PEIPC(1-棕榈酰-2-[5,6-环氧异丙烷E2]-sn-甘油-3-磷酸胆碱)。ApoA-I模拟物(例如，L-4F)也可以对促炎的氧化的脂质具有高亲和力并介导它们的去除，这增加了模拟物的高抗炎潜力。大多数AMD相关的脂质沉积物是细胞外的，并且适用于清理脂质的apoA-I模拟物。因此，apoA-I模拟物(例如，L-4F)可以用于AMD的任何阶段(包括从早期到晚期阶段的AMD)，以治疗AMD的重要上游因子-脂质沉积物(如BrM上的BlinD和亚RPE-BL空间中的软玻璃疣)的积累-并且通过去除这些沉积物来抑制或减少AMD的下游因子(例如局部炎症和氧化应激)。ApoA-I mimetics (eg, L-4F) can clean up lipid deposits in BrM, thereby remodeling BrM structure to a normal or healthier state and restoring BrM function, including reducing hydraulic resistivity and Improves RPE health by increasing the exchange of metabolites and micronutrients between choriocapillaries and RPE. In addition, apoA-I mimetics such as L-4F can promote the clearance of lipids, lipoproteins and lipoprotein components by BrM into the choriocapillary and systemic circulation, and ultimately lead to their metabolism in the liver and excretion into bile . In addition, apoA-I mimetics (eg, L-4F) can reduce local inflammation and oxidative stress by, for example, clearing lipid deposits from BrM, BLinD, and soft drusen. In addition, apoA-I mimetics (eg, L-4F) can protect phospholipids from oxidation by, for example, binding to seeding molecules required for the formation of pro-inflammatory oxidized phospholipids such as Ox -PAPC (PAPC is L-α-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), POVPC (1-palmitoyl-2-[5-oxyvaleryl]-sn -Glycerol-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine) and PEIPC (1-palmitoyl-2-[5,6-epoxy] isopropaneE2 ]-sn-glycero-3-phosphocholine). ApoA-I mimetics (eg, L-4F) can also have high affinity for pro-inflammatory oxidized lipids and mediate their removal, adding to the high anti-inflammatory potential of the mimetics. Most AMD-associated lipid deposits are extracellular and apoA-I mimetics suitable for clearing lipids. Therefore, apoA-I mimetics (eg, L-4F) can be used in any stage of AMD (including from early to advanced stages) to treat an important upstream factor of AMD - lipid deposits (such as BlinD on BrM) and soft drusen in the sub-RPE-BL space - and by removing these deposits inhibits or reduces the downstream factors of AMD (such as local inflammation and oxidative stress).
在一些实施方案中，载脂蛋白模拟物包括载脂蛋白的两亲性螺旋结构域，其与脂质结合/缔合并且能够去除/清理脂质。在某些实施方案中，载脂蛋白的脂质结合的两亲性螺旋结构域包括：In some embodiments, the apolipoprotein mimetic comprises the amphiphilic helical domain of apolipoprotein, which binds/associates with lipids and is capable of removing/clearing lipids. In certain embodiments, the lipid-binding amphipathic helical domain of an apolipoprotein comprises:
1)野生型(wt)人apoA-I的约氨基酸(aa)209至约aa 219的序列、约aa 220至约aa241的序列、和约aa 209至约aa 241的序列；1) a sequence of about amino acids (aa) 209 to about aa 219, a sequence of about aa 220 to about aa241, and a sequence of about aa 209 to about aa 241 of wild-type (wt) human apoA-I;
2)wt人apoA-II的约aa 39或40至约aa 50的序列、约aa 51至约aa 71或77的序列、约aa 39或40至约aa 71的序列、和约aa 39或40至约aa 77的序列；2) the sequence of about aa 39 or 40 to about aa 50, the sequence of about aa 51 to about aa 71 or 77, the sequence of about aa 39 or 40 to about aa 71, and the sequence of about aa 39 or 40 to about aa 71 of wt human apoA-II The sequence of about aa 77;
3)wt人apoC-I的约aa 7至约aa 32的序列、约aa 33至约aa 53的序列、和约aa 7至约aa 53的序列；3) a sequence of about aa 7 to about aa 32, a sequence of about aa 33 to about aa 53, and a sequence of about aa 7 to about aa 53 of wt human apoC-1;
4)wt人apoC-II的约aa43至约aa55的序列；4) the sequence of about aa43 to about aa55 of wt human apoC-II;
5)wt人apoC-III的约aa40至约aa67的序列；和5) the sequence of about aa40 to about aa67 of wt human apoC-III; and
6)wt人apoE的约aa203至约aa266的序列。6) The sequence of about aa203 to about aa266 of wt human apoE.
在进一步的实施方案中，载脂蛋白模拟物包括多肽(包括融合蛋白和嵌合体)，其包含载脂蛋白或其变体的这种结合脂质的两亲性螺旋结构域。In further embodiments, apolipoprotein mimetics include polypeptides (including fusion proteins and chimeras) comprising such lipid-binding amphipathic helical domains of apolipoproteins or variants thereof.
apoA-I模拟物的非限制性实例包括2F、3F、3F-1、3F-2、3F-14、4F(例如，L-4F和D-4F)、4F2、5A、5F、6F、7F、18F、37pA、4F-P-4F、4F-IHS-4F、ELK-2K2A2E(或ELK-2A2K2E)、FAMP(福冈apoA-I模拟肽)、FREL、KRES、apoJ(113-122)、Non-limiting examples of apoA-1 mimetics include 2F, 3F, 3F-1, 3F-2, 3F-14, 4F (eg, L-4F and D-4F), 4F2, 5A, 5F, 6F, 7F, 18F, 37pA, 4F-P-4F, 4F-IHS-4F, ELK-2K2A2E (or ELK-2A2K2E), FAMP (Fukuoka apoA-I mimetic peptide), FREL, KRES, apoJ(113-122),
CGVLESFKASFLSALEEWTKKLQ-NH2(单体、二聚体和三聚体)(SEQ.ID.NO.1)，CGVLESFKASFLSALEEWTKKLQ-NH2 (monomer, dimer and trimer) (SEQ. ID. NO. 1),
DWLKAFYDKVAEKLKE(单体、二聚体和三聚体)(SEQ.ID.NO.2)，DWLKAFYDKVAEKLKE (monomer, dimer and trimer) (SEQ.ID.NO.2),
DWFKAFYDKVAEKFKE(单体、二聚体和三聚体)(SEQ.ID.NO.3)，DWFKAFYDKVAEKFKE (monomer, dimer and trimer) (SEQ.ID.NO.3),
DWFKAFYDKVAEKFKEAF(4F)(单体、二聚体和三聚体)(SEQ.ID.NO.4)，DWFKAFYDKVAEKFKEAF(4F) (monomer, dimer and trimer) (SEQ. ID. NO. 4),
DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF(SEQ.ID.NO.5)，DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF(SEQ.ID.NO.6)，DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF(SEQ.ID.NO.7)，DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF(SEQ.ID.NO.8)，DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL(SEQ.ID.NO.9)，DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF(4F-P-4F)(SEQ.ID.NO.10)，并且DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF(SEQ.ID.NO.5)，DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF(SEQ.ID.NO.6)，DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF(SEQ.ID.NO.7)，DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF(SEQ.ID.NO.8)，DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL(SEQ.ID. NO.9), DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF(4F-P-4F) (SEQ.ID.NO.10), and
相应的apoA-I模拟物具有一个或多个或所有D-氨基酸(例如，具有所有D-氨基酸的D-4F)和/或相反顺序的氨基酸序列(例如，Rev-L-4F和REV-D-4F)。Corresponding apoA-I mimetics have one or more or all D-amino acids (eg, D-4F with all D-amino acids) and/or amino acid sequences in reverse order (eg, Rev-L-4F and REV-D -4F).
apoE模拟物的非限制性实例包括Ac-hE18A-NH2(AEM-28)(双结构域[apoE和apoA-I]模拟物)、Ac-[R]hE18A-NH2、AEM-28-14、mR18L、ATI-5261、COG-1410、apoE(130-149)单体和二聚体(包括N-乙酰化二聚体)、和apoE(141-155)单体和二聚体(包括N-乙酰化二聚体)。apoC-II模拟物的实例包括但不限于C-II-a。Non-limiting examples of apoE mimetics include Ac-hE18A-NH2 (AEM-28) (two-domain [apoE and apoA-I] mimetic), Ac-[R]hE18A-NH2 , AEM-28-14 , mR18L, ATI-5261, COG-1410, apoE(130-149) monomers and dimers (including N-acetylated dimers), and apoE(141-155) monomers and dimers (including N-acetylated dimers) -acetylated dimer). Examples of apoC-II mimetics include, but are not limited to, C-II-a.
本公开内容包括以下载脂蛋白肽模拟物：The present disclosure includes the following download lipoprotein peptidomimetics:
1)apo模拟物，其中所有氨基酸残基都具有L型立体化学；1) an apo mimetic in which all amino acid residues have L-shaped stereochemistry;
2)apo模拟物，其中一个或多个或所有氨基酸残基具有D型立体化学；2) an apo mimetic, wherein one or more or all amino acid residues have a D-shaped stereochemistry;
3)apo模拟物，其具有相反顺序的氨基酸序列并且其中所有氨基酸残基都具有L型立体化学；3) an apo mimetic having an amino acid sequence in reverse order and wherein all amino acid residues have an L-shaped stereochemistry;
4)apo模拟物，其具有相反顺序的氨基酸序列并且其中一个或多个或所有氨基酸残基具有D型立体化学；和4) an apo mimetic having an amino acid sequence in reverse order and wherein one or more or all amino acid residues have a D-stereochemistry; and
5)apo模拟物的多聚体(包括二聚体和三聚体)，其中两个或更多个apo模拟物单元彼此直接或间接连接，例如通过含有一个或多个氨基酸残基的接头或间隔基团或具有多个(例如，两个、三个或更多)连接点的基团。5) Multimers (including dimers and trimers) of apo mimetics, in which two or more apo mimetic units are directly or indirectly linked to each other, for example by a linker containing one or more amino acid residues or A spacer group or a group having multiple (eg, two, three, or more) points of attachment.
本文所述的载脂蛋白模拟物可在N-末端和/或C-末端具有保护基团。在一些实施方案中，apo模拟物具有N-末端保护基团，所述N-末端保护基团是未取代的或取代的C2-C10酰基(例如乙酰基、丙酰基、丁酰基、戊酰基或己酰基)、未取代或取代的苯甲酰基、苄氧羰基、或一个或两个未取代或取代的C1-C20或C2-C20烷基(例如，一个或两个甲基、乙基、丙基、丁基、戊基或己基)。此外，apo模拟物可以在C-末端具有-CO2H以外的官能团(例如C(O)NH2或-C(O)NR1R2酰胺基，其中R1和R2独立地是氢、烷基、环烷基、杂环基、芳基或杂芳基，或R1和R2以及它们所连接的氮原子形成杂环或杂芳基环)。C末端的酰胺基团可以被认为是C末端的保护基团。因此，本发明包括具有例如以下的apo模拟物：既具有N-末端的乙酰基也具有C-末端的-C(O)NH2基团。The apolipoprotein mimetics described herein may have protecting groups at the N-terminus and/or the C-terminus. In some embodiments, the apo mimetic has an N-terminal protecting group that is an unsubstituted or substituted C2-C10 acyl group (eg, acetyl, propionyl, butyryl, pentanoyl acyl or hexanoyl), unsubstituted or substituted benzoyl, benzyloxycarbonyl, or one or two unsubstituted or substitutedC1 -C20 or C2-C20 alkyl (for example, one or two methyl group, ethyl, propyl, butyl, pentyl or hexyl). Additionally, apo mimetics can have functional groups other than-CO2H at the C- terminus (eg, C(O)NH2 or-C (O)NR1R2 amide groups, where R1 and R2 are independentlyhydrogen , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R1 and R2 and the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring). The C-terminal amide group can be considered as the C-terminal protecting group. Thus, the present invention includes apo mimetics having, for example, both an N-terminal acetyl group and a C-terminal -C(O)NH2 group.
本公开内容还涵盖本文所述的载脂蛋白模拟物的变体，其中所述载脂蛋白模拟物的变体可包含一个或多个氨基酸添加/插入、缺失和/或取代。换句话说，本公开内容包括以下变体：其中本文所述的任何apo模拟物中添加或插入一个或多个天然和/或非天然氨基酸、从本文所述的任何apo模拟物缺失一个或多个氨基酸残基、或者本文所述的任何apo模拟物的一种或多种氨基酸残基被一个或多个天然和/或非天然氨基酸取代(保守的和/或非保守的取代)，或以上的任何组合或全部。非天然氨基酸可以具有与对应的天然氨基酸相同的化学结构但具有D型立体化学，或者它可以具有不同的化学结构和D型或L型立体化学。可以利用非天然氨基酸例如促进α-螺旋的形成和/或增加肽的稳定性(例如，抗蛋白水解降解)。例如，D-4F对肠肽酶具有抗性，并因此适合口服使用。非天然氨基酸的实例包括但不限于脯氨酸类似物(例如，CMePro)、苯丙氨酸类似物[例如Bip、Bip2EtMeO、Nal(1)、Nal(2)、2FPhe、Tmp、Tic、CMePhe和CMe2FPhe]、酪氨酸类似物(例如，Dmt和CMeTyr)、谷氨酰胺类似物(例如，瓜氨酸[Cit])、赖氨酸类似物(例如，高赖氨酸、鸟氨酸[Orn]和CMeLys)、精氨酸类似物(例如，高精氨酸[Har])、C-α-二取代氨基酸(例如，Aib、Ac4c、Ac5c，Ac6c和Deg)和US2015/031630和WO2014/081872中公开的其他非天然氨基酸。一个或多个肽模拟部分也可以用于添加/插入和/或取代。变体可以在N-末端和/或C-末端具有保护基团，例如N-末端的酰基(例如乙酰基)和/或在C-末端的酰胺基团[例如-C(O)NH2]。在一些实施方案中，apo模拟物的变体的生物学或药理学活性相对于具有本来的氨基酸序列的apo模拟物的生物学或药理学活性增强或与其基本上相似(例如，相对的减弱不超过约10％、20％或30％)。作为非限制性实例，本发明包括称为4F2的4F的变体，其具有序列DWFKAFYDKV-Aib-EKFKE-Aib-F(SEQ.ID.NO.11)，其中A11和A17被α-氨基异丁酸(Aib)取代。在某些实施方案中，4F2具有结构Ac-DWFKAFYDKV-Aib-EKFKE-Aib-F-NH2(SEQ.ID.NO.12)，其中所有氨基酸残基具有L-型(L-4F2)，或一个或多个或全部氨基酸残基具有D-型。The present disclosure also encompasses variants of the apolipoprotein mimetics described herein, wherein the variants of the apolipoprotein mimetics may comprise one or more amino acid additions/insertions, deletions and/or substitutions. In other words, the present disclosure includes variants wherein one or more natural and/or unnatural amino acids are added or inserted into any of the apo mimetics described herein, one or more amino acids are deleted from any of the apo mimetics described herein amino acid residues, or one or more amino acid residues of any of the apo mimetics described herein, are substituted with one or more natural and/or non-natural amino acids (conservative and/or non-conservative substitutions), or more any combination or all of them. An unnatural amino acid may have the same chemical structure as the corresponding natural amino acid but with D-stereochemistry, or it may have a different chemical structure and D- or L-stereochemistry. Unnatural amino acids can be utilized, for example, to promote alpha-helix formation and/or to increase peptide stability (eg, resistance to proteolytic degradation). For example, D-4F is resistant to intestinal peptidase and is therefore suitable for oral use. Examples of unnatural amino acids include, but are not limited to, proline analogs (eg, CMePro), phenylalanine analogs (eg, Bip, Bip, EtMeO, Nal(1), Nal(2), 2FPhe, Tmp, Tic, CMePhe, and CMe2FPhe], tyrosine analogs (eg, Dmt and CMeTyr), glutamine analogs (eg, citrulline [Cit]), lysine analogs (eg, homolysine, ornithine [Orn] ] and CMeLys), arginine analogs (eg, homoarginine [Har]), C-α-disubstituted amino acids (eg, Aib, Ac4c, Ac5c, Ac6c and Deg) and US2015/031630 and WO2014/081872 Other unnatural amino acids disclosed in. One or more peptidomimetic moieties can also be used for addition/insertion and/or substitution. Variants may have protecting groups at the N-terminus and/or C-terminus, such as an acyl group at the N-terminus (eg acetyl) and/or an amide group at the C-terminus [eg -C(O)NH2 ] . In some embodiments, the variant of the apo mimetic has enhanced or substantially similar biological or pharmacological activity relative to the biological or pharmacological activity of the apo mimetic having the native amino acid sequence (eg, the relative reduction is not more than about 10%, 20% or 30%). As a non-limiting example, the present invention includes a variant of 4F designated 4F2, which has the sequence DWFKAFYDKV-Aib-EKFKE-Aib-F (SEQ. ID. NO. 11), wherein A11 and A17 are alpha-amino groups Isobutyric acid (Aib) substitution. In certain embodiments, 4F2 has the structure Ac-DWFKAFYDKV-Aib-EKFKE-Aib-F-NH2 (SEQ. ID. NO. 12), wherein all amino acid residues have the L-form (L-4F2), or One or more or all amino acid residues have the D-form.
本文所述的载脂蛋白模拟物的变体还包括apo模拟物的类似物和衍生物，其具有替代的或额外的选自以下的另一种修饰：氨基酸添加/插入、缺失和/或取代。作为实例，apo模拟物的变体包括融合蛋白和嵌合体，所述融合蛋白和嵌合体包含载脂蛋白的结合脂质的两亲性螺旋结构域或其变体(例如，4F)，所述结构域或其变体直接或间接(例如，通过接头)连接至异源肽。异源肽可以赋予有益的性质，例如增加的半衰期。例如，异源肽可以是免疫球蛋白的Fc结构域(例如IgG，如IgG1)，或免疫球蛋白的修饰的Fc结构域，其具有例如一个或多个改变(例如减少)Fc结构域的效应子功能的氨基酸取代或突变。可以修饰Fc结构域以使其具有降低的能力，所述能力例如结合Fc受体、激活补体系统、刺激吞噬细胞的攻击、或干扰视网膜细胞的生理代谢或功能，或其任何组合或全部。在融合蛋白或嵌合体中包含Fc结构域可以允许融合蛋白或嵌合体的二聚化(例如，通过在两个Fc结构域之间形成分子间二硫键)，这可以增强融合蛋白或嵌合体的生物学或药理学活性。可选地，增强寿命的异源肽可以是例如衍生自人绒毛膜促性腺激素的β链的羧基末端肽(CTP)，例如WO 2014/159813中公开的CTP-001、CTP-002或CTP-003。作为另一个实例，apo模拟物(例如apoA-I模拟物(例如，L-4F)或apoE模拟物(例如，AEM-28-14))可以直接或间接(例如，通过接头)在N-末端、C-末端和/或一个或多个侧链连接至天然或合成聚合物(例如，聚乙二醇[PEG])。apo模拟物的PEG化(具有例如约2-20或2-10个PEG单元)可以增加蛋白酶抗性、稳定性和半衰期，减少聚集，增加溶解度并增强apo模拟物的活性。作为另一个实例，apo模拟物可以是糖基化的(包含碳水化合物或糖部分)，例如含有一个或多个唾液酸残基的apoC-III模拟物。作为又一个实例，apo模拟物可以是磷酸化的。作为另外的例子，apo模拟物可以与磷脂复合(例如，与DMPC[1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱]或POPC[1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱]复合的L-4F))。Variants of apolipoprotein mimetics described herein also include analogs and derivatives of apo mimetics, which have alternatively or additionally another modification selected from amino acid additions/insertions, deletions and/or substitutions . As examples, variants of apo mimetics include fusion proteins and chimeras comprising the lipid-binding amphipathic helical domain of apolipoprotein or variants thereof (eg, 4F) that The domain or variant thereof is linked directly or indirectly (eg, via a linker) to the heterologous peptide. Heterologous peptides can confer beneficial properties, such as increased half-life. For example, the heterologous peptide can be an Fc domain of an immunoglobulin (eg, IgG, such as IgGl), or a modified Fc domain of an immunoglobulin, which has, for example, one or more effects that alter (eg, reduce) the Fc domain Sub-function amino acid substitutions or mutations. An Fc domain can be modified to have a reduced ability, eg, to bind Fc receptors, activate the complement system, stimulate attack by phagocytes, or interfere with the physiological metabolism or function of retinal cells, or any combination or all thereof. Inclusion of an Fc domain in a fusion protein or chimera may allow dimerization of the fusion protein or chimera (eg, by forming an intermolecular disulfide bond between the two Fc domains), which may enhance the fusion protein or chimera biological or pharmacological activity. Alternatively, the lifespan-enhancing heterologous peptide may be, for example, a carboxy-terminal peptide (CTP) derived from the beta chain of human chorionic gonadotropin, such as CTP-001, CTP-002 or CTP- 003. As another example, an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) or an apoE mimetic (eg, AEM-28-14)) can be directly or indirectly (eg, via a linker) at the N-terminus , C-terminus, and/or one or more side chains attached to a natural or synthetic polymer (eg, polyethylene glycol [PEG]). PEGylation of apo mimetics (with, eg, about 2-20 or 2-10 PEG units) can increase protease resistance, stability and half-life, reduce aggregation, increase solubility and enhance the activity of apo mimetics. As another example, an apo mimetic can be glycosylated (comprising carbohydrate or sugar moieties), such as an apoC-III mimetic containing one or more sialic acid residues. As yet another example, an apo mimetic can be phosphorylated. As additional examples, apo mimetics can be complexed with phospholipids (eg, with DMPC [1,2-dimyristoyl-sn-glycero-3-phosphocholine] or POPC [1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine] complexed L-4F)).
除了使用载脂蛋白模拟物之外或作为其替代物，可以使用增加载脂蛋白(例如，apoE、apoA-I、apoA-V或apoC-II)水平(例如通过刺激其产生)的物质。例如，除了使用apoA-I模拟物之外或作为其替代，可以施用增加apoA-I水平的物质(例如，1,2-二肉豆蔻酰基-α-甘油-3-磷酸胆碱[DMPC])。In addition to or as an alternative to the use of apolipoprotein mimetics, substances that increase the levels of apolipoproteins (eg, apoE, apoA-I, apoA-V, or apoC-II) (eg, by stimulating their production) can be used. For example, in addition to or instead of using an apoA-I mimetic, a substance that increases apoA-I levels (eg, 1,2-dimyristoyl-alpha-glycero-3-phosphocholine [DMPC]) can be administered .
载脂蛋白肽模拟物或载脂蛋白模拟肽可根据本领域技术人员已知的方法制备。作为非限制性实例，可通过在合适的树脂支承上依次缩合受保护的氨基酸并除去保护基团，除去树脂支承，并通过本领域已知的方法纯化产物来制备apo模拟物及其盐。通过使用例如微波可以促进肽及其盐的固相合成，并且可以通过使用市售肽合成仪使肽及其盐的固相合成自动化。肽和其盐的固相合成描述于例如J.M.Palomo,RSCAdv.,4:32658-32672(2014)；M.Amblard et al., Biotechnol.,33(3):239-254(2006)；以及M.Stawikowski andG.B.Fields,Curr.Protoc.Protein Sci.,Unit 18.1:Introduction to PeptideSynthesis(2012)。适用于合成肽及其盐的保护基团描述于例如P.Wuts and T.Greene,Greene's Protective Groups in Organic Synthesis,4th Ed.,John Wiley and Sons(New York 2006)中。纯化肽及其盐的方法包括但不限于结晶、柱(例如，硅胶)色谱、高压液相色谱(包括反相HPLC)、疏水吸附色谱、硅胶吸附色谱、分配色谱、超临界流体色谱、反流分布法、离子交换色谱和使用碱性和酸性树脂的离子交换。Apolipoprotein peptidomimetics or apolipoprotein peptidomimetics can be prepared according to methods known to those skilled in the art. By way of non-limiting example, apo mimetics and salts thereof can be prepared by sequentially condensing protected amino acids on a suitable resin support and removing the protecting groups, removing the resin support, and purifying the product by methods known in the art. Solid-phase synthesis of peptides and their salts can be facilitated by using, for example, microwaves, and can be automated by using a commercially available peptide synthesizer. Solid-phase synthesis of peptides and their salts is described, for example, in JMPalomo, RSC Adv., 4:32658-32672 (2014); M. Amblard et al., Biotechnol., 33(3):239-254 (2006); and M. Stawikowski and G.B. Fields, Curr. Protoc. Protein Sci., Unit 18.1: Introduction to Peptide Synthesis (2012). Suitable protecting groups for the synthesis of peptides and their salts are described, for example, in P. Wuts and T. Greene, Greene's Protective Groups in Organic Synthesis, 4thEd ., John Wiley and Sons (New York 2006). Methods of purifying peptides and salts thereof include, but are not limited to, crystallization, column (eg, silica gel) chromatography, high pressure liquid chromatography (including reverse phase HPLC), hydrophobic adsorption chromatography, silica gel adsorption chromatography, partition chromatography, supercritical fluid chromatography, reflux Distribution methods, ion exchange chromatography, and ion exchange using basic and acidic resins.
IV.使用载脂蛋白模拟物治疗AMDIV.Treatment of AMD with Apolipoprotein Mimics
本公开的一些实施方案涉及治疗年龄相关性黄斑变性(AMD)的方法，其包括向需要治疗的对象施用治疗有效量的载脂蛋白(apo)模拟物。在一些实施方案中，所述apo模拟物以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量施用于眼局部、眼内、眼中或眼周，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量施用于眼局部、眼内、眼中或眼周。Some embodiments of the present disclosure relate to methods of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic. In some embodiments, the apo mimetic is administered topically, intraocularly, in the eye, or around the eye at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or at a dose of about 6 mg per injection. A total dose of about 0.5 or 1 mg to about 10 mg is administered topically, intraocularly, in or around the eye over a period of one month.
apo模拟物以基本上纯的形式使用。在某些实施方案中，apo模拟物具有至少约90％、95％、96％、97％、98％或99％(例如，至少约95％或98％)的纯度。可以纯化apo模拟物，即，基本上不含由其制备或分离产生的不期望的化学或生物化学组分，所述不期望的化学或生物化学组分不适合用于药物制剂，或者具有足够低的这种不期望的化学或生物化学组分的水平，以便在药物制剂中不会阻碍apo模拟物的使用。The apo mimetics are used in substantially pure form. In certain embodiments, the apo mimetic has a purity of at least about 90%, 95%, 96%, 97%, 98%, or 99% (eg, at least about 95% or 98%). The apo mimetic can be purified, i.e., substantially free of undesired chemical or biochemical components resulting from its preparation or isolation that are unsuitable for use in pharmaceutical formulations, or have sufficient Low levels of such undesired chemical or biochemical components so as not to hinder the use of apo mimetics in pharmaceutical formulations.
载脂蛋白模拟物的非限制性实例包括apoA-I模拟物和apoE模拟物，包括本文其他地方描述的那些。在一些实施方案中，所述apo模拟物包括apoE模拟物，或是apoE模拟物。在某些实施方案中，所述apoE模拟物包括AEM-28-14或其变体或盐，或是AEM-28-14或其变体或盐。Non-limiting examples of apolipoprotein mimetics include apoA-I mimetics and apoE mimetics, including those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or AEM-28-14 or a variant or salt thereof.
在进一步的实施方案中，所述apo模拟物包括apoA-I模拟物或是apoA-I模拟物，所述apoA-I模拟物是替代apoE模拟物(例如AEM-28-14)的或额外于apoE模拟物(例如AEM-28-14)的。在某些实施方案中，所述apoA-I模拟物包括4F或其变体或盐(例如乙酸盐)，或是4F或其变体或盐(例如乙酸盐)。在一些实施方案中，4F的所有氨基酸残基具有L型立体化学(L-4F)。在其他实施方案中，4F的一个或多个或全部氨基酸残基具有D型立体化学(例如，具有所有D型氨基酸的D-4F)。在其他实施方案中，apo模拟物具有相反顺序的4F氨基酸序列(例如，Rev-L-4F或Rev-D-4F)。apo模拟物可在N-末端和/或C-末端具有保护基团，例如N-末端的酰基(例如乙酰基)和/或C-末端的酰胺基团(例如-C(O)NH2)。在某些实施方案中，apo模拟物包括具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F，或者是具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F。当折叠成适当的二级结构时，L-4F是两亲性α-螺旋，其具有相反的极性和疏水面并且模拟apoA-I，所述apoA-I是HDL的主要载脂蛋白。In further embodiments, the apo mimetic comprises an apoA-I mimetic or an apoA-I mimetic that is in place of an apoE mimetic (eg, AEM-28-14) or in addition to of apoE mimetics (eg AEM-28-14). In certain embodiments, the apoA-I mimetic comprises 4F or a variant or salt thereof (eg, acetate), or 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues of 4F have L-shaped stereochemistry (L-4F). In other embodiments, one or more or all amino acid residues of 4F have D-form stereochemistry (eg, D-4F with all D-form amino acids). In other embodiments, the apo mimetic has the 4F amino acid sequence in reverse order (eg, Rev-L-4F or Rev-D-4F). The apo mimetic may have protecting groups at the N-terminus and/or the C-terminus, such as an N-terminal acyl group (eg, acetyl) and/or a C-terminal amide group (eg, -C(O)NH2 ) . In certain embodiments, the apo mimetic comprises L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13), or L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13 ) structure of L-4F. When folded into the appropriate secondary structure, L-4F is an amphiphilic alpha-helix with opposite polar and hydrophobic faces and mimics apoA-I, the major apolipoprotein of HDL.
apoA-I模拟物4F(包括L-4F和D-4F)具有抗血脂异常性质。例如，L-4F能够以比apoA-I本身更大的亲和力结合氧化的脂质和未氧化的脂质，并且例如在亚RPE-BL空间和布鲁赫膜(BrM)上减少脂质沉积物。L-4F是有效的脂质受体和清除剂，其从例如BrM和亚RPE-BL空间中去除细胞外脂质(和潜在的细胞内脂质)，所述脂质包括中性脂质、酯化胆固醇和磷脂，从而改善例如，BrM结构(例如，减小BrM厚度并使BrM的层排列正常化)和BrM功能(例如，降低BrM的水力阻率并增加RPE和脉络膜毛细血管之间的代谢物和微量营养物交换，包括促进携带这些营养物的多分子复合物)。在例如BrM处的细胞外年龄相关脂质沉积物形成疏水扩散屏障，所述屏障在例如RPE和视网膜中引起氧化应激和炎症，并且通过L-4F去除这种脂质沉积物减少了这种氧化应激和炎症。The apoA-I mimetic 4F, including L-4F and D-4F, has anti-dyslipidemic properties. For example, L-4F is able to bind oxidized and unoxidized lipids with greater affinity than apoA-I itself, and reduce lipid deposits, for example, in the sub-RPE-BL space and Bruch's membrane (BrM). L-4F is a potent lipid receptor and scavenger that removes extracellular lipids (and potentially intracellular lipids), including neutral lipids, from spaces such as BrM and sub-RPE-BL. Esterifies cholesterol and phospholipids, thereby improving, for example, BrM structure (eg, reducing BrM thickness and normalizing the layer alignment of BrM) and BrM function (eg, reducing BrM hydroresistivity and increasing the friction between RPE and choriocapillaris). Metabolite and micronutrient exchange, including the promotion of multimolecular complexes that carry these nutrients). Extracellular age-related lipid deposits at e.g. BrM form a hydrophobic diffusion barrier that causes oxidative stress and inflammation in e.g. RPE and retina, and removal of such lipid deposits by L-4F reduces this Oxidative stress and inflammation.
L-4F具有额外的有益特性。例如，L-4F表现出强烈的抗炎特性，部分原因在于其以高亲和力结合促炎的氧化的脂质(例如氧化的磷脂)和脂肪酸氢过氧化物及其对这种氧化的脂质的清理。L-4F还可以增强HDL-胆固醇保护LDL-胆固醇免受氧化的能力，从而减少促炎的氧化的脂质的形成。此外，L-4F抑制补体活化并降低补体因子D和膜攻击复合物的水平，这可能是其抗氧化和抗炎特性的其他原因，并且可以由其抑制脂质沉积的下游效应引起。此外，L-4F具有抗血管生成特性。亚RPE-BL空间中的细胞外富含脂质的沉积物提供了生物力学上脆弱的促炎环境，新血管可以进入所述环境中并增殖而不受RPE基底层与BrM其余部分连接的阻碍。通过L-4F去除这种脂质沉积物可以闭合或基本上减少这种促血管生成的解理面。L-4F has additional beneficial properties. For example, L-4F exhibits strong anti-inflammatory properties in part because it binds with high affinity to pro-inflammatory oxidized lipids (eg, oxidized phospholipids) and fatty acid hydroperoxides and their effects on such oxidized lipids clean up. L-4F also enhances the ability of HDL-cholesterol to protect LDL-cholesterol from oxidation, thereby reducing the formation of proinflammatory oxidized lipids. Furthermore, L-4F inhibits complement activation and reduces levels of complement factor D and membrane attack complexes, which may account for other reasons for its antioxidant and anti-inflammatory properties, and may result from its downstream effects of inhibiting lipid deposition. In addition, L-4F has anti-angiogenic properties. Extracellular lipid-rich deposits in the sub-RPE-BL space provide a biomechanically fragile pro-inflammatory environment into which new blood vessels can enter and proliferate without being hindered by the connection of the RPE basal layer to the rest of the BrM . Removal of this lipid deposit by L-4F can close or substantially reduce this pro-angiogenic cleavage plane.
在对人类早期AMD的猕猴模型进行的研究中并且如下所述，L-4F显示出以下的有效能力：清除中性脂质和酯化的胆固醇、使BrM恢复活力/正常化以及减少脂质沉积的下游效应(例如补体激活和局部炎症)。尽管在研究中没有对磷脂进行染色，但L-4F似乎也能有效清除磷脂，磷脂是促炎的氧化的脂质的主要来源。预计猕猴研究的结果可转化至人类中细胞外脂质沉积物发挥病理作用的所有阶段和形式的AMD，包括早期AMD、中期AMD和晚期AMD，并且包括萎缩性AMD和新生血管性AMD。玻璃疣富含酯化的胆固醇和磷脂，两者分别归因于RPE分泌的脂蛋白的核心和表面。此外，由于玻璃疣中的脂蛋白(天然的和修饰的两者)不与结构胶原蛋白和弹性蛋白纤维结合，所述玻璃疣中的脂蛋白与BrM中的脂蛋白不同，前者比后者更松散地结合，并且因此更容易去除。因此，猕猴研究中酯化的胆固醇和脂质沉积物从BrM大量减少证明了L-4F有效地减少软玻璃疣和清除包括BrM在内的眼组织中的脂质(包括酯化的胆固醇)的能力。尽管RPE具有活性蛋白酶，但在猕猴研究中玻璃体内注射的L-4F容易穿过RPE并到达BrM，并且有效地从BrM中去除脂质沉积物。通过L-4F去除BrM中的脂质沉积物使BrM的结构和功能正常化。此外，通过L-4F减少玻璃疣体积可以降低RPE层从BrM的升高，并从而可以减少视物变形症，并且可以预防非中央或中央地图样萎缩、延迟非中央或中央地图样萎缩的发作或减缓非中央或中央地图样萎缩的进展，并从而可以改善视力。可以使用光谱域光学相干断层扫描(SDOCT)和市售可得的软件来容易地量化人类玻璃疣体积的减少。In studies conducted in a rhesus monkey model of early AMD in humans and as described below, L-4F has shown potent abilities to scavenge neutral lipids and esterified cholesterol, rejuvenate/normalize BrM, and reduce lipid deposition downstream effects (eg, complement activation and local inflammation). Although phospholipids were not stained in the study, L-4F also appears to be effective in scavenging phospholipids, a major source of pro-inflammatory oxidized lipids. The results of the macaque study are expected to be translatable to all stages and forms of AMD in humans in which extracellular lipid deposits play a pathological role, including early AMD, intermediate AMD and late AMD, and including atrophic AMD and neovascular AMD. Drusen are rich in esterified cholesterol and phospholipids, both of which are attributed to the core and surface of lipoproteins secreted by RPE, respectively. Furthermore, the lipoproteins in drusen (both native and modified) are different from those in BrM, which are more It binds loosely and is therefore easier to remove. Thus, the substantial reduction of esterified cholesterol and lipid deposits from BrM in rhesus monkey studies demonstrates that L-4F is effective in reducing soft drusen and in clearing lipids (including esterified cholesterol) from ocular tissues including BrM. ability. Although RPE has an active protease, intravitreal injected L-4F readily crosses the RPE and reaches BrM in the rhesus monkey study, and effectively removes lipid deposits from BrM. Removal of lipid deposits in BrM by L-4F normalizes the structure and function of BrM. In addition, reduction of drusen volume by L-4F can reduce the rise of the RPE layer from BrM, and thus can reduce photomorphism, and can prevent, delay the onset of non-central or central geographic atrophy Or slow the progression of non-central or central geographic atrophy and thereby improve vision. The reduction in human drusen volume can be readily quantified using spectral domain optical coherence tomography (SDOCT) and commercially available software.
通过减少脂质沉积物，L-4F可以维持或改善RPE的健康，并从而可以预防或防止RPE萎缩(包括非中央或中央地图样萎缩)。因为RPE细胞继续分泌脂蛋白，软玻璃疣和玻璃疣色素上皮脱离(PED)随着时间的推移而发展。玻璃疣和玻璃疣PED上的RPE层随着时间的推移变得粗糙，并且RPE细胞从RPE层(优先于顶点，这里的RPE细胞离脉络膜毛细血管更远)迁移出来并且向前进入感觉神经视网膜，并因此从视网膜循环中寻找氧气。通过从玻璃疣中除去天然和修饰的脂质，L-4F可以预防RPE细胞的前向迁移，并从而可以使RPE细胞足够接近脉络膜毛细血管，使得RPE细胞不会在能量上和代谢上代偿失调，并因此不会萎缩。此外，从BrM中去除脂质沉积物改善了脉络膜毛细血管和RPE之间的微量营养物(包括维生素A)进入和废物排出的运输。通过减少玻璃疣和去除BrM中的脂质沉积物，L-4F可以维持RPE健康并防止RPE萎缩，并从而可以保留光感受器和视力。可以通过黄斑的SDOCT监测RPE上覆的玻璃疣的健康。By reducing lipid deposits, L-4F may maintain or improve the health of the RPE, and thereby may prevent or prevent RPE atrophy (including non-central or central geographic atrophy). As RPE cells continue to secrete lipoproteins, soft drusen and drusen pigmented epithelial detachment (PED) develop over time. The RPE layer on drusen and drusen PEDs roughens over time, and RPE cells migrate out of the RPE layer (preferentially at the apex, where RPE cells are further from the choriocapillaris) and forward into the sensory neural retina , and thus seek oxygen from the retinal circulation. By removing natural and modified lipids from drusen, L-4F can prevent forward migration of RPE cells and thus can bring RPE cells close enough to the choriocapillaries that RPE cells are not energetically and metabolically compensated out of balance, and therefore not shrinking. Furthermore, removal of lipid deposits from BrM improved the transport of micronutrients (including vitamin A) in and waste out between the choriocapillaries and the RPE. By reducing drusen and removing lipid deposits in BrM, L-4F maintains RPE health and prevents RPE atrophy, thereby preserving photoreceptors and vision. The health of the drusen overlying the RPE can be monitored by SDOCT of the macula.
脂质沉积物的减少在猕猴研究中具有下游益处，包括BrM和脉络膜毛细血管中存在的膜攻击复合物(MAC)的数量的大量减少。MAC(C5b-9)是补体系统激活的最终产物，并且在人的一生中从儿童期开始在BrM-脉络膜毛细血管复合体中建立。通过降低MAC的水平，L-4F可以改善BrM和脉络膜毛细血管内皮的健康，并从而可以改善外层视网膜的血液供应和脉络膜毛细血管与RPE之间的微量营养物的交换，并且可以促进由RPE分泌到体循环中的脂蛋白颗粒的清理。The reduction of lipid deposits has downstream benefits in rhesus monkey studies, including substantial reductions in BrM and the amount of membrane attack complex (MAC) present in the choriocapillaries. MAC (C5b-9) is the end product of complement system activation and is established in the BrM-choriocapillary complex throughout the human lifespan starting in childhood. By reducing the level of MAC, L-4F can improve BrM and choriocapillary endothelium health, and thereby can improve blood supply to the outer retina and exchange of micronutrients between choriocapillaries and RPE, and can promote RPE Clearance of lipoprotein particles secreted into the systemic circulation.
此外，通过去除脂质，L-4F可以预防或防止新生血管形成(NV)。基底线性沉积物和软玻璃疣是亚RPE-BL空间中潜在促炎性脂质的主要来源，所述亚RPE-BL空间中发生1型NV(最常见的NV类型)。如猕猴研究中所证明的，通过L-4F从眼组织去除天然脂质(包括脂蛋白沉积物中的酯化的胆固醇)减少了可用于修饰(例如过氧化)的天然脂质的量。修饰的脂质(包括过氧化的脂质)可以强烈促炎，并因此可以刺激NV。L-4F还可以清除任何过氧化的脂质和其他形成的修饰的脂质。此外，通过减少玻璃疣的体积大小，L-4F可以防止RPE细胞从运输营养物的脉络膜毛细血管中迁移，并从而防止它们分泌诱导损害的VEGF，所述VEGF是NV的有效刺激物。此外，由于通过L-4F从BrM去除脂质沉积物而使BrM正常化，所述BrM的正常化通过增强脉络膜毛细血管和亚RPE-BL空间之间的天然屏障来抑制脉络膜NV。因此，通过其清除天然的脂质和修饰的(例如，氧化的)脂质的能力，L-4F同血管生成剂(包括玻璃体内注射的抗VEGF剂)可以预防或减少NV(包括1型NV)，并且可以改善新生血管性AMD的治疗，并减少治疗负担。Furthermore, by removing lipids, L-4F can prevent or prevent neovascularization (NV). Basal linear deposits and soft drusen are major sources of potentially pro-inflammatory lipids in the sub-RPE-BL space where type 1 NV (the most common type of NV) occurs. Removal of natural lipids (including esterified cholesterol in lipoprotein deposits) from ocular tissue by L-4F reduces the amount of natural lipids available for modification (eg, peroxidation), as demonstrated in rhesus monkey studies. Modified lipids, including peroxidized lipids, can be strongly pro-inflammatory and thus can stimulate NV. L-4F also scavenges any peroxidized lipids and other formed modified lipids. Furthermore, by reducing the bulk size of drusen, L-4F can prevent RPE cells from migrating from the choriocapillaries that transport nutrients and thereby prevent them from secreting damage-inducing VEGF, which is a potent stimulator of NV. Furthermore, normalization of BrM due to the removal of lipid deposits from BrM by L-4F inhibits choroidal NV by enhancing the natural barrier between the choriocapillaris and the sub-RPE-BL space. Thus, through its ability to scavenge native lipids and modified (eg, oxidized) lipids, L-4F and angiogenic agents (including intravitreal injected anti-VEGF agents) can prevent or reduce NV (including type 1 NV) ), and may improve the treatment of neovascular AMD and reduce the treatment burden.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如，每次注射)约0.1-0.5mg、0.5-1mg或1-1.5mg的剂量局部施用。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如，每次注射)约0.1-0.3mg、0.3-0.5mg、0.5-0.75mg、0.75-1mg、1-1.25mg或1.25-1.5mg的剂量局部施用。apo模拟物也可以以每次施用(例如，每次注射)大于1.5mg的剂量局部施用，例如每次施用(例如，每次注射)至多约2mg或更多。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如，每次注射)约0.1-0.5mg或0.5-1mg的剂量局部施用。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered per administration (eg, per injection) ) is administered locally at a dose of about 0.1-0.5 mg, 0.5-1 mg or 1-1.5 mg. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at each administration (eg, each injection) topical administration at doses of about 0.1-0.3 mg, 0.3-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-1.25 mg, or 1.25-1.5 mg. The apo mimetic can also be administered topically at a dose of greater than 1.5 mg per administration (eg, per injection), eg, up to about 2 mg or more per administration (eg, per injection). In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at each administration (eg, each injection) topical administration at a dose of about 0.1-0.5 mg or 0.5-1 mg.
在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5或1-5mg或5-10mg的总剂量或累积剂量局部施用。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5或1-3mg、3-5mg、5-7.5mg或7.5-10mg的总剂量或累积剂量局部施用。apo模拟物也可以以在约6个月的时间内大于10mg的总剂量或累积剂量局部施用，例如在约6个月的时间内至多约15mg或更多。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5-3mg或3-5mg的总剂量或累积剂量局部施用。In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered within a period of about 6 months A total or cumulative dose of about 0.5 or 1-5 mg or 5-10 mg is administered topically. In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in about 6 months Topical administration in total or cumulative doses of 0.5 or 1-3 mg, 3-5 mg, 5-7.5 mg or 7.5-10 mg. The apo mimetic can also be administered topically in a total or cumulative dose of greater than 10 mg over a period of about 6 months, eg, up to about 15 mg or more over a period of about 6 months. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered within a period of about 6 months A total or cumulative dose of about 0.5-3 mg or 3-5 mg is administered topically.
在更进一步的实施方案中，对于整个或完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1或2-20mg或5-15mg的总剂量或累积剂量局部施用。在某些实施方案中，对于完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-5mg、5-10mg、10-15mg或15-20mg的总剂量或累积剂量局部施用。在一些实施方案中，对于完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-3mg、3-5mg、5-7.5mg、7.5-10mg、10-12.5mg、12.5-15mg、15-17.5mg或17.5-20mg的总剂量或累积剂量局部施用。对于完整治疗方案，apo模拟物也可以以大于20mg的总剂量或累积剂量局部施用，例如对于完整治疗方案至多为约25mg、30mg、40mg、50mg或更多。在某些实施方案中，对于完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-5mg或5-10mg的总剂量或累积剂量局部施用。In still further embodiments, for the entire or complete treatment regimen, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] with Topical administration in total or cumulative doses of about 1 or 2-20 mg or 5-15 mg. In certain embodiments, for a complete treatment regimen, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] at about 1- Topical administration in total or cumulative doses of 5 mg, 5-10 mg, 10-15 mg, or 15-20 mg. In some embodiments, for a complete treatment regimen, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at about 1-3 mg , 3-5 mg, 5-7.5 mg, 7.5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg total or cumulative dose topically. The apo mimetic can also be administered topically in a total or cumulative dose of greater than 20 mg for a complete treatment regimen, eg, up to about 25 mg, 30 mg, 40 mg, 50 mg, or more for a complete treatment regimen. In certain embodiments, for a complete treatment regimen, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] at about 1- Topical administration in total or cumulative doses of 5 mg or 5-10 mg.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]施用于眼局部、眼内、眼中或眼周。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]通过以下施用：注射(例如，玻璃体内、结膜下、视网膜下或特农(Tenon)氏囊下注射)、滴眼剂或植入物(例如玻璃体内、房水内、视网膜下或特农氏囊下植入物)。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]通过注射施用(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)。玻璃体内注射的apo模拟物可以容易地从玻璃体腔到达靶位点(例如亚RPE-BL空间和BrM)。在这样做时，apo模拟物可以分布在眼睛的不同组织层中，例如感觉神经视网膜、BrM和脉络膜。通过例如从内视网膜层和外视网膜层之间的多种组织层的连续和缓慢的再供应或“冲洗”，apo模拟物可以具有长的作用持续时间(例如，至少约2、3或4周或更长)，所述多种组织层中可以分布apo模拟物。在进一步的实施方案中，通过滴眼剂施用apo模拟物[例如apoA-I模拟物(例如L-4F)和/或apoE模拟物(例如AEM-28-14)]。在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]通过将装置或材料植入或注射到例如玻璃体室、视网膜下方的空间或房水而施用，所述装置或材料以受控和/或持续方式递送apo模拟物，所述装置或材料例如微器件、生物可吸收的聚合物材料或生物可吸收的微粒或纳米颗粒。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]通过将以下注射或植入眼中而施用：含有表达载脂蛋白模拟物的基因或表达构建体(例如质粒)的细胞(例如，含有表达载体的RPE细胞，所述载体包括编码apo模拟物的基因)或病毒(例如，腺病毒或慢病毒)载体。这种递送方法将具有以下益处：仅需要在眼睛中一次性注射或植入编码apo模拟物的表达构建体。如果使用两种或更多种apo模拟物[例如，apoA-I模拟物(例如，L-4F)和apoE模拟物(例如，AEM-28-14)]，则相同的表达构建体或不同的表达构建体可以表达两种或更多种的apo模拟物。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically, intraocularly, in the eye, or around the eyes. In some embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered by injection (eg, intravitreal) , subconjunctival, subretinal or sub-Tenon's capsule injection), eye drops or implants (eg intravitreal, intra-aqueous, subretinal or sub-Tenon's capsule implants). In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon's capsule injection). Intravitreal injected apo mimetics can easily reach target sites (eg sub-RPE-BL space and BrM) from the vitreous cavity. In doing so, apo mimetics can be distributed in different tissue layers of the eye, such as the sensory neural retina, BrM, and choroid. Apo mimetics can have a long duration of action (eg, at least about 2, 3, or 4 weeks) by, for example, continuous and slow resupply or "flushing" from various tissue layers between the inner and outer retinal layers or longer), apo mimetics can be distributed in the various tissue layers. In further embodiments, an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] is administered by eye drops. In additional embodiments, an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] is administered by implanting or injecting a device or material Administered to, for example, the vitreous compartment, the subretinal space, or the aqueous humor, the devices or materials, such as microdevices, bioabsorbable polymeric materials, or Bioabsorbable microparticles or nanoparticles. In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered by injecting or implanting into the eye : cells (e.g., RPE cells containing an expression vector comprising a gene encoding an apo mimetic) or virus (e.g., adenovirus or virus) vector. This method of delivery would have the benefit of requiring only a one-time injection or implantation of the expression construct encoding the apo mimetic in the eye. The same expression construct or different The expression construct can express two or more apo mimetics.
在将apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]施用于眼局部、眼内、眼中或眼周的实施方案中，每次施用的剂量、在约6个月的时间内的总剂量、以及完整治疗方案的总剂量在某些实施方案中是对于施用的每只眼睛，并且在其他实施方案中是对于双眼的。血液系统可允许局部施用(例如，注射)到一只眼睛内或在一只眼睛中的一些量(例如，治疗有效量)的apo模拟物被分布到另一只眼睛，在这种情况下apo模拟物的剂量可以考虑到另一只眼睛(其可能处于较少患病的状况)而任选的得到调整(例如，增加)，并且可以允许用apo模拟物同时治疗双眼而无需在另一只眼睛内或另一只眼睛中额外的施用(例如，注射)apo模拟物。例如，玻璃体内注射的apo模拟物可随着自然流体从玻璃体液通过视网膜和RPE流向脉络膜而移动并穿过血液-视网膜屏障(由视网膜血管内皮和RPE维持)到达两个靶区域(亚RPE-BL空间和布鲁赫膜)，apo模拟物可以从所述靶区域进入脉络膜毛细血管，并最终到达对应未施用的眼睛。也不受理论的束缚，一些量的apo模拟物可以通过房水途径进入对应未施用的眼睛，房水通过小梁网和流入血液系统的施莱姆管(Schlemm's canal)排出。因此，一些实施方案涉及治疗AMD的方法，其包括向需要治疗的对象施用治疗有效量的载脂蛋白模拟物，其中所述载脂蛋白模拟物施用于一只眼睛中的眼局部、眼内、眼中或眼周并且两只眼睛都有治疗效果。Implementation of topical, intraocular, intraocular, or periocular administration of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] In the regimen, the dose per administration, the total dose over a period of about 6 months, and the total dose for the complete treatment regimen are in certain embodiments for each eye administered, and in other embodiments for each eye. binocular. The blood system may allow topical administration (eg, injection) into one eye or some amount (eg, a therapeutically effective amount) in one eye of an apo mimetic to be distributed to the other eye, in which case apo The dose of the mimetic can optionally be adjusted (eg, increased) to take into account the other eye (which may be in a less diseased condition), and can allow simultaneous treatment of both eyes with the apo mimetic without Additional administration (eg, injection) of the apo mimetic in the eye or in the other eye. For example, intravitreal injected apo mimetics can travel with natural fluid flow from the vitreous humor through the retina and RPE to the choroid and cross the blood-retinal barrier (maintained by the retinal vascular endothelium and RPE) to two target areas (sub-RPE- BL space and Bruch's membrane), apo mimetics can enter the choriocapillaris from the target region and ultimately reach the corresponding unadministered eye. Also without being bound by theory, some amounts of apo mimetics can enter the corresponding unapplied eye via the aqueous humor route, which drains through the trabecular meshwork and Schlemm's canal into the blood system. Accordingly, some embodiments relate to methods of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein mimetic, wherein the apolipoprotein mimetic is administered topically, intraocularly, intraocularly, in one eye Treatment is effective in or around the eye and in both eyes.
在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在治疗的早期施用于眼局部、眼内、眼中或眼周，并且然后全身施用apo模拟物。作为非限制性实例，apo模拟物的初始施用(例如，前一至五次施用)可以是通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)的局部施用，并且然后随后可以全身性(例如口服、肠胃外(例如，皮下、肌肉内或静脉内)或外用(例如，鼻内或肺部))地施用apo模拟物。在其他实施方案中，apo模拟物(例如，通过注射、滴眼剂或植入物)仅在局部施用。在其他实施方案中，apo模拟物仅在全身施用。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically to the eye early in the treatment, The apo mimetic is administered intraocularly, in the eye or around the eye, and then systemically. As a non-limiting example, the initial administration (eg, the first one to five administrations) of an apo mimetic can be topical by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon injection), and then The apo mimetic can then be administered systemically (eg, orally, parenterally (eg, subcutaneously, intramuscularly, or intravenously) or topically (eg, intranasally or pulmonary)). In other embodiments, the apo mimetic (eg, by injection, eye drops, or implant) is administered topically only. In other embodiments, the apo mimetic is administered systemically only.
在一些实施方案中，无论是在局部(例如，通过玻璃体内注射)或全身，施用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]剂量浓度均为约1、2、3、4或5mg/mL至约12或15mg/mL。如果使用两种或更多种apo模拟物(例如，apo A-I模拟物和apoE模拟物)，它们可以以相同的制剂或不同的制剂施用。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-4mg/mL、4-8mg/mL、8-12mg/mL、1-5mg/mL、5-10mg/mL或10-15mg/mL的剂量浓度施用(例如，通过玻璃体内注射)。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-3mg/mL、3-5mg/mL、5-7.5mg/mL、6-8mg/mL、7.5-10mg/mL、10-12.5mg/mL或12.5-15mg/mL的剂量浓度施用(例如，通过玻璃体内注射)。无论是在局部(例如，通过玻璃体内注射)还是全身，apo模拟物也可以以大于15mg/mL的剂量浓度施用，例如至多为约20mg/mL或更高。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1-5mg/mL、5-10mg/mL或6-8mg/mL的剂量浓度施用(例如，通过玻璃体内注射)。In some embodiments, either locally (eg, by intravitreal injection) or systemically, an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM) is administered -28-14)] dosage concentrations are all about 1, 2, 3, 4 or 5 mg/mL to about 12 or 15 mg/mL. If two or more apo mimetics are used (eg, apo A-I mimetic and apoE mimetic), they can be administered in the same formulation or in different formulations. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at about 1-4 mg/mL, 4 - Administration (eg, by intravitreal injection) at dose concentrations of 8 mg/mL, 8-12 mg/mL, 1-5 mg/mL, 5-10 mg/mL, or 10-15 mg/mL. In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at about 1-3 mg/mL, 3- Dose concentrations of 5 mg/mL, 5-7.5 mg/mL, 6-8 mg/mL, 7.5-10 mg/mL, 10-12.5 mg/mL, or 12.5-15 mg/mL are administered (eg, by intravitreal injection). Apo mimetics can also be administered at dose concentrations greater than 15 mg/mL, eg, up to about 20 mg/mL or higher, whether locally (eg, by intravitreal injection) or systemically. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at about 1-5 mg/mL, 5 - Administered at dose concentrations of 10 mg/mL or 6-8 mg/mL (eg, by intravitreal injection).
在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约50-150μL或50-100μL的剂量体积局部施用(例如，通过玻璃体内注射)。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约50-75μL、75-100μL、100-125或125-150μL的剂量体积局部施用(例如，通过玻璃体内注射)。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约50μL、75μL、100μL、125μl或150μL的剂量体积局部施用(例如，通过玻璃体内注射)。只要施用的体积不显著增加眼压，apo模拟物还可以以大于150μL的剂量体积局部施用(例如，通过注射至眼部、眼内、眼中或眼周)，例如至多约200μL。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约100μl(0.1mL)的剂量体积局部施用(例如，通过玻璃体内注射)。In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in about 50-150 μL or 50-100 μL The dose volume is administered locally (eg, by intravitreal injection). In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in about 50-75 μL, 75-100 μL , 100-125, or 125-150 μL dose volumes are administered locally (eg, by intravitreal injection). In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in about 50 μL, 75 μL, 100 μL, 125 μL or A dose volume of 150 μL is administered topically (eg, by intravitreal injection). Apo mimetics can also be administered topically (eg, by injection into the eye, intraocular, intraocular, or periocular) in dose volumes greater than 150 μL, eg, up to about 200 μL, as long as the administered volume does not significantly increase intraocular pressure. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a dose of about 100 μl (0.1 mL) The volume is administered locally (eg, by intravitreal injection).
在另外的实施方案中，所述apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每月(4周)或每1.5个月(6周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，所述apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每2个月(8周)、每2.5个月(10周)或每3个月(12周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，所述apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每4、5或6个月局部施用(例如，通过玻璃体内注射或玻璃体内植入)一次。在一些实施方案中，在治疗的早期更频繁地和/或以更高的剂量局部施用(例如，通过玻璃体内注射)apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]。In additional embodiments, the apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] monthly (4 weeks) or Topical administration (eg, by intravitreal injection) once every 1.5 months (6 weeks). In other embodiments, the apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] every 2 months (8 weeks) , administered topically (eg, by intravitreal injection) every 2.5 months (10 weeks) or every 3 months (12 weeks). In other embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] every 4, 5, or 6 months Topical administration (eg, by intravitreal injection or intravitreal implantation) once. In some embodiments, the apo mimetics [eg, apoA-I mimetics (eg, L-4F) and /or an apoE mimetic (eg, AEM-28-14)].
在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在局部施用的施用(例如，玻璃体内注射)次数总共约15次或更少、12次或更少、9次或更少、6次或更少、或3次或更少。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在局部施用的施用(例如，玻璃体内注射)次数总共约3-6次、6-9次、9-12次或12-15次。apo模拟物也可以在局部施用的施用(例如，玻璃体内注射)次数总共超过15次，例如至多约20次或更多次的施用(例如，玻璃体内注射)。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在局部施用的施用(例如，玻璃体内注射)次数总共约15次、14次、13次、12次、11次或10次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在局部施用的施用(例如，玻璃体内注射)次数总共约9次、8次、7次、6次、5次、4次或3次。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在局部施用的施用(例如，玻璃体内注射)次数总共约3-6或7-10次。在将apo模拟物施用于眼局部、眼内、眼中或眼周的实施方案中，施用频率和施用(例如注射)总次数在某些实施方案中是对于施用的每只眼睛，并且由于apo模拟物也可以在对应未施用的眼睛中具有治疗效果，在其他实施方案中是对于双眼的。In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a topical administration (eg, a vitreous Intra-injection) in total about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a topical administration (eg, a vitreous Intra-injection) total about 3-6 times, 6-9 times, 9-12 times or 12-15 times. The apo mimetic may also be administered locally (eg, intravitreal injection) for a total of more than 15 times, eg, up to about 20 or more administrations (eg, intravitreal injection). In some embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered locally (eg, intravitreally) The number of injections) is about 15, 14, 13, 12, 11 or 10 in total. In other embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered locally (eg, intravitreally) The number of injections) was about 9, 8, 7, 6, 5, 4 or 3 in total. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a topical administration (eg, a vitreous Intra-injection) a total of about 3-6 or 7-10 times. In embodiments where the apo mimetic is administered topically, intraocularly, in the eye or periocular The drug may also have a therapeutic effect in the corresponding unadministered eye, in other embodiments both eyes.
对于每次施用的剂量、在约6个月的时间内总剂量、完整治疗方案的总剂量、施用频率和施用总次数，用载脂蛋白模拟物治疗的持续时间/时长可以根据需要进行调整，并且可以由治疗医师选择以最小化治疗负担并实现期望的结果，例如将脂质沉积物减少至期望的水平(例如，存在少量中等大小玻璃疣或不存在任何大的玻璃疣)并消除地图样萎缩(非中央或中央)或将地图样萎缩(非中央或中央)减少到期望的水平。在一些实施方案中，使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗方案持续约24个月或更短时间、18个月或更短时间、12个月或更短时间、或6个月或更短时间。在进一步的实施方案中，使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗方案持续约18-24个月、12-18个月或6-12个月。使用apo模拟物治疗也可持续超过24个月(2年)，例如长达约2.5年、3年、3.5年、4年或更长。在一些实施方案中，使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗方案持续约24、21、18、15、12、9或6个月。在某些实施方案中，使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗方案持续约6-12或12-24个月。The duration/duration of treatment with apolipoprotein mimetics can be adjusted as needed for the dose per administration, the total dose over a period of about 6 months, the total dose for the complete treatment regimen, the frequency of administration, and the total number of administrations, and can be selected by the treating physician to minimize treatment burden and achieve desired outcomes, such as reducing lipid deposits to desired levels (eg, presence of few medium-sized drusen or absence of any large drusen) and elimination of geographic pattern Atrophy (non-central or central) or reduce geographic atrophy (non-central or central) to the desired level. In some embodiments, the treatment regimen with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] continues for about 24 months or Lesser, 18 months or less, 12 months or less, or 6 months or less. In further embodiments, the treatment regimen with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] continues for about 18-24 months, 12-18 months or 6-12 months. Treatment with an apo mimetic can also continue for more than 24 months (2 years), eg, up to about 2.5 years, 3 years, 3.5 years, 4 years, or longer. In some embodiments, the treatment regimen with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] continues for about 24, 21, 18, 15, 12, 9 or 6 months. In certain embodiments, the treatment regimen with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] lasts about 6-12 or 12-24 months.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的晚期(后期)阶段施用。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的晚期阶段施用以治疗中央地图样萎缩(GA)或减缓中央地图样萎缩(GA)的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的晚期阶段施用以治疗或减缓新生血管性AMD的进展。In some embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in the late (late) stages of AMD . In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered to treat at least the advanced stages of AMD Central geographic atrophy (GA) or slow progression of central geographic atrophy (GA), and/or prevent neovascular AMD or delay the onset of neovascular AMD. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered to treat at least the advanced stages of AMD or slow the progression of neovascular AMD.
在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的中期阶段施用。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的中期阶段施用以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在中期AMD的初始阶段施用以预防非中央GA或延迟非中央GA的发作。中期AMD的特征在于大量汇合的软玻璃疣，其主要包括酯化的胆固醇和磷脂。使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]减少中期AMD中的汇合软玻璃疣可使得布鲁赫膜的厚度减小(“变薄”)并正常化，以及由于改善脉络膜毛细血管和RPE之间的微量营养物和代谢物的交换而恢复上覆的RPE细胞层。通过诸如光谱域光学相干断层扫描(SDOCT)的非侵入性技术可以观察到汇合的软玻璃疣的减少。In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in the mid-stage of AMD. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered to treat at least mid-stage AMD Non-central GA or slowing the progression of non-central GA, and/or preventing central GA and/or neovascular AMD or delaying the onset of central GA and/or neovascular AMD. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least during the initial phase of mid-stage AMD with To prevent or delay the onset of non-central GA. Mid-stage AMD is characterized by numerous confluent soft drusen, which mainly consist of esterified cholesterol and phospholipids. Reduction of confluent soft drusen in mid-stage AMD using an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] can reduce Bruch's membrane The thickness of the cells decreased ("thinned") and normalized, and the overlying RPE cell layer was restored due to improved exchange of micronutrients and metabolites between the choriocapillaries and the RPE. Reduction of confluent soft drusen can be observed by non-invasive techniques such as spectral domain optical coherence tomography (SDOCT).
在进一步的实施方案中，apo模拟物[例如apoA-I模拟物(例如L-4F)和/或apoE模拟物(例如AEM-28-14)]至少在AMD的早期阶段施用。apo模拟物可以在AMD的较早阶段(例如，早期阶段或中期阶段)施用以减缓或停止AMD的进展。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的早期阶段施用以预防非中央GA或延迟非中央GA的发作。在某些实施方案中，将apo模拟物在AMD的早期阶段施用于眼局部、眼内、眼中或眼周(例如，通过玻璃体内、结膜下、视网膜下或特农氏囊下注射或滴眼)。如果apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以侵入性方式局部施用(例如，通过玻璃体内、结膜下、视网膜下或特农氏囊下注射)，apo模拟物可以以较低频率施用(例如，每3或4个月或6个月注射一次)、以较少施用总次数率施用(例如，约1、2或3次注射)或以每次更高的施用剂量施用(例如，每次注射约0.5-1mg或1-1.5mg)，或其任何组合或全部，以使治疗负担最小化。apo模拟物不需要从眼睛中消除或去除全部或大部分异常脂质沉积物以对AMD具有治疗或预防效果。如果从眼睛中清理了阈值量的异常脂质，则自然运输机制(包括脉络膜毛细血管内皮和RPE层之间的流通)可以再次适当地起作用并且可以清理眼睛中残余的异常脂质。此外，脂质在数年内缓慢地在眼睛中积累(尽管可检测到较短时间范围内的玻璃疣体积的波动)。因此，以较低频率施用(例如，每约3、4或6个月的玻璃体内注射)和/或以较少总次数施用(例如，约1、2或3次玻璃体内注射)apo模拟物仍可对早期AMD具有治疗或预防效果。In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in the early stages of AMD. Apo mimetics can be administered at earlier stages of AMD (eg, early or mid-stage) to slow or stop the progression of AMD. In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in the early stages of AMD to prevent non- Central GA or delayed onset of non-central GA. In certain embodiments, the apo mimetic is administered topically, intraocularly, in the eye, or around the eye in the early stages of AMD (eg, by intravitreal, subconjunctival, subretinal, or subtenon's capsule injection or eye drops) ). If an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] is administered invasively topically (eg, by intravitreal, subconjunctival , subretinal, or subtenon's capsule), the apo mimetic can be administered less frequently (e.g., every 3 or 4 months or 6 months), at a lesser overall rate (e.g., about 1, 2, or 3 injections) or in higher doses per administration (eg, about 0.5-1 mg or 1-1.5 mg per injection), or any combination or all thereof, to minimize treatment burden. Apo mimetics are not required to eliminate or remove all or most of the abnormal lipid deposits from the eye to have a therapeutic or prophylactic effect on AMD. If a threshold amount of abnormal lipids is cleared from the eye, natural transport mechanisms, including the circulation between the choriocapillary endothelium and the RPE layer, can function properly again and the eye can be cleared of residual abnormal lipids. Furthermore, lipids accumulate slowly in the eye over several years (although fluctuations in drusen volume over shorter time frames can be detected). Thus, the apo mimetic is administered less frequently (eg, intravitreal injections every about 3, 4, or 6 months) and/or less overall (eg, about 1, 2, or 3 intravitreal injections) It can still have a therapeutic or preventive effect on early AMD.
在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，D-4F)和/或apoE模拟物(例如，AEM-28-14)]在AMD的早期阶段全身施用(例如，口服或胃肠外(例如静脉内)施用)。为了增加apo模拟肽对肽酶/蛋白酶的抗性，可以全身施用(或通过滴眼，因为眼表含有肽酶/蛋白酶)含有一个或多个或所有D型-氨基酸(例如，具有所有D-氨基酸残基的D-4F)的apo模拟物的变体。考虑到其全身分布及其潜在的全身性抗血脂异常作用(例如减少或去除全身血管系统中的动脉粥样硬化斑块，其可能是体循环中apo模拟物的主要靶标(并因此是藏垢区))，用于全身施用的apo模拟物的剂量可远高于其局部施用(例如，通过玻璃体内注射或滴眼)的剂量。在某些实施方案中，用于全身施用的apo模拟物[例如，apoA-I模拟物(例如，D-4F)和/或apoE模拟物(例如，AEM-28-14)]的剂量为至少比其局部施用剂量大约50、100、200、300、400、500或1,000倍(例如，至少约100或500倍)。在一些实施方案中，用于全身施用的apo模拟物[例如，apoA-I模拟物(例如，D-4F)和/或apoE模拟物(例如，AEM-28-14)]的剂量为每天至少约50mg、100mg、200mg、300mg、400mg或500mg(例如，如果静脉内施用则每天至少约50mg或100mg，或如果口服施用则每天至少约200或300mg))。在进一步的实施方案中，无论是全身性地(例如，口服或肠胃外(例如静脉内))或以非侵入性方式(例如，通过滴眼剂)局部施用，在AMD的早期阶段由主治医生选择一定时长(例如，至少约3个月、6个月、12个月、18个月、24个月或更长时间)或直到根据选定的测量标准的结果已经成功治疗疾病(例如，消除所有或大多数软玻璃疣或软玻璃疣的体积减少达到一定水平)，将apo模拟物每天一次、两次或更多次、每两天一次、每三天一次、每周一次、每两周一次或每月一次(例如，每天一次或每两天一次)施用到眼睛中。In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, D-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered systemically in the early stages of AMD (eg, Oral or parenteral (eg intravenous) administration). To increase the resistance of apo mimetic peptides to peptidases/proteases, systemic administration (or via eye drops, since the ocular surface contains peptidases/proteases) containing one or more or all D-amino acids (eg, with all D- Variants of apo mimetics of amino acid residues D-4F). Considering its systemic distribution and its potential systemic anti-dyslipidemic effects (such as reduction or removal of atherosclerotic plaques in the systemic vasculature, it may be the primary target of apo mimetics in the systemic circulation (and therefore fouling areas). )), the dose of apo mimetic for systemic administration can be much higher than that for local administration (eg, by intravitreal injection or eye drops). In certain embodiments, the dose of an apo mimetic [eg, an apoA-I mimetic (eg, D-4F) and/or an apoE mimetic (eg, AEM-28-14)] for systemic administration is at least About 50, 100, 200, 300, 400, 500 or 1,000 times (eg, at least about 100 or 500 times) the locally administered dose. In some embodiments, the dose of an apo mimetic [eg, an apoA-I mimetic (eg, D-4F) and/or an apoE mimetic (eg, AEM-28-14)] for systemic administration is at least daily About 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg (eg, at least about 50 mg or 100 mg per day if administered intravenously, or at least about 200 or 300 mg per day if administered orally)). In a further embodiment, either systemically (eg, orally or parenterally (eg, intravenously)) or locally in a non-invasive manner (eg, via eye drops), administered by the attending physician in the early stages of AMD Select a period of time (eg, at least about 3 months, 6 months, 12 months, 18 months, 24 months, or more) or until the disease has been successfully treated (eg, eliminated the All or most soft drusen or soft drusen to a certain level of volume reduction), administer apo mimetic once, twice or more daily, once every two days, once every three days, once a week, once every two weeks The eye is administered once or monthly (eg, once a day or once every two days).
在某些实施方案中，针对的AMD阶段越早，施用(例如，通过玻璃体内注射)apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的频率越低频率和/或剂量越小。更高剂量的apo模拟物也可以在AMD阶段的更早阶段施用。换句话说，在某些实施方案中，针对的AMD阶段越晚或AMD的病况越严重，施用(例如，通过玻璃体内注射)apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的频率更高(可以导致更多的施用总次数)和/或剂量更高(每次施用的剂量更高和/或完整治疗方案的总剂量更高)。作为非限制性实例，在中期AMD和晚期AMD(包括萎缩性AMD和新生血管性AMD)中，apo模拟物可以更频繁(例如，在中期AMD中每4-12或4-8周一次，并且在晚期AMD中每4-8周或4-6周一次)地、以更多的注射总次数(例如，在中期AMD中注射约4-8次或更多次，以及在晚期AMD中注射约8-12次)、以每次更高的注射剂量(例如，每次注射至多约1-1.5mg)、或以更大的完整治疗方案的总剂量(例如，在中期AMD中至多约10-15mg或更多，在晚期AMD中至多约15-20mg或更多)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)施用，或其任何组合或全部中，以从眼睛去除包括来自亚RPE-BL空间和布鲁赫膜的更大量的脂质沉积物(包括玻璃疣和基底线性沉积物)。In certain embodiments, an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, an apoE mimetic) is administered (eg, by intravitreal injection) the earlier the AMD stage is targeted. AEM-28-14)] the lower the frequency and/or the lower the dose. Higher doses of apo mimetics can also be administered earlier in the AMD stage. In other words, in certain embodiments, targeting a later stage of AMD or more severe AMD, administering (eg, by intravitreal injection) an apo mimetic [eg, an apoA-I mimetic (eg, L-4F ) and/or apoE mimetics (e.g., AEM-28-14)] more frequently (may result in more total number of administrations) and/or higher doses (higher dose per administration and/or complete treatment The total dose of the regimen is higher). As a non-limiting example, in intermediate AMD and advanced AMD (including atrophic AMD and neovascular AMD), apo mimetics may be more frequent (eg, every 4-12 or 4-8 weeks in intermediate AMD, and every 4-8 weeks or 4-6 weeks in advanced AMD), in a greater total number of injections (eg, about 4-8 injections or more in intermediate AMD, and about 4-8 injections in advanced AMD) 8-12 times), at higher doses per injection (e.g., up to about 1-1.5 mg per injection), or at a larger total dose of a complete treatment regimen (e.g., up to about 10-10 mg in mid-stage AMD) 15 mg or more, up to about 15-20 mg or more in advanced AMD) administered by injection (e.g., intravitreal, subconjunctival, subretinal, or subtenon's capsule), or any combination or all thereof, with Removal from the eye included larger amounts of lipid deposits (including drusen and basal linear deposits) from the sub-RPE-BL space and Bruch's membrane.
在AMD的早期、中期和晚期阶段以及萎缩性AMD和新生血管性AMD中，可以使用本领域已知的多种方法(为简单起见，本文称为“诊断”方法)监测AMD的进展和治疗。这些方法包括但不限于结构性SDOCT(其显示玻璃疣和RPE并且可以量化玻璃疣总体积和监测疾病的进展)、高光谱自发荧光(其可以检测玻璃疣和基底线性沉积物特有的荧光团)、彩色眼底照相术、定量眼底自发荧光(qAF)和OCT-荧光素血管造影(FA)，并且可以检查以下参数：诸如视锥细胞介导的视力(例如，最佳矫正的视敏度[BCVA，其持续到疾病后期]、用ETDRS图表检查的视敏度、用Pelli-Robson图表检查的对比灵敏度、低亮度视敏度[用中性密度滤光片以减少视网膜照度而测量的视敏度]和视物变形的发展)和视杆细胞介导的视力(例如，暗适应动力学[敏感地测量跟踪疾病进展的黄斑功能])。例如，治疗预期将保持稳定或改善由视锥光感受器介导的明视(日光)视觉和由视杆光感受器介导的暗视(夜间)视觉。作为另一个例子，可以用qAF评估RPE细胞的健康，其中qAF强度的稳定性或qAF强度的增加可以指示稳定的RPE健康或改善的RPE健康，因为qAF强度的降低可以表示RPE细胞的退化。正如在关于兰波利珠单抗(lampalizumab)的MAHALO II期研究中所做的，qAF可用于量化地图样萎缩的面积或大小，并从而监测非中央GA或中央GA的进展。RPE细胞的健康也可以用SDOCT评估，其中在视网膜内垂直位于玻璃疣上方的超反射性病灶的存在代表迁移的RPE细胞，这表明RPE层即将在RPE细胞和光感受器萎缩之前崩解。RPE健康状况不佳可能是萎缩性AMD和新生血管性AMD视力预后不良的指标。作为另一个例子，OCT-FA可以检测亚RPE-BL、视网膜下或视网膜内液体的存在，这可以表示新生血管形成活跃和液体从新血管中渗漏。In early, intermediate and late stages of AMD, as well as in atrophic AMD and neovascular AMD, the progression and treatment of AMD can be monitored using a variety of methods known in the art (referred to herein for simplicity as "diagnostic" methods). These methods include, but are not limited to, structural SDOCT (which displays drusen and RPE and can quantify total drusen volume and monitor disease progression), hyperspectral autofluorescence (which can detect fluorophores specific to drusen and basal linear deposits) , color fundus photography, quantitative fundus autofluorescence (qAF), and OCT-fluorescein angiography (FA), and can examine parameters such as cone-mediated visual acuity (eg, best-corrected visual acuity [BCVA]) , which persists into later stages of disease], visual acuity measured with the ETDRS chart, contrast sensitivity checked with the Pelli-Robson chart, low-light visual acuity [visual acuity measured with a neutral density filter to reduce retinal illumination ] and the development of visual aberrations) and rod-mediated vision (eg, dark-adaptation dynamics [sensitively measure macular function that tracks disease progression]). For example, treatment is expected to stabilize or improve photopic (daylight) vision mediated by cone photoreceptors and scotopic (night) vision mediated by rod photoreceptors. As another example, RPE cell health can be assessed with qAF, where stability of qAF intensity or an increase in qAF intensity can indicate stable RPE health or improved RPE health, as a decrease in qAF intensity can indicate RPE cell degeneration. As was done in the MAHALO Phase II study on lampalizumab, qAF can be used to quantify the area or magnitude of geographic atrophy and thereby monitor the progression of non-central GA or central GA. The health of RPE cells can also be assessed with SDOCT, where the presence of hyperreflective foci within the retina that lie vertically above the drusen represents migrating RPE cells, suggesting that the RPE layer is about to disintegrate before RPE cells and photoreceptors atrophy. Poor RPE health may be an indicator of poor visual outcomes in atrophic AMD and neovascular AMD. As another example, OCT-FA can detect the presence of sub-RPE-BL, subretinal or intraretinal fluid, which can indicate active neovascularization and fluid leakage from new vessels.
诊断方法的使用允许监测和调整治疗早期、中期或晚期AMD、或萎缩性AMD或新生血管性AMD的过程，所述治疗使用一种或多种治疗剂(例如，apo模拟物、抗血管生成剂或补体抑制剂，或其任何组合或其全部)。例如，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以通过注射施用(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)用以治疗早期、中期或晚期AMD、或萎缩性AMD或新生血管性AMD。在治疗的初始阶段，apo模拟物可以以一定的注射频率和每次注射以一定剂量施用。如果在显著时长的治疗后一种或多种诊断方法显示显著改善了疾病，或显示疾病的稳定性(例如，SDOCT显示软玻璃疣体积显著减少，或在显著时长的治疗后显示软玻璃疣体积的稳定性)，apo模拟物可以较低频率注射和/或每次以较低剂量注射，或者apo模拟物可以较低频率注射并且每次以较高剂量注射，从而在一定时间内施用基本相似的总剂量。另一方面，如果在初始治疗阶段后一种或多种诊断方法显示疾病的恶化或者疾病没有改变(特别是疾病到更严重形式，例如非中央或中央地图样性萎缩或新生血管性AMD)(例如，在治疗的初始阶段后SDOCT显示软玻璃疣体积增加，或软玻璃疣体积没有变化)，apo模拟物可以更频繁地注射和/或每次以更高的剂量注射。如果一种或多种诊断方法显示疾病明显改善(例如，SDOCT显示消除所有或大多数软玻璃疣)，则可以暂停或停止用apo模拟物治疗。然而，如果在一段时间后一种或多种诊断方法显示疾病复发(例如，SDOCT显示可观或显著量的软玻璃疣)，则可以恢复使用apo模拟物的治疗(例如已经导致显著改善的治疗方案)。可以使用诊断方法监测AMD的进展和治疗以相应地调整治疗。这种治疗方案可称为“按需”或“临机应变”方案。按需的方案涉及常规的门诊就诊(例如，每4、6或8周一次)，以便可以进行一种或多种诊断方法来监测AMD的进展和治疗，尽管根据诊断测试的结果可能不在门诊就诊期间施用治疗剂。The use of diagnostic methods allows monitoring and adjustment of the course of treatment of early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD, using one or more therapeutic agents (e.g., apo mimetics, antiangiogenic agents, etc.). or complement inhibitor, or any combination or all). For example, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] can be administered by injection (eg, intravitreal, subconjunctival, retinal subcapsular injection or sub-Tenon's capsule) for the treatment of early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD. During the initial phase of treatment, the apo mimetic can be administered at a certain frequency of injections and at a certain dose per injection. If one or more diagnostic methods show a significant improvement in disease after a significant period of treatment, or show stabilization of the disease (eg, SDOCT shows a significant reduction in soft drusen volume, or shows a soft drusen volume after a significant period of treatment stability), the apo mimetic can be injected less frequently and/or in lower doses per injection, or the apo mimetic can be injected less frequently and in higher doses per injection, so that the administration is substantially similar over time total dose. On the other hand, if one or more of the diagnostic methods show worsening of the disease or no change in the disease after the initial treatment phase (especially the disease to a more severe form, such as non-central or central geographic pattern atrophy or neovascular AMD) ( For example, where SDOCT shows an increase in soft drusen volume after the initial phase of treatment, or no change in soft drusen volume), the apo mimetic can be injected more frequently and/or at a higher dose each time. Treatment with apo-mimetic can be suspended or discontinued if one or more diagnostic methods show significant improvement in disease (eg, SDOCT shows elimination of all or most soft drusen). However, if one or more diagnostic methods show disease recurrence after a period of time (eg, SDOCT shows an appreciable or significant amount of soft drusen), treatment with apo-mimetic can be resumed (eg, a regimen that has resulted in significant improvement) ). AMD progression and treatment can be monitored using diagnostic methods to adjust treatment accordingly. This treatment regimen may be referred to as an "on-demand" or "on-demand" regimen. On-demand regimens involve routine outpatient visits (eg, every 4, 6, or 8 weeks) so that one or more diagnostics can be performed to monitor AMD progression and treatment, although outpatient visits may not be based on the results of diagnostic tests Therapeutic agent was administered during the period.
作为通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)施用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗早期、中期或晚期AMD、或萎缩性AMD或新生血管性AMD的另一个实例，可以在治疗的初始阶段期间将apo模拟物以一定的注射频率(例如，每月一次)施用，并且以每次一定剂量注射施用。在治疗的第二阶段期间，apo模拟物可以较低频率注射(例如，每6或8周一次)，并且每次注射的剂量与每次注射的初始剂量相同或者每次注射的剂量更高，以便在一段时间内施用的总剂量基本相似。治疗的第二阶段可以持续选定的一段时间。在任选的治疗的第三阶段期间，apo模拟物甚至可以较低频率注射(例如，每10或12周一次)，并且每次注射的剂量与每次注射的初始剂量相同或每次注射的剂量更高，以便在一段时间内施用的总剂量基本相似。任选的治疗的第三阶段可以持续选定的一段时间。等等。这种治疗方案可称为“治疗和延长”方案。在初始/第一阶段、第二阶段、任选的第三阶段和任何额外的任选治疗阶段，可以执行一种或多种诊断方法以监测AMD的进展和治疗，并且可能根据诊断测试结果调整治疗。例如，如果一种或多种诊断方法显示疾病恶化(例如，SDOCT显示软玻璃疣体积增加)，则可以更频繁地注射apo模拟物和/或每次注射以更高的剂量注射apo模拟物。相反，如果一种或多种诊断方法显示疾病稳定或疾病改善(例如，SDOCT显示软玻璃疣体积稳定或软玻璃疣体积减少)，则可以较低频率注射apo模拟物和/或每次注射以较低剂量注射apo模拟物，或者可以较低频率注射apo模拟物并且每次注射以较高剂量注射apo模拟物，以便在一定时间内施用基本相似的总剂量。与按需治疗方案不同，治疗和延长方案不涉及常规诊断就诊，而是在常规治疗就诊中施用治疗剂(其频率在治疗的第二阶段和任选的第三阶段中降低)，即使当时在医学上可能不需要治疗剂或所施用的剂量。频繁的门诊就诊(无论是用于监测和/或治疗)和频繁(例如，每月)注射可能具有负面后果，例如患者依从性降低、不良医疗效果(例如快速耐受)和增加的医疗保健成本。治疗和延长方案相对于按需方案的潜在优势在于它可以减少用于监测和治疗的门诊就诊总数。Administration of apo mimetics (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] In another example of treatment of early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD, the apo mimetic may be administered at a certain frequency (eg, monthly) during the initial phase of treatment once), and each dose is administered by injection. During the second phase of treatment, the apo mimetic can be injected less frequently (eg, every 6 or 8 weeks), and the dose per injection is the same as the initial dose per injection or a higher dose per injection, so that the total dose administered over a period of time is substantially similar. The second phase of treatment can continue for a selected period of time. During the optional third phase of treatment, the apo mimetic may be injected even less frequently (eg, every 10 or 12 weeks), and the dose per injection is the same as the initial dose per injection or Doses are higher so that the total dose administered over time is substantially similar. The optional third phase of treatment may continue for a selected period of time. and many more. Such a treatment regimen may be referred to as a "treatment and extension" regimen. During the initial/first stage, second stage, optional third stage and any additional optional treatment stages, one or more diagnostic methods may be performed to monitor AMD progression and treatment, and may be adjusted based on diagnostic test results treat. For example, if one or more diagnostic methods show disease progression (eg, SDOCT shows increased soft drusen volume), the apo mimetic may be injected more frequently and/or at a higher dose per injection. Conversely, if one or more of the diagnostic methods show stable disease or improvement in disease (eg, SDOCT shows stable soft drusen volume or soft drusen volume reduction), apo mimetic can be injected less frequently and/or each injection can be The apo mimetic is injected at lower doses, or the apo mimetic can be injected less frequently and at a higher dose per injection so that a substantially similar total dose is administered over a period of time. Unlike on-demand treatment regimens, treatment and extension regimens do not involve routine diagnostic visits, but rather the administration of the therapeutic agent (at a reduced frequency during the second and optional third stages of treatment) during routine treatment visits, even when The therapeutic agent or the administered dose may not be medically required. Frequent outpatient visits (whether for monitoring and/or treatment) and frequent (eg, monthly) injections may have negative consequences, such as reduced patient compliance, adverse medical outcomes (eg, tachyphylaxis), and increased healthcare costs . A potential advantage of the treatment and extension regimen over the on-demand regimen is that it can reduce the total number of outpatient visits for monitoring and treatment.
作为治疗和延长方案的非限制性实例，无论是单独使用还是与另一种治疗剂(例如，apo模拟物，例如apoA-I模拟物[例如，L-4F]或apoE模拟物[例如，AEM-28-14])组合使用，用于治疗新生血管性AMD的抗血管生成剂(例如抗VEGF剂，如阿比西普、贝伐单抗或雷珠单抗)可以每4、6或8周注射一次(例如，玻璃体内)，直到达到最大效果，例如在没有新的视网膜出血情况下基本上完全消退视网膜下液体和/或视网膜内液体、或者至少连续两次门诊就诊在没有新的视网膜出血情况下在OCT-FA中没有进一步减少的视网膜下液体和/或视网膜内液体。在这种情况下，可以较低频率(注射之间的间隔可以延长例如约2或4周)注射抗血管生成剂。如果疾病保持稳定，则注射之间的间隔可以延长例如约2或4周一次，并且总延长期可以达到例如约3、4、5或6个月。如果患者的疾病表现出相对轻微的恶化(例如，再次出现相对少量的视网膜下液体和/或视网膜内液体或其量相对小的增加)，则注射抗血管生成剂之间的间隔可以缩短例如大约1或2周。如果疾病恶化严重，可以恢复抗血管生成剂的频繁注射(例如，每4、6或8周一次)。类似的原理也适用于用任何其他类型的治疗剂治疗萎缩性AMD或新生血管性AMD的治疗和延长方案，所述任何其他类型的治疗剂包括但不限于apo模拟物(例如，apoA-I模拟物，例如L-4F或apoE模拟物如AEM-28-14)和补体抑制剂(例如补体因子D抑制剂如兰波利珠单抗)。As non-limiting examples of treatment and extended regimens, either alone or in combination with another therapeutic agent (eg, an apo mimetic, such as an apoA-I mimetic [eg, L-4F] or an apoE mimetic [eg, AEM] -28-14]) in combination, anti-angiogenic agents (eg, anti-VEGF agents such as abicept, bevacizumab, or ranibizumab) for the treatment of neovascular AMD may be administered every 4, 6, or 8 Weekly injections (eg, intravitreal) until maximal effect is achieved, such as substantially complete resolution of subretinal fluid and/or intraretinal fluid in the absence of new retinal hemorrhages, or at least two consecutive outpatient visits in the absence of new retinas There was no further reduction of subretinal fluid and/or intraretinal fluid in OCT-FA in the hemorrhagic setting. In this case, the anti-angiogenic agent may be injected less frequently (the interval between injections may be extended, eg, by about 2 or 4 weeks). If the disease remains stable, the interval between injections can be extended, for example, once every 2 or 4 weeks, and the total extended period can reach, for example, about 3, 4, 5, or 6 months. If the patient's disease exhibits a relatively mild deterioration (eg, reappearance of a relatively small amount of subretinal fluid and/or intraretinal fluid or a relatively small increase in the amount), the interval between injections of the antiangiogenic agent can be shortened, for example, by approximately 1 or 2 weeks. Frequent injections of the antiangiogenic agent (eg, every 4, 6, or 8 weeks) can be resumed if the disease worsens. Similar principles apply to treatment and prolonged regimens for the treatment of atrophic AMD or neovascular AMD with any other type of therapeutic agent, including, but not limited to, apo mimetics (e.g., apoA-I mimics). (eg L-4F or apoE mimetics such as AEM-28-14) and complement inhibitors (eg complement factor D inhibitors such as lambolizumab).
作为用于治疗早期、中期或晚期AMD、或萎缩性AMD或新生血管性AMD的按需方案或治疗和延长方案的替代方案，对于基本上由主治医师选择的完整治疗时长或直到一种或多种诊断方法根据选定的测量标准的结果表明已经成功治疗疾病，可以以基本上相同的频率施用和每次施用基本相同的剂量施用治疗剂(例如，apo模拟物、抗血管生成剂或补体抑制剂)。这种治疗方案可称为“固定常规”方案。As an alternative to on-demand regimens or treatment and extended regimens for the treatment of early, intermediate, or advanced AMD, or atrophic AMD or neovascular AMD, for the full duration of treatment or until one or more A diagnostic method based on the results of selected measures indicating that the disease has been successfully treated, a therapeutic agent (e.g., an apo mimetic, anti-angiogenic agent, or complement inhibition can be administered at substantially the same frequency and at substantially the same dose per administration) agent). This regimen may be referred to as a "fixed routine" regimen.
apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以作为组合物施用，所述组合物包含一种或多种药学上可接受的赋形剂或载体的。如果使用两种或更多种apo模拟物(例如，apoA-I模拟物和apoE模拟物)，它们可以以相同的组合物或不同的组合物施用。在一些实施方案中，相对于它们合计的量，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物包含以重量计或摩尔浓度计约75-95％(例如，约90％)的apo模拟物和约5-25％(例如，约10％)的相应的载脂蛋白(例如，apoA-I和/或apoE)或其活性部分或其结构域。在某些实施方案中，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物被配制用于注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)。用于注射到眼中的制剂的实例包括但不限于本文其他地方描述的那些。在其他实施方案中，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物被配制为滴眼剂或植入物(例如，玻璃体内、视网膜下或特农氏囊下植入物)。使用一次或两次滴眼剂或植入一次或两次植入物可以避免与重复注射相关的潜在问题。apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] can be administered as a composition comprising one or more A pharmaceutically acceptable excipient or carrier. If two or more apo mimetics are used (eg, apoA-I mimetic and apoE mimetic), they can be administered in the same composition or in different compositions. In some embodiments, a combination of apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] are contained relative to their combined amounts The compound comprises about 75-95% by weight or molar concentration (eg, about 90%) of the apo mimetic and about 5-25% (eg, about 10%) of the corresponding apolipoproteins (eg, apoA-I and /or apoE) or its active part or its domain. In certain embodiments, compositions containing an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] are formulated for injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule injection). Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In other embodiments, compositions containing an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] are formulated as eye drops or implants (eg, intravitreal, subretinal, or subtenon's capsule). Using one or two eye drops or implanting one or two implants can avoid potential problems associated with repeated injections.
在进一步的实施方案中，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物被配置用于缓释apo模拟物。缓释组合物的非限制性实例包括本文其他地方描述的那些。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]通过微粒施用，例如聚合物微粒或主要包含apo模拟物或基本上由apo模拟物组成的微粒。使用缓释组合物或此类微粒可以减少为了施用药物进行的潜在侵入性操作(例如，玻璃体内注射)的次数，并且可以改善一段时间递送至靶位点的药物量的分布。In further embodiments, compositions comprising an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] are configured for slowing down release apo mimics. Non-limiting examples of sustained release compositions include those described elsewhere herein. In certain embodiments, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] are administered via microparticles, such as polymeric microparticles or Microparticles comprising mainly apo mimetics or consisting essentially of apo mimetics. The use of sustained release compositions or such microparticles can reduce the number of potentially invasive procedures (eg, intravitreal injections) performed to administer the drug, and can improve the distribution of the amount of drug delivered to the target site over time.
在一些实施方案中，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物包含一种或多种赋形剂，所述赋形剂抑制肽/蛋白质聚集、增加肽/蛋白质溶解度、降低溶液粘度或增加肽/蛋白质稳定性，或其任何组合或全部。此类赋形剂的实例包括但不限于本文其他地方描述的那些。这些赋形剂可以改善含有apo模拟物的组合物的可注射性。因此，这种赋形剂使得在施用(例如通过玻璃体内注射)含有apo模拟物的组合物时能够使用具有较小规格(例如，小于30G)的针(例如注射针)。In some embodiments, compositions containing an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] comprise one or more An excipient that inhibits peptide/protein aggregation, increases peptide/protein solubility, reduces solution viscosity, or increases peptide/protein stability, or any combination or all thereof. Examples of such excipients include, but are not limited to, those described elsewhere herein. These excipients can improve the injectability of compositions containing apo mimetics. Thus, this excipient enables the use of needles of smaller gauge (eg, less than 30G) (eg, injection needles) when administering (eg, by intravitreal injection) compositions containing an apo mimetic.
因为这样的赋形剂抑制肽/蛋白质聚集并增加肽/蛋白质溶解度，所以例如可以运用它们来增加溶液或悬浮液中肽或蛋白质的浓度。肽/蛋白质浓度的增加减少了施用给定量的肽或蛋白质所需的体积，如果通过注射到眼睛中施用肽或蛋白质，则其可以具有有益效果(例如降低眼压)。此外，肽/蛋白质浓度的增加允许对于给定体积施用更大剂量的肽或蛋白质，这可以在一段时间内对于施用的给定总剂量允许较低频率地施用肽或蛋白质。较低频率的施用(例如，通过玻璃体内注射)肽或蛋白质可具有益处，例如由于较少执行侵入性程序而改善患者依从性和健康。Because such excipients inhibit peptide/protein aggregation and increase peptide/protein solubility, they can be employed, for example, to increase the concentration of peptides or proteins in solution or suspension. An increase in peptide/protein concentration reduces the volume required to administer a given amount of peptide or protein, which can have beneficial effects (eg, lowering intraocular pressure) if the peptide or protein is administered by injection into the eye. In addition, the increase in peptide/protein concentration allows for a larger dose of peptide or protein to be administered for a given volume, which may allow for less frequent administration of the peptide or protein over a period of time for a given total dose administered. Less frequent administration of peptides or proteins (eg, by intravitreal injection) may have benefits, such as improved patient compliance and health due to less invasive procedures being performed.
apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以单独使用或与一种或多种其他治疗剂组合使用来治疗AMD。其他治疗剂的实例包括但不限于本文其他地方描述的那些。如本文其他地方所述，在AMD的不同阶段(例如，AMD的早期阶段、中期阶段或晚期阶段)以及为了治疗不同表型的AMD(例如，地图样萎缩或新生血管性AMD)可以将一种或多种其他治疗剂与apo模拟物联合施用。apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] can be used alone or in combination with one or more other therapeutic agents to Treat AMD. Examples of other therapeutic agents include, but are not limited to, those described elsewhere herein. As described elsewhere herein, one can be used in different stages of AMD (eg, early, intermediate, or late stages of AMD) and for the treatment of different phenotypes of AMD (eg, geographic atrophy or neovascular AMD). or multiple other therapeutic agents are administered in combination with the apo mimetic.
载脂蛋白模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])(任选地与一种或多种其他治疗剂联合)可以用于治疗与AMD相关的任何症状或并发症。这些症状和并发症的实例包括但不限于在BrM上脂质(包括中性脂质和修饰的脂质)的积累、BrM的增厚、富含脂质的残骸的积累、RPE-BL和BrM ICL之间富含脂质的残骸(包括基底线性沉积物和玻璃疣)的沉积、在RPE和脉络膜毛细血管之间形成扩散屏障、光感受器退化、地图样萎缩(包括非中央和中央GA)、RPE萎缩、新生血管形成(包括1、2和3型NV)、眼内渗漏、出血和瘢痕、以及视力损害和丧失。Apolipoprotein mimetics (eg, apoA-I mimetics [eg, L-4F] and/or apoE mimetics [eg, AEM-28-14]) (optionally in combination with one or more other therapeutic agents) ) can be used to treat any symptoms or complications associated with AMD. Examples of such symptoms and complications include, but are not limited to, accumulation of lipids (including neutral and modified lipids) on BrM, thickening of BrM, accumulation of lipid-rich debris, RPE-BL and BrM Deposition of lipid-rich debris (including basal linear deposits and drusen) between ICLs, formation of a diffusion barrier between RPE and choriocapillaris, photoreceptor degeneration, geographic atrophy (including non-central and central GA), RPE atrophy, neovascularization (including types 1, 2, and 3 NV), intraocular leakage, bleeding and scarring, and visual impairment and loss.
作为非限制性实例，本公开的一些实施方案涉及预防与AMD相关的视力损害或丧失、延迟所述视力损害或丧失的发作、减缓所述视力损害或丧失的进展或减轻所述视力损害或丧失的程度的方法，包括向对象施用治疗有效量的apo模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])。可任选地施用一种或多种其他治疗剂。视力损害或丧失可与萎缩性AMD(包括非中央和/或中央地图样萎缩)或新生血管性AMD(包括1、2和/或3型新生血管形成)相关。By way of non-limiting example, some embodiments of the present disclosure relate to preventing AMD-related vision impairment or loss, delaying the onset of the vision impairment or loss, slowing the progression of the vision impairment or loss, or alleviating the vision impairment or loss A method comprising administering to the subject a therapeutically effective amount of an apo mimetic (eg, an apoA-I mimetic [eg, L-4F] and/or an apoE mimetic [eg, AEM-28-14]). One or more other therapeutic agents can optionally be administered. Visual impairment or loss can be associated with atrophic AMD (including non-central and/or central geographic atrophy) or neovascular AMD (including type 1, 2 and/or 3 neovascularization).
V.其他治疗剂的种类V.Types of other therapeutic agents
如上所述，AMD具有多种潜在因素，包括含脂质沉积物的形成、毒性副产物的形成、氧化、炎症、新生血管形成和细胞死亡。靶向AMD的多种潜在因子或具有不同作用机制的多种治疗剂可用于治疗AMD。可任选与载脂蛋白模拟物组合使用以治疗AMD的治疗剂包括但不限于：As noted above, AMD has a variety of underlying factors, including the formation of lipid-containing deposits, the formation of toxic by-products, oxidation, inflammation, neovascularization, and cell death. Multiple potential factors for AMD or multiple therapeutic agents with different mechanisms of action can be used to treat AMD. Therapeutic agents that may optionally be used in combination with an apolipoprotein mimetic to treat AMD include, but are not limited to:
1)抗血脂异常剂；1) Anti-dyslipidemic agents;
2)PPAR-α激动剂、PPAR-δ激动剂和PPAR-γ激动剂；2) PPAR-α agonists, PPAR-δ agonists and PPAR-γ agonists;
3)抗淀粉样蛋白剂；3) anti-amyloid agents;
4)脂褐素或其组分的抑制剂；4) inhibitors of lipofuscin or components thereof;
5)视觉/光周期调节剂和暗适应剂；5) Vision/photoperiod regulators and dark adaptors;
6)抗氧化剂；6) Antioxidants;
7)神经保护剂(神经保护试剂)；7) Neuroprotective agents (neuroprotective agents);
8)凋亡抑制剂和坏死抑制剂；8) Apoptosis inhibitors and necrosis inhibitors;
9)C-反应蛋白(CRP)抑制剂；9) C-reactive protein (CRP) inhibitor;
10)补体系统或其组分(例如蛋白质)的抑制剂；10) Inhibitors of the complement system or its components (eg proteins);
11)炎性体抑制剂；11) Inflammasome inhibitors;
12)抗炎剂；12) Anti-inflammatory agents;
13)免疫抑制剂；13) Immunosuppressants;
14)基质金属蛋白酶(MMP)的调节剂；和14) Modulators of matrix metalloproteinases (MMPs); and
15)抗血管生成剂。15) Anti-angiogenic agents.
特定治疗剂可以发挥一种以上的生物学或药理学作用，并且可以分类至多于一类。A particular therapeutic agent can exert more than one biological or pharmacological effect, and can be classified into more than one class.
治疗剂以治疗有效量使用。当与另一种治疗剂(例如，载脂蛋白模拟物)组合使用时，治疗剂可以与其他治疗剂基本上同时施用(例如在同一医生的就诊期间，或在彼此的约30或60分钟内)，或施用其他治疗剂之前或之后施用。当与另一种治疗剂同时施用时，治疗剂可以与其他治疗剂在相同的制剂中施用或在分开的制剂中施用。Therapeutic agents are used in therapeutically effective amounts. When used in combination with another therapeutic agent (eg, an apolipoprotein mimetic), the therapeutic agent can be administered substantially simultaneously with the other therapeutic agent (eg, during the same doctor's visit, or within about 30 or 60 minutes of each other) ), or before or after administration of other therapeutic agents. When administered concurrently with another therapeutic agent, the therapeutic agent can be administered in the same formulation as the other therapeutic agent or in a separate formulation.
富含脂质的沉积物的形成是AMD的重要上游原因，所述原因导致并发症(例如非中央和中央地图样萎缩和新生血管形成)。一种多管齐下来预防或最小化富含脂质的物质的积累的方法是抑制由RPE细胞产生脂质(如胆固醇和脂肪酸)和脂蛋白(如VLDL)，抑制RPE细胞摄取血脂(例如，胆固醇和脂肪酸)和脂蛋白(例如，VLDL)，抑制脂质(例如，胆固醇和脂肪酸)和脂蛋白(例如，VLDL)及其组分(例如，apoB和apoE)从RPE细胞分泌进入BrM、亚RPE-BL空间和视网膜下空间，以及清除BrM、亚RPE-BL空间和视网膜下空间的脂质(如胆固醇和氧化的脂质)和脂蛋白(如VLDL)及其组分(如apoB和apoE)。例如，apoB至少参与肝脏VLDL的形成，所述肝脏VLDL至少是血浆LDL的来源。RPE细胞对apoB产生的抑制和RPE细胞对可用于脂质化apoB的脂肪酸的摄取的抑制可以减少RPE细胞产生VLDL，并因此可能减少LDL的产生。The formation of lipid-rich deposits is an important upstream cause of AMD leading to complications such as non-central and central geographic atrophy and neovascularization. A multi-pronged approach to preventing or minimizing the accumulation of lipid-rich substances is to inhibit the production of lipids (such as cholesterol and fatty acids) and lipoproteins (such as VLDL) by RPE cells, and the uptake of blood lipids by RPE cells (e.g., Cholesterol and fatty acids) and lipoproteins (eg, VLDL), inhibit secretion of lipids (eg, cholesterol and fatty acids) and lipoproteins (eg, VLDL) and their components (eg, apoB and apoE) from RPE cells into BrM, subcutaneous RPE-BL space and subretinal space, and clearance of lipids (such as cholesterol and oxidized lipids) and lipoproteins (such as VLDL) and their components (such as apoB and apoE) from BrM, sub-RPE-BL space and subretinal space ). For example, apoB is involved in at least the formation of hepatic VLDL, which is at least a source of plasma LDL. Inhibition of apoB production by RPE cells and inhibition of RPE cell uptake of fatty acids available for lipidation of apoB may reduce VLDL production by RPE cells, and thus possibly LDL production.
抗血脂异常试剂尤其调节脂质、脂蛋白和其他物质的产生、摄取和清除，所述其他物质在视网膜内、视网膜下、亚RPE-BL空间、脉络膜(例如，BrM)中的含脂质沉积物的形成中起作用。一类抗血脂异常剂是贝特类，其激活过氧化物酶体增殖物激活受体-α(PPAR-α)。贝特类是降血脂剂，其可降低脂肪酸和甘油三酯的产生、诱导脂蛋白脂解作用但刺激高密度脂蛋白(HDL，介导胆固醇反向运输)的产生、增加从血浆中去除LDL，并刺激胆固醇从细胞向循环最终到肝脏(在这里胆固醇被代谢并排泄到胆汁中)的反向运输。(胆固醇也可通过例如由肠道对HDL-胆固醇酯的去除来清理。卵磷脂-胆固醇酰基转移酶[LCAT](一种由例如载脂蛋白A-I激活的血浆酶)将游离胆固醇转化为胆固醇酯，然后所述胆固醇酯被隔离在HDL颗粒的核心中。)贝特类的实例包括但不限于苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、洛非贝特(clinofibrate)、氯贝特酸(clofibric acid)、氯贝特(clofibrate)、氯贝特铝(aluminum clofibrate)、氯贝比(clofibride)、乙氧贝特(etofibrate)、非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil)、氯烟贝特(ronifibrate)、双贝特(simfibrate)及其类似物、衍生物和盐。其他降低甘油三酯剂包括ω-3脂肪酸，例如二十二碳六烯酸(DHA)和二十碳五烯酸(EPA)。Anti-dyslipidemic agents modulate, inter alia, the production, uptake, and clearance of lipids, lipoproteins, and other substances that contain lipid deposits in the intraretinal, subretinal, sub-RPE-BL spaces, choroid (eg, BrM) play a role in the formation of things. One class of anti-dyslipidemic agents is the fibrates, which activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Fibrates are hypolipidemic agents that reduce fatty acid and triglyceride production, induce lipoprotein lipolysis but stimulate high-density lipoprotein (HDL, which mediates reverse cholesterol transport) production, increase LDL removal from plasma , and stimulates the reverse transport of cholesterol from cells to the circulation and ultimately to the liver, where cholesterol is metabolized and excreted into bile. (Cholesterol can also be cleared, for example, by the removal of HDL-cholesteryl esters from the gut. Lecithin-cholesterol acyltransferase [LCAT], a plasma enzyme activated by, for example, apolipoprotein A-I) converts free cholesterol to cholesteryl esters , the cholesteryl ester is then sequestered in the core of the HDL particle.) Examples of fibrates include, but are not limited to, bezafibrate, ciprofibrate, clinofibrate, chlorine clofibric acid, clofibrate, aluminum clofibrate, clofibride, etofibrate, fenofibrate, gemfibro Gemfibrozil, ronifibrate, simfibrate and their analogs, derivatives and salts. Other triglyceride lowering agents include omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
另一类抗血脂异常试剂是HMG-CoA还原酶抑制剂(他汀类)。他汀类抑制胆固醇合成、减少VLDL和LDL apoB的产生(或含apoB的VLDL和LDL的产生)、降低apoB分泌、以及降低血脂水平。他汀类的实例包括但不限于阿托伐他汀(atorvastatin)、西立伐他汀(cerivastatin)、氟伐他汀(fluvastatin)、美伐他汀(mevastatin)、莫纳可林(monacolin)类(例如，莫纳可林K[洛伐他汀(lovastatin)])、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、罗苏伐他汀(rosuvastatin)、辛伐他汀(simvastatin)及其类似物、衍生物和盐。Another class of anti-dyslipidemic agents are HMG-CoA reductase inhibitors (statins). Statins inhibit cholesterol synthesis, reduce VLDL and LDL apoB production (or apoB-containing VLDL and LDL production), reduce apoB secretion, and lower blood lipid levels. Examples of statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, mevastatin, monacolins (eg, molar Nacolin K [lovastatin]), pitavastatin, pravastatin, rosuvastatin, simvastatin and their analogs, derivatives and Salt.
其他抗血脂异常剂包括乙酰辅酶A羧化酶(ACC)抑制剂。ACC抑制剂抑制脂肪酸和甘油三酯(TG)合成并减少VLDL-TG分泌。ACC抑制剂的非限制性实例包括花青素、燕麦曲菌素(avenaciolides)、苯并二氧杂环庚烯{例如，7-(4-丙氧基-苯乙炔基)-3,3-二甲基-3,4-二氢-2H-苯并[b][1,4]二氧杂环庚烯}、苯并噻吩[例如，N-乙基-N'-(3-{[4-(3,3-二甲基-1-氧代-2-氧杂-7-氮杂螺[4.5]癸-7-yl)哌啶-l-yl]-羰基}-l-苯并噻吩-2-yl)脲)、双哌啶基甲酰胺(如CP-640186)、氯乙酰化生物素、cyclodim、禾草灵(diclofop)、吡氟氯禾灵(haloxyfop)、联苯基-吡啶和3-苯基吡啶、苯氧基噻唑(phenoxythiazolcs){例如5-(3)-乙酰氨基丁-1-炔基}-2-(4-丙氧基苯氧基)噻唑]、哌嗪恶二唑、(4-哌啶基)-哌嗪、沙罗酚(soraphens)(如沙罗酚A1α)、螺-哌啶、螺-吡唑烷二酮、螺[色满]-2,4'-哌啶)-4-酮、5-(十四烷氧基)-2-呋喃甲酸酯(TOFA)、噻唑基苯基醚、噻吩[例如，1-(3-{[4-(3,3-二甲基-1-氧代-2-氧杂-7-氮杂螺[4.5]癸-7-yl)哌啶-1-yl]-羰基}-5-(吡啶-2-yl)-2-噻吩)-3-乙基脲]，及其类似物、衍生物及盐。Other anti-dyslipidemic agents include acetyl-CoA carboxylase (ACC) inhibitors. ACC inhibitors inhibit fatty acid and triglyceride (TG) synthesis and reduce VLDL-TG secretion. Non-limiting examples of ACC inhibitors include anthocyanins, avenaciolides, benzodioxins {eg, 7-(4-propoxy-phenylethynyl)-3,3- Dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepene}, benzothiophene [eg, N-ethyl-N'-(3-{[ 4-(3,3-Dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]deca-7-yl)piperidine-1-yl]-carbonyl}-1-benzo thiophene-2-yl)urea), bispiperidinylcarboxamide (such as CP-640186), chloroacetylated biotin, cyclodim, diclofop, haloxyfop, biphenyl- Pyridine and 3-phenylpyridine, phenoxythiazolcs {eg 5-(3)-acetamidobut-1-ynyl}-2-(4-propoxyphenoxy)thiazole], piperazine Oxadiazoles, (4-piperidinyl)-piperazine, soraphens (e.g. sarophenol A1α ), spiro-piperidines, spiro-pyrazolidinediones, spiro[chroman]-2 ,4'-piperidin)-4-one, 5-(tetradecyloxy)-2-furancarboxylate (TOFA), thiazolyl phenyl ether, thiophene [eg, 1-(3-{[4 -(3,3-Dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]deca-7-yl)piperidine-1-yl]-carbonyl}-5-(pyridine- 2-yl)-2-thiophene)-3-ethylurea], and analogs, derivatives and salts thereof.
酰基-CoA胆固醇酰基转移酶(ACAT)抑制剂也可用作抗血脂异常剂。ACAT抑制剂抑制胆固醇酯化并减少VLDL和LDL apoB的产生(或含apoB的VLDL和LDL的产生)。ACAT抑制剂的实例包括但不限于阿伐西米(avasimibe)、帕替米贝(pactimibe)、派立托胺(pellitorine)、terpendole C，及其类似物、衍生物和盐。Acyl-CoA cholesterol acyltransferase (ACAT) inhibitors are also useful as anti-dyslipidemic agents. ACAT inhibitors inhibit cholesterol esterification and reduce VLDL and LDL apoB production (or apoB-containing VLDL and LDL production). Examples of ACAT inhibitors include, but are not limited to, avasimibe, pactimibe, pellitorine, terpendole C, and analogs, derivatives, and salts thereof.
另一类抗血脂异常剂是胰高血糖素样肽-1(GLP-1)受体激动剂。GLP-1受体激动剂减少apoB和VLDL颗粒的产生，并从而减少VLDL-apoB和VLDL-TG、降低胆固醇和甘油三酯的细胞含量、以及通过减少肝脂肪生成来减少或逆转肝脂肪变性(脂肪肝)。GLP-1受体激动剂的非限制性实例包括艾塞那肽(exendin)-4、阿必鲁肽(albiglutide)、度拉糖肽(dulaglutide)、艾塞那肽(exenatide)、利拉鲁肽(liraglutide)、利西拉来(lixisenatide)、索马鲁肽(semaglutide)、他司鲁泰(taspoglutide)、CNT0736、CNT03649，及其类似物、衍生物和盐。由于GLP-1(GLP-1受体的内源性配体)被二肽基肽酶4(DPP-4)快速降解，因此虽然效力可能较低，但使用DPP-4抑制剂可以实现与GLP-1受体激动剂相似的抗血脂异常作用。DPP-4抑制剂的非限制性实例包括阿格列汀(alogliptin)、阿拉格列汀(anagliptin)、杜拓格利普汀(dutogliptin)、吉格列汀(gemigliptin)、利格列汀(linagliptin)、沙格列汀(saxagliptin)、西他列汀(sitagliptin)、特力利汀(teneligliptin)、维达列汀(vildagliptin)、小檗碱、羽扇豆醇(lupeol)，及其类似物、衍生物和盐。Another class of anti-dyslipidemic agents are glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 receptor agonists reduce the production of apoB and VLDL particles and thereby reduce VLDL-apoB and VLDL-TG, lower cellular content of cholesterol and triglycerides, and reduce or reverse hepatic steatosis by reducing hepatic lipogenesis ( fatty liver). Non-limiting examples of GLP-1 receptor agonists include exendin-4, albiglutide, dulaglutide, exenatide, liraru Liraglutide, lixisenatide, semaglutide, taspoglutide, CNT0736, CNT03649, and analogs, derivatives and salts thereof. Since GLP-1, the endogenous ligand of the GLP-1 receptor, is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), although potentially less potent, the use of DPP-4 inhibitors can achieve a similar Anti-dyslipidemic effects similar to -1 receptor agonists. Non-limiting examples of DPP-4 inhibitors include alogliptin, anagliptin, dutogliptin, gemigliptin, linagliptin ( linagliptin), saxagliptin, sitagliptin, teneligliptin, vildagliptin, berberine, lupeol, and analogs thereof, Derivatives and Salts.
另外的抗血脂异常剂包括微粒体甘油三酯转运蛋白(MTTP)的抑制剂，所述MTTP在RPE细胞中表达。MTTP催化胆固醇、甘油三酯和apoB与乳糜微粒和VLDL的组装。MTTP抑制剂抑制含apoB的乳糜微粒和VLDL的合成，并抑制这些脂蛋白的分泌。MTTP抑制剂的实例包括但不限于microRNA(例如，miRNA-30c)、英普他派(implitapide)、洛美他派(lomitapide)、得洛他派(dirlotapide)、米搓他派(mitratapide)、CP-346086、JTT-130、SLx-4090，及其类似物、衍生物和盐。全身施用MTTP抑制剂可导致肝脏脂肪变性(例如，肝脏中甘油三酯的积累)，其可通过以下来避免：例如局部施用MTTP抑制剂、使用非全身吸收的MTTP抑制剂(例如，SLx-4090)、或与GLP-1受体激动剂的共同施用，或其任何组合或全部。避免肝脏脂肪变性的另一种选择是使用miRNA-30c。miRNA-30c序列的一个区域降低MTTP表达和apoB分泌，而另一个区域降低脂肪酸合成，所述miRNA-30c对肝脏没有有害作用。Additional anti-dyslipidemic agents include inhibitors of the microsomal triglyceride transfer protein (MTTP), which is expressed in RPE cells. MTTP catalyzes the assembly of cholesterol, triglycerides and apoB with chylomicrons and VLDL. MTTP inhibitors inhibit the synthesis of apoB-containing chylomicrons and VLDL and inhibit the secretion of these lipoproteins. Examples of MTTP inhibitors include, but are not limited to, microRNA (eg, miRNA-30c), implitapide, lomitapide, dirlotapide, mitratapide, CP-346086, JTT-130, SLx-4090, and analogs, derivatives and salts thereof. Systemic administration of MTTP inhibitors can lead to hepatic steatosis (eg, accumulation of triglycerides in the liver), which can be avoided by, eg, topical administration of MTTP inhibitors, use of non-systemically absorbed MTTP inhibitors (eg, SLx-4090 ), or co-administration with a GLP-1 receptor agonist, or any combination or all thereof. Another option to avoid hepatic steatosis is to use miRNA-30c. One region of the miRNA-30c sequence reduces MTTP expression and apoB secretion, while another region reduces fatty acid synthesis, which miRNA-30c has no deleterious effect on the liver.
其他种类的抗血脂异常多核苷酸包括靶向apoB的mRNA的反义多核苷酸，包括apoB48和apoB100。ApoB在VLDL和随后的LDL的形成中是重要的。使用全部或部分(例如，至少约50％、60％、70％、80％、90％或95％)与apoB的mRNA互补的反义多核苷酸来阻断apoB的翻译表达并因此产生VLDL和LDL。靶向apoB的mRNA的反义多核苷酸的实例包括但不限于米泊美生(mipomersen)。其他抗血脂异常反义多核苷酸包括靶向miRNA-33a和miRNA-33b的那些。miRNA-33a和miRNA-33b抑制ATP结合盒转运蛋白ABCA1(胆固醇外排调节蛋白[CERP])的表达，所述ABCA1介导胆固醇和磷脂的流出。使用全部或部分(例如，至少约50％、60％、70％、80％、90％或95％)与miRNA-33a和/或miRNA-33b互补的反义多核苷酸增加了胆固醇反向运输和HDL的生产和降低VLDL-TG和脂肪酸的产生。增加ABCA1的表达也对AMD的血管生成具有保护作用。Other classes of anti-dyslipidemic polynucleotides include antisense polynucleotides targeting the mRNA of apoB, including apoB48 and apoB100. ApoB is important in the formation of VLDL and subsequent LDL. Block translational expression of apoB and thus produce VLDL and LDL. Examples of antisense polynucleotides targeting the mRNA of apoB include, but are not limited to, mipomersen. Other anti-dyslipidemic antisense polynucleotides include those targeting miRNA-33a and miRNA-33b. miRNA-33a and miRNA-33b inhibit the expression of the ATP-binding cassette transporter ABCA1 (cholesterol efflux regulator protein [CERP]), which mediates the efflux of cholesterol and phospholipids. Increased reverse cholesterol transport using antisense polynucleotides complementary to miRNA-33a and/or miRNA-33b in whole or in part (eg, at least about 50%, 60%, 70%, 80%, 90%, or 95%) and HDL production and reduce VLDL-TG and fatty acid production. Increased expression of ABCA1 also has a protective effect on angiogenesis in AMD.
此外，胆固醇转移蛋白(CETP)抑制剂可用作抗血脂异常剂。CETP将胆固醇从HDL转移至VLDL和LDL。CETP抑制剂增加HDL水平、降低VLDL和LDL水平、并增加胆固醇从细胞向循环最终到肝脏(在这里胆固醇被代谢并排泄到胆汁中)的反向运输。CETP抑制剂的实例包括但不限于安塞曲匹(anacetrapib)、达塞曲匹(dalcetrapib)、依塞曲匹(evacetrapib)、托彻普(torcetrapib)、AMG 899(TA-8995)，及其类似物、衍生物和盐。In addition, cholesterol transfer protein (CETP) inhibitors are useful as anti-dyslipidemic agents. CETP transfers cholesterol from HDL to VLDL and LDL. CETP inhibitors increase HDL levels, decrease VLDL and LDL levels, and increase the reverse transport of cholesterol from cells to the circulation and ultimately to the liver, where cholesterol is metabolized and excreted into bile. Examples of CETP inhibitors include, but are not limited to, anacetrapib, dalcetrapib, evacetrapib, torcetrapib, AMG 899 (TA-8995), and Analogs, derivatives and salts.
增加细胞脂质(例如胆固醇)外流的其他抗血脂异常剂包括肝X受体(LXR)激动剂和类视黄醇(retinoid)X受体(RXR)激动剂。LXR与专性伴侣RXR异二聚化。LXR/RXR异二聚体可以用LXR激动剂或RXR激动剂激活。LXR/RXR异二聚体的激活降低脂肪酸合成并增加脂质(例如胆固醇)从细胞向循环最终到肝脏(在这里脂质被代谢并排泄到胆汁中)的流出。LXR激动剂的非限制性实例包括内源性配体(例如氧甾醇(例如，22(R)-羟基胆固醇、24(S)-羟基胆固醇、27-羟基胆固醇和胆固醇酸))，和合成的激动剂(例如乙酰基-罗汉松酸二聚体(acetyl-podocarpic dimer)、降胆酰胺(hypocholamide)、N,N-二甲基-3β-羟基-胆烯酰胺(N,N-dimethyl-3β-hydroxy-cholenamide，DMHCA)、GW3965、T0901317)，及其类似物、衍生物和盐。RXR激动剂的非限制性实例包括内源性配体(例如9-顺式-视黄酸)，和合成的激动剂(例如贝沙罗汀(bexarotene)、AGN 191659、AGN 191701、AGN 192849、BMS649、LG100268、LG100754、LGD346)，及其类似物、衍生物和盐。Other anti-dyslipidemic agents that increase cellular lipid (eg, cholesterol) efflux include liver X receptor (LXR) agonists and retinoid X receptor (RXR) agonists. LXR heterodimerizes with its obligate partner RXR. LXR/RXR heterodimers can be activated with LXR agonists or RXR agonists. Activation of the LXR/RXR heterodimer reduces fatty acid synthesis and increases the efflux of lipids (eg, cholesterol) from cells to the circulation and ultimately to the liver, where lipids are metabolized and excreted into bile. Non-limiting examples of LXR agonists include endogenous ligands (eg, oxysterols (eg, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol acid)), and synthetic Agonists (eg, acetyl-podocarpic dimer, hypocholamide, N,N-dimethyl-3β-hydroxy-cholenamide (N,N-dimethyl-3β -hydroxy-cholenamide, DMHCA), GW3965, T0901317), and analogs, derivatives and salts thereof. Non-limiting examples of RXR agonists include endogenous ligands (eg, 9-cis-retinoic acid), and synthetic agonists (eg, bexarotene, AGN 191659, AGN 191701, AGN 192849, BMS649, LG100268, LG100754, LGD346), and analogs, derivatives and salts thereof.
PPAR-α激动剂和PPAR-γ激动剂也可用于治疗AMD。激活PPAR-α的贝特类的降血脂作用如上所述。贝特类还降低血管内皮生长因子(VEGF)和VEGF受体2(VEGFR2)的表达，所述VEGF和VEGFR2在包括CNV在内的新生血管形成的发展中起重要作用。PPAR-α激动剂的实例包括但不限于贝特类和全氟链烷酸(例如全氟辛酸和全氟壬酸)。激活PPAR-γ的噻唑烷二酮类(thiazolidinediones)也具有抗血脂异常作用。像LXR那样，PPAR-γ也与RXR异二聚化。噻唑烷二酮类降低脂质(例如脂肪酸和甘油三酯)的水平、增加HDL的水平(介导胆固醇反向运输)，并增加脂质(如胆固醇)从细胞向循环最终到肝脏(在这里脂质被代谢并排泄到胆汁中)的流出。与贝特类一样，噻唑烷二酮类也抑制VEGF诱导的血管生成。PPAR-γ激动剂的实例包括但不限于噻唑烷二酮类(例如，环格列酮(ciglitazone)、洛格列酮(lobeglitazone)、韦格列酮(netoglitazone)、吡格列酮(pioglitazone)、利福格列酮(rivoglitazone)、罗格列酮(rosiglitazone)和曲格列酮(troglitazone))、罗丹宁(rhodanine)、小檗碱、和厚朴酚(honokiol)、全氟壬酸，及其类似物、衍生物和盐。PPAR-alpha agonists and PPAR-gamma agonists are also useful in the treatment of AMD. The hypolipidemic effect of fibrates that activate PPAR-α is as described above. Fibrates also reduce the expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), which play an important role in the development of neovascularization, including CNV. Examples of PPAR-alpha agonists include, but are not limited to, fibrates and perfluoroalkanoic acids (eg, perfluorooctanoic acid and perfluorononanoic acid). Thiazolidinediones, which activate PPAR-γ, also have anti-dyslipidemic effects. Like LXR, PPAR-γ also heterodimerizes with RXR. Thiazolidinediones decrease levels of lipids (such as fatty acids and triglycerides), increase levels of HDL (which mediates reverse cholesterol transport), and increase lipids (such as cholesterol) from cells to the circulation and ultimately to the liver (here lipids are metabolized and excreted into bile). Like fibrates, thiazolidinediones also inhibit VEGF-induced angiogenesis. Examples of PPAR-gamma agonists include, but are not limited to, thiazolidinediones (eg, ciglitazone, lobeglitazone, netoglitazone, pioglitazone, rifazone) Rivoglitazone, rosiglitazone and troglitazone), rhodanine, berberine, and honokiol, perfluorononanoic acid, and the like compounds, derivatives and salts.
其他抗血脂异常PPAR调节剂包括PPAR-δ激动剂。PPAR-δ激动剂增加HDL水平、降低VLDL水平、并增加胆固醇流出转运蛋白(例如ABCA1)的表达。PPAR-δ激动剂的非限制性实例包括GFT505(PPAR-α/δ双重激动剂)、GW0742、GW501516、索格列扎(sodelglitazar)(GW677954)、MBX-8025，及其类似物、衍生物和盐。Other anti-dyslipidemic PPAR modulators include PPAR-delta agonists. PPAR-delta agonists increase HDL levels, decrease VLDL levels, and increase the expression of cholesterol efflux transporters such as ABCA1. Non-limiting examples of PPAR-delta agonists include GFT505 (PPAR-alpha/delta dual agonist), GW0742, GW501516, sodelglitazar (GW677954), MBX-8025, and analogs, derivatives and Salt.
抗血脂异常剂还包括载脂蛋白肽模拟物，其在本文其他地方描述。Anti-dyslipidemic agents also include apolipoprotein peptidomimetics, which are described elsewhere herein.
增加胆固醇从细胞中流出的另一种方法是增加线粒体内膜的心磷脂的水平。增加心磷脂含量也可以预防或减少线粒体功能障碍。增加线粒体内膜的心磷脂水平的物质的非限制性实例是依拉普肽(elamipretide)(MTP-131)、心磷脂过氧化物酶抑制剂和线粒体靶向肽。Another way to increase cholesterol efflux from cells is to increase levels of cardiolipin in the inner membrane of mitochondria. Increasing cardiolipin content may also prevent or reduce mitochondrial dysfunction. Non-limiting examples of substances that increase cardiolipin levels in the inner mitochondrial membrane are elamipretide (MTP-131), cardiolipin peroxidase inhibitors, and mitochondrial targeting peptides.
如果全身施用增加脂质流出(例如，胆固醇反向运输)的抗血脂异常剂导致肝脏脂肪变性或血液中脂质水平异常，或者存在肝脏脂肪变性或脂质水平异常的风险，可以通过例如向眼睛局部施用抗血脂异常剂、共同使用减少或逆转肝脂肪变性的物质、或共同使用降低血液中脂质水平的物质，或其任何组合或全部，来避免或治疗肝脂肪变性或血液中脂质异常。减少或逆转肝脏脂肪变性的物质的实例包括但不限于减少肝脏脂肪生成的物质，例如GLP-1受体激动剂，其可以为了此目的例如全身施用。降低血液中脂质水平的物质的非限制性实例是他汀类，其可以出于此目的而全身施用。If systemic administration of an anti-dyslipidemic agent that increases lipid efflux (eg, reverse cholesterol transport) results in, or is at risk of, hepatic steatosis or abnormal lipid levels in the blood Topical administration of an anti-dyslipidemic agent, co-administration of a substance that reduces or reverses hepatic steatosis, or co-administration of a substance that reduces blood lipid levels, or any combination or all thereof, to avoid or treat hepatic steatosis or abnormal blood lipids . Examples of substances that reduce or reverse hepatic steatosis include, but are not limited to, substances that reduce hepatic lipogenesis, such as GLP-1 receptor agonists, which can be administered, eg, systemically, for this purpose. Non-limiting examples of substances that reduce lipid levels in the blood are statins, which can be administered systemically for this purpose.
也可以使用结合并中和脂质和毒性脂质副产物(例如氧化的脂质)和/或促进脂质和毒性脂质副产物(例如氧化的脂质)的清理的其他化合物。例如，环糊精具有亲水外部但具有疏水内部，并因此可与疏水分子形成水溶性复合物。因此，环糊精(包括α-环糊精(6-元糖环分子)、β-环糊精(7-元糖环分子)、γ-环糊精(8-元糖环分子)及其衍生物(例如甲基-β-环糊精))可以与脂质(例如胆固醇)和有毒的脂质副产物(例如，氧化的脂质)形成水溶性包合复合物，并从而可以中和它们的作用和/或促进它们的去除。Other compounds that bind to and neutralize lipids and toxic lipid by-products (eg, oxidized lipids) and/or facilitate cleanup of lipids and toxic lipid by-products (eg, oxidized lipids) can also be used. For example, cyclodextrins have a hydrophilic exterior but a hydrophobic interior, and thus can form water-soluble complexes with hydrophobic molecules. Therefore, cyclodextrins (including α-cyclodextrin (6-membered sugar ring molecule), β-cyclodextrin (7-membered sugar ring molecule), γ-cyclodextrin (8-membered sugar ring molecule) and its Derivatives (e.g. methyl-beta-cyclodextrin) can form water-soluble inclusion complexes with lipids (e.g. cholesterol) and toxic lipid by-products (e.g. oxidized lipids) and thereby neutralize their effect and/or facilitate their removal.
另一种抗血脂异常剂是内质网(ER)调节剂，所述调节剂恢复适当的ER功能，所述调节剂包括但不限于阿左胺(Azoramide)。ER在脂质代谢中起重要作用。ER功能障碍和慢性ER应激与许多病理相关，包括肥胖和炎症。阿左胺可提高ER蛋白折叠能力并激活ER伴侣蛋白的能力以保护细胞免受ER应激。Another anti-dyslipidemic agent is an endoplasmic reticulum (ER) modulator that restores proper ER function, including, but not limited to, Azoramide. ER plays an important role in lipid metabolism. ER dysfunction and chronic ER stress are associated with many pathologies, including obesity and inflammation. Alevamine increases ER protein folding capacity and activates ER chaperone proteins to protect cells from ER stress.
据报道，AMD与apoE和淀粉样蛋白-β(Aβ)的细胞外沉积物有关(包括在玻璃疣中)。据报道，Aβ沉积物参与炎症事件。因此，抗淀粉样蛋白剂(例如，Aβ形成或聚集成斑块/沉积物的抑制剂，以及Aβ清理的促进子)可潜在地用于治疗AMD。抗淀粉样蛋白剂(例如，抗Aβ剂)的实例包括但不限于抗Aβ抗体(例如，巴品珠单抗(bapineuzumab)、索拉珠单抗(solanezumab)、GSK933776、RN6G[PF4382923]、AN-1792、2H6和去糖基化的2H6)、抗apoE抗体(例如，HJ6.3)、apoE模拟物(例如，AEM-28)、半胱氨酸蛋白酶抑制剂C(cystatin C)、小檗碱、L-3-正丁基苯酞、T0901317，及其类似物、衍生物、片段和盐。AMD has been reported to be associated with extracellular deposits of apoE and amyloid-beta (Abeta), including in drusen. Aβ deposits have been reported to be involved in inflammatory events. Thus, anti-amyloid agents (eg, inhibitors of A[beta] formation or aggregation into plaques/deposits, and promoters of A[beta] clearance) can potentially be used to treat AMD. Examples of anti-amyloid agents (eg, anti-Aβ agents) include, but are not limited to, anti-Aβ antibodies (eg, bapineuzumab, solanezumab, GSK933776, RN6G [PF4382923], AN -1792, 2H6 and deglycosylated 2H6), anti-apoE antibodies (eg, HJ6.3), apoE mimetics (eg, AEM-28), cystatin C, barberry Base, L-3-n-butylphthalide, T0901317, and analogs, derivatives, fragments and salts thereof.
其他有毒副产物的水平的升高也与AMD有关。例如，AMD的患者(尤其是萎缩性AMD患者)中存在水平升高的毒性醛(例如4-羟基壬烯醛(HNE)和丙二醛(MDA))。抑制毒性醛形成、与它们结合并降低其水平、或促进其分解或清理的物质(例如醛捕获剂NS2)可用于治疗AMD。Elevated levels of other toxic byproducts are also associated with AMD. For example, patients with AMD, especially patients with atrophic AMD, have elevated levels of toxic aldehydes (eg, 4-hydroxynonenal (HNE) and malondialdehyde (MDA)). Substances that inhibit the formation of toxic aldehydes, bind to them and reduce their levels, or promote their breakdown or clearance (eg, the aldehyde trap NS2) can be used to treat AMD.
此外，据报道，脂褐素及其组分(例如，A2E)作为视觉周期的副产物随着年龄在RPE中积累。据报道脂褐素双炔类A2E抑制RPE中的溶酶体降解功能和胆固醇代谢、诱导补体系统和介导蓝光诱导的细胞凋亡，并因此与RPE细胞的萎缩和细胞死亡有关。因此，脂褐素或其组分(例如A2E)的抑制剂(包括它们的形成或积累的抑制剂和它们的分解或清理的促进剂)可以潜在地用于治疗AMD。脂褐素或其组分(例如A2E)的抑制剂的实例包括但不限于异维A酸，其抑制A2E的形成和脂褐素色素的积累；索雷普兰(soraprazan)，其促进脂褐素从RPE细胞中释放；和视黄醇结合蛋白4(RBP4)拮抗剂(例如，Al120和化合物43[环戊基稠合的吡咯烷])，其抑制脂褐素双二氢类体素如A2E的形成。Furthermore, lipofuscin and its components (eg, A2E) have been reported to accumulate in the RPE with age as a by-product of the visual cycle. Lipofuscin diacetylene A2E has been reported to inhibit lysosomal degradation function and cholesterol metabolism in RPE, induce the complement system and mediate blue light-induced apoptosis, and thus be associated with atrophy and cell death of RPE cells. Thus, inhibitors of lipofuscin or its components (eg, A2E), including inhibitors of their formation or accumulation and promoters of their breakdown or clearance, can potentially be used in the treatment of AMD. Examples of inhibitors of lipofuscin or its components (eg, A2E) include, but are not limited to, isotretinoin, which inhibits A2E formation and accumulation of lipofuscin pigment; soraprazan, which promotes lipofuscin Released from RPE cells; and retinol-binding protein 4 (RBP4) antagonists (eg, A1120 and compound 43 [cyclopentyl-fused pyrrolidine]), which inhibit lipofuscin dihydrovoxins such as A2E Formation.
预防或减少脂褐素双萜类化合物(例如A2E)积聚的另一种可能方式是干扰光感受器中的视觉/光周期。例如，视觉/光周期调节剂芬维A胺(fenretinide)降低视黄醇和RBP4的血清水平并抑制视黄醇与RBP4的结合，这降低了光周期类视黄醇的水平并且停止了脂褐素双二氢甙(bisretinoid)类(例如A2E)的积累。其他视觉/光周期调节剂包括但不限于反式-顺式-视黄醇异构酶RPE65的抑制剂(例如，emixustat[ACU-4429]和视黄酸胺)，其通过在RPE中抑制全反式视黄醇转化为11-顺式视黄醇，来减少可用的视黄醇的量及其下游副产物A2E。用光周期调节剂治疗可以减慢患者的视杆细胞介导的暗适应的速率。为了加快暗适应的速度，可以施用暗适应剂。暗适应剂的非限制性实例包括类胡萝卜素(例如，胡萝卜素，例如β-胡萝卜素)、类视黄醇(例如，全反式视黄醇[维生素A]、11-顺式视黄醇、全反式视黄醛[维生素A醛]、11-顺式视黄醛、全反式视黄酸[维甲酸]及其酯、9-顺式-视黄酸[阿利维A酸]及其酯、11-顺式视黄酸及其酯、13-顺式-视黄酸[异维A酸]及其酯、依曲替酯(etretinate)、阿维A(acitretin)、阿达帕林(adapalene)、贝沙罗汀和他扎罗汀(tazarotene))，及其类似物、衍生物和盐。Another possible way to prevent or reduce the accumulation of lipofuscin diterpenoids (eg A2E) is to interfere with the vision/photoperiod in photoreceptors. For example, the vision/photoperiod modulator fenretinide reduces serum levels of retinol and RBP4 and inhibits retinol binding to RBP4, which reduces photoperiod retinoid levels and stops lipofuscin Accumulation of bisretinoids such as A2E. Other visual/photoperiod modulators include, but are not limited to, inhibitors of trans-cis-retinol isomerase RPE65 (e.g., emixustat [ACU-4429] and retinoic acid amine), which inhibit the Trans-retinol is converted to 11-cis-retinol to reduce the amount of available retinol and its downstream by-product A2E. Treatment with photoperiod modulators can slow the rate of rod-mediated dark adaptation in patients. To speed up the dark adaptation, dark adaptation agents can be applied. Non-limiting examples of dark-adapting agents include carotenoids (eg, carotenes such as beta-carotene), retinoids (eg, all-trans retinol [vitamin A], 11-cis retinol) , all-trans retinal [vitamin A aldehyde], 11-cis retinal, all-trans retinoic acid [retinoic acid] and its esters, 9-cis-retinoic acid [alretinic acid] and Its esters, 11-cis retinoic acid and its esters, 13-cis-retinoic acid [isotretinoin] and its esters, etretinate, acitretin, adapalene (adapalene), bexarotene and tazarotene), and analogs, derivatives and salts thereof.
氧化事件在AMD的发病机制中起重要作用。例如，过氧化脂质的积累可导致炎症和新生血管形成。为了预防AMD、延迟AMD的发作或减缓AMD的进展，可以施用抗氧化剂。此外，抗氧化剂可通过预防或减少视网膜中的毒性和干扰细胞死亡途径而具有神经保护作用。例如，靶向线粒体的电子清除剂XJB-S-131抑制心磷脂(一种线粒体特异性多不饱和磷脂)的氧化，从而减少细胞死亡(包括在脑中)。另一个例子是藏红花素(crocin)和藏红花酸(crocetin)(藏红花中发现的类胡萝卜素)可以保护细胞免受细胞凋亡。作为又一个例子，叶黄素类(例如，叶黄素和玉米黄质)可以保护RPE处免受玻璃疣样病变的发展、黄斑色素的丧失和光诱导的光感受器的细胞凋亡。作为又一个例子，鼠尾草酸(一种在迷迭香和鼠尾草中发现的苯二酚二乙烯二萜)可以上调抗氧化酶、保护视网膜细胞免受过氧化氢毒性、并增加外核层的厚度。作为另一个实例，在姜黄中发现的类姜黄素(例如，姜黄素)可以上调血红素氧合酶-1，从而保护RPE细胞免受过氧化氢诱导的细胞凋亡。作为更进一步的实例，锌提高过氧化氢酶和谷胱甘肽过氧化物酶的活性，从而保护RPE细胞和光感受器免受过氧化氢和叔丁基过氧化氢的影响，并保护光感受器和其他视网膜细胞免于半胱天冬酶介导的细胞死亡。作为又一个实例，环戊烯酮前列腺素(cyclopentenone prostaglandins)(例如，环戊烯酮15-脱氧-Δ-前列腺素J2[15d-PGJ2]，一种PPAR-γ的配体)可通过例如上调谷胱甘肽(一种抗氧化剂)的合成来保护RPE细胞免受氧化损伤。环戊烯酮前列腺素还具有抗炎特性。Oxidative events play an important role in the pathogenesis of AMD. For example, the accumulation of lipid peroxides can lead to inflammation and neovascularization. Antioxidants may be administered to prevent AMD, delay the onset of AMD, or slow the progression of AMD. In addition, antioxidants may have neuroprotective effects by preventing or reducing toxicity and interfering with cell death pathways in the retina. For example, the mitochondria-targeted electron scavenger XJB-S-131 inhibits the oxidation of cardiolipin, a mitochondria-specific polyunsaturated phospholipid, thereby reducing cell death (including in the brain). Another example is that crocin and crocetin (carotenoids found in saffron) can protect cells from apoptosis. As yet another example, luteins (eg, lutein and zeaxanthin) can protect the RPE from the development of drusen-like lesions, loss of macular pigment, and light-induced apoptosis of photoreceptors. As yet another example, carnosic acid, a divinyl diterpene found in rosemary and sage, upregulates antioxidant enzymes, protects retinal cells from hydrogen peroxide toxicity, and increases outer nuclear layer thickness. As another example, curcuminoids (eg, curcumin) found in turmeric can upregulate heme oxygenase-1, thereby protecting RPE cells from hydrogen peroxide-induced apoptosis. As a further example, zinc increases catalase and glutathione peroxidase activity, thereby protecting RPE cells and photoreceptors from hydrogen peroxide and tert-butyl hydroperoxide, and protecting photoreceptors and Other retinal cells are protected from caspase-mediated cell death. As yet another example, cyclopentenone prostaglandins (eg, cyclopentenone 15-deoxy-delta-prostaglandin J2 [15d-PGJ2 ], a ligand for PPAR-γ) can be passed through For example, up-regulation of glutathione (an antioxidant) synthesis protects RPE cells from oxidative damage. Cyclopentenone prostaglandins also have anti-inflammatory properties.
抗氧化剂的非限制性实例包括花青素、载脂蛋白模拟物(例如，apoA-I模拟物和apoE模拟物)、苯二酚松香烷二萜(例如鼠尾草酸)、肌肽、类胡萝卜素(例如胡萝卜素[例如β-胡萝卜素]、叶黄素类[例如，叶黄素、玉米黄质和内消旋玉米黄质]、以及藏红花中的类胡萝卜素[例如，藏红花素和藏红花酸])、类姜黄素(例如姜黄素)、环戊烯酮前列腺素(例如15d-PGJ2)、类黄酮(例如，银杏(Ginkgo biloba)中的类黄酮[例如，杨梅素(myricetin)和槲皮素(quercetin)])、异戊二烯类黄酮(例如，异黄腐醇(isoxanthohumol))、类视黄醇(retinoids)、芪类(stilbenoid)(例如白藜芦醇(resveratrol))、尿酸、维生素A、维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸)、维生素B6(如吡哆醛、吡哆胺、4-吡哆酸和吡哆醇)、维生素B9(叶酸)、维生素B12(钴胺素)、维生素C、维生素E(如生育酚和生育三烯酚)、硒、锌(如锌单半胱氨酸)、脂质过氧化以及其副产物的抑制剂和清除剂(例如，维生素E[例如α-生育酚]、替拉扎特(tirilazad)、NXY-059和XJB-5-131)、核因子(红细胞衍生的2)样2(NFE2L2或NRF2)的活化剂(例如，OT-551)、超氧化物歧化酶(SOD)模拟物(例如，OT-551)，及其类似物、衍生物和盐。Non-limiting examples of antioxidants include anthocyanins, apolipoprotein mimetics (eg, apoA-I mimetics and apoE mimetics), quinol rosinane diterpenes (eg, carnosic acid), carnosine, carotenoids (e.g. carotenoids [e.g. beta-carotene], xanthophylls [e.g. lutein, zeaxanthin, and meso-zeaxanthin], and carotenoids in saffron [e.g., crocin and saffronic acid] ]), curcuminoids (eg, curcumin), cyclopentenone prostaglandins (eg, 15d-PGJ2 ), flavonoids (eg, those in Ginkgo biloba (eg, myricetin and quercetin) quercetin]), isoprene flavonoids (eg, isoxanthohumol), retinoids, stilbenoids (eg, resveratrol), Uric acid, vitaminA , vitamin B1 (thiamine), vitamin B2( riboflavin), vitaminB3 (niacin), vitamin B6 (such as pyridoxal, pyridoxamine,4 -pyridoxine and pyridoxine), vitaminB9 (folic acid), vitaminB12 (cobalamin), vitamin C, vitamin E (as tocopherols and tocotrienols), selenium, zinc (as zinc monocysteine), Inhibitors and scavengers of lipid peroxidation and its by-products (eg, vitamin E [eg alpha-tocopherol], tirilazad, NXY-059 and XJB-5-131), nuclear factor (erythrocyte Derivatized 2) activators of like 2 (NFE2L2 or NRF2) (eg, OT-551), superoxide dismutase (SOD) mimetics (eg, OT-551), and analogs, derivatives, and salts thereof.
抗氧化剂可以通过例如膳食补充剂提供，所述膳食补充剂例如AREDS或AREDS2制剂、制剂、制剂、Saffron 2020TM或如果补充剂含有相对高含量的锌(例如，醋酸锌、氧化锌或硫酸锌)，则可任选地将铜(例如氧化铜或硫酸铜)与锌共同施用以预防与高锌摄入量相关的缺铜性贫血。Saffron 2020TM含有藏红花、白藜芦醇、叶黄素、玉米黄质、维生素A、B2、C和E、锌和铜。包含乙酰基-L-肉碱、ω-3脂肪酸和辅酶Q10。示例性的年龄相关性眼病研究(AREDS)制剂包括β-胡萝卜素、维生素C、维生素E、锌(例如氧化锌)和铜(例如氧化铜)。示例性AREDS2制剂包含：Antioxidants can be provided, for example, by dietary supplements such as AREDS or AREDS2 formulations, preparation, Preparation, Saffron 2020TM or If the supplement contains relatively high levels of zinc (eg, zinc acetate, zinc oxide, or zinc sulfate), copper (eg, copper oxide or copper sulfate) may optionally be co-administered with zinc to prevent the association with high zinc intake of copper deficiency anemia. Saffron 2020TM contains saffron, resveratrol, lutein, zeaxanthin, vitaminsA , B2, C and E, zinc and copper. Contains acetyl-L-carnitine, omega-3 fatty acids and coenzyme Q10 . Exemplary Age-Related Eye Disease Study (AREDS) formulations include beta-carotene, vitamin C, vitamin E, zinc (eg, zinc oxide), and copper (eg, copper oxide). Exemplary AREDS2 formulations include:
1)β-胡萝卜素，维生素C，维生素E和锌；或1) beta-carotene, vitamin C, vitamin E and zinc; or
2)维生素C，维生素E，锌和铜；或2) Vitamin C, Vitamin E, Zinc and Copper; or
3)维生素C，维生素E和锌；或3) Vitamin C, Vitamin E and Zinc; or
4)β-胡萝卜素，维生素C，维生素E，ω-3脂肪酸，锌和铜；或4) beta-carotene, vitamin C, vitamin E, omega-3 fatty acids, zinc and copper; or
5)β-胡萝卜素，维生素C，维生素E，叶黄素，玉米黄质，锌和铜；或5) beta-carotene, vitamin C, vitamin E, lutein, zeaxanthin, zinc and copper; or
6)β-胡萝卜素，维生素C，维生素E，叶黄素，玉米黄质，ω-3脂肪酸，锌和铜。6) Beta-carotene, vitamin C, vitamin E, lutein, zeaxanthin, omega-3 fatty acids, zinc and copper.
示例性制剂包括：Exemplary Formulations include:
1)维生素A，维生素C，维生素E，锌和铜；或1) Vitamin A, Vitamin C, Vitamin E, Zinc and Copper; or
2)维生素A，维生素B2，维生素C，维生素E，叶黄素，玉米黄质，锌，铜和硒。2 ) Vitamin A, Vitamin B2, Vitamin C, Vitamin E, Lutein, Zeaxanthin, Zinc, Copper and Selenium.
示例性制剂包含：Exemplary The preparation contains:
1)维生素C，维生素E，叶黄素，玉米黄质，锌和铜；或1) Vitamin C, Vitamin E, Lutein, Zeaxanthin, Zinc and Copper; or
2)维生素C，维生素E，叶黄素，玉米黄质，ω-3脂肪酸，锌和铜；或2) Vitamin C, Vitamin E, Lutein, Zeaxanthin, Omega-3 Fatty Acids, Zinc and Copper; or
3)维生素A，维生素C，维生素E，叶黄素，玉米黄质，锌，铜和硒。3) Vitamin A, Vitamin C, Vitamin E, Lutein, Zeaxanthin, Zinc, Copper and Selenium.
作为抗氧化剂的替代或补充，可以施用其他神经保护剂(神经保护试剂)来治疗AMD。神经保护剂可用于例如促进视网膜中细胞的健康和/或生长，和/或防止细胞死亡，而不管起始事件如何。例如，睫状神经营养因子(CNTF)拯救光感受器免于退化。作为另一个实例，醋酸格拉替雷(glatiramer acetate)减少视网膜小胶质细胞毒性(和炎症)。神经保护剂的实例包括但不限于小檗碱、醋酸格拉替雷、α2-肾上腺素能受体激动剂(例如，阿可乐定(apraclonidine)和溴莫尼定(brimonidine))、血清素5-HT1A受体激动剂(例如，AL-8309B和氮杂萘酮[例如丁螺环酮(buspirone)、吉吡隆(gepirone)和坦度螺酮(tandospirone)])、神经保护素(neuroprotectin)类(例如，神经保护素A、B和D1)、内源性神经保护剂(例如，肌肽、CNTF、胶质细胞源性神经营养因子(GDNF)家族(例如，GDNF、artemin、neurturin和persephin)和神经营养素(例如，脑源神经营养因子[BDNF]、神经生长因子[NGF]、神经营养素-3[NT-3]和神经营养素-4[NT-4])}、前列腺素类似物(如异丙基乌诺前列酮(unoprostone isopropyl)[UF-021])，及其类似物、衍生物、片段和盐。As an alternative to or in addition to antioxidants, other neuroprotective agents (neuroprotective agents) may be administered to treat AMD. Neuroprotective agents can be used, for example, to promote the health and/or growth of cells in the retina, and/or prevent cell death, regardless of the initiating event. For example, ciliary neurotrophic factor (CNTF) rescues photoreceptors from degeneration. As another example, glatiramer acetate reduces retinal microglia toxicity (and inflammation). Examples of neuroprotective agents include, but are not limited to, berberine, glatiramer acetate,α2 -adrenergic receptor agonists (eg, apraclonidine and brimonidine), serotonin 5 - HT1A receptor agonists (eg, AL-8309B and azepinones [eg buspirone, gepirone and tandospirone]), neuroprotectin ) classes (eg, neuroprotectins A, B, and D1), endogenous neuroprotectants (eg, carnosine, CNTF, the glial cell-derived neurotrophic factor (GDNF) family (eg, GDNF, artemin, neurturin, and persephin) ) and neurotrophins (eg, brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF], neurotrophin-3 [NT-3] and neurotrophin-4 [NT-4])}, prostaglandin analogs ( Such as isopropyl unoprostone (unoprostone isopropyl) [UF-021]), and its analogs, derivatives, fragments and salts.
此外，可用于治疗AMD的其他神经保护剂包括通过细胞凋亡(程序性细胞死亡)和/或坏死(以细胞肿胀和破裂为特征)防止视网膜相关细胞(例如，RPE细胞和光感受器)死亡的物质。例如，核苷逆转录酶抑制剂(NRTI)通过抑制P2X7介导的NLRP3炎性体激活半胱天冬酶-1来阻断RPE细胞的死亡，并减少地图样萎缩和CNV。如果细胞凋亡减少(例如，通过抑制半胱天冬酶)，坏死可能会增加以补偿细胞凋亡的减少，因此预防或减少视网膜相关细胞死亡的有效策略可涉及抑制细胞凋亡和坏死两者。凋亡抑制剂的非限制性实例包括以下的抑制剂：半胱天冬酶(例如，半胱天冬酶家族[例如，Q-VD(OMe)-OPh(SEQ.ID.NO.14)、Boc-D-FMK(SEQ.ID.NO.15)、Z-VAD(SEQ.ID.NO.16)和Z-VAD-FMK(SEQ.ID.NO.17)]、半胱天冬酶-1[例如，Z-YVAD-FMK(SEQ.ID.NO.18)、半胱天冬酶-2[例如，Z-VDVAD-FMK(SEQ.ID.NO.19)]、半胱天冬酶-3[例如，Q-DEVD-OPh(SEQ.ID.NO.20)、Z-DEVD-FMK(SEQ.ID.NO.21)和Z-DQMD-FMK(SEQ.ID.NO.22)]、半胱天冬酶-4[例如，Z-LEVD-FMK(SEQ.ID.NO.23)]、半胱天冬酶-5[例如，Z-WEHD-FMK(SEQ.ID.NO.24)]、半胱天冬酶-6[例如，Z-VEID-FMK(SEQ.ID.NO.25)]、半胱天冬酶-8[例如，Q-IETD-OPh(SEQ.ID.NO.26)和Z-IETD-FMK(SEQ.ID.NO.27)]、半胱天冬酶-9[例如，Q-LEHD-OPh(SEQ.ID.NO.28)和Z-LEHD-FMK(SEQ.ID.NO.29)]、半胱天冬酶-10[例如，AEVD-FMK(SEQ.ID.NO.30)]、半胱天冬酶-12[例如，Z-ATAD-FMK(SEQ.ID.NO.31)]和半胱天冬酶-13[例如，LEED-FMK(SEQ.ID.NO.32)])、炎性体抑制剂、P2X7介导了NLRP3激活半胱天冬酶-1的抑制剂(例如，NRTI，例如阿巴卡韦(abacavir)[ABC]、拉米夫定(lamivudine)[3TC]、司他夫定(stavudine)[d4T1、me-d4T和齐多夫定(zidovudine)[AZT])、神经保护素，及其类似物、衍生物和盐。坏死抑制剂的实例包括但不限于半胱天冬酶抑制剂、受体相互作用蛋白(RIP)激酶的抑制剂(例如，坏死性凋亡抑制剂(necrostatin)，例如坏死性凋亡抑制剂1、5和7)、Necrox化合物(例如，Necrox-2和Necrox-5)、Nec-1，及其类似物、衍生物和盐。In addition, other neuroprotective agents that can be used to treat AMD include substances that prevent the death of retinal-associated cells (eg, RPE cells and photoreceptors) through apoptosis (programmed cell death) and/or necrosis (characterized by cell swelling and rupture) . For example, nucleoside reverse transcriptase inhibitors (NRTIs) blocked RPE cell death and reduced geographic atrophy and CNV by inhibiting P2X7-mediated NLRP3 inflammasome activation of caspase-1. If apoptosis is reduced (eg, by inhibition of caspases), necrosis may increase to compensate for the reduction in apoptosis, so an effective strategy to prevent or reduce retinal-related cell death may involve inhibition of both apoptosis and necrosis . Non-limiting examples of apoptosis inhibitors include inhibitors of caspases (eg, the caspase family [eg, Q-VD(OMe)-OPh (SEQ. ID. NO. 14), Boc-D-FMK (SEQ.ID.NO.15), Z-VAD (SEQ.ID.NO.16) and Z-VAD-FMK (SEQ.ID.NO.17)], caspase- 1 [eg, Z-YVAD-FMK (SEQ.ID.NO.18), caspase-2 [eg, Z-VDVAD-FMK (SEQ.ID.NO.19)], caspase -3 [eg, Q-DEVD-OPh (SEQ.ID.NO.20), Z-DEVD-FMK (SEQ.ID.NO.21) and Z-DQMD-FMK (SEQ.ID.NO.22)] , caspase-4 [eg, Z-LEVD-FMK (SEQ.ID.NO.23)], caspase-5 [eg, Z-WEHD-FMK (SEQ.ID.NO.24 )], caspase-6 [eg, Z-VEID-FMK (SEQ.ID.NO.25)], caspase-8 [eg, Q-IETD-OPh (SEQ.ID.NO. .26) and Z-IETD-FMK (SEQ.ID.NO.27)], caspase-9 [eg, Q-LEHD-OPh (SEQ.ID.NO.28) and Z-LEHD-FMK (SEQ.ID.NO.29)], Caspase-10 [eg, AEVD-FMK (SEQ.ID.NO.30)], Caspase-12 [eg, Z-ATAD-FMK (SEQ.ID.NO.31)] and caspase-13 [eg, LEED-FMK (SEQ.ID.NO.32)]), inflammasome inhibitor, P2X7 mediates NLRP3 activation of cysteine Inhibitors of asparaginase-1 (eg, NRTIs such as abacavir [ABC], lamivudine [3TC], stavudine [d4T1, me-d4T and zidovudine [AZT]), neuroprotectin, and analogs, derivatives, and salts thereof. Examples of necrosis inhibitors include, but are not limited to, caspase inhibitors, inhibitors of receptor interacting protein (RIP) kinases (eg, necrostatins, eg, necroptosis inhibitor 1) , 5 and 7), Necrox compounds (eg, Necrox-2 and Necrox-5), Nec-1, and analogs, derivatives and salts thereof.
在患有AMD的患者的血液和眼睛中发现C-反应蛋白(CRP)的水平升高。升高的CRP水平可以增加VEGF的产生，并从而导致新生血管形成。此外，CRP涉及炎症的发病机理，并通过下调胆固醇流出蛋白ABCA1和ABCG1来抑制胆固醇流出。此外，单体CRP可以与补体蛋白C1q结合并随后激活经典补体途径，其与替代补体途径串联可以导致膜攻击复合物(MAC)的形成并最终导致细胞裂解。因此，降低CRP水平(例如，通过减少产生或增加分解或清理)或减少CRP活性的CRP抑制剂可用于治疗AMD。CRP抑制剂的实例包括但不限于DPP-4抑制剂、噻唑烷二酮类、芪类、他汀类、表没食子儿茶素-3-没食子酸酯(EGCG)、CRP-i2，及其类似物、衍生物和盐。Elevated levels of C-reactive protein (CRP) are found in the blood and eyes of patients with AMD. Elevated CRP levels can increase the production of VEGF and thereby lead to neovascularization. Furthermore, CRP is involved in the pathogenesis of inflammation and inhibits cholesterol efflux by downregulating the cholesterol efflux proteins ABCA1 and ABCG1. Furthermore, monomeric CRP can bind to complement protein C1q and subsequently activate the classical complement pathway, which in tandem with the alternative complement pathway can lead to the formation of membrane attack complexes (MACs) and ultimately to cell lysis. Thus, CRP inhibitors that reduce CRP levels (eg, by reducing production or increasing breakdown or clearance) or reducing CRP activity are useful in the treatment of AMD. Examples of CRP inhibitors include, but are not limited to, DPP-4 inhibitors, thiazolidinediones, stilbenes, statins, epigallocatechin-3-gallate (EGCG), CRP-i2, and analogs thereof , derivatives and salts.
先天免疫系统的补体系统涉及AMD的发病机制。例如，导致补体因子H(CFH)有缺陷或不足(deficient)的CFH基因变体与AMD的风险密切相关。此外，替代补体途径可以通过载脂蛋白(例如apoE)和脂褐素或其组分(例如A2E)的积累来激活。此外，膜攻击复合物(MAC，C5b-9)已记录在脉络膜血管、布鲁赫膜(BrM)和RPE上，并与异常的RPE细胞相关，这提示在AMD中补体介导的细胞裂解可加速RPE功能不良和死亡。此外，在衰老的黄斑的BrM和脉络膜毛细血管内皮中存在明显的MAC累积。补体系统在炎症和氧化事件中也起着重要作用。例如，过敏毒素C3a、C4a和C5a介导炎症和细胞毒性氧自由基的产生。例如，C3a和C5a分别与C3a和C5a受体的结合导致炎症反应，例如通过组胺释放刺激肥大细胞介导的炎症。补体级联和局部炎症的激活涉及例如玻璃疣形成，这是可导致新生血管性AMD的萎缩性AMD的标志。此外，补体系统涉及新生血管形成(包括CNV)。例如，补体系统的激活可导致在脉络膜毛细血管内皮中形成MAC，所述脉络膜毛细血管内皮被MAC破坏可导致缺氧并因此导致CNV。此外，一些补体组分(例如，C5a)表现出促血管生成特性-例如，C5a受体介导RPE细胞中VEGF分泌增加。此外，MAC释放促血管生成分子(例如，PDGF和VEGF)。The complement system of the innate immune system is involved in the pathogenesis of AMD. For example, variants of the CFH gene that result in defective or deficient complement factor H (CFH) are strongly associated with the risk of AMD. Furthermore, the alternative complement pathway can be activated by the accumulation of apolipoproteins (eg apoE) and lipofuscin or components thereof (eg A2E). Furthermore, membrane attack complexes (MAC, C5b-9) have been documented on choroidal vessels, Bruch's membrane (BrM) and RPE and associated with abnormal RPE cells, suggesting that complement-mediated cell lysis in AMD may Accelerates RPE dysfunction and death. In addition, there was significant MAC accumulation in the BrM and choriocapillary endothelium of the aged macula. The complement system also plays an important role in inflammatory and oxidative events. For example, anaphylatoxins C3a, C4a and C5a mediate inflammation and the production of cytotoxic oxygen free radicals. For example, the binding of C3a and C5a to C3a and C5a receptors, respectively, leads to inflammatory responses, such as mast cell-mediated inflammation through stimulation of histamine release. Activation of the complement cascade and local inflammation is involved, for example, in drusen formation, a hallmark of atrophic AMD that can lead to neovascular AMD. In addition, the complement system is involved in neovascularization (including CNV). For example, activation of the complement system can lead to the formation of MACs in the choriocapillary endothelium, and destruction of the choriocapillary endothelium by MAC can lead to hypoxia and thus CNV. In addition, some complement components (eg, C5a) exhibit pro-angiogenic properties - eg, C5a receptors mediate increased VEGF secretion in RPE cells. In addition, MAC releases pro-angiogenic molecules (eg, PDGF and VEGF).
作为对替代补体途径的抑制的替代或补充，抑制凝集素补体途径(和/或经典补体途径)可有益于治疗萎缩性AMD和/或新生血管性AMD。例如，使用例如抗体或其片段(例如，OMS721，一种抗MASP-2抗体)抑制结合甘露聚糖的凝集素丝氨酸蛋白酶(或甘露糖相关丝氨酸蛋白酶[MASP])(例如，MASP-1、-2或-3)可以抑制补体活化的扩增和其后遗症(例如炎症)。在凝集素途径中，MASP裂解C2和C4以形成C2aC4b(一种C3-转化酶)。在凝集素和替代途径的边界处，C3-转化酶将C3切割成C3a和C3b。C3b与C2aC4b结合形成C5转化酶，所述C5转化酶将C5切割成C5a和C5b。C5b、C6、C7、C8和C9一起形成膜攻击复合物(MAC)，所述MAC可通过细胞膨胀和破裂导致细胞裂解。例如，补体因子H和I使C3b失活并下调旁路途径，从而抑制炎症。通过抑制C3转化酶C2aC4b的形成，MASP抑制剂可用于治疗萎缩性AMD和/或新生血管性AMD。As an alternative to or in addition to inhibition of the alternative complement pathway, inhibition of the lectin complement pathway (and/or the classical complement pathway) may be beneficial in the treatment of atrophic AMD and/or neovascular AMD. For example, inhibition of mannan-binding lectin serine proteases (or mannose-associated serine proteases [MASP]) (eg, MASP-1, - 2 or -3) can inhibit the amplification of complement activation and its sequelae (eg, inflammation). In the lectin pathway, MASP cleaves C2 and C4 to form C2aC4b (a C3-convertase). At the boundary between the lectin and the alternative pathway, C3-convertase cleaves C3 into C3a and C3b. C3b combines with C2aC4b to form C5 convertase, which cleaves C5 into C5a and C5b. C5b, C6, C7, C8 and C9 together form a membrane attack complex (MAC) which can lead to cell lysis by cell swelling and rupture. For example, complement factors H and I inactivate C3b and downregulate alternative pathways, thereby suppressing inflammation. MASP inhibitors are useful in the treatment of atrophic AMD and/or neovascular AMD by inhibiting the formation of the C3 convertase C2aC4b.
因此，可以使用补体系统或其组分(例如，蛋白质和因子)(例如，CFB、CFD、C2、C2a、C2b、C4、C4a、C4b、C3-转化酶[例如，C2aC4b和C3bBb]、C3、C3a、C3b、C3a受体、C3[H2O]、C3[H2O]Bb、C5-转化酶[例如，C2aC3bC4b和C3bBbC3b]、C5、C5a、C5b、C5a受体、C6、C7、C8、C9和MAC[C5b-9])的抑制剂来治疗AMD。作为说明性实例，兰波利珠单抗是靶向补体因子D(CFD)的人源化单克隆抗体的抗原结合片段(Fab)，所述CFD是参与替代补体途径(ACP)活化的限速酶。CFD将CFB切割成蛋白质活性因子Bb。Bb与自发水解的C3[C3(H2O)]结合，这导致C5-转化酶C3bBbC3b的形成。ACP的过度活跃与AMD(包括地图样萎缩(GA))的发展有关。兰波利珠单抗抑制补体激活和炎症，并可用于治疗或减缓AMD(包括GA)的进展。具有补体因子I(CFI)突变的萎缩性AMD患者似乎对于兰波利珠单抗治疗表现出更积极的反应。在MAHALO的II期试验中，与接受安慰剂的患者相比，根据眼底自发荧光，每月在一只眼睛中接受10mg兰波利珠单抗玻璃体内注射18个月的患者表现出注射眼睛的地图样萎缩面积减少约20％。CFI生物标志物阳性并且每月接受10mg兰波利珠单抗玻璃体内注射18个月的患者亚组表现出地域萎缩面积减少约44％。CFI(一种C3b/C4b灭活剂)通过切割结合细胞的C3b和C4b或液相C3b和C4b来调节补体激活。Thus, the complement system or its components (eg, proteins and factors) (eg, CFB, CFD, C2, C2a, C2b, C4, C4a, C4b, C3-convertase [eg, C2aC4b and C3bBb], C3, C3a, C3b, C3a acceptor, C3[H2O ], C3[H2O ]Bb, C5-convertase [eg, C2aC3bC4b and C3bBbC3b], C5, C5a, C5b, C5a acceptor, C6, C7, C8 , C9 and MAC [C5b-9]) inhibitors for the treatment of AMD. As an illustrative example, lambolizumab is an antigen-binding fragment (Fab ) of a humanized monoclonal antibody targeting complement factor D (CFD), a limiting factor involved in the activation of the alternative complement pathway (ACP). Fast enzymes. CFD cleaves CFB into the protein active factor Bb. Bb binds to spontaneously hydrolyzed C3 [C3(H2 O)], which leads to the formation of the C5-convertase C3bBbC3b. Hyperactivity of ACP is associated with the development of AMD, including geographic atrophy (GA). Lambolizumab inhibits complement activation and inflammation, and may be used to treat or slow the progression of AMD, including GA. Atrophic AMD patients with complement factor I (CFI) mutations appear to respond more positively to lambolizumab treatment. In the phase II trial of MAHALO, patients who received monthly intravitreal injections of 10 mg of lambolizumab in one eye for 18 months showed increased risk for the injected eye based on fundus autofluorescence compared with patients who received placebo. The shrinking area of the map was reduced by about 20%. The subgroup of patients who were positive for the CFI biomarker and who received monthly intravitreal injections of 10 mg of lambolizumab for 18 months showed an approximately 44% reduction in the area of geographic atrophy. CFI, a C3b/C4b inactivator, regulates complement activation by cleaving cell-bound C3b and C4b or liquid-phase C3b and C4b.
补体系统或其组分的抑制剂非限制性实例包括sCR1(促进C3bBb降解并抑制经典和替代补体途径的可溶形式的补体受体1[CR1])、TT30(含有补体受体2[CR2]的结构域和CFH(其抑制旁路途径)的融合蛋白)、抗CFB抗体及其片段(例如TA106)，抗CFD抗体及其片段(例如，兰波利珠单抗[FCFD4514S])、C3补体抑制素(compstatin)及其衍生物(例如，POT-4[AL-78898A])(抑制C3和MAC形成)、霉酚酸-葡糖胺缀合物(C3的下调剂)、可溶形式的作为C3抑制剂的蛋白质或其片段(例如，CR1、衰变加速因子[DAF])和膜辅因子蛋白[MCP或CD46])、3E7(抗C3b/iC3b单克隆抗体)、抗C5抗体及其片段(例如，依库珠单抗[抑制C5和MAC形成]和LFG316)、抗C5适体(例如，ARC 1905(C5裂解抑制剂))、其他C5抑制剂(如Coversin)、C5a受体拮抗剂(如JPE-1375、JSM-7717、PMX-025、Ac-F[OPdChaWR]{PMX-53}、和抗C5aR抗体及其片段[例如，努哲单抗(neutrazimab)])、apoA-I模拟物(例如，L-4F(补体激活抑制剂))、CD59和具有糖脂锚的修饰的CD59(MAC的抑制剂)、坦度螺酮(减少补体沉积物)、锌(补体活化和MAC沉积的抑制剂)，及其类似物、衍生物、片段和盐。Non-limiting examples of inhibitors of the complement system or components thereof include sCR1 (a soluble form of complement receptor 1 [CR1] that promotes C3bBb degradation and inhibits the classical and alternative complement pathways), TT30 (complement receptor 2 [CR2] containing domain of CFH (which inhibits the alternative pathway) fusion protein), anti-CFB antibodies and fragments thereof (e.g. TA106), anti-CFD antibodies and fragments thereof (e.g., lambolizumab [FCFD4514S]), C3 complement Compstatins and derivatives thereof (eg, POT-4 [AL-78898A]) (inhibits C3 and MAC formation), mycophenolic acid-glucosamine conjugates (down-regulators of C3), soluble forms of Proteins or fragments thereof that are C3 inhibitors (eg, CR1, decay accelerating factor [DAF]) and membrane cofactor protein [MCP or CD46]), 3E7 (anti-C3b/iC3b monoclonal antibody), anti-C5 antibody and fragments thereof (eg, eculizumab [inhibits C5 and MAC formation] and LFG316), anti-C5 aptamers (eg, ARC 1905 (C5 cleavage inhibitor)), other C5 inhibitors (such as Coversin), C5a receptor antagonists (such as JPE-1375, JSM-7717, PMX-025, Ac-F[OPdChaWR]{PMX-53}, and C5aR antibodies and fragments thereof [eg, neutrazimab]), apoA-I mimetics (eg, L-4F (inhibitor of complement activation)), CD59, and modified CD59 with glycolipid anchors (MAC's inhibitor), tandospirone (reduces complement deposition), zinc (inhibitor of complement activation and MAC deposition), and analogs, derivatives, fragments and salts thereof.
炎症也是AMD发病机理的重要贡献者。例如，炎性反应可能参与玻璃疣的形成，并且可以上调VEGF和其他引起新生血管形成(包括CNV)的促血管生成因子的表达。炎症可以由细胞免疫系统(例如，树突细胞)和/或体液免疫系统(例如补体系统)介导。炎症也可以由炎性体介导，所述炎性体是先天免疫系统的组分。例如，BrM中物质(例如，脂蛋白样颗粒、脂质和可能的脂褐素或其组分[例如A2E])的积累可以激活NLRP3炎性体，导致慢性炎症反应。此外，响应于细胞应激信号的炎性体(例如，NLRP3)的组装激活半胱天冬酶(例如，半胱天冬酶-1)，其导致炎症(例如，通过产生促炎性白细胞介素-1β)并最终导致例如RPE细胞的细胞死亡。Inflammation is also an important contributor to AMD pathogenesis. For example, inflammatory responses may be involved in drusen formation and may upregulate the expression of VEGF and other pro-angiogenic factors responsible for neovascularization, including CNV. Inflammation can be mediated by the cellular immune system (eg, dendritic cells) and/or the humoral immune system (eg, the complement system). Inflammation can also be mediated by inflammasomes, which are components of the innate immune system. For example, accumulation of substances (eg, lipoprotein-like particles, lipids, and possibly lipofuscin or its components [eg, A2E]) in BrM can activate the NLRP3 inflammasome, leading to a chronic inflammatory response. In addition, assembly of the inflammasome (eg, NLRP3) in response to cellular stress signals activates caspases (eg, caspase-1), which lead to inflammation (eg, through the production of pro-inflammatory leukocytes) β-1β) and eventually lead to cell death such as RPE cells.
本公开中提及的许多物质除了对于描述的内容的一种或多种性质之外还具有抗炎特性。其他抗炎剂包括但不限于羟化氯喹(hydroxychloroquine)、皮质类固醇(例如氟轻松(fluocinolone acetonide)和曲安奈德(triamcinolone acetonide))、具有很少糖皮质激素活性的类固醇(例如，阿奈可他(anecortave)[醋酸阿奈可他(anecortaveacetate)])、非甾体抗炎药(例如，非选择性环氧合酶[COX]1/COX-2抑制剂[例如，阿司匹林]和COX-2选择性抑制剂[例如，昔布类(coxibs)])、肥大细胞稳定剂和炎性体抑制剂。炎性体抑制剂(例如，其组装或功能的抑制剂)的实例包括但不限于NLRP3(NALP3)抑制剂(例如白细胞介素-4[IL-4]、ω-3脂肪酸、蒽醌类(anthraquinone)[例如大黄酚(chrysophanol)]、倍半萜内酯(sesquiterpene lactone)[例如，小白菊内酯(parthenolide)])、磺酰脲类(sulfonylurea)[例如格列本脲(glyburide)]、三萜类(triterpenoid)[例如，积雪草酸(asiatic acid)]和乙烯砜类[例如Bay 11-7082])、NLRP3/AIM2抑制剂(例如二芳基磺酰脲类(diarylsulfonylurea)[例如，CP-456,773])、NLRP1抑制剂(例如，Bcl-2、Bcl-2的环区和Bcl-X[L])、NLRP1B抑制剂(例如，金诺芬(auranofin))，及其类似物、衍生物、片段和盐。Many of the substances mentioned in this disclosure have anti-inflammatory properties in addition to one or more of the properties described. Other anti-inflammatory agents include, but are not limited to, hydroxychloroquine, corticosteroids (eg, fluocinolone acetonide and triamcinolone acetonide), steroids with little glucocorticoid activity (eg, anacorticosteroids) anecortave [anecortaveacetate]), non-steroidal anti-inflammatory drugs (eg, nonselective cyclooxygenase [COX]1/COX-2 inhibitors [eg, aspirin] and COX- 2 Selective inhibitors [eg, coxibs]), mast cell stabilizers, and inflammasome inhibitors. Examples of inflammasome inhibitors (eg, inhibitors of their assembly or function) include, but are not limited to, NLRP3 (NALP3) inhibitors (eg, interleukin-4 [IL-4], omega-3 fatty acids, anthraquinones ( anthraquinone) [eg chrysophanol], sesquiterpene lactone [eg parthenolide]), sulfonylurea [eg glyburide] , triterpenoids (eg, asiatic acid) and vinyl sulfones (eg, Bay 11-7082), NLRP3/AIM2 inhibitors (eg, diarylsulfonylurea) [eg , CP-456,773]), NLRP1 inhibitors (eg, Bcl-2, the loop region of Bcl-2, and Bcl-X[L]), NLRP1B inhibitors (eg, auranofin), and analogs thereof , derivatives, fragments and salts.
皮质类固醇(不包括盐皮质激素)的非限制性实例包括氢化可的松(hydrocortisone)类型(例如，可的松(cortisone)、氢化可的松[皮质醇(cortisol)]、泼尼松龙(prednisolone)、甲基泼尼松龙(methylprednisolone)、泼尼松(prednisone)和替可的松(tixocortol))、倍他米松(betamethasone)类型(例如，倍他米松(betamethasone)、地塞米松(dexamethasone)和氟可龙(fluocortolone))、卤代类固醇(halogenated steroid)(例如，阿氯米松(alclometasone)、倍氯米松(beclometasone)、氯倍他索(clobetasol)、氯倍他松(clobetasone)、去羟米松(desoximetasone)、二氟拉松(difiorasone)、二氟可龙(difiucortolone)、氟泼尼定(fluprednidene)、氟替卡松(fluticasone)、哈倍他索(halobetasol)[乌倍他索(ulobetasol)]、卤米松(halometasone)以及莫米松(mometasone))、缩丙酮类(acetonides)及相关物质(例如，安西缩松(amcinonide)、布多奈德(budononide)、环索奈德(ciclesonide)、地索奈德(desonide)、醋酸氟轻松(fluocinonide)、氟轻松、氟氢缩松(flurandrenolide)[氟西缩松(fludroxycortide)]、哈西奈德(halcinonide)、曲安奈德及曲安西龙(triamcinolone))、碳酸盐(例如，泼尼卡酯(prednicarbate))，及其类似物、衍生物和盐。Non-limiting examples of corticosteroids (excluding mineralocorticoids) include types of hydrocortisone (eg, cortisone, hydrocortisone [cortisol], prednisolone ( prednisolone), methylprednisolone, prednisone, and tixocortol), betamethasone types (eg, betamethasone, dexamethasone ( dexamethasone and fluocortolone), halogenated steroids (eg, aclomethasone, beclometasone, clobetasol, clobetasone) , desoximetasone, difiorasone, difiucortolone, fluprednidene, fluticasone, halobetasol [Ubetasol ( ulobetasol], halometasone and mometasone), acetonides and related substances (eg, amcinonide, budononide, ciclesonide ), desonide, fluocinonide, fluocinolone acetonide, flurandrenolide [fludroxycortide], halcinonide, triamcinolone acetonide, and triamcinolone triamcinolone), carbonates (eg, prednicarbate), and analogs, derivatives, and salts thereof.
非甾体抗炎药(NSAID)的实例包括但不限于：Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to:
乙酸衍生物，例如醋氯芬酸(aceclofenac)、溴芬酸(bromfenac)、双氯芬酸(diclofenac)、依托度酸(etodolac)、吲哚美辛(indomethacin)、酮咯酸(ketorolac)、萘丁美酮(nabumetone)、舒林酸(sulindac)、舒林酸硫化物(sulindac sulfide)、舒林酸砜(sulindac sulfone)和托美汀(tolmetin)；Acetic acid derivatives such as aceclofenac, bromfenac, diclofenac, etodolac, indomethacin, ketorolac, nabume nabumetone, sulindac, sulindac sulfide, sulindac sulfone, and tolmetin;
邻氨基苯甲酸衍生物(芬那酸类(fenamates))，例如氟苯甲酸(flufenamicacid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)和托芬那酸(tolfenamic acid)；Anthranilic acid derivatives (fenamates), such as flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid );
烯醇酸衍生物(昔康类(oxicams))，如屈恶昔康(droxicam)、伊索昔康(isoxicam)、氯诺昔康(lornoxicam)、美洛昔康(meloxicam)、吡罗昔康(piroxicam)和替诺昔康(tenoxicam)；Enolic acid derivatives (oxicams), such as droxicam, isoxicam, lornoxicam, meloxicam, piroxicam ( piroxicam) and tenoxicam;
丙酸衍生物，如非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、右旋布洛芬(dexibuprofen)、酮洛芬(ketoprofen)、右旋酮洛芬、洛索洛芬(loxoprofen)、萘普生(naproxen)和奥沙普嗪(oxaprozin)；Propionic acid derivatives such as fenoprofen, flurbiprofen, ibuprofen, dexibuprofen, ketoprofen, dexketoprofen , loxoprofen (loxoprofen), naproxen (naproxen) and oxaprozin (oxaprozin);
水杨酸盐，如二氟尼柳(diflunisal)、水杨酸、乙酰水杨酸(阿司匹林)、胆碱三水杨酸镁(choline magnesium trisalicylate)和双水杨酸酯(salsalate)；Salicylates, such as diflunisal, salicylic acid, acetylsalicylic acid (aspirin), choline magnesium trisalicylate, and salsalate;
COX-2选择性抑制剂，如阿利考昔(apricoxib)、塞来昔布(celecoxib)、艾托考昔(etoricoxib)、非罗考昔(firocoxib)、弗罗考昔(fluorocoxib)(例如，弗罗考昔A-C)、罗美昔布(lumiracoxib)、吗伐考昔(mavacoxib)、帕瑞考昔(parecoxib)、罗非考昔(rofecoxib)、替马考昔(tilmacoxib)(JTE-522)、伐地考昔(valdecoxib)、4-O-甲基和厚朴酚(4-O-methylhonokiol)、尼氟灭酸(niflumic acid)、DuP-697、CGI 00649、GW406381、NS-398、SC-58125，苯并噻吩并[3,2-d]嘧啶-4-酮磺酰胺硫代衍生物(benzothieno[3,2-d]pyrimidin-4-one sulfonamide thio-derivatives)、和来自蒺藜(Tribulus terrestris)的COX-2抑制剂；COX-2 selective inhibitors such as apricoxib, celecoxib, etoricoxib, firocoxib, fluorocoxib (eg, Frocoxib A-C), lumiracoxib, mavacoxib, parecoxib, rofecoxib, tilmacoxib (JTE-522 ), valdecoxib, 4-O-methyl and honokiol (4-O-methylhonokiol), niflumic acid, DuP-697, CGI 00649, GW406381, NS-398, SC-58125 , benzothieno[3,2-d]pyrimidin-4-one sulfonamide thio-derivatives, and from Tribulus terrestris COX-2 inhibitors;
其他种类NSAID，如苯胺基吡啶羧酸(anilinopyridinecarboxylic acid)(如氯尼辛(clonixin))、磺酰苯胺(sulfonanilides)(如尼美舒利(nimesulide))、脂氧合酶(如5-LOX)和环加氧酶(如COX-2)的双重抑制剂(如诃子鞣酸(chebulagic acid)、利克飞龙(licofelone)、2-(3,4,5-三甲氧基苯基)-4-(N-甲基吲哚-3-yl)噻吩和二叔丁基苯酚类化合物[例如DTPBHZ、DTPINH、DTPNHZ和DTPSAL])；及Other types of NSAIDs, such as anilinopyridinecarboxylic acid (such as clonixin), sulfonanilides (such as nimesulide), lipoxygenase (such as 5-LOX) ) and dual inhibitors of cyclooxygenases (such as COX-2) (such as chebulagic acid, licofelone, 2-(3,4,5-trimethoxyphenyl)-4 -(N-methylindole-3-yl)thiophene and di-tert-butylphenolic compounds [eg DTPBHZ, DTPINH, DTPNHZ and DTPSAL]); and
以上的类似物、衍生物和盐。Analogs, derivatives and salts of the above.
在非中央和中央地图样萎缩中，肥大细胞在脉络膜中脱粒、释放组胺和其他炎症介质。肥大细胞稳定剂阻断肥大细胞脱粒所必需的钙通道、稳定肥大细胞，并从而阻止组胺和其他免疫介质的释放。肥大细胞稳定剂的实例包括但不限于β2-肾上腺素能受体激动剂、色甘酸(cromoglicic acid)、酮替芬(ketotifen)、甲基黄嘌呤(methylxanthines)、奈多罗米(nedocromil)、奥洛他定(olopatadine)、奥马珠单抗(omalizumab)、哌罗来斯(pemirolast)、槲皮素、曲尼司特(tranilast)，及其类似物、衍生物和盐。短效β2-肾上腺素能激动剂的实例包括但不限于比托特罗(bitolterol)、非诺特罗(fenoterol)、喘息定(isoprenaline)(异丙肾上腺素(isoproterenol))、左旋柳丁氨醇(levosalbutamol)(左旋沙丁胺醇(levalbuterol))、降钙素(orciprenaline)(异丙肾上腺素(metaproterenol))、吡布特罗(pirbuterol)、丙卡特罗(procaterol)、利托君(ritodrine)、柳丁氨醇(salbutamol)(沙丁胺醇(albuterol))、特布他林(terbutaline)、衍生物和其盐。长效β2-肾上腺素能激动剂的非限制性实例包括阿福特罗(arformoterol)、班布特罗(bambuterol)、克伦特罗(clenbuterol)、福莫特罗(formoterol)、沙美特罗(salmeterol)，及其类似物、衍生物和盐。超长效β2-肾上腺素能激动剂的实例包括但不限于卡莫特罗(carmoterol)、茚达特罗(indacaterol)、米维特罗(milveterol)、奥达特罗(olodaterol)、维兰特罗(vilanterol)，及其类似物、衍生物和盐。In noncentral and central geographic atrophy, mast cells degranulate in the choroid, releasing histamine and other inflammatory mediators. Mast cell stabilizers block calcium channels necessary for mast cell degranulation, stabilize mast cells, and thereby prevent the release of histamine and other immune mediators. Examples of mast cell stabilizers include, but are not limited to, β2- adrenergic receptor agonists, cromoglicic acid, ketotifen, methylxanthines, nedocromil, Olopatadine, omalizumab, pemirolast, quercetin, tranilast, and analogs, derivatives and salts thereof. Examples of short-acting β2- adrenergic agonists include, but are not limited to, bitolterol, fenoterol, isoprenaline (isoproterenol), levorotene Levosalbutamol (levalbuterol), orciprenaline (metaproterenol), pirbuterol, procaterol, ritodrine , salbutamol (albuterol), terbutaline, derivatives and salts thereof. Non-limiting examples of long-acting beta2- adrenergic agonists include arformoterol, bambuterol, clenbuterol, formoterol, salmeterol (salmeterol), and analogs, derivatives and salts thereof. Examples of ultra-long-acting β2- adrenergic agonists include, but are not limited to, carmoterol, indacaterol, milveterol, olodaterol, vilan vilanterol, and analogs, derivatives and salts thereof.
总之，抗炎剂的实例包括但不限于羟化氯喹、抗淀粉样蛋白剂、抗氧化剂、载脂蛋白模拟物(例如，apoA-I模拟物和apoE模拟物)、C反应蛋白抑制剂、补体抑制剂、炎性体抑制剂、神经保护剂(例如，醋酸格拉替雷)、皮质类固醇、具有很少糖皮质激素活性的类固醇(例如，阿奈可他)、非甾体抗炎药(NSAID)、肥大细胞稳定剂、环戊烯酮前列腺素、抗血管生成剂(例如，抗VEGF/VEGFR剂)和免疫抑制剂。In summary, examples of anti-inflammatory agents include, but are not limited to, hydroxychloroquine, anti-amyloid agents, antioxidants, apolipoprotein mimetics (eg, apoA-I mimetics and apoE mimetics), C-reactive protein inhibitors, complement Inhibitors, inflammasome inhibitors, neuroprotective agents (eg, glatiramer acetate), corticosteroids, steroids with little glucocorticoid activity (eg, anectostat), nonsteroidal anti-inflammatory drugs (NSAIDs) ), mast cell stabilizers, cyclopentenone prostaglandins, anti-angiogenic agents (eg, anti-VEGF/VEGFR agents), and immunosuppressive agents.
可用于治疗萎缩性AMD和/或新生血管性AMD的其他治疗剂包括免疫抑制剂。免疫抑制剂可具有抗炎特性。免疫抑制剂的实例包括但不限于白细胞介素-2(IL-2)信号传导、产生或分泌的抑制剂(例如，IL-2受体α亚基的拮抗剂[例如，巴利昔单抗和达利珠单抗]、mTOR抑制剂[例如，雷帕霉素(西罗莫司(sirolimus))、息斯敏(deforolimus)(地磷莫司(ridaforolimus))、依维莫司(everolimus)、替西罗莫司(temsirolimus)、优美莫司(umirolimus)(biolimus A9)和咗他莫司(zotarolimus)]、和钙调神经磷酸酶抑制剂[例如环孢菌素(cyclosporine)、吡美莫司(pimecrolimus)和他克莫司(tacrolimus)]和肿瘤坏死因子(如TNF-α)抑制剂(例如，阿达木单抗(adalimumab)、赛妥珠单抗(certolizumabpegol)、依那西普(etanercept)、戈利木单抗(golimumab)和英夫利昔单抗(infliximab))。作为使用免疫抑制剂的潜在益处的非限制性实例，免疫抑制剂可以减少抗血管生成剂在治疗新生血管性AMD中的施用次数或频率(例如，注射抗VEGF/VEGFR剂的次数或频率)。Other therapeutic agents that can be used to treat atrophic AMD and/or neovascular AMD include immunosuppressive agents. Immunosuppressants may have anti-inflammatory properties. Examples of immunosuppressive agents include, but are not limited to, inhibitors of interleukin-2 (IL-2) signaling, production, or secretion (eg, antagonists of the IL-2 receptor alpha subunit [eg, basiliximab] and daclizumab], mTOR inhibitors [eg, rapamycin (sirolimus), deforolimus (ridaforolimus), everolimus ), temsirolimus, umirolimus (biolimus A9), and zotarolimus], and calcineurin inhibitors (eg, cyclosporine, pyridoxine pimecrolimus and tacrolimus] and tumor necrosis factor (eg, TNF-α) inhibitors (eg, adalimumab, certolizumabpegol, etanercil etanercept, golimumab, and infliximab). As a non-limiting example of the potential benefit of using immunosuppressive agents, immunosuppressive agents may reduce the Number or frequency of administrations (eg, number or frequency of injections of anti-VEGF/VEGFR agents) in vascular AMD.
基质金属蛋白酶(MMP)降解细胞外基质(ECM)蛋白，并在细胞迁移(分散和粘附)、细胞增殖、细胞分化、血管生成和细胞凋亡中发挥重要作用。例如，随着AMD进展到晚期阶段，MMP水平升高会使布鲁赫膜(BrM)、ECM和脉络膜的一部分变性。内皮细胞沿着ECM迁移到损伤部位、增殖、形成内皮管、并成熟为新的血管，这些血管由脉络膜中的毛细血管产生并穿过破裂的BrM生长。此外，BrM中的破坏可允许内皮细胞迁移到亚RPE-BL空间中并形成有漏点的和迂回的未成熟血管并且可延伸到视网膜下空间中。最终结果是新生血管形成(包括CNV)和新生血管性AMD的发展。MMP还可以切割细胞表面受体的肽键，释放促凋亡配体(例如FAS)。MMP抑制剂可用于例如抑制血管生成和细胞凋亡，以及治疗新生血管性AMD(包括1、2和/或3型新生血管形成)或萎缩性AMD(包括非中央和/或中央地图样萎缩)。例如，强力霉素减少光感受器的丧失。MMP抑制剂的非限制性实例包括金属蛋白酶的组织抑制剂(例如，TIMP 1、2、3和4)、四环素类(tetracyclines)(例如多西环素(doxycycline)、因环素(incyclinide)和米诺环素(minocycline))、二氯亚甲基二膦酸(dichloromethylenediphosphonic acid)、巴马司他(batimastat)、西马司他(cipemastat)、伊洛马司他(ilomastat)、马马司他(marimastat)、普马司他(prinomastat)、利巴马司他(rebimastat)、坦诺司他(tanomastat)、ABT-770、MMI-166、MMI-270、Ro 28-2653、RS-130830、CAS Reg No.(CRN)239796-97-5、CRN 420121-84-2、CRN544678-85-5、CRN 556052-30-3、CRN 582311-81-7、CRN 848773-43-3、CRN 868368-30-3，及其类似物、衍生物、片段和盐。Matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM) proteins and play important roles in cell migration (dispersion and adhesion), cell proliferation, cell differentiation, angiogenesis and apoptosis. For example, as AMD progresses to an advanced stage, elevated MMP levels degenerate parts of Bruch's membrane (BrM), the ECM, and the choroid. Endothelial cells migrate along the ECM to the site of injury, proliferate, form endothelial tubes, and mature into new blood vessels that arise from capillaries in the choroid and grow through ruptured BrM. Furthermore, disruption in BrM may allow endothelial cells to migrate into the sub-RPE-BL space and form leaky and tortuous immature blood vessels and may extend into the subretinal space. The end result is neovascularization (including CNV) and the development of neovascular AMD. MMPs can also cleave peptide bonds of cell surface receptors, releasing pro-apoptotic ligands (eg, FAS). MMP inhibitors can be used, for example, to inhibit angiogenesis and apoptosis, and to treat neovascular AMD (including type 1, 2 and/or 3 neovascularization) or atrophic AMD (including non-central and/or central geographic atrophy) . For example, doxycycline reduces photoreceptor loss. Non-limiting examples of MMP inhibitors include tissue inhibitors of metalloproteinases (eg, TIMP 1, 2, 3, and 4), tetracyclines (eg, doxycycline, incyclinide, and minocycline), dichloromethylenediphosphonic acid, batimastat, cipemastat, ilomastat, mamas Marimastat, Prinomastat, Rebimastat, Tanomastat, ABT-770, MMI-166, MMI-270, Ro 28-2653, RS-130830 , CAS Reg No.(CRN) 239796-97-5, CRN 420121-84-2, CRN544678-85-5, CRN 556052-30-3, CRN 582311-81-7, CRN 848773-43-3, CRN 868368 -30-3, and analogs, derivatives, fragments and salts thereof.
作为MMP抑制剂的替代或补充，可以使用其他种类的细胞迁移抑制剂。例如，rho激酶(ROCK)抑制剂(包括ROCK1和ROCK2抑制剂)阻断细胞迁移(包括在新生血管形成的早期阶段的内皮细胞迁移)。ROCK抑制剂的实例包括但不限于法舒地尔(fasudil)、奈他地尔(netarsudil)、瑞帕舒地尔(ripasudil)、GSK-429286A、RKJ-1447、Y-27632和Y-30141。Instead of or in addition to MMP inhibitors, other classes of cell migration inhibitors can be used. For example, rho kinase (ROCK) inhibitors, including ROCK1 and ROCK2 inhibitors, block cell migration, including endothelial cell migration in the early stages of neovascularization. Examples of ROCK inhibitors include, but are not limited to, fasudil, netarsudil, ripasudil, GSK-429286A, RKJ-1447, Y-27632, and Y-30141.
在一些情况下，可能需要使用MMP活化剂而不是MMP抑制剂。由MMP和TIMP介导，BrM经历恒定的周转。BrM随着年龄逐渐增厚，部分原因是TIMP水平升高，并导致ECM周转减少。BrM中ECM随着年龄增厚可能导致BrM保留RPE分泌的脂蛋白，最终导致BLinD和玻璃疣的形成。富含脂质的BLinD和基底层状沉积物(BlamD，其在增厚的RPE-BL中是过量的细胞外基质)的积累延长了脉络膜毛细血管和RPE之间的扩散距离。MMP活化剂可用于实现增加BrM周转和减少BrM增厚，但不能达到用于BrM变得如此变性以至于新血管可穿过BrM生长的程度。MMP活化剂的实例包括但不限于basigin(细胞外基质金属蛋白酶诱导剂[EMMPRIN]或CD147)、伴刀豆球蛋白(concanavalin)A、细胞松弛素(cytochalasin)D，及其类似物、衍生物、片段和盐。类似地，可以使用基质金属蛋白酶来减少持续存在于BrM上的BLamD的厚度。In some cases, it may be desirable to use MMP activators instead of MMP inhibitors. Mediated by MMPs and TIMPs, BrM undergoes constant turnover. BrM gradually thickens with age, partly due to elevated TIMP levels, and leads to reduced ECM turnover. Thickening of the ECM in BrM with age may lead to the retention of lipoproteins secreted by RPE in BrM, ultimately leading to the formation of BLinD and drusen. Accumulation of lipid-rich BLinD and basal lamellar deposits (BlamD, which is excess extracellular matrix in thickened RPE-BL) prolongs the diffusion distance between choriocapillaries and RPE. MMP activators can be used to achieve increased BrM turnover and reduced BrM thickening, but not to the extent that BrM becomes so denatured that new blood vessels can grow through BrM. Examples of MMP activators include, but are not limited to, basigin (extracellular matrix metalloproteinase inducer [EMMPRIN] or CD147), concanavalin A, cytochalasin D, and analogs, derivatives thereof , Fragments and Salts. Similarly, matrix metalloproteinases can be used to reduce the thickness of BLamD persisting on BrM.
血管生成是新生血管形成(包括1、2和3型)的潜在机制，其可以在AMD的晚期阶段发生以导致新生血管性AMD并且如果不治疗则视力严重丧失。新生血管性AMD的特征在于脉络膜、亚RPE-BL空间、视网膜下空间和神经视网膜中的血管生长和液体渗漏。与新生血管的生长相比，血管渗漏对新生血管性AMD相关的视力丧失更有责任。血管内皮生长因子(VEGF)在新生血管性AMD的发病机制中起关键作用。VEGF是有效的分泌的内皮细胞有丝分裂原，其刺激内皮细胞的迁移和增殖，并增加新血管的渗透性，导致流体、血液和蛋白质从其中渗漏。此外，VEGF增加MMP的水平，其进一步使ECM变性。此外，VEGF增强炎症反应。然而，VEGF或其受体不是抗血管生成剂的唯一潜在靶标。例如，使用整联蛋白(integrin)抑制剂(例如，ALG-1001)靶向与受体酪氨酸激酶相关的整联蛋白抑制新血管的产生和生长并降低血管的渗透性(渗漏)。还可以通过抑制其他靶标来抑制血管生成，所述其他靶标包括但不限于激酶(例如酪氨酸激酶，例如受体酪氨酸激酶)和磷酸酶(例如酪氨酸磷酸酶，例如受体酪氨酸磷酸酶)。Angiogenesis is a potential mechanism of neovascularization, including types 1, 2, and 3, which can occur in advanced stages of AMD to lead to neovascular AMD and severe vision loss if left untreated. Neovascular AMD is characterized by vascular growth and fluid leakage in the choroid, sub-RPE-BL space, subretinal space, and neural retina. Vascular leakage is more responsible for the vision loss associated with neovascular AMD than the growth of new blood vessels. Vascular endothelial growth factor (VEGF) plays a key role in the pathogenesis of neovascular AMD. VEGF is a potent secreted endothelial cell mitogen that stimulates endothelial cell migration and proliferation and increases the permeability of new blood vessels, leading to leakage of fluid, blood and proteins therefrom. Furthermore, VEGF increases the level of MMPs, which further degenerates the ECM. Furthermore, VEGF enhances the inflammatory response. However, VEGF or its receptors are not the only potential targets for anti-angiogenic agents. For example, targeting integrins associated with receptor tyrosine kinases using integrin inhibitors (eg, ALG-1001) inhibits the production and growth of new blood vessels and reduces the permeability (leakage) of blood vessels. Angiogenesis can also be inhibited by inhibiting other targets including, but not limited to, kinases (eg, tyrosine kinases, such as receptor tyrosine kinases) and phosphatases (eg, tyrosine phosphatases, such as receptor tyrosine kinases) amino acid phosphatase).
抗血管生成剂可用于预防或减少新生血管形成(包括1、2和3型)，并降低血管的渗透性/渗漏。例如，白细胞介素-18(IL-18)将VEGF从眼睛中消除，从而抑制视网膜后面的损伤性血管的形成。抗血管生成剂的非限制性实例包括VEGF的抑制剂(例如，角鲨胺、PAN-90806、抗VEGF抗体及其片段(例如贝伐单抗雷珠单抗ESBA1008和ESBA903)、抗VEGF适体(如哌加他尼(pegaptanib))、抗VEGF设计的锚蛋白重复蛋白[DARPins](如培阿比西帕(abicipar pegol)[AGN-150998或MP0112])、可溶性VEGFR[例如VEGFR1]，以及含有一种或多种VEGFR[例如VEGFR1和VEGFR2]的一个或多个细胞外结构域的可溶性融合蛋白(例如阿柏西普(aflibercept)和康柏西普(conbercept))、VEGF受体(VEGFR)抑制剂(例如，阿西替尼(axitinib)、帕唑帕尼(pazopanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、X-82、PF-337210、异黄腐醇、和抗VEGFR抗体及其片段)、血小板衍生生长因子(PDGF)抑制剂(如角鲨胺、抗PDGF适体(如E10030)、抗PDGF抗体及其片段、和可溶性PDGFR)或其受体(PDGFR)抑制剂(例如，阿西替尼、帕唑帕尼、索拉非尼、舒尼替尼、X-82和抗PDGFR抗体及其片段[例如，REGN2176-3])、成纤维细胞生长因子(FGF)的抑制剂(例如，角鲨胺、抗FGF抗体及其片段、抗FGF适体和可溶性FGFR)或其受体(FGFR)抑制剂(例如，抗FGFR抗体及其片段)、血管生成素的抑制剂(例如，抗血管生成素抗体及其片段(例如奈弗库单抗(nesvacumab)[REGN910]和REGN910-3)，以及可溶性血管生成素受体)或其受体抑制剂(例如，抗血管生成素受体的抗体和其片段、整联蛋白的抑制剂(例如，ALG-1001、JSM-6427和抗整联蛋白抗体及其片段)、阿奈可他(醋酸阿奈可他)、血管抑制素(例如血管抑制素K1-3)、αvβ3抑制剂(例如，依他拉珠单抗(etaracizumab))、apoA-I模拟物(例如L-4F和L-5F)、小檗碱、博来霉素(bleomycins)、疏螺旋体素(borrelidin)、羧酰胺三唑(carboxyamidotriazole)、软骨源血管生成抑制剂(例如，软骨调节素(chondromodulin)I和肌钙蛋白(troponin)I)、栗精胺(castanospermine)、CM101、补体系统的抑制剂、环丙烯脂肪酸(如苹婆酸(sterculicacid))、α-二氟甲基鸟氨酸(difluoromethylornithine)、内皮抑素(endostatin)、依维莫司、烟曲霉素(fumagillin)、染料木黄酮(genistein)、干扰素-α、白细胞介素-12、白细胞介素-18、伊曲康唑(itraconazole)、利诺胺(linomide)、MMP抑制剂、2-甲氧基雌二醇、色素上皮衍生因子(PEDF)、血小板因子-4、PPAR-α激动剂(如贝特类)、PPAR-γ激动剂(如噻唑烷二酮类)、催乳素、抗血管生成siRNA、鞘氨醇-1-磷酸盐抑制剂(如，森纳西珠单抗(sonepcizumab))、角鲨烯、星孢菌素(staurosporine)、血管抑制类固醇(如四氢皮质醇)加肝素、芪类、苏拉明、SUS416、他喹莫德(tasquinimod)、特科加兰(tecogalan)、四硫钼酸盐(tetrathiomolybdate)、沙利度胺(thalidomide)及其衍生物(如来那度胺(lenalidomide)和泊马度胺(pomalidomide))、噻苯达唑(thiabendazole)、血小板反应蛋白(如血小板反应蛋白1)、TNP-470、曲尼司特(tranilast)、Withaferin A，及其类似物、衍生物、片段和盐。Anti-angiogenic agents can be used to prevent or reduce neovascularization (including types 1, 2 and 3) and reduce vascular permeability/leakage. For example, interleukin-18 (IL-18) eliminates VEGF from the eye, thereby inhibiting the formation of damaged blood vessels behind the retina. Non-limiting examples of anti-angiogenic agents include inhibitors of VEGF (eg, squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (eg, bevacizumab) ranibizumab ESBA1008 and ESBA903), anti-VEGF aptamers (eg pegaptanib) ), anti-VEGF designed ankyrin repeat proteins [DARPins] (eg, abicipar pegol [AGN-150998 or MP0112]), soluble VEGFRs [eg VEGFR1], and containing one or more VEGFRs [eg Soluble fusion proteins of one or more extracellular domains of VEGFR1 and VEGFR2] (eg aflibercept) and conbercept), VEGF receptor (VEGFR) inhibitors (eg, axitinib, pazopanib, sorafenib, sunitinib ( sunitinib), X-82, PF-337210, isoflavol, and anti-VEGFR antibodies and fragments thereof), platelet-derived growth factor (PDGF) inhibitors (such as squalamine, anti-PDGF aptamers (such as E10030) ), anti-PDGF antibodies and fragments thereof, and soluble PDGFR) or inhibitors of its receptor (PDGFR) (eg, axitinib, pazopanib, sorafenib, sunitinib, X-82 and anti-PDGFR) PDGFR antibodies and fragments thereof [eg, REGN2176-3]), inhibitors of fibroblast growth factor (FGF) (eg, squalamine, anti-FGF antibodies and fragments thereof, anti-FGF aptamers, and soluble FGFR) or their receptors Antibody (FGFR) inhibitors (eg, anti-FGFR antibodies and fragments thereof), inhibitors of angiogenin (eg, anti-angiopoietin antibodies and fragments thereof (eg, nesvacumab) [REGN910] and REGN910- 3), and soluble angiopoietin receptor) or its receptor inhibitors (eg, anti-angiopoietin receptor antibodies and fragments thereof, inhibitors of integrins (eg, ALG-1001, JSM-6427 and anti-angiopoietin receptors) Integrin antibodies and fragments thereof), anectostat (anacorta acetate), angiostatins (eg, angiostatin K1-3), αvβ3 inhibitors (eg,etaracizumab ) ), apoA-I mimetics (e.g. L-4F and L-5F), berberine, bleomycins, borrelidin, carboxyamidotriazole, cartilage-derived angiogenesis inhibition agents (eg, chondromodulin I and troponin I), castanospermine, CM101, inhibitors of the complement system, cyclopropene fatty acids (such as sterculic acid), alpha -difluoromethylornithine, endostatin, everolimus, fumagillin, genistein, interferon-alpha, interleukin-12, Interleukin-18, itraconazole, linomide, MMP inhibitor, 2-methoxyestradiol, pigment epithelium-derived factor (PEDF), platelet factor-4, PPAR-α Agonists (eg, fibrates), PPAR-gamma agonists (eg, thiazolidinediones), prolactin, anti-angiogenic siRNAs, sphingosine-1-phosphate inhibitors (eg, senacizumab ( sonepcizumab), squalene, staurosporine, vasostatic steroids (such as tetrahydrocortisol) plus heparin, stilbene, suramin, SUS416, tasquinimod, tecogalan (tecogalan), tetrathiomolybdate (tetrathiomolybdate), thalidomide (tha lidomide) and its derivatives (such as lenalidomide and pomalidomide), thiabendazole, thrombospondins (such as thrombospondin 1), TNP-470, tranilast (tranilast), Withaferin A, and analogs, derivatives, fragments and salts thereof.
可以在适当的时间施用一种或多种抗血管生成剂以预防或降低发展病理的风险，所述发展病理可能导致视力的严重丧失。在某些实施方案中，在发生瘢痕形成(纤维化)或其大量发生之前施用一种或多种抗血管生成剂。One or more anti-angiogenic agents may be administered at an appropriate time to prevent or reduce the risk of developing pathologies that may result in severe loss of vision. In certain embodiments, one or more anti-angiogenic agents are administered prior to the occurrence of scarring (fibrosis) or its proliferation.
本文所述的抗血管生成剂可具有额外的有益特性。例如，抗PDGF适体E10030还可以通过减少视网膜下纤维化而具有抗纤维化作用，所述视网膜下纤维化可导致约10-15％的新生血管性AMD患者的中心视力丧失。The anti-angiogenic agents described herein can have additional beneficial properties. For example, the anti-PDGF aptamer E10030 may also have anti-fibrotic effects by reducing subretinal fibrosis, which can lead to central vision loss in approximately 10-15% of neovascular AMD patients.
在一些实施方案中，靶向不同血管生成机制的两种或更多种抗血管生成剂用于抑制新生血管形成(包括1、2和3型)、降低血管的渗透性/渗漏并治疗新生血管性AMD。在某些实施方案中，两种或更多种抗血管生成剂包含抗VEGF/VEGFR剂(例如阿柏西普、贝伐单抗或雷珠单抗)和靶向不同血管生成机制的物质。在一些实施方案中，两种或更多种抗血管生成剂包含抗VEGF/VEGFR剂和抗PDGF/PDGFR剂，例如贝伐单抗或雷珠单抗和E10030，或阿柏西普和REGN2176-3。E10030阻断PDGF-B与周细胞上的天然受体结合，导致周细胞从新形成的异常血管中剥离。在未受保护的情况下，内皮细胞非常容易受到抗VEGF剂的影响。由于这种剥离周细胞的能力，E10030可能对稍晚的疾病过程中的未成熟血管和较成熟的血管有影响。在进一步的实施方案中，两种或更多种抗血管生成剂包含抗VEGF/VEGFR剂和抗血管生成素/血管生成素受体剂，例如阿柏西普和奈弗库单抗或REGN910-3。In some embodiments, two or more anti-angiogenic agents targeting different angiogenic mechanisms are used to inhibit neovascularization (including types 1, 2, and 3), reduce vascular permeability/leakage, and treat neovascularization Vascular AMD. In certain embodiments, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent (eg, aflibercept, bevacizumab, or ranibizumab) and substances that target different angiogenic mechanisms. In some embodiments, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent and an anti-PDGF/PDGFR agent, eg, bevacizumab or ranibizumab and E10030, or aflibercept and REGN2176- 3. E10030 blocks the binding of PDGF-B to natural receptors on pericytes, resulting in the detachment of pericytes from newly formed abnormal blood vessels. In the unprotected condition, endothelial cells are very susceptible to anti-VEGF agents. Due to this ability to strip pericytes, E10030 may have effects on immature and more mature vessels later in the disease process. In a further embodiment, the two or more anti-angiogenic agents comprise an anti-VEGF/VEGFR agent and an anti-angiopoietin/angiopoietin receptor agent, such as aflibercept and nefukuzumab or REGN910- 3.
可选地，可以使用靶向不同血管生成机制的抗血管生成剂来治疗例如新生血管性AMD。例如，可以使用靶向VEGF/VEGFR和PDGF/PDGFR的双特异性抗体或DARPin，或靶向VEGF/VEGFR和血管生成素/血管生成素受体的双特异性抗体或DARPin。Alternatively, anti-angiogenic agents targeting different angiogenic mechanisms can be used to treat eg neovascular AMD. For example, bispecific antibodies or DARPins targeting VEGF/VEGFR and PDGF/PDGFR, or bispecific antibodies or DARPins targeting VEGF/VEGFR and angiopoietin/angiopoietin receptors can be used.
AMD还可以用其他类型的疗法治疗，包括激光光凝治疗(LPT)、光动力疗法(POT)和放射疗法(RT)。LPT采用例如氩(Ar)激光、微脉冲激光或纳秒激光或其任何组合，并且可以减少或消除患有萎缩性AMD或新生血管性AMD的患者的玻璃疣。激光手术也可以用于破坏眼睛中的异常血管，并且如果异常血管的生长不太广泛并且异常血管不接近中央凹则通常是合适的。PDT利用激光与化合物(例如维替泊芬)组合，该化合物在被特定波长的光激活时损伤靶细胞而不损伤正常细胞。可任选地在PDT中施用类固醇。PDT通常用于治疗息肉状新生血管病变，所述病变是亚洲人群中最常见的新生血管形成的形式。RT的实例包括但不限于外部束照射、局灶性放射(例如，通过玻璃体内、经玻璃体或经瞳孔递送)(例如，锶90[90Sr]X射线以15Gy或24Gy的剂量经玻璃体递送)，和结合抗-VEGF/VEGFR剂的辐射(例如，90Sr X射线以单一24Gy剂量与贝伐单抗组合，或以16Gy X射线与雷珠单抗组合而经玻璃体递送)。可以提供PDT或RT以减少新血管形成(例如CNV)并限制视力丧失或改善新生血管性AMD患者的视力。在一些实施方案中，将LPT、PDT或RT，或其任何组合或全部提供给患有新血管性AMD的患者，所述患者对抗血管生成剂(例如，抗VEGF/VEGFR剂)的治疗没有充分响应。AMD can also be treated with other types of therapy, including laser photocoagulation therapy (LPT), photodynamic therapy (POT), and radiation therapy (RT). LPT employs, for example, an argon (Ar) laser, a micropulse laser, or a nanosecond laser, or any combination thereof, and can reduce or eliminate drusen in patients with atrophic AMD or neovascular AMD. Laser surgery can also be used to destroy abnormal blood vessels in the eye, and is usually appropriate if the abnormal blood vessel growth is not too extensive and the abnormal blood vessel is not close to the fovea. PDT utilizes a laser in combination with a compound, such as verteporfin, that, when activated by light of a specific wavelength, damages target cells without damaging normal cells. Steroids can optionally be administered in PDT. PDT is commonly used to treat polypoid neovascular lesions, the most common form of neovascularization in Asian populations. Examples of RT include, but are not limited to, external beam irradiation, focal radiation (eg, intravitreal, transvitreal, or transpupillary delivery) (eg, strontium 90 [90 Sr] X-rays delivered via the vitreous at a dose of 15 Gy or 24 Gy) , and radiation combined with anti-VEGF/VEGFR agents (eg,90 Sr X-rays delivered via the vitreous in a single 24 Gy dose in combination with bevacizumab, or 16 Gy X-rays in combination with ranibizumab). PDT or RT can be provided to reduce neovascularization (eg, CNV) and limit vision loss or improve vision in patients with neovascular AMD. In some embodiments, LPT, PDT, or RT, or any combination or all thereof, is provided to a patient with neovascular AMD who is under-treated with an anti-angiogenic agent (eg, an anti-VEGF/VEGFR agent) response.
此外，细胞替代疗法和基于干细胞的疗法(例如源自干细胞的视网膜色素上皮(RPE)细胞)可用于治疗AMD。作为说明性实例，载脂蛋白模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以与RPE细胞替代组合使用以治疗例如晚期阶段的AMD(包括中央地图样萎缩和新生血管性AMD)。由于亚RPE-BL空间和BrM上的脂质沉积猖獗，RPE细胞可能萎缩并死亡。从亚RPE-BL空间和BrM去除脂质沉积物使BrM结构和功能正常化并改善脉络膜毛细血管与RPE之间微量营养物(包括维生素A)进入和废物排出的运输，并从而改善RPE细胞的健康。因此，晚期阶段的AMD患者可以首先用清理脂质的apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]进行治疗，并然后接受RPE细胞替换(例如，通过在例如视网膜下方的空间中的一次或多次注射或植入)。RPE细胞可以是例如源自干细胞的RPE细胞(例如，人胚胎干细胞[hESC]、人神经干细胞[hNSC]、骨髓干细胞和诱导多能干细胞[iPSC](包括自体干细胞))，或从全层视网膜的易位获得的RPE细胞。通过apo模拟物去除眼睛中的脂质沉积物可以产生有益效果，例如减少局部炎症、氧化应激和补体激活，这可以帮助预防或防止RPE细胞萎缩和死亡。In addition, cell replacement therapy and stem cell-based therapies, such as retinal pigment epithelium (RPE) cells derived from stem cells, can be used to treat AMD. As an illustrative example, apolipoprotein mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] can be used in combination with RPE cell replacement to treat Examples include advanced stages of AMD (including central geographic atrophy and neovascular AMD). RPE cells may shrink and die due to rampant lipid deposition on the sub-RPE-BL space and BrM. Removal of lipid deposits from the sub-RPE-BL space and BrM normalizes BrM structure and function and improves the transport of micronutrients (including vitamin A) in and waste out between the choriocapillaries and the RPE, and thereby improves RPE cell performance healthy. Thus, advanced stage AMD patients can be treated first with lipid-clearing apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] , and then undergo RPE cell replacement (eg, by one or more injections or implants in, eg, the subretinal space). RPE cells can be, for example, RPE cells derived from stem cells (eg, human embryonic stem cells [hESCs], human neural stem cells [hNSCs], bone marrow stem cells, and induced pluripotent stem cells [iPSCs] (including autologous stem cells)), or from full-thickness retinal RPE cells obtained by translocation. Removal of lipid deposits in the eye by apo mimetics can have beneficial effects, such as reducing local inflammation, oxidative stress, and complement activation, which can help prevent or prevent RPE cell shrinkage and death.
作为RPE细胞替代疗法的实例，可将RPE细胞作为聚合物或其他合适的载体材料上的薄层引入，所述薄层允许细胞与剩余的光感受器相互交错并恢复重要的吞噬作用和维生素A转移功能等其他功能。清理脂质的apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]改善了穿过BrM的营养物进入和废物排出的流通，并从而改善了周围地区细胞的健康。任选地与物质(例如，基质金属蛋白酶)组合，所述物质减少仍然在BrM上的基底层状沉积物(BLamD)的厚度，apo模拟物有助于为RPE细胞薄层制备合适的移植床，这得益于从脉络膜毛细血管到移植支架的明确路径。As an example of RPE cell replacement therapy, RPE cells can be introduced as a thin layer on a polymer or other suitable carrier material that allows the cells to interdigitate with the remaining photoreceptors and restore important phagocytosis and vitamin A transfer function and other functions. Lipid-scavenging apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] improve nutrient entry and waste efflux across BrM circulation and thereby improve the health of cells in the surrounding area. Optionally combined with substances (e.g., matrix metalloproteinases) that reduce the thickness of basal lamellar deposits (BLamD) still on BrM, apo mimetics help prepare a suitable graft bed for a thin layer of RPE cells , thanks to a well-defined pathway from the choriocapillaries to the graft stent.
作为RPE细胞替代疗法的另一个实例，可以通过非手术方法将细胞引入眼睛。可以重新编程骨髓细胞使其安顿在RPE层上并停留在天然RPE细胞之间。apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]增加了穿过BrM的营养物进入和废物排出的运输，并从而改善了RPE层中细胞的健康，所述apo模拟物任选地与物质(例如，基质金属蛋白酶)组合，所述物质减少仍然在BrM上的BLamD的厚度。As another example of RPE cell replacement therapy, cells can be introduced into the eye by non-surgical methods. Bone marrow cells can be reprogrammed to settle on the RPE layer and stay between native RPE cells. apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] increase nutrient entry and waste efflux transport across BrM, and Thus improving the health of cells in the RPE layer, the apo mimetics are optionally combined with substances (eg, matrix metalloproteinases) that reduce the thickness of BLamD still on BrM.
还可以实施RPE再生。例如，可以注射自由漂浮的细胞(例如，脐带细胞)以为现有细胞(例如，神经元和RPE细胞)提供营养支持。清理脂质的apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]改善了穿过BrM的营养物进入和废物排出的流通，并从而改善了脉络膜流域区域的细胞的健康。任选地与物质(例如，基质金属蛋白酶)组合，所述物质减少仍然在BrM上的BLamD的厚度，apo模拟物有助于为注射的细胞制备合适的分散床。RPE regeneration can also be performed. For example, free-floating cells (eg, umbilical cord cells) can be injected to provide nutrient support to existing cells (eg, neurons and RPE cells). Lipid-scavenging apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] improve nutrient entry and waste efflux across BrM circulation and thereby improve the health of cells in the choroidal drainage area. Optionally combined with substances (eg, matrix metalloproteinases) that reduce the thickness of BLamD remaining on BrM, the apo mimetics help to prepare a suitable dispersed bed for injected cells.
另外，AMD可以通过脉络膜毛细血管的细胞替代疗法来治疗。例如，脉络膜毛细血管内皮可以用源自干细胞的脉络膜毛细血管内皮细胞取代。Alternatively, AMD can be treated by cell replacement therapy of the choriocapillaries. For example, the choriocapillary endothelium can be replaced with stem cell-derived choriocapillary endothelial cells.
脉络膜毛细血管的血管丢失(dropout)/损失和脉络膜血流减少可以在AMD的发病机制早期发生。在早期AMD中，脉络膜毛细血管的血管密度与亚RPE-BL沉积物(例如玻璃疣和BLinD)的密度呈负相关，并且“幽灵”血管(先前健康的毛细血管的残余物)的数量与亚RPE-BL沉积密度正相关。补体系统的激活和脉络膜毛细血管中MAC的形成可以引起血管内皮细胞的损失，所述激活和形成可以通过使用补体抑制剂(例如MAC形成、沉积或功能的抑制剂)来抑制。内皮功能障碍也可能由以下原因引起：1)一氧化氮的量减少，所述减少可能是由于二甲基精氨酸(干扰L-精氨酸刺激的一氧化氮合成)的水平高，并且可以通过使用物质来纠正，所述物质增加一氧化氮的水平(例如，一氧化氮合成的刺激物或二甲基精氨酸形成的抑制剂；2)活性氧物质的增加，所述增加可以损害一氧化氮的合成和活性，并且可以通过使用抗氧化剂(例如，活性氧物质的清除剂)来抑制；以及3)炎症事件，所述炎症事件可以被抑制内皮炎症事件的物质(例如，apoA-I模拟物，例如Rev-D-4F)来抑制。通过使用增加CBF的物质可以改善脉络膜血流量(CBF)的降低，所述增加CBF的物质例如CBF促进剂(例如，MC-1101)或血管扩张剂(例如，超极化介导的[钙通道阻滞剂，例如腺苷]、cAMP介导的[例如，前列环素]、cGMP介导的[例如，一氧化氮]、抑制磷酸二酯酶[PDE]的[例如，莫西韦林或西地那非{一种PDE5抑制剂}]、或抑制引起平滑肌收缩的补体多肽[例如，C3a、C4a和C5a])的。增加CBF可以防止BrM破裂。为了治疗血管损失和/或降低CBF，在AMD早期可以至少施用一种或多种治疗剂，所述治疗剂保持或改善内皮的健康和/或眼睛血管系统的血流，包括本文所述的治疗剂。Choroidal capillary dropout/loss and reduced choroidal blood flow can occur early in the pathogenesis of AMD. In early AMD, choriocapillary vascular density is inversely correlated with the density of sub-RPE-BL deposits such as drusen and BLinD, and the number of "ghost" vessels (remnants of previously healthy capillaries) is associated with sub-RPE-BL deposits such as drusen and BLinD. RPE-BL deposition density was positively correlated. Activation of the complement system and formation of MACs in the choriocapillaries can cause loss of vascular endothelial cells, which activation and formation can be inhibited by the use of complement inhibitors, such as inhibitors of MAC formation, deposition or function. Endothelial dysfunction may also be caused by: 1) a reduction in the amount of nitric oxide, possibly due to high levels of dimethylarginine (which interferes with L-arginine-stimulated nitric oxide synthesis), and This can be corrected by the use of substances that increase levels of nitric oxide (eg, stimulators of nitric oxide synthesis or inhibitors of dimethylarginine formation; 2) increases in reactive oxygen species, which can Impairs nitric oxide synthesis and activity, and can be inhibited by the use of antioxidants (eg, scavengers of reactive oxygen species); and 3) inflammatory events, which can be inhibited by substances that inhibit endothelial inflammatory events (eg, apoA -I mimetics such as Rev-D-4F) to inhibit. The reduction in choroidal blood flow (CBF) can be ameliorated by the use of CBF-increasing substances, such as CBF enhancers (eg, MC-1101) or vasodilators (eg, hyperpolarization-mediated [calcium channel] Blockers such as adenosine], cAMP-mediated [eg, prostacyclin], cGMP-mediated [eg, nitric oxide], phosphodiesterase [PDE] inhibitory [eg, mosivirine or Sildenafil {a PDE5 inhibitor}], or inhibition of complement polypeptides [eg, C3a, C4a, and C5a]) that cause smooth muscle contraction. Increasing CBF can prevent the rupture of BrM. To treat vascular loss and/or reduce CBF, at least one or more therapeutic agents may be administered early in AMD that maintain or improve endothelial health and/or blood flow in the vascular system of the eye, including the treatments described herein agent.
在一些实施方案中，载脂蛋白模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])与一种或多种额外的治疗AMD的治疗剂联合使用。在某些实施方案中，apo模拟物和一种或多种额外的治疗剂具有协同效应。In some embodiments, an apolipoprotein mimetic (eg, an apoA-I mimetic [eg, L-4F] and/or an apoE mimetic [eg, AEM-28-14]) is combined with one or more additional Combinations of therapeutic agents for the treatment of AMD. In certain embodiments, the apo mimetic and one or more additional therapeutic agents have a synergistic effect.
VI.用载脂蛋白模拟物和抗血管生成剂治疗AMDVI.Treatment of AMD with Apolipoprotein Mimics and Antiangiogenic Agents
本公开的一些实施方案涉及治疗AMD的方法，所述方法包括向需要治疗的对象施用治疗有效量的载脂蛋白(apo)模拟物和治疗有效量的抗血管生成剂，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量施用于眼局部、眼内、眼中或眼周，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量施用于眼局部、眼内、眼中或眼周。涉及用载脂蛋白模拟物治疗AMD的所有实施方案也适用于用apo模拟物和抗血管生成剂治疗AMD，所述实施方案在本文IV部分和其它地方描述。Some embodiments of the present disclosure relate to methods of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic and a therapeutically effective amount of an antiangiogenic agent, whether the apo mimetic is or Not at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection) locally, intraocularly, in the eye, or around the eye, or at a dose of about 0.5 or 1 mg to about 0.5 or 1 mg over a period of about 6 months A total dose of about 10 mg is administered topically, intraocularly, in or around the eye. All of the embodiments that relate to the treatment of AMD with apolipoprotein mimetics are also applicable to the treatment of AMD with apo mimetics and anti-angiogenic agents, described in Section IV and elsewhere herein.
载脂蛋白模拟物(包括apoA-I模拟物和apoE模拟物)的实例包括但不限于本文其他地方描述的那些。在一些实施方案中，apo模拟物包括apoA-I模拟物或是apoA-I模拟物。在某些实施方案中，apoA-I模拟物包括4F或其变体或盐(例如乙酸盐)，或是4F或其变体或盐(例如乙酸盐)。在一些实施方案中，4F的所有氨基酸残基都具有L型(L-4F)。在其他实施方案中，4F的一个或多个或全部氨基酸残基具有D型(例如，具有所有D型氨基酸残基的D-4F)。4F可在N-末端具有保护基团(例如酰基，如乙酰基)和/或在C-末端具有保护基团(例如酰胺基团，如-C(O)NH2)。在某些实施方案中，apoA-I模拟物包括具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F，或者是具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F。在进一步的实施方案中，apo模拟物包括apoE模拟物，或是apoE模拟物。在某些实施方案中，apoE模拟物包括AEM-28-14或其变体或盐，或是AEM-28-14或其变体或盐。Examples of apolipoprotein mimetics, including apoA-I mimetics and apoE mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or an apoA-I mimetic. In certain embodiments, the apoA-I mimetic comprises 4F or a variant or salt thereof (eg, acetate), or 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues of 4F have the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F have the D-form (eg, D-4F with all D-form amino acid residues). 4F may have a protecting group at the N-terminus (eg, an acyl group such as acetyl) and/or a protecting group at the C-terminus (eg, an amide group such as -C(O)NH2 ). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13), or L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. .13) Structure of L-4F. In further embodiments, the apo mimetic includes an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or AEM-28-14 or a variant or salt thereof.
抗血管生成剂的实例包括但不限于本文其他地方描述的那些。在一些实施方案中，抗血管生成剂包括抑制血管内皮生长因子作用的物质(抗VEGF剂)，或者是抑制血管内皮生长因子作用的物质(抗VEGF剂)，所述抗VEGF剂包括但不限于VEGF-A、VEGF-B和胎盘生长因子(PGF)。抗VEGF剂的非限制性实例包括本文其他地方描述的那些。在某些实施方案中，抗VEGF剂包括阿柏西普贝伐单抗或雷珠单抗或者是阿柏西普贝伐单抗或雷珠单抗或其任何组合或全部。在进一步的实施方案中，抗血管生成剂包括抑制血小板衍生生长因子的作用的物质(抗PDGF剂)，或者是抑制血小板衍生生长因子的作用的物质(抗PDGF剂)，所述抗PDGF剂包括但不限于PDGF-A、PDGF-B、PDGF-C、PDGF-D和PDGF-A/B。抗PDGF剂的非限制性实例包括本文其他地方描述的那些。在某些实施方案中，抗PDGF剂包括或者是E10030Examples of anti-angiogenic agents include, but are not limited to, those described elsewhere herein. In some embodiments, the anti-angiogenic agent includes a substance that inhibits the action of vascular endothelial growth factor (anti-VEGF agent), or is a substance that inhibits the action of vascular endothelial growth factor (anti-VEGF agent), including but not limited to VEGF-A, VEGF-B and placental growth factor (PGF). Non-limiting examples of anti-VEGF agents include those described elsewhere herein. In certain embodiments, the anti-VEGF agent includes aflibercept Bevacizumab or ranibizumab or aflibercept Bevacizumab or ranibizumab or any combination or all thereof. In further embodiments, the anti-angiogenic agent comprises a substance that inhibits the action of platelet-derived growth factor (anti-PDGF agent), or is a substance that inhibits the action of platelet-derived growth factor (anti-PDGF agent), said anti-PDGF agent comprising But not limited to PDGF-A, PDGF-B, PDGF-C, PDGF-D and PDGF-A/B. Non-limiting examples of anti-PDGF agents include those described elsewhere herein. In certain embodiments, the anti-PDGF agent includes or is E10030
在一些实施方案中，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量局部施用，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量局部施用，抗血管生成剂(例如，抗VEGF剂)以低于常规或推荐给药频率的频率施用，和/或以低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的抗血管生成剂的。在一些实施方案中，相比于抗血管生成剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。在某些实施方案中，抗血管生成剂(例如，抗VEGF剂)每2、3、4、5或6个月施用于眼局部、眼内、眼中或眼周(例如通过玻璃体内注射)一次。在进一步的实施方案中，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗减少了施用抗血管生成剂(例如，抗VEGF剂)的总次数(例如，注射的总次数)。在某些实施方案中，抗血管生成剂(例如，抗VEGF剂)的施用(例如，通过玻璃体内注射)不超过约20、18、15、12或10次。在另外的实施方案中，相比于抗血管生成剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约10-30％、30-50％或50-70％的剂量施用(例如，通过玻璃体内注射)。In some embodiments, whether the apo mimetic is or is not administered topically at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or at a dose of about 0.5 or about 0.5 mg over a period of about 6 months Topically administered in a total dose of 1 mg to about 10 mg, with an anti-angiogenic agent (eg, an anti-VEGF agent) administered less frequently than conventional or recommended dosing, and/or administered at a dose less than conventional or recommended, the Usual or recommended dosing frequency or routine or recommended dose for those not treated with an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] Cases of antiangiogenic agents. In some embodiments, the conventional or recommended dosing frequency of the anti-angiogenic agent is compared to the normal or recommended dosing frequency of the anti-angiogenic agent in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F ) and/or an apoE mimetic (eg, AEM-28-14)], the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) at least about less frequently 1.5 times, 2 times, 3 times, 4 times, 5 times, or 6 times (eg, at least about 2 times). In certain embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered topically, intraocularly, in the eye, or around the eye (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months . In further embodiments, treatment with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] reduces administration of an antiangiogenic The total number of doses (eg, total number of injections) of the agent (eg, anti-VEGF agent). In certain embodiments, the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times. In additional embodiments, the conventional or recommended dose is compared to the conventional or recommended dose of the anti-angiogenic agent in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and anti-angiogenic agent (eg, anti-VEGF agent) at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70% of the dose is administered (eg, by intravitreal injection).
用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)治疗AMD可具有协同作用。例如，用apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)治疗可以增强抗血管生成剂的功效，和/或反之亦然。例如，L-4F可以显著减少布鲁赫膜(BrM)的脂质沉积物，并在结构上将BrM重塑为正常或更健康的状态，从而降低BrM对以下的敏感性：在1型和2型新生血管形成(NV)中从脉络膜长出穿过BrM并进入亚RPE-BL空间和视网膜下空间的新血管的侵入。作为另一个例子，L-4F减少炎症(NV的重要刺激物)的能力(通过抑制例如补体系统的激活和促炎氧化脂质的形成)，可以减少所需的施用(例如，通过注射)次数和/或抗血管生成剂的剂量。apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)与抗血管生成剂之间的协同作用可以允许但不要求例如抗血管生成剂以低于常规或者推荐的给药频率的频率和/或低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或剂量是对于没有用apo模拟物(例如apoA-I模拟物和/或apoE模拟物)治疗的情况下的抗血管生成剂的。Treatment of AMD with apo mimetics (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and anti-angiogenic agents (eg, anti-VEGF agents) have a synergistic effect. For example, treatment with an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) can enhance the efficacy of an antiangiogenic agent, and/or vice versa. For example, L-4F can significantly reduce Bruch's membrane (BrM) lipid deposits and structurally remodel BrM to a normal or healthier state, thereby reducing BrM susceptibility to type 1 and Invasion of new blood vessels that grow from the choroid through the BrM and into the sub-RPE-BL space and the subretinal space in type 2 neovascularization (NV). As another example, the ability of L-4F to reduce inflammation (an important stimulator of NV) (by inhibiting, for example, the activation of the complement system and the formation of pro-inflammatory oxidized lipids), may reduce the number of administrations (eg, by injection) required and/or doses of antiangiogenic agents. Synergy between an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and an anti-angiogenic agent may allow, but does not require, for example, an anti-angiogenic agent to be administered at a frequency lower than conventional or recommended and/or administered at a dose lower than the usual or recommended dose frequency or dose for anti-resistance in the absence of treatment with an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic). Angiogenic agents.
施用较低剂量的抗血管生成剂可具有益处，例如由于较少的副作用而具有更好的安全性。以较低频率的施用(例如，通过玻璃体内注射)抗血管生成剂也可具有益处，例如由于执行的侵入性程序较少而使得患者舒适性、便利性、依从性和健康更大/更好。由于频繁的用于测试、监测和治疗的门诊就诊，频繁施用可以使得护理提供者和患者都具有负担。此外，抗血管生成剂(例如，抗VEGF剂)在重复使用时可能变得不太有效，这种现象称为快速耐受。此外，玻璃体内注射的风险包括眼内压升高、细菌性和无菌性眼内炎、白内障形成、出血和视网膜脱离，重复注射可导致视网膜变薄和地图样萎缩。Administration of lower doses of antiangiogenic agents may have benefits, such as better safety due to fewer side effects. Less frequent administration of anti-angiogenic agents (eg, by intravitreal injection) may also have benefits, such as greater/better patient comfort, convenience, compliance and health due to less invasive procedures performed . Frequent administration can be burdensome for both care providers and patients due to frequent outpatient visits for testing, monitoring and treatment. In addition, anti-angiogenic agents (eg, anti-VEGF agents) may become less effective with repeated use, a phenomenon known as tachyphylaxis. In addition, the risks of intravitreal injections include increased intraocular pressure, bacterial and aseptic endophthalmitis, cataract formation, hemorrhage, and retinal detachment, and repeated injections can lead to retinal thinning and geographic atrophy.
在某些实施方案中，抗血管生成剂包括阿柏西普或者是阿柏西普并且相比于阿柏西普的常规或推荐剂量和给药频率为治疗前3个月以2mg每月施用一次之后以2mg每2个月玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，阿柏西普以约1-1.5mg或1.5-2mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约1-1.5mg或1.5-2mg的剂量每月施用一次之后，或者在前1.5或3个月以约1-1.5mg或1.5-2mg的剂量每6周施用一次之后，阿柏西普以约1-1.5mg或1.5-2mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。据估计，阿柏西普的玻璃体内半衰期约为9.0天。In certain embodiments, the anti-angiogenic agent includes aflibercept or aflibercept And compared to the usual or recommended dose and dosing frequency of aflibercept of 2 mg administered once monthly for the first 3 months of treatment followed by 2 mg administered as an intravitreal injection every 2 months, the usual or recommended dose and dosing frequency Dosing frequency is for aflibercept in the absence of treatment with an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] Administer (eg, by intravitreal injection) once every 3, 4, 5, or 6 months at a dose of about 1-1.5 mg or 1.5-2 mg, optionally in the first 1, 2 After monthly administration at a dose of about 1-1.5 mg or 1.5-2 mg for 1 month or 3 months, or every 6 weeks for the first 1.5 or 3 months at a dose of about 1-1.5 mg or 1.5-2 mg, Aflibercept is administered (eg, by intravitreal injection) once every 3, 4, 5, or 6 months at a dose of about 1-1.5 mg or 1.5-2 mg. The estimated intravitreal half-life of aflibercept is approximately 9.0 days.
在其他实施方案中，抗血管生成剂包括阿柏西普或者是阿柏西普，并且在以与阿柏西普的常规或推荐给药频率基本相似或相同的频率下，所述常规或推荐给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，阿柏西普以约1-1.25mg、1.25-1.5mg或1.5-1.75mg的剂量施用(例如，通过玻璃体内注射)。In other embodiments, the anti-angiogenic agent comprises or is aflibercept at substantially similar or the same frequency as the conventional or recommended dosing frequency of aflibercept. Dosing frequency is for the absence of treatment with apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)], aflibercept The drug is administered (eg, by intravitreal injection) at a dose of about 1-1.25 mg, 1.25-1.5 mg, or 1.5-1.75 mg.
在进一步的实施方案中，抗血管生成剂包括雷珠单抗或者是雷珠单抗并且相比于雷珠单抗的常规或推荐剂量和给药频率为以0.5mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，雷珠单抗以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地前1、2或3个月以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每个月施用一次之后，或者在前1.5或3个月以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每6周施用一次之后，雷珠单抗以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。据估计，雷珠单抗的玻璃体内半衰期约为7.1天。In further embodiments, the anti-angiogenic agent comprises ranibizumab or ranibizumab And compared to the usual or recommended dose and frequency of administration of ranibizumab at 0.5 mg administered by intravitreal injection once a month for the absence of an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] treatment, ranibizumab at about 0.2-0.3 mg, 0.3-0.4 mg, or A dose of 0.4-0.5 mg is administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months, optionally with a dose of about After a dose of 0.2-0.3 mg, 0.3-0.4 mg or 0.4-0.5 mg once monthly, or for the first 1.5 or 3 months at a dose of about 0.2-0.3 mg, 0.3-0.4 mg or 0.4-0.5 mg every After 6-week administration, ranibizumab is administered every 2, 3, 4, 5, or 6 months at doses of about 0.2-0.3 mg, 0.3-0.4 mg, or 0.4-0.5 mg ( For example, by intravitreal injection) once. The estimated intravitreal half-life of ranibizumab is approximately 7.1 days.
在其他实施方案中，抗血管生成剂包括雷珠单抗或者是雷珠单抗，并且雷珠单抗以约0.2-0.3mg或0.3-0.4mg的剂量每月施用(例如，通过玻璃体内注射)一次。In other embodiments, the anti-angiogenic agent comprises or is ranibizumab, and ranibizumab is administered monthly (eg, by intravitreal injection) at a dose of about 0.2-0.3 mg or 0.3-0.4 mg )once.
在另外的实施方案中，抗血管生成剂包括贝伐单抗或者是贝伐单抗并且相比于贝伐单抗用于治疗AMD的常规或推荐剂量和给药频率为以约1.25mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，贝伐单抗以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1、2或3个月以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每个月施用一次之后或在前一个1.5或3个月以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每6周施用一次之后，贝伐单抗以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。据估计，贝伐单抗的玻璃体内半衰期约为9.8天。In additional embodiments, the anti-angiogenic agent comprises bevacizumab or bevacizumab And compared to the usual or recommended dose and dosing frequency of bevacizumab for the treatment of AMD of approximately 1.25 mg administered by intravitreal injection once a month, the usual or recommended dose and dosing frequency are for those without apo. In the case of mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] therapy, bevacizumab is administered at about 0.5-0.75 mg, A dose of 0.75-1 mg or 1-1.25 mg is administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months, optionally in the first 1, 2 or 3 months at a dose of about 0.5-0.75 mg, 0.75-1 mg, or 1-1.25 mg after monthly administration or for the previous 1.5 or 3 months at about 0.5-0.75 mg, 0.75-1 mg, or 1-1.25 mg Bevacizumab at doses of approximately 0.5-0.75 mg, 0.75-1 mg, or 1-1.25 mg every 2, 3, 4, 5, or 6 months Administration (eg, by intravitreal injection) once. The estimated intravitreal half-life of bevacizumab is approximately 9.8 days.
在其他实施方案中，抗血管生成剂包括贝伐单抗或者是贝伐单抗，并且贝伐单抗以约0.5-0.75mg或0.75-1mg的剂量每月施用(例如，通过玻璃体内注射)一次。In other embodiments, the anti-angiogenic agent comprises or is bevacizumab, and bevacizumab is administered monthly (eg, by intravitreal injection) at a dose of about 0.5-0.75 mg or 0.75-1 mg once.
在一些实施方案中，用抗血管生成剂(例如，抗VEGF剂)治疗的持续时间/时长不超过约36、30、24、18或12个月。在某些实施方案中，用抗血管生成剂(例如抗VEGF剂)治疗的时长不超过约24、18或12个月。在进一步的实施方案中，用抗血管生成剂(例如抗VEGF剂)治疗的时长为约6-12、12-18或18-24个月。In some embodiments, the duration/duration of treatment with an anti-angiogenic agent (eg, an anti-VEGF agent) does not exceed about 36, 30, 24, 18, or 12 months. In certain embodiments, the duration of treatment with an anti-angiogenic agent (eg, an anti-VEGF agent) does not exceed about 24, 18, or 12 months. In further embodiments, the duration of treatment with an anti-angiogenic agent (eg, an anti-VEGF agent) is about 6-12, 12-18, or 18-24 months.
在一些实施方案中，施用抗血管生成剂(例如，抗VEGF剂)以治疗或减缓新生血管性(湿性)AMD(包括1、2和3型新生血管形成(NV)并且包括当存在新生血管形成活跃的迹象时)的进展。亚RPE-BL、视网膜下或视网膜内液体的存在(其可以表示新生血管形成活跃和新血管中的液体渗漏)可以通过诸如OCT-荧光血管造影术的技术来检测。在某些实施方案中，当检测到视网膜下或视网膜内液体的存在时，施用抗血管生成剂(例如，抗VEGF剂)。当检测到亚RPE-BL液体时，也可以使用抗血管生成剂(例如，抗VEGF剂)，尽管由亚RPE-BL液体引起的色素上皮脱离可以在相对长的时间内保持稳定并且可以不需要抗血管生成疗法。在进一步的实施方案中，至少在AMD的晚期阶段施用抗血管生成剂(例如，抗VEGF剂)以预防新生血管性AMD、延迟新生血管性AMD的发作或减缓新生血管性AMD的进展。在某些实施方案中，相比于治疗或减缓新生血管性AMD的进展，对于预防新生血管性AMD、延迟新生血管性AMD的发作或减缓新生血管性AMD的进展则以较低频率和/或较低剂量施用(例如，通过玻璃体内注射)抗血管生成剂(例如，抗VEGF剂)。In some embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered to treat or slow neovascular (wet) AMD (including type 1, 2, and 3 neovascularization (NV) and include when neovascularization is present signs of activity). The presence of sub-RPE-BL, subretinal or intraretinal fluid, which may indicate active neovascularization and fluid leakage in the new vessels, can be detected by techniques such as OCT-fluorescein angiography. In certain embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered when the presence of subretinal or intraretinal fluid is detected. Anti-angiogenic agents (eg, anti-VEGF agents) may also be used when sub-RPE-BL fluid is detected, although pigment epithelial detachment caused by sub-RPE-BL fluid may remain stable for relatively long periods of time and may not be required Antiangiogenic therapy. In further embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered to prevent neovascular AMD, delay the onset of neovascular AMD, or slow the progression of neovascular AMD, at least in the advanced stages of AMD. In certain embodiments, preventing neovascular AMD, delaying the onset of neovascular AMD, or slowing the progression of neovascular AMD is performed at a lower frequency and/or compared to treating or slowing the progression of neovascular AMD Anti-angiogenic agents (eg, anti-VEGF agents) are administered (eg, by intravitreal injection) at lower doses.
关于apo模拟物，在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如，每次注射)约0.1或0.3-1.5mg、0.1-0.5mg、0.5-1mg、1-1.5mg、0.1-0.3mg、0.3-0.5mg、0.5-0.75mg、0.75-1mg、1-1.25mg或1.25-1.5mg(例如，约0.1-0.5mg或0.5-1mg)的剂量施用于(例如，通过玻璃体内注射)眼局部、眼内、眼中或者眼周。apo模拟物也可以以每次施用大于1.5mg的剂量局部施用，例如每次施用(例如，每次注射)至多约2mg或更多。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5或1-10mg、0.5或1-5mg、5-10mg、0.5或1-3mg、3-5mg、5-7.5mg或7.5-10mg(例如，约0.5-3mg或3-5mg)的总剂量局部施用(例如，通过玻璃体内注射或通过缓释组合物)，其中用apo模拟物治疗的持续时间/时长可以是例如约6-12、12-18或18-24个月或更长时间。apo模拟物也可以以在约6个月的时间内大于10mg的总剂量局部施用，例如在约6个月的时间内至多约15mg或更多。在更进一步的实施方案中，对于使用apo模拟物的整个/完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1或2-20mg、5-15mg、1-5mg、5-10mg、10-15mg、15-20mg、1-3mg、3-5mg、5-7.5mg、7.5-10mg、10-12.5mg、12.5-15mg、15-17.5mg或17.5-20mg(例如，约1-5mg或5-10mg)的总剂量局部施用。对于完整治疗方案，apo模拟物也可以以大于20mg的总剂量局部施用，例如对于完整治疗方案至多约25mg、30mg、40mg、50mg或更多的总剂量。With respect to apo mimetics, in certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered per administration (eg, per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0.3 mg, 0.3-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1- A dose of 1.25 mg or 1.25-1.5 mg (eg, about 0.1-0.5 mg or 0.5-1 mg) is administered (eg, by intravitreal injection) locally, intraocularly, in the eye, or around the eye. The apo mimetic can also be administered topically in doses greater than 1.5 mg per administration, eg, up to about 2 mg or more per administration (eg, per injection). In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered within a period of about 6 months A total dose of about 0.5 or 1-10 mg, 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg, 3-5 mg, 5-7.5 mg, or 7.5-10 mg (eg, about 0.5-3 mg or 3-5 mg) Topical administration (eg, by intravitreal injection or by slow release composition), wherein the duration/duration of treatment with the apo mimetic can be, eg, about 6-12, 12-18, or 18-24 months or more. The apo mimetic can also be administered topically at a total dose of greater than 10 mg over a period of about 6 months, eg, up to about 15 mg or more over a period of about 6 months. In still further embodiments, for an entire/complete treatment regimen using an apo mimetic, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28) -14)] with about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10 - Topical administration at a total dose of 12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg). The apo mimetic can also be administered topically in a total dose of greater than 20 mg for a complete treatment regimen, eg, up to a total dose of about 25 mg, 30 mg, 40 mg, 50 mg or more for a complete treatment regimen.
在将apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]施用于眼局部、眼内、眼中或眼周的实施方案中，每次施用的剂量、在约6个月的时间内的总剂量、以及整个治疗方案的总剂量在某些实施方案中是对于施用的每只眼睛，并且在其他实施方案中是对于双眼的。血液系统可允许局部施用(例如，注射)到一只眼睛内或在一只眼睛中的一些量(例如，治疗有效量)的apo模拟物被分布到另一只眼睛，在这种情况下apo模拟物的剂量可以考虑到另一只眼睛(其可能处于较少患病的状况)而任选的得到调整(例如，增加)，并且可以允许用apo模拟物同时治疗双眼而无需在另一只眼睛内或另一只眼睛中额外的施用(例如，注射)apo模拟物。例如，玻璃体内注射的apo模拟物可以穿过血液-视网膜屏障到达两个靶区域(即亚RPE-BL空间和布鲁赫膜)，apo模拟物可以从所述靶区域进入脉络膜毛细血管，并最终到达对应未施用的眼睛。也不受理论的束缚，一些量的apo模拟物可以通过房水途径进入对应未施用的眼睛，房水通过小梁网和流入血液系统的施莱姆管排出。因此，一些实施方案涉及治疗AMD的方法，其包括向需要治疗的对象施用治疗有效量的载脂蛋白模拟物和治疗有效量的抗血管生成剂，其中所述载脂蛋白模拟物施用于一只眼睛中的眼局部、眼内、眼中或眼周并且两只眼睛都有治疗效果。Implementation of topical, intraocular, intraocular, or periocular administration of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] In the regimen, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are in certain embodiments for each eye administered, and in other embodiments for each eye. binocular. The blood system may allow topical administration (eg, injection) into one eye or some amount (eg, a therapeutically effective amount) in one eye of an apo mimetic to be distributed to the other eye, in which case apo The dose of the mimetic can optionally be adjusted (eg, increased) to take into account the other eye (which may be in a less diseased condition), and can allow simultaneous treatment of both eyes with the apo mimetic without Additional administration (eg, injection) of the apo mimetic in the eye or in the other eye. For example, intravitreal injected apo mimetics can cross the blood-retinal barrier to two target areas (ie, the sub-RPE-BL space and Bruch's membrane) from which the apo mimetics can enter the choriocapillaris and ultimately Reach the corresponding unapplied eye. Also not to be bound by theory, some amount of apo mimetic can enter the corresponding non-administered eye via the aqueous humor route, which drains through the trabecular meshwork and Schlemm's canal into the blood system. Accordingly, some embodiments relate to methods of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein mimetic and a therapeutically effective amount of an antiangiogenic agent, wherein the apolipoprotein mimetic is administered to a Partially in the eye, in the eye, in the eye or around the eye and in both eyes.
在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每月(4周)或每1.5个月(6周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每2个月(8周)、每2.5个月(10周)或每3个月(12周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每4、5或6个月局部施用(例如，通过玻璃体内注射或通过缓释组合物)一次。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以总共约15次或更少、12次或更少、9次或更少、6次或更少、或3次或更少(例如，3-6次或7-10次)的施用(例如注射)在局部施用。也可以在局部施用apo模拟物总共超过15次施用(例如注射)，例如至多约20次或更多次施用(例如注射)。在将apo模拟物施用于眼局部、眼内、眼中或眼周的实施方案中，施用频率和施用(例如注射)总次数在某些实施方案中是对于施用的每只眼睛，并且由于apo模拟物也可以在对应未施用的眼睛中具有治疗效果，在其他实施方案中是对于双眼的。In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] monthly (4 weeks) or every 1.5 Topical administration (eg, by intravitreal injection) once a month (6 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] every 2 months (8 weeks), every Topical administration (eg, by intravitreal injection) once every 2.5 months (10 weeks) or every 3 months (12 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically every 4, 5, or 6 months (eg, by intravitreal injection or by slow release composition) once. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a total of about 15 times or less, 12 or less, 9 or less, 6 or less, or 3 or less (eg, 3-6 or 7-10) administrations (eg, injections) are administered locally. The apo mimetic may also be administered topically for a total of more than 15 administrations (eg, injections), eg, up to about 20 or more administrations (eg, injections). In embodiments where the apo mimetic is administered topically, intraocularly, in the eye or periocular The drug may also have a therapeutic effect in the corresponding unadministered eye, in other embodiments both eyes.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的晚期阶段施用以治疗或减缓新生血管性AMD(包括1、2和3型NV)的进展。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的晚期施用以治疗中央地图样萎缩(GA)或减缓中央地图样萎缩(GA)的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的中期阶段施用以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in advanced stages of AMD to treat or Slows the progression of neovascular AMD, including NV types 1, 2, and 3. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered at least in late stages of AMD to treat central Geographic atrophy (GA) or slow the progression of central geographic atrophy (GA), and/or prevent neovascular AMD or delay the onset of neovascular AMD. In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered to treat at least the intermediate stages of AMD Non-central GA or slowing the progression of non-central GA, and/or preventing central GA and/or neovascular AMD or delaying the onset of central GA and/or neovascular AMD.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或抗血管生成剂(例如，抗VEGF剂)施用于眼局部、眼内、眼中或眼周。本文其他地方描述了潜在的途径、部位和局部施用方式。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或抗血管生成剂(例如，抗VEGF剂)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如，玻璃体内、视网膜下或特农氏囊下植入物)施用。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)施用。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或抗血管生成剂(例如，抗VEGF剂)通过缓释组合物施用。缓释组合物的非限制性实例包括本文其他地方描述的那些。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or an anti-angiogenic agent (eg, anti-VEGF agents) are administered topically, intraocularly, in the eye or around the eye. Potential routes, sites and modes of topical administration are described elsewhere herein. In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or an anti-angiogenic agent (eg, Anti-VEGF agents) by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), eye drops, or implants (eg, intravitreal, subretinal, or subtenon's capsule) ) applied. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and an anti-angiogenic agent (eg, an anti-angiogenic agent) VEGF agents) are administered by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule). In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or an anti-angiogenic agent (eg, , anti-VEGF agents) are administered by slow release compositions. Non-limiting examples of sustained release compositions include those described elsewhere herein.
在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在治疗的早期阶段施用于眼局部、眼内、眼中或眼周，并然后全身施用apo模拟物。作为非限制性实例，apo模拟物的初始施用(例如，前一至五次施用)可以是局部通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)，并然后随后可以全身性的施用apo模拟物，例如口服，肠胃外(例如，皮下、肌肉内或静脉内)，或外用(例如，鼻内或肺部)。在其他实施方案中，apo模拟物仅在局部施用。在其他实施方案中，apo模拟物仅在全身施用。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically to the eye during an early stage of treatment , intraocular, intraocular or periocular, and then systemically administered the apo mimetic. As a non-limiting example, the initial administration (eg, the first one to five administrations) of an apo mimetic can be topically by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), and then subsequently can be The apo mimetic is administered systemically, eg, orally, parenterally (eg, subcutaneously, intramuscularly, or intravenously), or topically (eg, intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.
apo模拟物[例如，apoA-I模拟物(例如，L-4F或其变体或盐)和/或apoE模拟物(例如，AEM-28-14或其变体或盐)]和抗血管生成剂(例如，抗VEGF剂，如阿柏西普、贝伐单抗和/或雷珠单抗)可以通过同一药物组合物或分开的药物组合物施用，其中所述组合物还包含一种或多种药学上可接受的赋形剂或载体。如果apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和抗血管生成剂通过同一组合物施用，则这种组合物可以预先制备或者可以在施用(例如通过注射)制剂之前不久或刚好之前通过将apo模拟物和抗血管生成剂组合到同一制剂中来制备。与分开施用治疗剂相比，在同一组合物中施用apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和抗血管生成剂减少了对患者进行的潜在侵入性操作(例如，玻璃体内注射)的次数，这可以具有以下益处：例如由于较少执行侵入性操作而改善患者依从性和健康。apo mimetics [eg, apoA-I mimetics (eg, L-4F or a variant or salt thereof) and/or apoE mimetics (eg, AEM-28-14 or a variant or salt thereof)] and antiangiogenic The agent (eg, an anti-VEGF agent such as aflibercept, bevacizumab, and/or ranibizumab) can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions, wherein the composition further comprises one or Various pharmaceutically acceptable excipients or carriers. If the apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and the antiangiogenic agent are administered by the same composition, such composition may be pre-prepared or may be administered (eg, by injection) shortly before the formulation Or just before prepared by combining the apo mimetic and the anti-angiogenic agent in the same formulation. Administration of an apo mimetic (e.g., apoA-I mimetic and/or apoE mimetic) and an anti-angiogenic agent in the same composition reduces potentially invasive procedures on the patient compared to separate administration of the therapeutic agent (e.g., intravitreal injections), which may have benefits such as improved patient compliance and health due to less invasive procedures being performed.
在某些实施方案中，相对于它们合计的量，无论是否含有抗血管生成剂(例如，抗VEGF剂)，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物包含以重量计或摩尔浓度计约75-95％(例如，约90％)的apo模拟物和约5-25％(例如，约10％)的相应的载脂蛋白(例如，apoA-I和/或apoE)或其活性部分或其结构域。In certain embodiments, relative to their combined amounts, with or without an anti-angiogenic agent (eg, an anti-VEGF agent), an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or or apoE mimetic (eg, AEM-28-14)] comprising about 75-95% (eg, about 90%) by weight or molarity of the apo mimetic and about 5-25% (eg, about 90%) 10%) of the corresponding apolipoproteins (eg, apoA-I and/or apoE) or their active parts or domains thereof.
在一些实施方案中，无论是同一组合物还是分开的组合物，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物和/或含有抗血管生成剂(例如，抗VEGF剂)的组合物包含一种或多种赋形剂，所述赋形剂抑制肽/蛋白质聚集、增加肽/蛋白质溶解度、降低溶液粘度或增加肽/蛋白质稳定性，或其任何组合或全部。此类赋形剂的实例包括但不限于本文其他地方描述的那些，并且这些赋形剂的使用可具有如本文其他地方所述的益处。例如，这样的赋形剂可以改善组合物的可注射性，并因此可以使用具有较小规格的针进行注射。此外，使用这些赋形剂可以减少施用给定量的肽或蛋白质所需的体积，并因此如果通过注射到眼睛中施用肽或蛋白质，则可以降低眼压。此外，使用这样的赋形剂可以允许对于给定体积施用更大剂量的肽或蛋白质，这可以在一段时间内对于施用的给定总剂量允许较低频率地施用肽或蛋白质。In some embodiments, whether the same composition or separate compositions, contain an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14 )] and/or compositions containing an anti-angiogenic agent (eg, an anti-VEGF agent) comprising one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein solubility, Decrease solution viscosity or increase peptide/protein stability, or any combination or all. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of such excipients may have benefits as described elsewhere herein. For example, such excipients can improve the injectability of the composition and thus allow the use of needles with smaller gauges for injection. Furthermore, the use of these excipients can reduce the volume required to administer a given amount of peptide or protein, and thus can reduce intraocular pressure if the peptide or protein is administered by injection into the eye. In addition, the use of such excipients may allow greater doses of the peptide or protein to be administered for a given volume, which may allow for less frequent administration of the peptide or protein over a period of time for a given total dose administered.
在一些实施方案中，抗血管生成剂(例如，抗VEGF剂)以高于常规或推荐剂量的剂量施用(例如，通过玻璃体内注射)，并且以低于常规或推荐给药频率的频率施用，所述常规或推荐剂量或给药频率是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的抗血管生成剂的。在某些实施方案中，相比于抗血管生成剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)以高出至少约10％、20％、30％、50％、75％、100％、150％或200％(例如，至少约30％)、或约10-30％、30-50％、50-100％、100-150％或150-200％(例如，约50-100％)的剂量施用(例如通过玻璃体内注射)。在进一步的实施方案中，相比于抗血管生成剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。In some embodiments, the anti-angiogenic agent (eg, anti-VEGF agent) is administered at a higher dose (eg, by intravitreal injection) than conventional or recommended doses, and is administered less frequently than conventional or recommended dosing, The usual or recommended dose or frequency of dosing is for the absence of treatment with an apo mimetic (eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] of antiangiogenic agents. In certain embodiments, the conventional or recommended dose is compared to the conventional or recommended dose of the anti-angiogenic agent in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or or apoE mimetics (eg, AEM-28-14)], anti-angiogenic agents (eg, anti-VEGF agents) at least about 10%, 20%, 30%, 50%, 75% higher , 100%, 150%, or 200% (eg, at least about 30%), or about 10-30%, 30-50%, 50-100%, 100-150%, or 150-200% (eg, about 50- 100%) of the dose (eg, by intravitreal injection). In further embodiments, the routine or recommended dosing frequency is compared to the routine or recommended dosing frequency of the anti-angiogenic agent in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L- 4F) and/or an apoE mimetic (eg, AEM-28-14)], the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) at least less frequently About 1.5 times, 2 times, 3 times, 4 times, 5 times, or 6 times (eg, at least about 2 times).
在某些实施方案中，抗血管生成剂包括阿柏西普或者是阿柏西普并且相比于阿柏西普的常规或推荐剂量和给药频率为治疗前3个月以2mg每月施用一次之后以2mg每2个月玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，阿柏西普以约2.2-2.5mg、2.5-3mg、3-3.5mg或3.5-4mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约2.2-2.5mg、2.5-3mg、3-3.5mg或3.5-4mg的剂量每月施用一次之后，或者在前1.5或3个月以约2.2-2.5mg、2.5-3mg、3-3.5mg或3.5-4mg的剂量每6周施用一次之后，阿柏西普以约2.2-2.5mg、2.5-3mg、3-3.5mg或3.5-4mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。In certain embodiments, the anti-angiogenic agent includes aflibercept or aflibercept And compared to the usual or recommended dose and dosing frequency of aflibercept of 2 mg administered once monthly for the first 3 months of treatment followed by 2 mg administered as an intravitreal injection every 2 months, the usual or recommended dose and dosing frequency Dosing frequency is for aflibercept in the absence of treatment with an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] Administer (eg, by intravitreal injection) once every 3, 4, 5, or 6 months at a dose of about 2.2-2.5 mg, 2.5-3 mg, 3-3.5 mg, or 3.5-4 mg, optionally After monthly administration at a dose of about 2.2-2.5 mg, 2.5-3 mg, 3-3.5 mg, or 3.5-4 mg for the first 1, 2, or 3 months, or for the first 1.5 or 3 months Aflibercept at a dose of about 2.2-2.5 mg, 2.5-3 mg, 3-3.5 mg, or 3.5-4 mg every 6 weeks The doses of ® are administered (eg, by intravitreal injection) every 3, 4, 5, or 6 months.
在其他实施方案中，抗血管生成剂包括雷珠单抗或者是雷珠单抗并且相比于雷珠单抗的常规或推荐剂量和给药频率为以0.5mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，雷珠单抗以约0.55-0.75mg、0.75-1mg、1-1.25mg或者1.25-1.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地前1、2或3个月以约0.55-0.75mg、0.75-1mg、1-1.25mg或者1.25-1.5mg的剂量每个月施用一次之后，或者在前1.5或3个月以约0.55-0.75mg、0.75-1mg、1-1.25mg或者1.25-1.5mg的剂量每6周施用一次之后，雷珠单抗以约0.55-0.75mg、0.75-1mg、1-1.25mg或者1.25-1.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。In other embodiments, the anti-angiogenic agent comprises ranibizumab or ranibizumab And compared to the usual or recommended dose and frequency of administration of ranibizumab at 0.5 mg administered by intravitreal injection once a month for the absence of an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] treatment, ranibizumab at about 0.55-0.75 mg, 0.75-1 mg, 1 mg - A dose of 1.25 mg or 1.25-1.5 mg administered once every 2, 3, 4, 5 or 6 months (eg, by intravitreal injection), optionally the first 1, 2 or 3 Monthly after monthly administration at a dose of about 0.55-0.75 mg, 0.75-1 mg, 1-1.25 mg, or 1.25-1.5 mg, or for the first 1.5 or 3 months at about 0.55-0.75 mg, 0.75-1 mg, Ranibizumab is administered at doses of approximately 0.55-0.75 mg, 0.75-1 mg, 1-1.25 mg, or 1.25-1.5 mg every 2 months, 3 Administration (eg, by intravitreal injection) once a month, 4 months, 5 months, or 6 months.
在其他实施方案中，抗血管生成剂包括贝伐单抗或者是贝伐单抗并且相比于贝伐单抗用于治疗AMD的常规或推荐剂量和给药频率为以约1.25mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，贝伐单抗以约1.4-1.75mg、1.75-2mg、2-2.5mg或2.5-3mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1、2或3个月以约1.4-1.75mg、1.75-2mg、2-2.5mg或2.5-3mg的剂量每个月施用一次之后或在前一个1.5或3个月以约1.4-1.75mg、1.75-2mg、2-2.5mg或2.5-3mg的剂量每6周施用一次之后，贝伐单抗以约1.4-1.75mg、1.75-2mg、2-2.5mg或2.5-3mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。In other embodiments, the anti-angiogenic agent comprises bevacizumab or bevacizumab And compared to the usual or recommended dose and dosing frequency of bevacizumab for the treatment of AMD of approximately 1.25 mg administered by intravitreal injection once a month, the usual or recommended dose and dosing frequency are for those without apo. In the case of mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] therapy, bevacizumab is administered at about 1.4-1.75 mg, Doses of 1.75-2 mg, 2-2.5 mg, or 2.5-3 mg administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months, optionally before 1, 2 or 3 months at a dose of about 1.4-1.75 mg, 1.75-2 mg, 2-2.5 mg, or 2.5-3 mg administered once a month or in the preceding 1.5 or 3 months at a dose of about 1.4-1.75 mg, Bevacizumab at doses of approximately 1.4-1.75 mg, 1.75-2 mg, 2-2.5 mg, or 2.5-3 mg every 2 months following administration at doses of 1.75-2 mg, 2-2.5 mg, or 2.5-3 mg every 6 weeks , 3 months, 4 months, 5 months, or 6 months (eg, by intravitreal injection) once.
本文所述的一种或多种其他治疗剂可与apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)组合使用用于治疗AMD。在一些实施方案中，所述额外的治疗剂包括以下或者是以下：抗血脂异常剂(例如，他汀类药物，如阿托伐他汀)，抗氧化剂(例如，维生素、藏红花类胡萝卜素和/或锌)或补体抑制剂(例如，C5抑制剂(如ARC 1905或LFG316)，或补体因子D抑制剂(如兰波利珠单抗))，或其任何组合或全部。使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以增强一种或多种其他治疗剂的功效，例如，改善改变的脂质体内平衡、减少氧化应激和/或减少炎症。在某些实施方案中，额外的治疗剂包括ARC1905或LFG316，或是ARC1905或LFG316。One or more other therapeutic agents described herein can be combined with apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and anti- Angiogenic agents (eg, anti-VEGF agents) are used in combination for the treatment of AMD. In some embodiments, the additional therapeutic agents include or are the following: anti-dyslipidemic agents (eg, statins, such as atorvastatin), antioxidants (eg, vitamins, saffron carotenoids, and/or zinc) or a complement inhibitor (eg, a C5 inhibitor (eg, ARC 1905 or LFG316), or a complement factor D inhibitor (eg, lambolizumab)), or any combination or all thereof. The efficacy of one or more other therapeutic agents can be enhanced using an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)], eg, Improves altered lipid homeostasis, reduces oxidative stress and/or reduces inflammation. In certain embodiments, the additional therapeutic agent comprises ARC1905 or LFG316, or ARC1905 or LFG316.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)与抗炎剂(例如，NSAID(例如溴芬酸)和/或皮质类固醇(例如曲安奈德))或免疫抑制剂(例如IL-2抑制剂(例如达利珠单抗或雷帕霉素)或TNF-α抑制剂(如英夫利昔单抗))联合使用治疗新生血管性AMD。炎症是NV的刺激物，并因此抗炎剂或免疫抑制剂可以抑制NV。因此，使用抗炎剂或免疫抑制剂可以减少抗血管生成剂的施用(例如，注射)的次数或频率。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)与神经保护剂(例如，内源性神经保护剂(例如CNTF))组合使用。使用神经保护剂可以预防或减少视网膜细胞(例如光感受器)的退化。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and an anti-angiogenic agent (eg, an anti-VEGF agents) with anti-inflammatory agents (eg, NSAIDs (eg, bromfenac) and/or corticosteroids (eg, triamcinolone acetonide)) or immunosuppressants (eg, IL-2 inhibitors (eg, daclizumab or rapamycin) TNF-α inhibitors (eg, infliximab) in combination with neovascular AMD. Inflammation is a stimulator of NV, and thus anti-inflammatory or immunosuppressive agents can inhibit NV. Thus, the use of anti-inflammatory or immunosuppressive agents can reduce the number or frequency of administrations (eg, injections) of anti-angiogenic agents. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and an anti-angiogenic agent (eg, an anti-angiogenic agent) VEGF agents) in combination with neuroprotective agents (eg, endogenous neuroprotective agents (eg CNTF)). The use of neuroprotective agents can prevent or reduce the degeneration of retinal cells such as photoreceptors.
在一些实施方案中，至少在AMD的晚期阶段施用额外的治疗剂。在进一步的实施方案中，至少在AMD的中期阶段施用额外的治疗剂。在更进一步的实施方案中，至少在AMD的早期阶段施用额外的治疗剂。在某些实施方案中，至少在AMD早期阶段施用的额外的治疗剂包括以下或者是以下：减少脂质产生的抗血脂异常剂(例如他汀类)和任选的抗氧化剂(例如，维生素、藏红花类胡萝卜素和/或锌)和/或抗炎剂(例如，NSAID)，并且所述额外的治疗剂经全身(例如，口服)或局部(例如通过滴眼剂)施用。In some embodiments, the additional therapeutic agent is administered at least in advanced stages of AMD. In a further embodiment, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In still further embodiments, the additional therapeutic agent is administered at least in the early stages of AMD. In certain embodiments, additional therapeutic agents administered at least in the early stages of AMD include or are the following: anti-dyslipidemic agents (eg, statins) that reduce lipid production and optional antioxidants (eg, vitamins, saffron) carotenoids and/or zinc) and/or anti-inflammatory agents (eg, NSAIDs), and the additional therapeutic agents are administered systemically (eg, orally) or topically (eg, by eye drops).
apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]与抗血管生成剂(例如，抗VEGF剂(如阿柏西普、贝伐单抗或雷珠单抗)，和/或抗PDGF剂(如E10030))组合也可用于治疗除AMD之外的其他眼部疾病和病症。可以用这种组合治疗的其他眼部疾病或病症的非限制性实例包括：糖尿病性黄斑病变(DMP)(包括部分缺血性DMP)、糖尿病性黄斑水肿(DME)(包括临床上显著的DME[CSME]、局灶性DME和弥漫性DME)、糖尿病性视网膜病变(包括在DME患者中的)、视网膜静脉阻塞(RVO)、中央RVO(包括伴黄斑囊样水肿[CME]的中央RVO)、分支RVO(包括伴有CME的分支RVO)、RVO(包括中央RVO和分支RVO)后的黄斑水肿、Irvine-Gass综合征(术后黄斑水肿)和葡萄膜炎(包括CME后发性葡萄膜炎)。apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的有益特性(例如它们的强抗炎特性)可以增加抗血管生成剂(例如，抗VEGF剂)治疗这些眼部疾病和病症的有效性。涉及apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗血管生成剂(例如，抗VEGF剂)组合使用治疗AMD的实施方案也适用于使用该组合治疗其他眼部疾病和病症。apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] are combined with anti-angiogenic agents (eg, anti-VEGF agents (eg, africa , bevacizumab, or ranibizumab), and/or anti-PDGF agents (eg, E10030)) in combination can also be used to treat other ocular diseases and disorders in addition to AMD. Non-limiting examples of other ocular diseases or conditions that can be treated with this combination include: diabetic macular degeneration (DMP) (including partially ischemic DMP), diabetic macular edema (DME) (including clinically significant DME) [CSME], focal and diffuse DME), diabetic retinopathy (including in patients with DME), retinal vein occlusion (RVO), central RVO (including central RVO with cystoid macular edema [CME]) , branch RVO (including branch RVO with CME), macular edema after RVO (including central RVO and branch RVO), Irvine-Gass syndrome (post-operative macular edema), and uveitis (including post-CME uvea) inflammation). The beneficial properties of apo mimetics (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] (eg, their strong anti-inflammatory properties) may increase anti-vascular The effectiveness of generating agents (eg, anti-VEGF agents) in the treatment of these ocular diseases and disorders. Treatment involving the combined use of apo mimetics (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and anti-angiogenic agents (eg, anti-VEGF agents) Embodiments of AMD are also applicable to the use of the combination to treat other ocular diseases and disorders.
VII.用载脂蛋白模拟物和补体抑制剂治疗AMDVII.Treatment of AMD with Apolipoprotein Mimics and Complement Inhibitors
本公开的其他实施方案涉及治疗AMD的方法，所述方法包括向需要治疗的对象施用治疗有效量的载脂蛋白(apo)模拟物和治疗有效量的补体抑制剂，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量施用于眼局部、眼内、眼中或眼周，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量施用于眼局部、眼内、眼中或眼周。涉及用载脂蛋白模拟物治疗AMD的所有实施方案也适用于用apo模拟物和补体抑制剂治疗AMD，所述实施方案在本文IV部分和其它地方描述。Other embodiments of the present disclosure relate to methods of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic and a therapeutically effective amount of a complement inhibitor, whether the apo mimetic or not Topically, intraocularly, in or around the eye at a dose of from about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or from about 0.5 or 1 mg to about 0.5 or 1 mg over a period of about 6 months A total dose of 10 mg is administered topically, intraocularly, in the eye or around the eye. All embodiments relating to the treatment of AMD with apolipoprotein mimetics, described in Section IV and elsewhere herein, also apply to the treatment of AMD with apo mimetics and complement inhibitors.
载脂蛋白模拟物(包括apoA-I模拟物和apoE模拟物)的实例包括但不限于本文其他地方描述的那些。在一些实施方案中，apo模拟物包括apoA-I模拟物或是apoA-I模拟物。在某些实施方案中，apoA-I模拟物包括4F或其变体或盐(例如乙酸盐)，或是4F或其变体或盐(例如乙酸盐)。在一些实施方案中，4F的所有氨基酸残基都具有L型(L-4F)。在其他实施方案中，4F的一个或多个或全部氨基酸残基具有D型(例如，具有所有D型氨基酸残基的D-4F)。4F可在N-末端具有保护基团(例如酰基，如乙酰基)和/或在C-末端具有保护基团(例如酰胺基团，如-C(O)NH2)。在某些实施方案中，apoA-I模拟物包括具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F，或者是具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F。在进一步的实施方案中，apo模拟物包括apoE模拟物，或是apoE模拟物。在某些实施方案中，apoE模拟物包括AEM-28-14或其变体或盐，或是AEM-28-14或其变体或盐。Examples of apolipoprotein mimetics, including apoA-I mimetics and apoE mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or an apoA-I mimetic. In certain embodiments, the apoA-I mimetic comprises 4F or a variant or salt thereof (eg, acetate), or 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues of 4F have the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F have the D-form (eg, D-4F with all D-form amino acid residues). 4F may have a protecting group at the N-terminus (eg, an acyl group such as acetyl) and/or a protecting group at the C-terminus (eg, an amide group such as -C(O)NH2 ). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13), or L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. .13) Structure of L-4F. In further embodiments, the apo mimetic includes an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or AEM-28-14 or a variant or salt thereof.
补体抑制剂的非限制性实例包括本文其他地方描述的那些。在一些实施方案中，补体抑制剂包括兰波利珠单抗、LFG316或ARC1905或是兰波利珠单抗、LFG316或ARC1905或其任何组合或全部。在某些实施方案中，补体抑制剂包括兰波利珠单抗，或是兰波利珠单抗。在一些实施方案中，对象在编码补体因子I(CFI)的基因中具有突变，所述CFI可以是对使用兰波利珠单抗治疗具有更积极反应的生物标志物。CFI(一种C3b/C4b灭活剂)通过切割结合细胞的C3b和C4b或液相C3b和C4b来调节补体激活。Non-limiting examples of complement inhibitors include those described elsewhere herein. In some embodiments, the complement inhibitor includes lambolizumab, LFG316, or ARC1905 or Lambolizumab, LFG316 or ARC1905 or any combination or all thereof. In certain embodiments, the complement inhibitor comprises rambolizumab, or rambolizumab. In some embodiments, the subject has a mutation in a gene encoding complement factor 1 (CFI), which can be a biomarker for a more positive response to treatment with rambolizumab. CFI, a C3b/C4b inactivator, regulates complement activation by cleaving cell-bound C3b and C4b or liquid-phase C3b and C4b.
在一些实施方案中，施用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)用于治疗地图样萎缩(GA)。在一些实施方案中，施用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)用于预防中央GA、延迟中央GA的发作或减缓中央GA进展。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)至少在萎缩性(干性)AMD的晚期(后期)阶段施用，以治疗中央GA或减缓中央GA的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)至少在AMD的中期阶段施用，以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)至少在AMD的早期阶段或中期AMD的初始阶段施用，以预防非中央GA或延迟非中央GA的发作。在某些实施方案中，相比于治疗中央GA或减缓中央GA的进展，对于预防非中央或中央GA或延迟非中央或中央GA的发作则以较低频率和/或较低剂量施用补体抑制剂(例如，兰波利珠单抗)和/或apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud) are administered rilizumab) for the treatment of geographic atrophy (GA). In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud) are administered Lituzumab) is used to prevent central GA, delay the onset of central GA, or slow the progression of central GA. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud rilizumab) is administered at least in the late (late) stages of atrophic (dry) AMD to treat central GA or slow the progression of central GA, and/or prevent neovascular AMD or delay the onset of neovascular AMD. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud rilizumab) administered at least in the mid-stage of AMD to treat or slow the progression of non-central GA, and/or prevent central GA and/or neovascular AMD or delay central GA and/or neovascular AMD outbreak. In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud rilizumab) is administered at least in the early stages of AMD or at the initial stage of mid-AMD to prevent or delay the onset of non-central GA. In certain embodiments, complement inhibition is administered less frequently and/or at a lower dose for preventing non-central or central GA or delaying the onset of non-central or central GA than for treating central GA or slowing the progression of central GA agent (eg, lambolizumab) and/or apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)].
在某些实施方案中，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)的治疗减慢中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)至少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％或40％)、或约20-40％、40-60％或60-80％。在进一步的实施方案中，相比于没有用apo模拟物治疗而用补体抑制剂治疗的情况下，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)的治疗减缓中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)比其至少多约10％、20％、30％、50％、100％、150％、200％或300％(例如，至少约20％或30％)、或约10-30％、30-50％、50-100％、100-200％或200-300％(例如，约50-100％)。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, blue Treatment with polizumab) slows the progression of central GA and/or non-central GA (eg, reduces the rate of GA progression, or reduces the size or size of GA lesions) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20% or 40%), or about 20-40%, 40-60% or 60-80%. In further embodiments, the apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] and complement inhibitors (eg, lambolizumab) slow the progression of central GA and/or non-central GA (eg, reduce the rate of GA progression, or reduce GA lesions area or size) at least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30% , 30-50%, 50-100%, 100-200%, or 200-300% (eg, about 50-100%).
用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)治疗AMD(包括中央和非中央GA)可具有协同作用。例如，用apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)治疗可以增强补体抑制剂的功效，和/或反之亦然。例如，L-4F可以清理布鲁赫膜上的脂质屏障，这改善从脉络膜毛细血管到RPE细胞和光感受器的营养物(包括维生素A)的交换，从而减少RPE和光感受器细胞的死亡。作为另一个实例，L-4F减轻炎症的能力可以减少所需的施用(例如通过注射)次数和/或补体抑制剂的剂量。apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)与补体抑制剂之间的协同作用可以允许但不要求例如补体抑制剂的施用以低于常规或者推荐的给药频率的频率和/或低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或剂量是对于没有用apo模拟物治疗的情况下的补体抑制剂的。施用较低剂量的补体抑制剂可具有益处，例如由于较少的副作用而具有更好的安全性。如本文其他地方所述，以较低频率施用(例如，通过玻璃体内注射)补体抑制剂可对患者和护理提供者具有显著益处。Treatment with apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and complement inhibitors (eg, lambolizumab) AMD (including central and non-central GA) can have a synergistic effect. For example, treatment with an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) can enhance the efficacy of a complement inhibitor, and/or vice versa. For example, L-4F can clear the lipid barrier on Bruch's membrane, which improves the exchange of nutrients, including vitamin A, from choriocapillaries to RPE cells and photoreceptors, thereby reducing RPE and photoreceptor cell death. As another example, the ability of L-4F to reduce inflammation may reduce the number of administrations (eg, by injection) and/or the dose of a complement inhibitor required. Synergy between an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and a complement inhibitor may allow but not require, for example, administration of a complement inhibitor at a frequency lower than conventional or recommended dosing frequency and/or administered at a dose lower than the usual or recommended dosage frequency or dose for a complement inhibitor in the absence of treatment with an apo mimetic. Administration of lower doses of complement inhibitors may have benefits, such as better safety due to fewer side effects. As described elsewhere herein, less frequent administration of complement inhibitors (eg, by intravitreal injection) can have significant benefits for patients and care providers.
在一些实施方案中，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量局部施用，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量局部施用，补体抑制剂(例如，兰波利珠单抗)以低于常规或推荐给药频率的频率施用，和/或以低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的补体抑制剂的。在一些实施方案中，相比于补体抑制剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，补体抑制剂(例如，兰波利珠单抗)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。在某些实施方案中，补体抑制剂(例如，兰波利珠单抗)每2、3、4、5或6个月(例如，每2个月)施用于眼局部、眼内、眼中或眼周(例如通过玻璃体内注射)一次。在进一步的实施方案中，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的治疗减少了施用补体抑制剂(例如，兰波利珠单抗)的总次数(例如，注射的总数)。在某些实施方案中，补体抑制剂(例如，兰波利珠单抗)局部施用(例如，通过玻璃体内注射)不超过约20、18、15、12或10次。在另外的实施方案中，相比于补体抑制剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，补体抑制剂(例如，兰波利珠单抗)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约10-30％、30-50％或50-70％的剂量施用(例如，通过玻璃体内注射)。In some embodiments, whether the apo mimetic is or is not administered topically at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or at a dose of about 0.5 or about 0.5 mg over a period of about 6 months Topical administration at a total dose of 1 mg to about 10 mg, with a complement inhibitor (eg, lambolizumab) administered less frequently than usual or recommended dosing, and/or at a dose less than usual or recommended, The usual or recommended dosing frequency or usual or recommended dose is for the absence of an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] Therapeutic cases of complement inhibitors. In some embodiments, the routine or recommended dosing frequency is compared to the routine or recommended dosing frequency of the complement inhibitor in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)], a complement inhibitor (eg, lambolizumab) is administered (eg, by intravitreal injection) at least less frequently About 1.5 times, 2 times, 3 times, 4 times, 5 times, or 6 times (eg, at least about 2 times). In certain embodiments, the complement inhibitor (eg, rambolizumab) is administered topically, intraocularly, in the eye, or every 2, 3, 4, 5, or 6 months (eg, every 2 months) Once around the eye (eg, by intravitreal injection). In further embodiments, treatment with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] reduces administration of a complement inhibitor (eg, Lambolizumab) total number of times (eg, total number of injections). In certain embodiments, the complement inhibitor (eg, rambolizumab) is administered topically (eg, by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times. In additional embodiments, the conventional or recommended dose is compared to the conventional or recommended dose of a complement inhibitor for use in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or or apoE mimetic (eg, AEM-28-14)], complement inhibitor (eg, lambolizumab) at least about 10%, 20%, 30%, 40% less , 50%, 60%, 70%, or 80% (eg, at least about 20%), or about 10-30%, 30-50%, or 50-70% of the dose administered (eg, by intravitreal injection).
在某些实施方案中，补体抑制剂包括兰波利珠单抗或是兰波利珠单抗，并且相比于兰波利珠单抗的常规或推荐剂量和给药频率为以约10mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，兰波利珠单抗以约4-6mg、6-8mg或8-10mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约4-6mg、6-8mg或8-10mg的剂量每月施用一次之后，或在前1.5或3个月以约4-6mg、6-8mg或8-10mg的剂量每6周施用一次之后，兰波利珠单抗以约4-6mg、6-8mg或8-10mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。In certain embodiments, the complement inhibitor comprises rambolizumab or rambolizumab, and is compared to the usual or recommended dose and dosing frequency of rambolizumab at about 10 mg per Administer once a month by intravitreal injection at the usual or recommended dose and dosing frequency for those without an apo mimetic (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM -28-14)] treatment, lambolizumab at a dose of approximately 4-6 mg, 6-8 mg, or 8-10 mg every 2, 3, 4, 5, or Administration (eg, by intravitreal injection) once every 6 months, optionally after monthly administration at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg for the first 1, 2, or 3 months , or after administration at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg every 6 weeks for the first 1.5 or 3 months, lambolizumab at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg The doses of ® are administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months.
在其他实施方案中，补体抑制剂包括兰波利珠单抗或是兰波利珠单抗，并且兰波利珠单抗以约3-5mg、5-7mg或7-9mg的剂量每月(4周)或1.5个月(6周)施用(例如，通过玻璃体内注射)一次。In other embodiments, the complement inhibitor comprises rambolizumab or rambolizumab, and rambolizumab is administered at a dose of about 3-5 mg, 5-7 mg, or 7-9 mg per month ( 4 weeks) or once every 1.5 months (6 weeks) (eg, by intravitreal injection).
在一些实施方案中，用补体抑制剂(例如，兰波利珠单抗)治疗的持续时间/时长不超过约36、30、24、18或12个月。在某些实施方案中，用补体抑制剂(例如，兰波利珠单抗)治疗的时长不超过约24、18或12个月。在进一步的实施方案中，用补体抑制剂(例如，兰波利珠单抗)治疗的时长为约6-12、12-18或18-24个月。In some embodiments, the duration/duration of treatment with a complement inhibitor (eg, rambolizumab) does not exceed about 36, 30, 24, 18, or 12 months. In certain embodiments, the duration of treatment with a complement inhibitor (eg, rambolizumab) does not exceed about 24, 18, or 12 months. In further embodiments, the duration of treatment with a complement inhibitor (eg, rambolizumab) is about 6-12, 12-18, or 18-24 months.
关于apo模拟物，在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如每次注射)约0.1或0.3-1.5mg、0.1-0.5mg、0.5-1mg、1-1.5mg、0.1-0.3mg、0.3-0.5mg、0.5-0.75mg、0.75-1mg、1-1.25mg或1.25-1.5mg(例如，约0.1-0.5mg或0.5-1mg)的剂量施用(例如，通过玻璃体内注射)于眼局部、眼内、眼中或眼周。apo模拟物也可以以每次施用大于1.5mg的剂量局部施用，例如每次施用(例如，每次注射)至多约2mg或更多。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5或1-10mg、0.5或1-5mg、5-10mg、0.5或1-3mg、3-5mg、5-7.5mg或7.5-10mg(例如，约0.5-3mg或3-5mg)的总剂量局部施用(例如，通过玻璃体内注射或通过缓释组合物)，其中用apo模拟物治疗的持续时间/时长可以是例如约6-12、12-18或18-24个月或更长时间。apo模拟物也可以以在约6个月的时间内大于10mg的总剂量局部施用，例如在约6个月的时间内至多约15mg或更多。在更进一步的实施方案中，对于使用apo模拟物的整个/完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1或2-20mg、5-15mg、1-5mg、5-10mg、10-15mg、15-20mg、1-3mg、3-5mg、5-7.5mg、7.5-10mg、10-12.5mg、12.5-15mg、15-17.5mg或17.5-20mg(例如，约1-5mg或5-10mg)的总剂量局部施用。对于完整治疗方案，apo模拟物也可以以大于20mg的总剂量局部施用，例如对于完整治疗方案至多约25mg、30mg、40mg、50mg或更多的总剂量。With respect to apo mimetics, in certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered per administration (eg per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0.3 mg, 0.3-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-1.25 mg A dose of mg or 1.25-1.5 mg (eg, about 0.1-0.5 mg or 0.5-1 mg) is administered (eg, by intravitreal injection) topically, intraocularly, in or around the eye. The apo mimetic can also be administered topically in doses greater than 1.5 mg per administration, eg, up to about 2 mg or more per administration (eg, per injection). In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered within a period of about 6 months A total dose of about 0.5 or 1-10 mg, 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg, 3-5 mg, 5-7.5 mg, or 7.5-10 mg (eg, about 0.5-3 mg or 3-5 mg) Topical administration (eg, by intravitreal injection or by slow release composition), wherein the duration/duration of treatment with the apo mimetic can be, eg, about 6-12, 12-18, or 18-24 months or more. The apo mimetic can also be administered topically at a total dose of greater than 10 mg over a period of about 6 months, eg, up to about 15 mg or more over a period of about 6 months. In still further embodiments, for an entire/complete treatment regimen using an apo mimetic, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28) -14)] with about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10 - Topical administration at a total dose of 12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg). The apo mimetic can also be administered topically in a total dose of greater than 20 mg for a complete treatment regimen, eg, up to a total dose of about 25 mg, 30 mg, 40 mg, 50 mg or more for a complete treatment regimen.
在将apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]施用于眼局部、眼内、眼中或眼周的实施方案中，每次施用的剂量、在约6个月的时间内的总剂量、以及整个治疗方案的总剂量在某些实施方案中是对于施用的每只眼睛，并且在其他实施方案中是对于双眼的。血液系统可允许局部施用(例如，注射)到一只眼睛内或在一只眼睛中的一些量(例如，治疗有效量)的apo模拟物被分布到另一只眼睛，在这种情况下apo模拟物的剂量可以考虑到另一只眼睛(其可能处于较少患病的状况)而任选的得到调整(例如，增加)，并且可以允许用apo模拟物同时治疗双眼而无需在另一只眼睛内或另一只眼睛中额外的施用(例如，注射)apo模拟物。例如，玻璃体内注射的apo模拟物可以穿过血液-视网膜屏障到达两个靶区域(即亚RPE-BL空间和布鲁赫膜)，apo模拟物可以从所述靶区域进入脉络膜毛细血管，并最终到达对应未施用的眼睛。也不受理论束缚，一些量的apo模拟物可以通过房水途径进入对应未施用的眼睛，房水通过小梁网和流入血液系统的施莱姆管排出。因此，一些实施方案涉及治疗AMD的方法，其包括向需要治疗的对象施用治疗有效量的载脂蛋白模拟物和治疗有效量的补体抑制剂，其中所述载脂蛋白模拟物施用于一只眼睛中的眼局部、眼内、眼中或眼周并且两只眼睛都有治疗效果。Implementation of topical, intraocular, intraocular, or periocular administration of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] In the regimen, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are in certain embodiments for each eye administered, and in other embodiments for each eye. binocular. The blood system may allow topical administration (eg, injection) into one eye or some amount (eg, a therapeutically effective amount) in one eye of an apo mimetic to be distributed to the other eye, in which case apo The dose of the mimetic can optionally be adjusted (eg, increased) to take into account the other eye (which may be in a less diseased condition), and can allow simultaneous treatment of both eyes with the apo mimetic without Additional administration (eg, injection) of the apo mimetic in the eye or in the other eye. For example, intravitreal injected apo mimetics can cross the blood-retinal barrier to two target areas (ie, the sub-RPE-BL space and Bruch's membrane) from which the apo mimetics can enter the choriocapillaris and ultimately Reach the corresponding unapplied eye. Also without being bound by theory, some amount of the apo mimetic can enter the corresponding non-administered eye via the aqueous humor route, which drains through the trabecular meshwork and Schlemm's canal into the blood system. Accordingly, some embodiments relate to a method of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein mimetic and a therapeutically effective amount of a complement inhibitor, wherein the apolipoprotein mimetic is administered to one eye Partial, intraocular, intraocular, or periocular in the ocular and both eyes have a therapeutic effect.
在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每月(4周)或每1.5个月(6周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每2个月(8周)、每2.5个月(10周)或每3个月(12周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每4、5或6个月局部施用(例如，通过玻璃体内注射或通过缓释组合物)一次。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以总共约15次或更少、12次或更少、9次或更少、6次或更少、或3次或更少(例如，3-6次或7-10次)的施用(例如注射)在局部施用。在局部施用apo模拟物也可以在总共超过15次施用(例如注射)，例如至多约20次或更多次施用(例如注射)。在将apo模拟物施用于眼局部、眼内、眼中或眼周的实施方案中，施用频率和施用(例如注射)总次数在某些实施方案中是对于施用的每只眼睛，并且由于apo模拟物也可以在对应未施用的眼睛中具有治疗效果，在其他实施方案中是对于双眼的。In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] monthly (4 weeks) or every 1.5 Topical administration (eg, by intravitreal injection) once a month (6 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] every 2 months (8 weeks), every Topical administration (eg, by intravitreal injection) once every 2.5 months (10 weeks) or every 3 months (12 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically every 4, 5, or 6 months (eg, by intravitreal injection or by slow release composition) once. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a total of about 15 times or less, 12 or less, 9 or less, 6 or less, or 3 or less (eg, 3-6 or 7-10) administrations (eg, injections) are administered locally. Topical administration of an apo mimetic can also be over a total of 15 administrations (eg, injections), eg, up to about 20 or more administrations (eg, injections). In embodiments where the apo mimetic is administered topically, intraocularly, in the eye or periocular The drug may also have a therapeutic effect in the corresponding unadministered eye, in other embodiments both eyes.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或补体抑制剂(例如，兰波利珠单抗)施用于眼局部、眼内、眼中或眼周。本文其他地方描述了潜在的途径、部位和局部施用方式。在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或补体抑制剂(例如，兰波利珠单抗)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如，玻璃体内，视网膜下或特农氏囊下植入物)施用。在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂(例如，兰波利珠单抗)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)施用。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或补体抑制剂(例如，兰波利珠单抗)是通过缓释组合物施用。缓释组合物的非限制性实例包括本文其他地方描述的那些。In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or a complement inhibitor (eg, blue polizumab) is administered topically, intraocularly, in or around the eye. Potential routes, sites and modes of topical administration are described elsewhere herein. In some embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or a complement inhibitor (eg, blue Polivizumab) by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), eye drops, or implants (eg, intravitreal, subretinal, or subtenon's capsule) intake) administration. In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Rimbaud rilizumab) is administered by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule). In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and/or a complement inhibitor (eg, Lambolizumab) is administered in a sustained-release composition. Non-limiting examples of sustained release compositions include those described elsewhere herein.
在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在治疗的早期阶段施用于眼局部、眼内、眼中或眼周，并然后全身施用apo模拟物。作为非限制性实例，apo模拟物的初始施用(例如，前一至五次施用)可以是局部通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)，并然后随后可以全身性的施用apo模拟物，例如口服，肠胃外(例如，皮下、肌肉内或静脉内)，或外用(例如，鼻内或肺部)。在其他实施方案中，apo模拟物仅在局部施用。在其他实施方案中，apo模拟物仅在全身施用。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically to the eye during an early stage of treatment , intraocular, intraocular or periocular, and then systemically administered the apo mimetic. As a non-limiting example, the initial administration (eg, the first one to five administrations) of an apo mimetic can be topically by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), and then subsequently can be The apo mimetic is administered systemically, eg, orally, parenterally (eg, subcutaneously, intramuscularly, or intravenously), or topically (eg, intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.
apo模拟物[例如，apoA-I模拟物(例如，L-4F或其变体或盐)和/或apoE模拟物(例如，AEM-28-14或其变体或盐)]和补体抑制剂(例如，兰波利珠单抗)可以通过同一药物组合物或分开的药物组合物施用，其中所述组合物还包含一种或多种药学上可接受的赋形剂或载体。如果apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和补体抑制剂通过同一组合物施用，则这种组合物可以预先制备或者可以在施用(例如通过注射)制剂之前不久或刚好之前通过将apo模拟物和补体抑制剂组合到同一制剂中来制备。与分开施用治疗剂相比，在同一组合物中施用apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和补体抑制剂减少了对患者进行的潜在侵入性操作(例如，玻璃体内注射)的次数，这可以对患者和护理提供者具有如本文其他地方所述的显著益处。apo mimetics [eg, apoA-I mimetics (eg, L-4F or a variant or salt thereof) and/or apoE mimetics (eg, AEM-28-14 or a variant or salt thereof)] and complement inhibitors (eg, Lambolizumab) can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions, wherein the compositions further comprise one or more pharmaceutically acceptable excipients or carriers. If the apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and the complement inhibitor are administered by the same composition, such composition may be pre-prepared or may be administered (eg, by injection) shortly before the formulation or Prepared just before by combining an apo mimetic and a complement inhibitor in the same formulation. Administration of an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and a complement inhibitor in the same composition reduces potentially invasive procedures on the patient (eg, vitreous intra-injection), which can have significant benefits for patients and care providers as described elsewhere herein.
在一些实施方案中，无论是同一组合物还是分开的组合物，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物和/或含有补体抑制剂(例如，兰波利珠单抗)的组合物被配制成可注射的溶液或悬浮液(例如，用于玻璃体内、结膜下、视网膜下或特农氏囊下注射)。用于注射到眼睛中的制剂的实例包括但不限于本文其他地方描述的那些。在其他实施方案中，无论是同一组合物还是分开的组合物，含有apo模拟物的组合物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和/或含有补体抑制剂(例如，兰波利珠单抗)的组合物被配制成滴眼剂或植入物(例如玻璃体内、视网膜下或特农氏囊下植入物)。使用滴眼剂或将植入物植入一次或两次可以避免与重复注射相关的潜在问题。在进一步的实施方案中，无论是同一组合物还是分开的组合物，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物和/或含有补体抑制剂(例如，兰波利珠单抗)的组合物被配置用于缓释apo模拟物和/或补体抑制剂。缓释组合物的非限制性实例包括本文其他地方描述的那些。使用缓释组合物可以减少为了施用药物进行的潜在侵入性操作(例如，玻璃体内注射)的次数，并且可以改善在一段时间内递送至靶位点的药物量的分布。In some embodiments, whether the same composition or separate compositions, contain an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14 )] and/or compositions containing a complement inhibitor (eg, lambolizumab) are formulated as injectable solutions or suspensions (eg, for intravitreal, subconjunctival, subretinal or special sub-bursal injection). Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In other embodiments, whether in the same composition or separate compositions, compositions containing an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM- 28-14)] and/or compositions containing a complement inhibitor (eg, lambolizumab) are formulated as eye drops or implants (eg, intravitreal, subretinal, or subtenon's capsule) thing). Potential problems associated with repeated injections can be avoided by using eye drops or placing the implant once or twice. In further embodiments, whether the same composition or separate compositions, contain an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28- 14)] and/or a composition comprising a complement inhibitor (eg, lambolizumab) is configured for sustained release of an apo mimetic and/or a complement inhibitor. Non-limiting examples of sustained release compositions include those described elsewhere herein. The use of sustained-release compositions can reduce the number of potentially invasive procedures (eg, intravitreal injections) performed to administer the drug, and can improve the distribution of the amount of drug delivered to the target site over time.
在某些实施方案中，相对于它们合计的量，无论是否含有补体抑制剂(例如，兰波利珠单抗)，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物包含以重量计或摩尔浓度计约75-95％(例如，约90％)的apo模拟物和约5-25％(例如，约10％)的相应载脂蛋白(例如，apoA-I和/或apoE)或其活性部分或其结构域。In certain embodiments, relative to their combined amounts, with or without a complement inhibitor (eg, lambolizumab), an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] comprising about 75-95% (eg, about 90%) by weight or molarity of an apo mimetic and about 5-25% (eg, about 90%) , about 10%) of the corresponding apolipoproteins (eg, apoA-I and/or apoE) or their active parts or domains thereof.
在一些实施方案中，无论是同一组合物还是分开的组合物，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物和/或含有补体抑制剂(例如，兰波利珠单抗)的组合物，包含一种或多种赋形剂，所述赋形剂抑制肽/蛋白质聚集、增加肽/蛋白质溶解度、降低溶液粘度或增加肽/蛋白质稳定性，或其任何组合或全部。此类赋形剂的实例包括但不限于本文其他地方描述的那些，并且这些赋形剂的使用可具有如本文其他地方所述的益处。例如，这样的赋形剂可以改善组合物的可注射性，并因此可以使用具有较小规格的针进行注射。此外，使用这些赋形剂可以减少施用给定量的肽或蛋白质所需的体积，并因此如果通过注射到眼睛中施用肽或蛋白质，则可以降低眼压。此外，使用这样的赋形剂可以允许对于给定体积施用更大剂量的肽或蛋白质，这可以在一段时间内对于施用的给定总剂量允许较低频率地施用肽或蛋白质。In some embodiments, whether the same composition or separate compositions, contain an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14 )] and/or compositions containing a complement inhibitor (eg, lambolizumab), comprising one or more excipients that inhibit peptide/protein aggregation, increase peptide/protein aggregation Protein solubility, decrease solution viscosity, or increase peptide/protein stability, or any combination or all thereof. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of such excipients may have benefits as described elsewhere herein. For example, such excipients can improve the injectability of the composition and thus allow the use of needles with smaller gauges for injection. Furthermore, the use of these excipients can reduce the volume required to administer a given amount of peptide or protein, and thus can reduce intraocular pressure if the peptide or protein is administered by injection into the eye. In addition, the use of such excipients may allow greater doses of the peptide or protein to be administered for a given volume, which may allow for less frequent administration of the peptide or protein over a period of time for a given total dose administered.
在一些实施方案中，补体抑制剂(例如，兰波利珠单抗)以高于常规或推荐剂量的剂量施用(例如，通过玻璃体内注射)，并且以低于常规或推荐给药频率的频率施用，所述常规或推荐剂量或给药频率是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的补体抑制剂的。在某些实施方案中，相比于补体抑制剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，补体抑制剂(例如，兰波利珠单抗)以高出至少约10％、20％、30％、50％、75％、100％、150％或200％(例如，至少约30％)、或约10-30％、30-50％、50-100％、100-150％或150-200％(例如，约50-100％)的剂量施用(例如通过玻璃体内注射)。在进一步的实施方案中，相比于补体抑制剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，补体抑制剂(例如，兰波利珠单抗)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。In some embodiments, the complement inhibitor (eg, lambolizumab) is administered at a higher dose (eg, by intravitreal injection) than conventional or recommended doses, and at a lower frequency than conventional or recommended dosing frequency Administration, the usual or recommended dose or frequency of dosing is for the absence of treatment with an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] the case of complement inhibitors. In certain embodiments, the conventional or recommended dose is compared to the conventional or recommended dose of the complement inhibitor for use in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] treatment, complement inhibitor (eg, lambolizumab) at least about 10%, 20%, 30%, 50%, 75% higher %, 100%, 150%, or 200% (eg, at least about 30%), or about 10-30%, 30-50%, 50-100%, 100-150%, or 150-200% (eg, about 50%) -100%) dose administration (eg by intravitreal injection). In further embodiments, the routine or recommended dosing frequency is compared to the routine or recommended dosing frequency of the complement inhibitor in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F ) and/or apoE mimetics (eg, AEM-28-14)], a complement inhibitor (eg, lambolizumab) is administered (eg, by intravitreal injection) less frequently than At least about 1.5 times, 2 times, 3 times, 4 times, 5 times, or 6 times (eg, at least about 2 times).
在某些实施方案中，补体抑制剂包括兰波利珠单抗或者是兰波利珠单抗，并且相比于兰波利珠单抗的常规或推荐剂量和给药频率为以约10mg每月玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，兰波利珠单抗以约12-14mg、14-16mg、16-18mg或18-20mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约12-14mg、14-16mg、16-18mg或18-20mg的剂量每月施用一次之后，或者在前1.5或3个月以约12-14mg、14-16mg、16-18mg或18-20mg的剂量每6周施用一次之后，兰波利珠单抗以约12-14mg、14-16mg、16-18mg或18-20mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。In certain embodiments, the complement inhibitor comprises or is rambolizumab, and is compared to the usual or recommended dose and dosing frequency of rambolizumab at about 10 mg per Administer once monthly intravitreal injection at the usual or recommended dose and dosing frequency for those without an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM- 28-14)] treatment, lambolizumab at a dose of approximately 12-14 mg, 14-16 mg, 16-18 mg or 18-20 mg every 2 months, 3 months, 4 months, 5 Administration (eg, by intravitreal injection) once a month or 6 months, optionally at about 12-14 mg, 14-16 mg, 16-18 mg, or 18-20 mg in the first 1, 2, or 3 months After monthly administration of a dose of Doses of 12-14 mg, 14-16 mg, 16-18 mg, or 18-20 mg are administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months.
在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂至少在AMD的晚期阶段施用以进一步预防新生血管性(湿性)AMD或延迟新生血管性(湿性)AMD的发作，和/或治疗湿性AMD或减缓湿性AMD的进展，所述湿性AMD包括1、2和3型新生血管形成。用于治疗湿性AMD的补体抑制剂可以与用于治疗干性AMD(包括地图样萎缩)的补体抑制剂相同、不同或相加。在某些实施方案中，补体抑制剂包括ARC 1905或LFG316，或者是ARC 1905或LFG316。在一些实施方案中，抗血管生成剂与apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂联合使用用于治疗湿性AMD。在某些实施方案中，抗血管生成剂包括以下或者是以下：抗VEGF剂(例如，阿柏西普贝伐单抗或雷珠单抗或其任何组合或全部)和/或抗PDGF剂(例如，E10030)。In additional embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor at least in the late stages of AMD Staged administration to further prevent neovascular (wet) AMD or delay the onset of neovascular (wet) AMD, and/or treat or slow the progression of wet AMD, including type 1, 2, and 3 neovascularization form. The complement inhibitor used in the treatment of wet AMD can be the same, different or additive as the complement inhibitor used in the treatment of dry AMD, including geographic atrophy. In certain embodiments, the complement inhibitor includes ARC 1905 or LFG316, or ARC 1905 or LFG316. In some embodiments, the anti-angiogenic agent is combined with an apo mimetic (eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and a complement inhibitor Use for the treatment of wet AMD. In certain embodiments, the anti-angiogenic agent includes or is the following: an anti-VEGF agent (eg, aflibercept Bevacizumab or ranibizumab or any combination or all thereof) and/or an anti-PDGF agent (e.g., E10030 ).
在一些实施方案中，抗血管生成剂(例如，抗VEGF剂)和/或补体抑制剂(例如，ARC1905)以低于常规或推荐给药频率的频率施用，和/或以低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的抗血管生成剂和/或补体抑制剂的。在某些实施方案中，相比于抗血管生成剂和/或补体抑制剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)和/或补体抑制剂(例如，ARC 1905)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。在进一步的实施方案中，相比于抗血管生成剂和/或补体抑制剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗血管生成剂(例如，抗VEGF剂)和/或补体抑制剂(例如，ARC1905)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约10-30％、30-50％或50-70％的剂量施用(例如，通过玻璃体内注射)。本文其他地方提供了阿柏西普、贝伐单抗和雷珠单抗的给药频率和剂量的非限制性实例。In some embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) and/or a complement inhibitor (eg, ARC1905) is administered less frequently than conventional or recommended dosing, and/or less frequently than conventional or recommended Dosage administration at the usual or recommended frequency of dosing or usual or recommended doses for those without an apo mimetic [e.g. apoA-I mimetic (e.g. 28-14)] treatment of anti-angiogenic agents and/or complement inhibitors. In certain embodiments, the conventional or recommended dosing frequency is compared to the conventional or recommended dosing frequency of the anti-angiogenic agent and/or complement inhibitor in the absence of an apo mimetic [eg, apoA-I mimetic anti-angiogenic agents (eg, anti-VEGF agents) and/or complement inhibitors (eg, AEM-28-14)] therapy ARC 1905) is administered (eg, by intravitreal injection) at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold less frequently (eg, at least about 2-fold). In further embodiments, the conventional or recommended dose is compared to the conventional or recommended dose of the anti-angiogenic agent and/or complement inhibitor for use in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, an apoA-I mimetic). , L-4F) and/or apoE mimetics (eg, AEM-28-14)], anti-angiogenic agents (eg, anti-VEGF agents) and/or complement inhibitors (eg, ARC1905) with at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% (eg, at least about 20%), or about 10-30%, 30-50%, or 50% less than -70% of the dose administered (eg, by intravitreal injection). Non-limiting examples of dosing frequencies and doses of aflibercept, bevacizumab, and ranibizumab are provided elsewhere herein.
本文所述的一种或多种其他治疗剂可与apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和补体抑制剂组合使用用于治疗干性或湿性AMD。在一些实施方案中，所述额外的治疗剂包括以下或者是以下：抗氧化剂(例如，维生素、藏红花类胡萝卜素和/或锌)、抗血脂异常剂(例如他汀类(如阿托伐他汀))、抗炎剂(例如，NSAID(例如溴芬酸)，和/或皮质类固醇(例如氟轻松，或曲安奈德))，或神经保护剂(例如，内源性神经保护剂(例如CNTF))，或其任何组合或全部。使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以增强一种或多种其他治疗剂的功效，例如，减少氧化应激、改善改变的脂质体内平衡、减少炎症或减少RPE细胞和视网膜细胞(例如，光感受器)的退化，或其任何组合或全部。One or more other therapeutic agents described herein can be combined with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and complement Inhibitor combinations are used to treat dry or wet AMD. In some embodiments, the additional therapeutic agent includes or is the following: antioxidants (eg, vitamins, saffron carotenoids, and/or zinc), anti-dyslipidemic agents (eg, statins (eg, atorvastatin) ), anti-inflammatory agents (eg, NSAIDs (eg, bromfenac), and/or corticosteroids (eg, fluocinolone acetonide, or triamcinolone acetonide)), or neuroprotective agents (eg, endogenous neuroprotective agents (eg, CNTF) ), or any combination or all thereof. The efficacy of one or more other therapeutic agents can be enhanced using an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)], eg, Reduce oxidative stress, improve altered lipid homeostasis, reduce inflammation, or reduce degeneration of RPE cells and retinal cells (eg, photoreceptors), or any combination or all thereof.
在一些实施方案中，至少在AMD的晚期阶段施用额外的治疗剂。在进一步的实施方案中，至少在AMD的中期阶段施用额外的治疗剂。在更进一步的实施方案中，至少在AMD的早期阶段施用额外的治疗剂。在某些实施方案中，至少在AMD早期阶段施用的额外的治疗剂包括以下或者是以下：减少脂质产生的抗血脂异常剂(例如他汀类)和任选的抗氧化剂(例如，维生素、藏红花类胡萝卜素和/或锌)和/或抗炎剂(例如，NSAID)，并且额外的治疗剂经全身(例如，口服)或局部(例如通过滴眼剂)施用。In some embodiments, the additional therapeutic agent is administered at least in advanced stages of AMD. In a further embodiment, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In still further embodiments, the additional therapeutic agent is administered at least in the early stages of AMD. In certain embodiments, additional therapeutic agents administered at least in the early stages of AMD include or are the following: anti-dyslipidemic agents (eg, statins) that reduce lipid production and optional antioxidants (eg, vitamins, saffron) carotenoids and/or zinc) and/or anti-inflammatory agents (eg, NSAIDs), and additional therapeutic agents are administered systemically (eg, orally) or topically (eg, by eye drops).
VIII.用载脂蛋白模拟物和抗氧化剂治疗AMDVIII.Treatment of AMD with Apolipoprotein Mimics and Antioxidants
本公开的另外的实施方案涉及治疗AMD的方法，所述方法包括向需要治疗的对象施用治疗有效量的载脂蛋白(apo)模拟物和治疗有效量的抗氧化剂，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量施用于眼局部、眼内、眼中或眼周，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量施用于眼局部、眼内、眼中或眼周。此外，矿物质(例如，锌或硒，其中每一种也可以起抗氧化剂作用)可以与apo模拟物和抗氧化剂联合使用用于治疗AMD。涉及用载脂蛋白模拟物治疗AMD的所有实施方案也适用于用apo模拟物和抗氧化剂(和任选的矿物质)治疗AMD，所述实施方案在本文IV部分和其它地方描述。Additional embodiments of the present disclosure relate to methods of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic and a therapeutically effective amount of an antioxidant, whether the apo mimetic is or is not Topically, intraocularly, in or around the eye at a dose of from about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or from about 0.5 or 1 mg to about 0.5 or 1 mg over a period of about 6 months A total dose of 10 mg is administered topically, intraocularly, in the eye or around the eye. In addition, minerals (eg, zinc or selenium, each of which can also function as antioxidants) can be used in combination with apo mimetics and antioxidants for the treatment of AMD. All of the embodiments directed to the treatment of AMD with apolipoprotein mimetics are also applicable to the treatment of AMD with apo mimetics and antioxidants (and optionally minerals), described in Section IV and elsewhere herein.
载脂蛋白模拟物(包括apoA-I模拟物和apoE模拟物)的实例包括但不限于本文其他地方描述的那些。在一些实施方案中，apo模拟物包括apoA-I模拟物或是apoA-I模拟物。在某些实施方案中，apoA-I模拟物包括4F或其变体或盐(例如乙酸盐)，或是4F或其变体或盐(例如乙酸盐)。在一些实施方案中，4F的所有氨基酸残基都具有L型(L-4F)。在其他实施方案中，4F的一个或多个或全部氨基酸残基具有D型(例如，具有所有D型氨基酸残基的D-4F)。4F可以在N-末端具有保护基团(例如酰基，如乙酰基)和/或在C-末端具有保护基团(例如酰胺基团，例如-C(O)NH2)。在某些实施方案中，apoA-I模拟物包括具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F，或者是具有Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)结构的L-4F。在进一步的实施方案中，apo模拟物包括apoE模拟物，或是apoE模拟物。在某些实施方案中，apoE模拟物包括AEM-28-14或其变体或盐，或是AEM-28-14或其变体或盐。Examples of apolipoprotein mimetics, including apoA-I mimetics and apoE mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apo mimetic comprises an apoA-I mimetic or an apoA-I mimetic. In certain embodiments, the apoA-I mimetic comprises 4F or a variant or salt thereof (eg, acetate), or 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues of 4F have the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F have the D-form (eg, D-4F with all D-form amino acid residues). 4F may have a protecting group at the N-terminus (eg, an acyl group, such as acetyl) and/or a protecting group at the C-terminus (eg, an amide group, eg, -C(O)NH2 ). In certain embodiments, the apoA-I mimetic comprises L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13), or L-4F having the structure of Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. .13) Structure of L-4F. In further embodiments, the apo mimetic includes an apoE mimetic, or is an apoE mimetic. In certain embodiments, the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or AEM-28-14 or a variant or salt thereof.
抗氧化剂的实例包括但不限于本文其他地方描述的那些。在某些实施方案中，抗氧化剂包含一种或多种维生素(例如，维生素B6、维生素C和维生素E)，一种或多种类胡萝卜素(例如，叶黄素类[例如，叶黄素、玉米黄质和内消旋玉米黄质]和藏红花中的类胡萝卜素[例如，藏红花素和藏红花酸])，或锌，或其任何组合或全部，例如，本文其他地方描述的AREDS或AREDS2制剂、制剂、制剂或Saffron 2020TM。除了降低氧化应激的能力外，抗氧化剂还具有其他有益的特性。例如，藏红花类胡萝卜素具有抗炎和细胞保护作用，以及抗氧化作用。Examples of antioxidants include, but are not limited to, those described elsewhere herein. In certain embodiments, the antioxidant comprises one or more vitamins (eg, vitaminB6 , vitamin C, and vitamin E), one or more carotenoids (eg, lutein [eg, lutein] , zeaxanthin and meso-zeaxanthin] and carotenoids in saffron [e.g., crocin and saffron acid]), or zinc, or any combination or all thereof, e.g., AREDS or AREDS2 described elsewhere herein preparation, preparation, formulation or Saffron 2020™ . In addition to their ability to reduce oxidative stress, antioxidants have other beneficial properties. For example, saffron carotenoids have anti-inflammatory and cytoprotective effects, as well as antioxidant effects.
在一些实施方案中，无论apo模拟物是或不是以每次施用(例如每次注射)约0.1或0.3mg至约1.5mg的剂量局部施用，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量局部施用，抗氧化剂(例如，维生素和/或类胡萝卜素)以低于常规或推荐剂量的剂量施用，和/或以低于常规或推荐给药频率的频率施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的抗氧化剂的。施用较低剂量的抗氧化剂可以对对象有益，例如副作用较少。例如，摄入更多的β-胡萝卜素会增加吸烟者患肺癌的风险。另一个例子是，摄入更多的维生素E会增加高危人群的心力衰竭风险。在一些实施方案中，相比于抗氧化剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗氧化剂(例如，维生素和/或类胡萝卜素)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，在至少约20％)、或约10-30％、30-50％或50-70％的剂量施用。在进一步的实施方案中，相比于抗氧化剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗氧化剂(例如，维生素和/或类胡萝卜素)的施用(例如，通过玻璃体内注射)频率比其低至少约2、3、5、7或10倍(例如，至少约2倍)。在某些实施方案中，无论是经全身(例如，口服)还是局部地以非侵入性方式(例如通过滴眼剂)，相比于抗氧化剂的常规或推荐给药频率为每天至少一次口服，所述常规或推荐给药频率是对于在没有用apo模拟物[例如apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]治疗的情况下的，抗氧化剂(例如，维生素和/或类胡萝卜素)每两或三天施用一次。In some embodiments, whether the apo mimetic is or is not administered topically at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or at a dose of about 0.5 or about 0.5 mg over a period of about 6 months Topical administration in a total dose of 1 mg to about 10 mg, with antioxidants (e.g., vitamins and/or carotenoids) administered at lower doses than conventional or recommended doses, and/or at lower frequencies than conventional or recommended dosing, The usual or recommended dosing frequency or usual or recommended dose is for the absence of an apo mimetic [eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] Antioxidants in the case of treatment. Administration of lower doses of antioxidants may benefit the subject, such as fewer side effects. For example, higher intake of beta-carotene increases the risk of lung cancer in smokers. Another example is that higher intake of vitamin E increases the risk of heart failure in high-risk groups. In some embodiments, the conventional or recommended dose is compared to a conventional or recommended dose of an antioxidant in the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)], antioxidants (eg, vitamins and/or carotenoids) at least about 10%, 20%, 30%, 40%, 50% less %, 60%, 70%, or 80% (eg, at at least about 20%), or about 10-30%, 30-50%, or 50-70% of the dose. In further embodiments, the routine or recommended dosing frequency is for the absence of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) compared to the usual or recommended dosing frequency of an antioxidant). and/or apoE mimics (eg, AEM-28-14)], antioxidants (eg, vitamins and/or carotenoids) are administered (eg, by intravitreal injection) at least less frequently About 2, 3, 5, 7 or 10 times (eg, at least about 2 times). In certain embodiments, whether administered systemically (eg, orally) or locally in a non-invasive manner (eg, by eye drops), compared to the usual or recommended frequency of administration of antioxidants of at least once daily oral administration, The usual or recommended dosing frequency is for the absence of treatment with an apo mimetic (eg, apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] Yes, antioxidants (eg, vitamins and/or carotenoids) are administered every two or three days.
用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)治疗AMD可能具有协同作用。例如，用apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)治疗可以增强抗氧化剂的功效，和/或反之亦然。例如，L-4F可显著减少布鲁赫膜和亚RPE-BL空间的脂质沉积物，从而减少易氧化的脂质的量。作为另一个实例，L-4F减少脂质氧化和清理促炎的氧化的脂质的能力可降低抗氧化剂的所需剂量和/或施用频率。apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)与抗氧化剂之间的协同作用可允许但不要求例如抗氧化剂以低于常规或推荐剂量的剂量和/或低于常规或者推荐的给药频率的频率施用，所述常规或推荐给药频率或剂量是对于没有用apo模拟物治疗的情况下的抗氧化剂的。Treatment with apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or carotenoids) AMD may be synergistic. For example, treatment with apo mimetics (eg, apoA-I mimetics and/or apoE mimetics) can enhance the efficacy of antioxidants, and/or vice versa. For example, L-4F significantly reduces lipid deposits in Bruch's membrane and the sub-RPE-BL space, thereby reducing the amount of easily oxidized lipids. As another example, the ability of L-4F to reduce lipid oxidation and scavenge pro-inflammatory oxidized lipids may reduce the required dose and/or frequency of administration of antioxidants. Synergy between apo mimetics (eg, apoA-I mimetics and/or apoE mimetics) and antioxidants may allow, but do not require, for example, antioxidants at lower than conventional or recommended doses and/or lower than conventional or Administration at the frequency of the recommended dosing frequency, conventional or recommended dosing frequency or dose for the antioxidant in the absence of treatment with apo mimetic.
关于apo模拟物，在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以每次施用(例如，每次注射)约0.1或0.3-1.5mg、0.1-0.5mg、0.5-1mg、1-1.5mg、0.1-0.3mg、0.3-0.5mg、0.5-0.75mg、0.75-1mg、1-1.25mg或1.25-1.5mg(例如，约0.1-0.5mg或0.5-1mg)的剂量施用(例如，通过玻璃体内注射)于眼局部、眼内、眼中或者眼周。apo模拟物也可以以每次施用大于1.5mg的剂量局部施用，例如每次施用(例如，每次注射)至多约2mg或更多。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以在约6个月的时间内约0.5或1-10mg、0.5或1-5mg、5-10mg、0.5或1-3mg、3-5mg、5-7.5mg或7.5-10mg(例如，约0.5-3mg或3-5mg)的总剂量局部施用(例如，通过玻璃体内注射或通过缓释组合物)，其中用apo模拟物治疗的持续时间/时长可以是例如约6-12、12-18或18-24个月或更长时间。apo模拟物也可以以在约6个月的时间内大于10mg的总剂量局部施用，例如在约6个月的时间内至多约15mg或更多。在更进一步的实施方案中，对于使用apo模拟物的整个/完整治疗方案，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以约1或2-20mg、5-15mg、1-5mg、5-10mg、10-15mg、15-20mg、1-3mg、3-5mg、5-7.5mg、7.5-10mg、10-12.5mg、12.5-15mg、15-17.5mg或17.5-20mg(例如，约1-5mg或5-10mg)的总剂量局部施用。对于完整治疗方案，apo模拟物也可以以大于20mg的总剂量局部施用，例如对于完整治疗方案至多约25mg、30mg、40mg、50mg或更多的总剂量。With respect to apo mimetics, in certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered per administration (eg, per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0.3 mg, 0.3-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1- A dose of 1.25 mg or 1.25-1.5 mg (eg, about 0.1-0.5 mg or 0.5-1 mg) is administered (eg, by intravitreal injection) locally, intraocularly, in the eye, or around the eye. The apo mimetic can also be administered topically in doses greater than 1.5 mg per administration, eg, up to about 2 mg or more per administration (eg, per injection). In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered within a period of about 6 months A total dose of about 0.5 or 1-10 mg, 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg, 3-5 mg, 5-7.5 mg, or 7.5-10 mg (eg, about 0.5-3 mg or 3-5 mg) Topical administration (eg, by intravitreal injection or by slow release composition), wherein the duration/duration of treatment with the apo mimetic can be, eg, about 6-12, 12-18, or 18-24 months or more. The apo mimetic can also be administered topically at a total dose of greater than 10 mg over a period of about 6 months, eg, up to about 15 mg or more over a period of about 6 months. In still further embodiments, for an entire/complete treatment regimen using an apo mimetic, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28) -14)] with about 1 or 2-20mg, 5-15mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, 1-3mg, 3-5mg, 5-7.5mg, 7.5-10mg, 10 - Topical administration at a total dose of 12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg). The apo mimetic can also be administered topically in a total dose of greater than 20 mg for a complete treatment regimen, eg, up to a total dose of about 25 mg, 30 mg, 40 mg, 50 mg or more for a complete treatment regimen.
在将apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]施用于眼局部、眼内、眼中或眼周的实施方案中，每次施用的剂量、在约6个月的时间内的总剂量、以及整个治疗方案的总剂量在某些实施方案中是对于施用的每只眼睛，并且在其他实施方案中是对于双眼的。血液系统可允许局部施用(例如，注射)到一只眼睛内或在一只眼睛中的一些量(例如，治疗有效量)的apo模拟物被分布到另一只眼睛，在这种情况下apo模拟物的剂量可以考虑到另一只眼睛(其可能处于较少患病的状况)而任选的得到调整(例如，增加)，并且可以允许用apo模拟物同时治疗双眼而无需在另一只眼睛内或另一只眼睛中额外的施用(例如，注射)apo模拟物。例如，玻璃体内注射的apo模拟物可以穿过血液-视网膜屏障到达两个靶区域(即亚RPE-BL空间和布鲁赫膜)，apo模拟物可以从所述靶区域进入脉络膜毛细血管，并最终到达对应未施用的眼睛。也不受理论的束缚，一些量的apo模拟物可以通过房水途径进入对应未施用的眼睛，房水通过小梁网和流入血液系统的施莱姆管排出。因此，一些实施方案涉及治疗AMD的方法，其包括向需要治疗的对象施用治疗有效量的载脂蛋白模拟物和治疗有效量的抗氧化剂，其中所述载脂蛋白模拟物施用于一只眼睛中的眼局部、眼内、眼中或眼周并且两只眼睛都有治疗效果。Implementation of topical, intraocular, intraocular, or periocular administration of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] In the regimen, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are in certain embodiments for each eye administered, and in other embodiments for each eye. binocular. The blood system may allow topical administration (eg, injection) into one eye or some amount (eg, a therapeutically effective amount) in one eye of an apo mimetic to be distributed to the other eye, in which case apo The dose of the mimetic can optionally be adjusted (eg, increased) to take into account the other eye (which may be in a less diseased condition), and can allow simultaneous treatment of both eyes with the apo mimetic without Additional administration (eg, injection) of the apo mimetic in the eye or in the other eye. For example, intravitreal injected apo mimetics can cross the blood-retinal barrier to two target areas (ie, the sub-RPE-BL space and Bruch's membrane) from which the apo mimetics can enter the choriocapillaris and ultimately Reach the corresponding unapplied eye. Also not to be bound by theory, some amount of apo mimetic can enter the corresponding non-administered eye via the aqueous humor route, which drains through the trabecular meshwork and Schlemm's canal into the blood system. Accordingly, some embodiments relate to a method of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein mimetic and a therapeutically effective amount of an antioxidant, wherein the apolipoprotein mimetic is administered in one eye Partially, intraocularly, in or around the eye, and in both eyes.
在另外的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每月(4周)或1.5个月(6周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每2个月(8周)、2.5个月(10周)或3个月(12周)局部施用(例如，通过玻璃体内注射)一次。在其他实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每4、5或6个月局部施用(例如，通过玻璃体内注射或通过缓释组合物)一次。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]以总共约15次或更少、12次或更少、9次或更少、6次或更少、或3次或更少(例如，3-6次或7-10次)施用(例如，注射)在局部施用。也可以在局部施用apo模拟物总共更多次施用(例如注射)，例如至多约20次或更多次施用(例如注射)。在将apo模拟物施用于眼局部、眼内、眼中或眼周的实施方案中，施用频率和施用(例如注射)总次数在某些实施方案中是对于施用的每只眼睛，并且由于apo模拟物也可以在对应未施用的眼睛中具有治疗效果，在其他实施方案中是对于双眼的。In additional embodiments, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] per month (4 weeks) or 1.5 Topical administration (eg, by intravitreal injection) once a month (6 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] every 2 months (8 weeks), 2.5 Topical administration (eg, by intravitreal injection) once a month (10 weeks) or 3 months (12 weeks). In other embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically every 4, 5, or 6 months (eg, by intravitreal injection or by slow release composition) once. In further embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered in a total of about 15 times or less, 12 or less, 9 or less, 6 or less, or 3 or less (eg, 3-6 or 7-10) administrations (eg, injections) are administered locally. The apo mimetic may also be administered topically for a total of more administrations (eg, injections), eg, up to about 20 or more administrations (eg, injections). In embodiments where the apo mimetic is administered topically, intraocularly, in the eye or periocular The drug may also have a therapeutic effect in the corresponding unadministered eye, in other embodiments both eyes.
在一些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)至少在AMD的晚期阶段施用以治疗中央地图样萎缩(GA)和/或新生血管性AMD(包括1、2和3型NV)或减缓中央地图样萎缩(GA)和/或新生血管性AMD(包括1、2和3型NV)的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。抗氧化剂的使用可以抑制氧化的脂质的形成，所述氧化的脂质可以是强烈促炎性的并因此是促血管生成的。在进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)至少在AMD的中期阶段施用以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。在更进一步的实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素))至少在AMD的早期阶段或中期AMD的初始阶段施用以预防非中央GA或延迟非中央GA的发作。在另外的实施方案中，抗氧化剂(例如，维生素和/或类胡萝卜素)和任选的apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]至少在AMD的早期阶段施用。In some embodiments, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or Carotenoids) are administered at least in advanced stages of AMD to treat central geographic atrophy (GA) and/or neovascular AMD (including types 1, 2 and 3 NV) or to slow central geographic atrophy (GA) and/or neovascularization Progression of vascular AMD (including NV types 1, 2 and 3), and/or prevention of neovascular AMD or delay of onset of neovascular AMD. The use of antioxidants can inhibit the formation of oxidized lipids, which can be strongly pro-inflammatory and thus pro-angiogenic. In further embodiments, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or or carotenoids) at least in the mid-stage of AMD to treat non-central GA or slow the progression of non-central GA, and/or prevent central GA and/or neovascular AMD or delay the progression of central GA and/or neovascular AMD attack. In still further embodiments, apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and /or carotenoids)) are administered at least in the early stages of AMD or in the initial stages of mid-AMD to prevent or delay the onset of non-central GA. In additional embodiments, antioxidants (eg, vitamins and/or carotenoids) and optional apo mimetics (eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, , AEM-28-14)] at least in the early stages of AMD.
在某些实施方案中，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素)治疗和/或类胡萝卜素)的治疗减缓中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)至少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约20-40％、40-60％或60-80％。在进一步的实施方案中，相比于没有用apo模拟物治疗而用抗氧化剂治疗的情况下，用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)的治疗减缓中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)比其至少多约10％、20％、30％、50％、100％、150％、200％或300％(例如，至少约20％或30％)、或约10-30％、30-50％、50-100％、100-200％或200-300％(例如，约50-100％)。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] and an antioxidant (eg, a vitamin) Treatment and/or carotenoids) slows the progression of central GA and/or non-central GA (eg, reduces the rate of GA progression, or reduces the area or size of GA lesions) by at least about 10%, 20%, 30%, 40% , 50%, 60%, 70%, or 80% (eg, at least about 20%), or about 20-40%, 40-60%, or 60-80%. In further embodiments, treatment with an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or carotenoids) slow the progression of central and/or noncentral GA (eg, reduce the rate of GA progression, or reduce the size of GA lesions) or size) at least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200-300% (eg, about 50-100%).
apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)可以通过任何合适的方法施用。在一些实施方案中，apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和/或抗氧化剂施用于眼局部、眼内、眼中或眼周，例如通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如玻璃体内、视网膜下或特农氏囊下植入物)。在某些实施方案中，apo模拟物(例如apoA-I模拟物和/或apoE模拟物)经局部(例如，通过玻璃体内、结膜下、视网膜下或特农氏囊下注射)施用。在其他实施方案中，apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和/或抗氧化剂经全身(例如，静脉内或口服)施用。在某些实施方案中，抗氧化剂经全身(例如，口服)施用。在一些实施方案中，apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和/或抗氧化剂通过缓释组合物施用。apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or carotenoids) can be administered by any suitable method. In some embodiments, the apo mimetics (eg, apoA-I mimetics and/or apoE mimetics) and/or antioxidants are administered topically, intraocularly, in the eye, or around the eye, such as by injection (eg, intravitreal) , subconjunctival, subretinal, or subtenon's capsule), eye drops or implants (eg, intravitreal, subretinal, or subtenon's capsule). In certain embodiments, an apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) is administered topically (eg, by intravitreal, subconjunctival, subretinal, or subtenon's capsule injection). In other embodiments, the apo mimetics (eg, apoA-I mimetics and/or apoE mimetics) and/or antioxidants are administered systemically (eg, intravenously or orally). In certain embodiments, the antioxidant is administered systemically (eg, orally). In some embodiments, apo mimetics (eg, apoA-I mimetics and/or apoE mimetics) and/or antioxidants are administered via a sustained release composition.
在某些实施方案中，apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]在治疗的早期阶段施用于眼局部、眼内、眼中或眼周，并然后全身施用apo模拟物。作为非限制性实例，apo模拟物的初始施用(例如，前一至五次施用)可以是局部通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)，并然后随后可以全身性的施用apo模拟物，例如口服，肠胃外(例如，皮下、肌肉内或静脉内)，或外用(例如，鼻内或肺部)。在其他实施方案中，apo模拟物仅在局部施用。在其他实施方案中，apo模拟物仅在全身施用。In certain embodiments, an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] is administered topically to the eye during an early stage of treatment , intraocular, intraocular or periocular, and then systemically administered the apo mimetic. As a non-limiting example, the initial administration (eg, the first one to five administrations) of an apo mimetic can be topically by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), and then subsequently can be The apo mimetic is administered systemically, eg, orally, parenterally (eg, subcutaneously, intramuscularly, or intravenously), or topically (eg, intranasally or pulmonary). In other embodiments, the apo mimetic is administered topically only. In other embodiments, the apo mimetic is administered systemically only.
apo模拟物[例如，apoA-I模拟物(例如，L-4F或其变体或盐)和/或apoE模拟物(例如，AEM-28-14或其变体或盐)]和抗氧化剂(例如，维生素和/或类胡萝卜素)可以通过同一药物组合物或分开的药物组合物施用。如果apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和抗氧化剂在同一组合物中施用，则这种组合物可以预先制备或者可以在施用(例如通过注射)制剂之前不久或刚好之前通过将apo模拟物和抗氧化剂组合到同一制剂中来制备。在一些实施方案中，apo模拟物(例如，apoA-I模拟物和/或apoE模拟物)和抗氧化剂在同一组合物中通过以下局部施用于眼内、眼中或眼周：例如通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如，玻璃体内，视网膜下或特农氏囊下植入物)。apo mimetics [eg, apoA-I mimetics (eg, L-4F or a variant or salt thereof) and/or apoE mimetics (eg, AEM-28-14 or a variant or salt thereof)] and antioxidants ( For example, vitamins and/or carotenoids) can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions. If the apo mimetic (eg, apoA-I mimetic and/or apoE mimetic) and the antioxidant are administered in the same composition, such composition may be pre-prepared or may be administered (eg, by injection) shortly before the formulation or Prepared just before by combining the apo mimetic and antioxidant into the same formulation. In some embodiments, an apo mimetic (eg, an apoA-I mimetic and/or an apoE mimetic) and an antioxidant are administered topically in, in, or around the eye in the same composition, such as by injection (e.g., , intravitreal, subconjunctival, subretinal, or subtenon's capsule), eye drops, or implants (eg, intravitreal, subretinal, or subtenon's capsule).
在某些实施方案中，相对于它们合计的量，无论是否含有抗氧化剂(例如，维生素和/或类胡萝卜素)，含有apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]的组合物包含以重量计或摩尔浓度计约75-95％(例如，约90％)的apo模拟物和约5-25％(例如，约10％)的相应的载脂蛋白(例如，apoA-I和/或apoE)或其活性部分或其结构域。In certain embodiments, relative to their combined amounts, with or without antioxidants (eg, vitamins and/or carotenoids), apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetic (eg, AEM-28-14)] comprising about 75-95% (eg, about 90%) by weight or molarity of an apo mimetic and about 5-25% (eg, about 90%) , about 10%) of the corresponding apolipoproteins (eg, apoA-I and/or apoE) or active parts or domains thereof.
本文描述的一种或多种其他治疗剂可以与apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]和抗氧化剂(例如，维生素和/或类胡萝卜素)联合使用用于治疗萎缩性(干性)或新生血管性(湿性)AMD。在一些实施方案中，所述额外的治疗剂包括以下或者是以下：抗血管生成剂(例如，抗VEGF剂(例如阿柏西普、贝伐单抗或雷珠单抗)，和/或抗PDGF剂(例如E10030))，补体抑制剂(例如，C15抑制剂(例如ARC 1905或LFG316)和/或补体因子D抑制剂(例如兰波利珠单抗))，抗炎剂(例如，NSAID(例如溴芬酸)，和/或皮质类固醇(例如氟轻松或曲安奈德))，神经保护剂(例如醋酸格拉替雷和/或CNTF)、或抗血脂异常剂(例如他汀类(例如阿托伐他汀))，或其任何组合或全部。使用apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]可以增强一种或多种其他治疗剂的功效，例如，减少新血管的生长和渗漏、减少炎症、减少氧化应激、减少RPE细胞和视网膜细胞(例如光感受器)的退化，或改善改变的脂质体内平衡，或其任何组合或全部。One or more other therapeutic agents described herein can be combined with apo mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and/or carotenoids) in combination for the treatment of atrophic (dry) or neovascular (wet) AMD. In some embodiments, the additional therapeutic agent includes or is an anti-angiogenic agent (eg, an anti-VEGF agent (eg, aflibercept, bevacizumab, or ranibizumab), and/or an anti-angiogenic agent (eg, an anti-VEGF agent such as aflibercept, bevacizumab, or ranibizumab) PDGF agents (eg, E10030), complement inhibitors (eg, C15 inhibitors (eg, ARC 1905 or LFG316) and/or complement factor D inhibitors (eg, lambolizumab)), anti-inflammatory agents (eg, NSAIDs) (eg, bromfenac), and/or corticosteroids (eg, fluocinolone acetonide or triamcinolone acetonide), neuroprotective agents (eg, glatiramer acetate and/or CNTF), or anti-dyslipidemic agents (eg, statins (eg, adderallamine) atorvastatin)), or any combination or all thereof. The efficacy of one or more other therapeutic agents can be enhanced using an apo mimetic [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)], eg, Reduced growth and leakage of new blood vessels, reduced inflammation, reduced oxidative stress, reduced degeneration of RPE cells and retinal cells (eg, photoreceptors), or improved altered lipid homeostasis, or any combination or all thereof.
在一些实施方案中，至少在AMD的晚期阶段施用额外的治疗剂。在某些实施方案中，额外的治疗剂包括以下或者是以下：抗血管生成剂(例如，抗VEGF剂)和任选的神经保护剂(例如，内源性神经保护剂(例如CNTF))，并且至少在AMD的晚期阶段施用以用于治疗或减缓湿性AMD的进展(包括1、2和3型新生血管形成)。在其他实施方案中，额外的治疗剂包括以下或是以下：补体抑制剂(例如，兰波利珠单抗)和/或神经保护剂(例如，内源性神经保护剂(例如CNTF))并且至少在AMD的晚期阶段施用以治疗或减缓中央地图样萎缩(GA)的进展。In some embodiments, the additional therapeutic agent is administered at least in advanced stages of AMD. In certain embodiments, additional therapeutic agents include or are the following: anti-angiogenic agents (eg, anti-VEGF agents) and optional neuroprotective agents (eg, endogenous neuroprotective agents (eg, CNTF)), And at least in advanced stages of AMD for treating or slowing the progression of wet AMD (including type 1, 2 and 3 neovascularization). In other embodiments, additional therapeutic agents include or include complement inhibitors (eg, lambolizumab) and/or neuroprotective agents (eg, endogenous neuroprotective agents (eg, CNTF)) and Administration to treat or slow the progression of central geographic atrophy (GA) at least in advanced stages of AMD.
在进一步的实施方案中，至少在AMD的中期阶段施用额外的治疗剂。在某些实施方案中，额外的治疗剂包括以下或是以下：补体抑制剂(例如，兰波利珠单抗)和/或神经保护剂(例如醋酸格拉替雷和/或CNTF)，并且至少在AMD的中期阶段施用以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA或延迟中央GA的发作，或至少在AMD的早期阶段或中期AMD的初始阶段施用以预防非中央GA或延迟非中央GA的发作。在更进一步的实施方案中，至少在AMD的早期阶段施用额外的治疗剂。在某些实施方案中，至少在AMD早期阶段施用的额外的治疗剂包括以下或者是以下：减少脂质产生的抗血脂异常剂(例如，他汀类)和任选的抗炎剂(例如，NSAID)，并且额外的治疗剂经全身(例如，口服)或局部(例如，通过滴眼剂)施用。In a further embodiment, the additional therapeutic agent is administered at least during the intermediate stage of AMD. In certain embodiments, additional therapeutic agents include or include complement inhibitors (eg, lambolizumab) and/or neuroprotective agents (eg, glatiramer acetate and/or CNTF), and at least Administration in the intermediate stages of AMD to treat or slow the progression of non-central GA, and/or prevent central GA or delay the onset of central GA, or at least in the initial stages of early or intermediate AMD to prevent non-central GA GA or delayed onset of noncentral GA. In still further embodiments, the additional therapeutic agent is administered at least in the early stages of AMD. In certain embodiments, additional therapeutic agents administered at least in the early stages of AMD include or are the following: anti-dyslipidemic agents (eg, statins) that reduce lipid production and optional anti-inflammatory agents (eg, NSAIDs) ), and the additional therapeutic agent is administered systemically (eg, orally) or topically (eg, via eye drops).
IX.治疗其他眼部疾病IX.Treatment of other eye diseases
除了年龄相关性黄斑变性(AMD)之外，本文所述的治疗剂还可用于治疗其他眼部疾病和病症。可用本文所述的一种或多种治疗剂治疗的其他眼部疾病和病症的非限制性实例包括青少年黄斑变性(例如，Stargardt病)、黄斑病(例如，年龄相关性黄斑病[ARM]和糖尿病性黄斑病[DMP][包括部分缺血性DMP])、黄斑水肿(例如，糖尿病性黄斑水肿[DME][包括临床上显著的DME、局灶性DME和弥漫性DME]、Irvine-Gass综合征[术后黄斑水肿]和RVO[包括中央RVO和分支RVO]后的黄斑水肿)、视网膜病变(例如，糖尿病性视网膜病变[包括在DME患者中的]、Purtscher视网膜病变和放射性视网膜病变)、视网膜动脉阻塞(RAO)(例如，中央和分支RAO)、视网膜静脉阻塞(RVO)(例如，中央RVO[包括伴黄斑囊样水肿{CME}的中央RVO]和分支RVO[包括伴有CME的分支RVO])，青光眼(包括低张力、正常张力和高张力性青光眼)、高眼压症、视网膜炎(例如，Coats病[渗出性视网膜炎]和视网膜色素变性)、脉络膜视网膜炎、脉络膜炎(例如，匍行性脉络膜炎)、葡萄膜炎(包括伴或不伴有CME的前葡萄膜炎、伴或不伴有CME的中间葡萄膜炎、伴或不伴有CME的后葡萄膜炎、和全葡萄膜炎)、视网膜色素上皮(RPE)脱离、和除了AMD之外与增加的细胞内或细胞外脂质储存或积累相关的疾病。In addition to age-related macular degeneration (AMD), the therapeutic agents described herein can be used to treat other ocular diseases and disorders. Non-limiting examples of other ocular diseases and disorders that can be treated with one or more of the therapeutic agents described herein include juvenile macular degeneration (eg, Stargardt disease), macular degeneration (eg, age-related macular disease [ARM], and Diabetic macular disease [DMP] [including partially ischemic DMP]), macular edema (eg, diabetic macular edema [DME] [including clinically significant DME, focal DME, and diffuse DME], Irvine-Gass Syndromes [postoperative macular edema] and RVO (macular edema following central RVO and branch RVO), retinopathy (eg, diabetic retinopathy [including in DME patients], Purtscher retinopathy, and radiation retinopathy) , retinal artery occlusion (RAO) (eg, central and branch RAO), retinal vein occlusion (RVO) (eg, central RVO [including central RVO with cystoid macular edema {CME}] and branch RVO [including [branch RVO]), glaucoma (including hypotonic, nortonic, and hypertonic glaucoma), ocular hypertension, retinitis (eg, Coats disease [exudative retinitis] and retinitis pigmentosa), chorioretinitis, choroid Uveitis (eg, creeping choroiditis), uveitis (including anterior uveitis with or without CME, intermediate uveitis with or without CME, posterior uveitis with or without CME inflammation, and panuveitis), retinal pigment epithelium (RPE) detachment, and diseases other than AMD associated with increased intracellular or extracellular lipid storage or accumulation.
在一些实施方案中，载脂蛋白模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])单独使用或与一种或多种其他治疗剂组合使用用于治疗AMD以外的眼部疾病或病症。在某些实施方案中，具有抗炎特性的apo模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])单独施用或与另一种治疗剂组合施用用于治疗炎性眼部疾病或病症(例如葡萄膜炎)。在这种情况下，apo模拟物(例如，L-4F)充当抗炎剂并且可以用于代替甾体或非甾体抗炎药。将apo模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])与抗血管生成剂(例如抗-VEGF剂)联合使用治疗本文其他地方描述的除AMD之外的眼部疾病和病症。在进一步的实施方案中，apo模拟物(例如，apoA-I模拟物[例如，L-4F]和/或apoE模拟物[例如，AEM-28-14])与抗VEGF剂、神经保护剂、激酶抑制剂或c-肽(连接肽)或其任何组合或全部联合施用以治疗糖尿病性视网膜病。涉及将apo模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]单独使用或与另一种治疗剂(例如，抗血管生成剂[例如，抗VEGF剂]，补体抑制剂或抗氧化剂)以及本文其他地方描述的那些组合使用用来治疗AMD的实施方案也适用于将apo模拟物单独使用或与给定类型的治疗剂组合使用来治疗其他眼部疾病和病症。In some embodiments, an apolipoprotein mimetic (eg, an apoA-I mimetic [eg, L-4F] and/or an apoE mimetic [eg, AEM-28-14]) is used alone or in combination with one or more Use in combination with one or more other therapeutic agents for the treatment of ocular diseases or conditions other than AMD. In certain embodiments, an apo mimetic with anti-inflammatory properties (eg, an apoA-I mimetic [eg, L-4F] and/or an apoE mimetic [eg, AEM-28-14]) is administered alone or in combination with Another therapeutic agent is administered in combination for the treatment of inflammatory ocular diseases or disorders (eg, uveitis). In this case, apo mimetics (eg, L-4F) act as anti-inflammatory agents and can be used in place of steroidal or non-steroidal anti-inflammatory drugs. Combination therapy with apo mimetics (eg, apoA-I mimetics [eg, L-4F] and/or apoE mimetics [eg, AEM-28-14]) with anti-angiogenic agents (eg, anti-VEGF agents) Eye diseases and conditions other than AMD described elsewhere herein. In further embodiments, an apo mimetic (eg, an apoA-I mimetic [eg, L-4F] and/or an apoE mimetic [eg, AEM-28-14]) is combined with an anti-VEGF agent, neuroprotective agent, Kinase inhibitors or c-peptides (linker peptides), or any or all combinations thereof, are administered in combination to treat diabetic retinopathy. Involves the use of an apo mimetic [eg, an apoA-I mimetic (eg, L-4F) and/or an apoE mimetic (eg, AEM-28-14)] alone or with another therapeutic agent (eg, an antivascular Generating agents [eg, anti-VEGF agents], complement inhibitors or antioxidants) and those described elsewhere herein for the treatment of AMD in combination with the embodiments also apply to the use of apo mimetics alone or with a given type of therapeutic Used in combination to treat other eye diseases and conditions.
X.治疗剂的施用X.Administration of Therapeutic Agents
本文所述的治疗剂可通过任何合适的方法施用于对象，包括用于局部或全身施用的任何合适的手段。在某些实施方案中，治疗剂通过以下施用：玻璃体内注射或植入、结膜下注射或植入、视网膜下注射或植入、特农氏囊下注射或植入、眼球周注射、滴眼剂、口服摄入或静脉内注射或输注。The therapeutic agents described herein can be administered to a subject by any suitable method, including any suitable means for local or systemic administration. In certain embodiments, the therapeutic agent is administered by intravitreal injection or implantation, subconjunctival injection or implantation, subretinal injection or implantation, subtenon's capsule injection or implantation, periocular injection or eye drop dose, oral ingestion, or intravenous injection or infusion.
在一些实施方案中，一种或多种或所有治疗剂经局部施用。局部施用治疗剂可以更有效地将所述试剂递送到靶部位、避免首过代谢并且所述试剂需要较低的施用剂量，并从而可以减少由所述试剂引起的任何副作用。由于AMD的病理事件发生在眼睛中，用于治疗AMD的治疗剂可局部施用于眼睛以进行更有效的治疗。例如，在布鲁赫膜(BrM)、亚RPE-BL空间和视网膜下空间积聚的含脂质物质(例如，脂质、脂蛋白和载脂蛋白)似乎是眼内来源的(例如，由视网膜色素上皮[RPE]细胞分泌)。因此，为了更有效地减少这种物质的积聚可以涉及将一种或多种抗血脂异常剂局部施用到眼睛中的靶位点。In some embodiments, one or more or all of the therapeutic agents are administered topically. Topical administration of a therapeutic agent may more efficiently deliver the agent to the target site, avoid first-pass metabolism and require a lower dose of the agent to be administered, and thus may reduce any side effects caused by the agent. Since the pathological events of AMD occur in the eye, therapeutic agents for treating AMD can be administered topically to the eye for more effective treatment. For example, lipid-containing species (eg, lipids, lipoproteins, and apolipoproteins) that accumulate in Bruch's membrane (BrM), the sub-RPE-BL space, and the subretinal space appear to be of intraocular origin (eg, by retinal secreted by pigment epithelium [RPE] cells). Therefore, to more effectively reduce the accumulation of this substance may involve the topical administration of one or more anti-dyslipidemic agents to a target site in the eye.
局部施用的潜在途径/方式包括但不限于房(房水)内、眼球周、眼球后、脉络膜上腔、结膜下、眼内、眼周、视网膜下、巩膜内、后部巩膜旁(posterior juxtascleral)、经巩膜、特农氏囊下、玻璃体内和经玻璃体。视网膜下施用是在视网膜下方施用治疗剂，例如视网膜下空间、RPE、亚RPE-BL空间或脉络膜，或其任何组合或全部。局部施用的潜在部位包括但不限于前房(房水)和眼后房、玻璃体液(玻璃体)、视网膜(包括黄斑和/或光感受器层)、视网膜下空间、RPE、亚RPE-BL空间、脉络膜(包括BrM和脉络膜毛细血管内皮)、巩膜和特农氏囊下/空间。Potential routes/modes of topical administration include, but are not limited to, intra-atrial (aqueous), periocular, retrobulbar, suprachoroidal, subconjunctival, intraocular, periocular, subretinal, intrascleral, posterior juxtascleral ), transscleral, subtenon's capsule, intravitreal and transvitreal. Subretinal administration is the administration of a therapeutic agent under the retina, such as the subretinal space, the RPE, the sub-RPE-BL space, or the choroid, or any combination or all thereof. Potential sites for topical application include, but are not limited to, the anterior chamber (aqueous humor) and posterior chamber of the eye, vitreous humor (vitreous body), retina (including macula and/or photoreceptor layer), subretinal space, RPE, sub-RPE-BL space, Choroid (including BrM and choriocapillary endothelium), sclera, and subtenon's capsule/space.
在一些实施方案中，治疗剂通过巩膜和脉络膜递送至玻璃体液，从所述玻璃体液它可以扩散至靶组织，所述靶组织例如视网膜(例如，光感受器)、视网膜下腔、RPE、亚RPE-BL空间或BrM，或其任何组合或全部。在其他实施方案中，治疗剂穿过巩膜和脉络膜递送至靶组织，所述靶组织例如视网膜(例如，光感受器)、视网膜下空间、RPE和/或亚RPE-BL空间，如果BrM是靶组织，所述治疗剂可以从例如视网膜(例如，光感受器)、视网膜下空间、RPE和/或亚RPE-BL空间扩散到BrM。在进一步的实施方案中，将治疗剂眼内施用到例如眼睛的前房或后房、玻璃体液、视网膜或视网膜下空间中。In some embodiments, the therapeutic agent is delivered through the sclera and choroid to the vitreous humor, from which it can diffuse to target tissues, such as retina (eg, photoreceptors), subretinal space, RPE, sub-RPE - BL space or BrM, or any combination or all thereof. In other embodiments, the therapeutic agent is delivered across the sclera and choroid to target tissue, such as the retina (eg, photoreceptors), subretinal space, RPE and/or sub-RPE-BL space if BrM is the target tissue , the therapeutic agent can diffuse to BrM from, for example, the retina (eg, photoreceptors), subretinal space, RPE and/or sub-RPE-BL space. In further embodiments, the therapeutic agent is administered intraocularly, eg, into the anterior or posterior chamber, vitreous humor, retina, or subretinal space of the eye.
局部施用的潜在手段包括但不限于注射、植入和用于局部外用施用至眼睛的手段(例如滴眼剂和隐形眼镜)。在一些实施方案中，一种或多种或所有治疗剂通过玻璃体内(例如，微玻璃体内)、结膜下、视网膜下或特农氏囊下注射或植入来施用。作为实例，在某些实施方案中，根据治疗医师确定的用于治疗例如萎缩性AMD(包括非中央和/或中央地图样萎缩)和/或新生血管性AMD，将一种或多种载脂蛋白模拟物[例如，apoA-I模拟物(例如，L-4F)和/或apoE模拟物(例如，AEM-28-14)]每4周(1个月)、6周、8周(2个月)、10周、12周(3个月)，4个月、5个月或6个月(例如，约6个月、12个月、18个月或24个月或更长)注射到眼的玻璃体液中、结膜下方、视网膜下方或特农氏囊下中至少一次。Potential means of topical administration include, but are not limited to, injection, implantation, and means for topical application to the eye (eg, eye drops and contact lenses). In some embodiments, one or more or all of the therapeutic agents are administered by intravitreal (eg, microvitreous), subconjunctival, subretinal, or subtenon's capsule injection or implantation. By way of example, in certain embodiments, one or more lipid-laden is added to the treating physician as determined by the treating physician for use in the treatment of, for example, atrophic AMD (including non-central and/or central geographic atrophy) and/or neovascular AMD. Protein mimetics [eg, apoA-I mimetics (eg, L-4F) and/or apoE mimetics (eg, AEM-28-14)] every 4 weeks (1 month), 6 weeks, 8 weeks (2 month), 10 weeks, 12 weeks (3 months), 4 months, 5 months, or 6 months (eg, about 6 months, 12 months, 18 months, or 24 months or longer) injections At least once into the vitreous humor of the eye, under the conjunctiva, under the retina, or under Tenon's capsule.
可以比玻璃体内注射更低频率地施用治疗剂的方法是后部巩膜旁腔隙施用。例如，是钝的、有色的、后部巩膜旁腔隙套管，其将一定量(例如，大约15mg)的醋酸阿奈可他递送到直接在黄斑后面的巩膜上，同时使球体保持完整。与每月或每两月通过玻璃体内注射雷珠单抗或阿柏西普相比，使用这种递送方法可以每6个月施用醋酸阿奈可他一次。此外，后部巩膜旁腔隙施用方法大大降低了眼内感染、眼内炎和视网膜脱离的风险。A method by which therapeutic agents can be administered less frequently than intravitreal injection is posterior parascleral space administration. E.g, is a blunt, tinted, posterior parascleral space cannula that delivers an amount (eg, approximately 15 mg) of anacorta acetate to the sclera directly behind the macula while leaving the spheroid intact. Using this method of delivery, anectostat acetate can be administered every 6 months compared to monthly or bimonthly intravitreal injections of ranibizumab or aflibercept. In addition, the posterior parascleral space administration method greatly reduces the risk of intraocular infection, endophthalmitis, and retinal detachment.
尽管向眼睛局部施用治疗剂以治疗AMD或另一种眼部病症可具有诸如更高功效和减少副作用的优点，但在某些情况下可能需要全身施用治疗剂。例如，如果例如用于局部递送的外用制剂(例如，滴眼剂或隐形眼镜)不能制成用于治疗剂，则口服施用治疗剂可以由于易于使用和非侵入性而增加患者依从性。另一个例子，AMD的病理事件可能具有非局部组分。例如，RPE细胞分泌到BrM、亚RPE-BL空间和视网膜下空间的含脂物质的量可能部分受到RPE细胞摄取血浆脂质(例如胆固醇和脂肪酸)和脂蛋白(例如LDL)的影响。在这种情况下，可能需要全身施用一种或多种抗血脂异常剂，其减少肝脏产生这种脂质和脂蛋白。While topical administration of therapeutic agents to the eye to treat AMD or another ocular disorder may have advantages such as greater efficacy and reduced side effects, systemic administration of therapeutic agents may be desirable in certain circumstances. For example, if topical formulations such as for topical delivery (eg, eye drops or contact lenses) cannot be formulated for the therapeutic, oral administration of the therapeutic may increase patient compliance due to ease of use and non-invasiveness. As another example, pathological events in AMD may have a non-local component. For example, the amount of lipid-containing substances secreted by RPE cells into BrM, the sub-RPE-BL space, and the subretinal space may be partially influenced by the uptake of plasma lipids (eg, cholesterol and fatty acids) and lipoproteins (eg, LDL) by RPE cells. In such cases, systemic administration of one or more anti-dyslipidemic agents, which reduce hepatic production of such lipids and lipoproteins, may be required.
在一些实施方案中，一种或多种治疗剂经全身施用。全身施用的潜在途径包括但不限于口服，肠胃外(例如，皮内、皮下、肌肉内、血管内、静脉内、动脉内、髓内和鞘内)，腔内，腹膜内和外用(例如透皮、经粘膜、鼻内[例如，通过鼻腔喷雾或滴剂]、肺部[例如通过吸入]、口腔、舌下、直肠和阴道)。In some embodiments, the one or more therapeutic agents are administered systemically. Potential routes of systemic administration include, but are not limited to, oral, parenteral (eg, intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intracavitary, intraperitoneal, and topical (eg, permeabilized). Dermal, transmucosal, intranasal [eg, by nasal spray or drops], pulmonary [eg, by inhalation], buccal, sublingual, rectal, and vaginal).
在某些实施方案中，一种或多种抗血脂异常剂经全身施用。例如，在某些实施方案中，口服施用贝特类和/或他汀类药物，和/或皮下施用GLP-1受体激动剂。在进一步的实施方案中，一种或多种抗氧化剂经全身施用。例如，在某些实施方案中，口服施用维生素、藏红花类胡萝卜素和/或锌。在更进一步的实施方案中，一种或多种抗炎剂经全身施用。例如，在某些实施方案中，口服施用NSAID(例如，昔布类)，和/或静脉内施用补体抑制剂(例如，抗C5抗体(例如LFG316))。In certain embodiments, one or more anti-dyslipidemic agents are administered systemically. For example, in certain embodiments, the fibrate and/or statin is administered orally, and/or the GLP-1 receptor agonist is administered subcutaneously. In further embodiments, the one or more antioxidants are administered systemically. For example, in certain embodiments, vitamins, saffron carotenoids, and/or zinc are administered orally. In still further embodiments, the one or more anti-inflammatory agents are administered systemically. For example, in certain embodiments, an NSAID (eg, coxibs) is administered orally, and/or a complement inhibitor (eg, an anti-C5 antibody (eg, LFG316)) is administered intravenously.
在一些实施方案中，一种或多种多肽治疗剂(例如，内源性血管生成抑制剂(如可溶性VEGFR[例如VEGFR1]或血管抑制素)和/或内皮抑素)通过表达多肽治疗剂的病毒(例如，腺病毒或慢病毒)载体的手段施用。例如，AVA-101包含腺相关病毒2(AAV2)载体，其含有编码可溶性VEGFR1(FLT-1)的基因。将AVA-101局部施用到眼睛中(例如，RPE或脉络膜毛细血管内皮)导致宿主视网膜细胞表达可溶性VEGFR1。可溶性VEGFR1蛋白在细胞外空间中与VEGF结合，这阻止VEGF与结合膜的VEGFR结合并从而抑制血管生成。AVA-101可以作为例如单次视网膜下注射施用以用于治疗例如新生血管性AMD(包括1、2和/或3型新生血管形成)，这排除了多次或频繁注射的需要。In some embodiments, one or more polypeptide therapeutic agents (eg, an endogenous angiogenesis inhibitor (eg, soluble VEGFR [eg, VEGFRl] or angiostatin) and/or endostatin) are expressed by expression of the polypeptide therapeutic agent. Administration by means of viral (eg, adenoviral or lentiviral) vectors. For example, AVA-101 comprises an adeno-associated virus 2 (AAV2) vector containing a gene encoding soluble VEGFR1 (FLT-1). Topical administration of AVA-101 into the eye (eg, RPE or choriocapillary endothelium) results in host retinal cells expressing soluble VEGFR1. Soluble VEGFRl protein binds to VEGF in the extracellular space, which prevents VEGF from binding to membrane-bound VEGFR and thereby inhibits angiogenesis. AVA-101 can be administered, for example, as a single subretinal injection for the treatment of, for example, neovascular AMD (including type 1, 2, and/or 3 neovascularization), which obviates the need for multiple or frequent injections.
在另外的实施方案中，通过基因工程化的细胞(例如，NTC-201细胞)的方式施用一种或多种多肽治疗剂(例如，神经保护剂[例如，睫状神经营养因子]或抗血管生成剂[例如，抗VEGF剂(例如可溶性VEGFR)])，所述基因工程化的细胞产生多肽治疗剂并包封在聚合物颗粒或聚合物植入物中。例如，将含有编码睫状神经营养因子(CNTF)的基因的表达载体转染到RPE细胞中以产生基因工程化的NTC-201细胞。将NTC-201细胞包封在例如半透性中空纤维膜囊中，所述半透性中空纤维膜囊包含在六股聚对苯二甲酸乙二醇酯纱线的支架中。囊和支架维持细胞(例如，生长支持和营养物的递送)。在植入包封的基于细胞的药物递送系统(例如，通过巩膜通道)后，NTC-201细胞通过半透性囊产生并分泌CNTF。这种包封的细胞技术(例如，NT-501)为CNTF提供受控的、连续的和持续的递送，并且将CNTF的半衰期延长约1-3分钟至约20-50个月。使用这种包封细胞技术而将CNTF眼内递送可以例如减少与视网膜细胞退化相关的光感受器损失，并因此可以用于治疗例如地图样萎缩。In additional embodiments, one or more polypeptide therapeutic agents (eg, neuroprotective agents [eg, ciliary neurotrophic factor] or anti-vascular agents) are administered by means of genetically engineered cells (eg, NTC-201 cells). generating agents [eg, anti-VEGF agents (eg, soluble VEGFR)]), the genetically engineered cells produce polypeptide therapeutics and are encapsulated in polymeric particles or polymeric implants. For example, an expression vector containing a gene encoding ciliary neurotrophic factor (CNTF) is transfected into RPE cells to generate genetically engineered NTC-201 cells. NTC-201 cells are encapsulated, for example, in semipermeable hollow fiber membrane capsules contained in a scaffold of six strands of polyethylene terephthalate yarn. Capsules and scaffolds maintain cells (eg, growth support and delivery of nutrients). After implantation of the encapsulated cell-based drug delivery system (eg, through the scleral channel), NTC-201 cells produce and secrete CNTF through the semipermeable sac. This encapsulated cell technology (eg, NT-501) provides controlled, continuous and sustained delivery of CNTF and extends the half-life of CNTF by about 1-3 minutes to about 20-50 months. Intraocular delivery of CNTF using this encapsulated cell technology can, for example, reduce photoreceptor loss associated with retinal cell degeneration, and thus can be used to treat, for example, geographic atrophy.
还可以通过施用产生和释放这些试剂的天然存在的细胞来递送一种或多种多肽治疗剂。例如，源自脐带组织的细胞可以据报道通过产生和释放神经保护剂(如神经营养因子)来拯救光感受器和视觉功能。One or more polypeptide therapeutic agents can also be delivered by administering naturally occurring cells that produce and release these agents. For example, cells derived from umbilical cord tissue can reportedly rescue photoreceptors and visual function by producing and releasing neuroprotective agents such as neurotrophic factors.
用于治疗AMD或另一种眼部病症的特定治疗剂的治疗有效量和施用频率以及治疗持续时间可取决于多种因素，包括眼部疾病、疾病的严重程度、施用方式、对象的年龄、体重、一般健康状况、性别和饮食、以及对象对治疗的反应，并且可以由治疗医师确定。在一些实施方案中，一种或多种或所有治疗剂的给药方案包括一个或多个负荷剂量，然后是一个或多个维持剂量。设计一个或多个负荷剂量以相对快速地在靶位点建立相对高或治疗有效水平的治疗剂，并且设计一个或多个维持剂量以在治疗期间建立治疗有效水平的治疗剂。可以在治疗开始时例如通过施用比维持剂量大(例如，大2、3、4或5倍)的剂量，或者通过更频繁地(例如，更频繁2倍、3倍、4倍或5倍)施用与维持剂量基本相似的剂量来提供负荷剂量。例如，对于新生血管性AMD(包括1、2和/或3型新生血管形成)的治疗，在某些实施方案中，通过玻璃体内注射(每月约2mg，持续3个月)施用三次负荷剂量的抗血管生成剂阿柏西普，然后在由治疗医师确定的一段时间内每2个月施用一次维持剂量(约2mg)。The therapeutically effective amount and frequency of administration and duration of treatment of a particular therapeutic agent for the treatment of AMD or another ocular disorder may depend on a variety of factors, including the ocular disease, the severity of the disease, the mode of administration, the age of the subject, Body weight, general health, gender and diet, and the subject's response to treatment, and can be determined by the treating physician. In some embodiments, the dosing regimen of one or more or all therapeutic agents includes one or more loading doses followed by one or more maintenance doses. One or more loading doses are designed to establish relatively high or therapeutically effective levels of the therapeutic agent at the target site relatively rapidly, and one or more maintenance doses are designed to establish therapeutically effective levels of the therapeutic agent during treatment. Treatment can be initiated, for example, by administering a larger (eg, 2, 3, 4, or 5 times greater) dose than the maintenance dose, or by more frequent (eg, 2, 3, 4, or 5 times more frequent) A loading dose is provided by administering a dose substantially similar to the maintenance dose. For example, for the treatment of neovascular AMD (including type 1, 2 and/or 3 neovascularization), in certain embodiments, three loading doses are administered by intravitreal injection (about 2 mg per month for 3 months) of the antiangiogenic agent aflibercept, followed by maintenance doses (about 2 mg) every 2 months for a period of time determined by the treating physician.
XI.药物组合物、递送系统和试剂盒XI.Pharmaceutical Compositions, Delivery Systems and Kits
治疗剂可以作为包含一种或多种药学上可接受的载体或赋形剂的药物组合物施用。如果两种或更多种治疗剂用于治疗AMD或另一种眼部疾病，则它们可以在同一药物组合物或分开的药物组合物中施用。The therapeutic agent can be administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients. If two or more therapeutic agents are used to treat AMD or another ocular disease, they can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions.
药学上可接受的载体和赋形剂包括药学上可接受的材料、载体和物质。赋形剂的非限制性实例包括液体和固体填充剂、稀释剂、粘合剂、润滑剂、助流剂、表面活性剂、分散剂、崩解剂、乳化剂、润湿剂、悬浮剂、增稠剂、溶剂、等张/等渗剂、缓冲剂、pH调节剂、吸收延迟剂、甜味剂、调味剂、着色剂、稳定剂、防腐剂、抗氧化剂、抗微生物剂、抗菌剂、抗真菌剂、佐剂、包封材料和包衣材料。在药物制剂中使用这些赋形剂是本领域已知的。除非任何常规载体或赋形剂与治疗剂不相容，否则本公开内容包括在含有本文所述治疗剂的制剂中使用常规载体和赋形剂。参见，例如，Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott Williams&Wilkins(Philadelphia,Pennsylvania[2005])；Handbook of Pharmaceutical Excipients,5th Ed.,Rowe et al.,Eds.,ThePharmaceutical Press and the American Pharmaceutical Association(2005)；Handbook of Pharmaceutical Additives,3rd Ed.,Ash and Ash,Eds.,GowerPublishing Co.(2007)；以及Pharmaceutical Preform ulation and Formulation,Gibson,Ed.,CRC Press LLC(Boca Raton,Florida[2004])。Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable materials, carriers and substances. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, Thickeners, solvents, isotonic/isotonic agents, buffers, pH adjusters, absorption delaying agents, sweeteners, flavoring agents, colorants, stabilizers, preservatives, antioxidants, antimicrobial agents, antibacterial agents, Antifungal agents, adjuvants, encapsulating materials and coating materials. The use of these excipients in pharmaceutical formulations is known in the art. Unless any conventional carrier or excipient is incompatible with the therapeutic agent, the present disclosure includes the use of conventional carriers and excipients in formulations containing the therapeutic agents described herein. See, eg, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania [2005]); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preform ulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida [ 2004]).
用于本公开的组合物和制剂(例如可注射制剂)可以以无菌形式制备。根据本领域技术人员已知的药物级灭菌标准混合或制造无菌药物制剂，例如United StatesPharmacopeia Chapters 797,1072和1211；California Business&Professions Code4127.7；16 California Code of Regulations 1751；以及21 Code of FederalRegulations 211所公开或要求的那些。Compositions and formulations (eg, injectable formulations) for use in the present disclosure can be prepared in sterile form. Sterile pharmaceutical formulations are mixed or manufactured according to pharmaceutical grade sterilization standards known to those skilled in the art, eg, United States Pharmacopeia Chapters 797, 1072 and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751; and 21 Code of Federal Regulations 211 those disclosed or required.
作为说明性实例，可以配制一种或多种治疗剂用于递送到眼睛中(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射或滴眼剂)。可用于制备这样的制剂的赋形剂和载体包括但不限于溶剂(例如，水性溶剂，例如水、盐水和磷酸盐缓冲盐水)、等张/等渗剂(例如，NaCl和糖[例如，蔗糖])、pH调节剂(例如，磷酸二氢钠和磷酸氢二钠)和乳化剂(例如，非离子表面活性剂，例如聚山梨醇酯[例如，聚山梨酸醇酯20])。如果一种或多种治疗剂包括肽或蛋白质，则此类制剂(和任何其他种类的制剂)可含有一种或多种以下物质：抑制肽/蛋白质聚集、增加肽/蛋白质溶解度、降低溶液粘度或增加肽/蛋白质稳定性，或其任何组合或全部，例如非疏水性氨基酸(例如精氨酸和组氨酸)、多元醇(例如肌醇和山梨糖醇)、糖(例如葡萄糖、乳糖、蔗糖和海藻糖)、渗透剂(例如，海藻糖、氨基酸[例如，甘氨酸、脯氨酸和肌氨酸]和甜菜碱[例如，三甲基甘氨酸])、非离子表面活性剂(例如，烷基多糖苷)和烷基糖(例如，与长链脂肪酸或相应的长链醇偶联的二糖[例如，麦芽糖或蔗糖])。因为这些物质增加了肽/蛋白质的溶解度，它们可以用于增加肽/蛋白质浓度，并从而减少施用给定量的肽或蛋白质所需的体积，这可以具有有益效果例如降低眼压(例如，在玻璃体内注射中)。此外，这些物质可用于在制备、储存和重建亲脂性肽和蛋白质期间稳定肽和蛋白质。As an illustrative example, one or more therapeutic agents may be formulated for delivery into the eye (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule injection or eye drops). Excipients and carriers that can be used to prepare such formulations include, but are not limited to, solvents (eg, aqueous solvents such as water, saline, and phosphate buffered saline), isotonic/isotonic agents (eg, NaCl, and sugars [eg, sucrose]. ]), pH adjusters (eg, sodium dihydrogen phosphate and disodium hydrogen phosphate), and emulsifiers (eg, nonionic surfactants such as polysorbates [eg, polysorbate 20]). If the one or more therapeutic agents include peptides or proteins, such formulations (and any other class of formulations) may contain one or more of the following: inhibit peptide/protein aggregation, increase peptide/protein solubility, reduce solution viscosity or increase peptide/protein stability, or any combination or all thereof, such as non-hydrophobic amino acids (eg, arginine and histidine), polyols (eg, inositol and sorbitol), sugars (eg, glucose, lactose, sucrose) and trehalose), osmotic agents (eg, trehalose, amino acids [eg, glycine, proline, and sarcosine], and betaines [eg, trimethylglycine]), nonionic surfactants (eg, alkyl polyglycosides) and Alkyl sugars (eg, disaccharides [eg, maltose or sucrose] coupled to long-chain fatty acids or corresponding long-chain alcohols). Because these substances increase the solubility of the peptide/protein, they can be used to increase the peptide/protein concentration and thereby reduce the volume required to administer a given amount of peptide or protein, which can have beneficial effects such as lowering intraocular pressure (eg, in the vitreous). intra-injection). In addition, these substances can be used to stabilize peptides and proteins during preparation, storage and reconstitution of lipophilic peptides and proteins.
在一些实施方案中，一种或多种或所有治疗剂独立地从缓释组合物递送。如本文所用，术语“缓释组合物”包括持续释放、长期释放、延迟释放、减缓释放和控制释放的组合物、系统和装置。缓释组合物的使用可以具有益处，例如改善在一段时间内递送至靶位点的药物量的分布，以及由于更少的为了进行药物施用的侵入性程序(例如，注射到眼睛中)而改善的患者依从性和健康。在一些实施方案中，缓释组合物是药物包封系统，例如由例如可生物降解的聚合物和/或水凝胶制成的纳米颗粒、微粒、圆栓体或胶囊。在某些实施方案中，缓释组合物包含水凝胶。可以组成水凝胶的聚合物的非限制性实例包括聚乙烯醇、丙烯酸酯聚合物(例如聚丙烯酸钠)，以及具有大量亲水基团(例如羟基和/或羧酸基团)的其它均聚物和共聚物。在其他实施方案中，缓释药物包封系统包括膜封闭的储库，其中储库包含药物并且所述膜对药物是可渗透的。In some embodiments, one or more or all of the therapeutic agents are delivered independently from the sustained release composition. As used herein, the term "sustained release composition" includes sustained release, long term release, delayed release, slow release and controlled release compositions, systems and devices. The use of sustained release compositions can have benefits such as improved distribution of the amount of drug delivered to the target site over time, and improved due to fewer invasive procedures (eg, injection into the eye) for drug administration of patient compliance and health. In some embodiments, the sustained release composition is a drug encapsulation system, such as nanoparticles, microparticles, pegs, or capsules made of, for example, biodegradable polymers and/or hydrogels. In certain embodiments, the sustained release composition comprises a hydrogel. Non-limiting examples of polymers that can make up hydrogels include polyvinyl alcohol, acrylate polymers (eg, sodium polyacrylate), and other homopolymers with a large number of hydrophilic groups (eg, hydroxyl and/or carboxylic acid groups). polymers and copolymers. In other embodiments, the sustained release drug encapsulation system includes a membrane-enclosed reservoir, wherein the reservoir contains the drug and the membrane is permeable to the drug.
在某些实施方案中，缓释组合物由通过组合纤维素聚合物(例如，羟丙基甲基纤维素或其衍生物)和聚苯乙烯纳米颗粒形成的水凝胶组成。这种水凝胶可以通过例如滴眼、注射或植入局部施用于眼睛。纤维素聚合物和聚苯乙烯纳米颗粒的聚合物链可以在压力下形成松弛的键，这使得水凝胶在被针推过时容易流动，但是在压力释放的几秒内可以形成固化的键，这使得水凝胶在眼睛中转化成携带药物的胶囊。在某些实施方案中，水凝胶负载有肽或蛋白质，例如载脂蛋白模拟物或抗VEGF/VEGFR剂。当水凝胶的边缘通过暴露于眼睛中的水而逐渐侵蚀时，肽或蛋白质可以从水凝胶中释放，这允许肽或蛋白质在数月甚至数年的过程中从水凝胶中释放。In certain embodiments, the sustained release composition consists of a hydrogel formed by combining a cellulose polymer (eg, hydroxypropyl methylcellulose or a derivative thereof) and polystyrene nanoparticles. Such hydrogels can be administered topically to the eye, for example, by instillation, injection, or implantation. The polymer chains of cellulose polymers and polystyrene nanoparticles can form relaxed bonds under pressure, which allows the hydrogel to flow easily when pushed by a needle, but solidified bonds can be formed within seconds of the pressure release, This allows the hydrogel to transform into a drug-carrying capsule in the eye. In certain embodiments, the hydrogel is loaded with a peptide or protein, such as an apolipoprotein mimetic or an anti-VEGF/VEGFR agent. Peptides or proteins can be released from the hydrogel as the edges of the hydrogel are gradually eroded by exposure to water in the eye, which allows the peptide or protein to be released from the hydrogel over the course of months or even years.
在一些实施方案中，缓释组合物是聚合物植入物(例如，圆栓体、胶囊或任何其它合适的形式)或聚合物纳米颗粒或微粒，其中聚合物颗粒可以例如通过滴眼剂或注射或植入物递入。在一些实施方案中，聚合物植入物或聚合物纳米颗粒或微粒由可生物降解的聚合物(一种或多种可生物降解的均聚物，一种或多种可生物降解的共聚物或其混合物)组成。在某些实施方案中，可生物降解的聚合物包含乳酸和/或乙醇酸[例如，基于L-乳酸的共聚物，例如聚(L-丙交酯-共-乙交酯)或聚(L-乳酸-共-D,L-2-羟基辛烷酸])。可以选择聚合物植入物或聚合物纳米颗粒或微粒的可生物降解的聚合物，使得聚合物在预期治疗期大约在该时间结束时基本上完全降解，并且使得聚合物的降解的副产物(如聚合物)是生物相容的。In some embodiments, the sustained-release composition is a polymeric implant (eg, a plug, capsule, or any other suitable form) or polymeric nanoparticles or microparticles, wherein the polymeric particles can be administered, for example, by eye drops or Injection or implant delivery. In some embodiments, the polymeric implants or polymeric nanoparticles or microparticles are composed of biodegradable polymers (one or more biodegradable homopolymers, one or more biodegradable copolymers or a mixture thereof). In certain embodiments, the biodegradable polymer comprises lactic acid and/or glycolic acid [eg, L-lactic acid based copolymers such as poly(L-lactide-co-glycolide) or poly(L-lactide-co-glycolide) -lactic acid-co-D,L-2-hydroxyoctanoic acid]). The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles may be selected such that the polymer is substantially completely degraded at approximately the end of the intended treatment period, and such that a by-product of the degradation of the polymer ( such as polymers) are biocompatible.
可生物降解的聚合物的非限制性实例包括聚酯、聚(α-羟基酸)、聚丙交酯、聚乙交酯、聚(ε-己内酯)、聚二恶烷酮、聚(羟基链烷酸酯)、聚(羟基丙酸酯)、聚(3-羟基丙酸酯)、聚(羟基丁酸酯)、聚(3-羟基丁酸酯)、聚(4-羟基丁酸酯)、聚(羟基戊酸盐)、聚(3-羟基戊酸盐)、聚(羟基戊酸酯)、聚(3-羟基戊酸酯)，聚(4-羟基戊酸酯)、聚(羟基辛酸酯)、聚(2-羟基辛酸酯)、聚(3-羟基辛酸酯)、聚水杨酸盐/聚水杨酸、聚碳酸酯、聚(三亚甲基碳酸酯)、聚(碳酸亚乙酯)、聚(碳酸亚丙酯)、酪氨酸衍生的聚碳酸酯、L-酪氨酸衍生的聚碳酸酯、聚亚氨基碳酸酯、聚(DTH亚氨基碳酸酯)、聚(双酚A亚氨基碳酸酯)、聚(氨基酸)、聚(谷氨酸乙酯)、聚(丙基富马酸酯)、聚酸酐、聚原酸酯、聚(DETOSU-1,6HD)、聚(DETOSU-t-CDM)、聚氨酯、聚磷腈、聚酰亚胺、聚酰胺、尼龙、尼龙12、聚氧乙烯化蓖麻油、聚(乙二醇)、聚乙烯吡咯烷酮、聚(L-丙交酯-共-D-丙交酯)、聚(L-丙交酯-共-D,L-丙交酯)、聚(D-丙交酯-共-D,L-丙交酯)、聚(丙交酯-共-乙交酯)、聚(丙交酯-共-ε-己内酯)、聚(乙交酯-共-ε-己内酯)、聚(丙交酯-共-二恶烷酮)、聚(乙交酯-共-二恶烷酮)、聚(丙交酯-共-三亚甲基碳酸酯)、聚(乙交酯-共-三亚甲基碳酸酯)、聚(丙交酯-共-碳酸亚乙酯)、聚(乙交酯-共-碳酸亚乙酯)、聚(丙交酯-共-碳酸亚丙酯)、聚(乙交酯-共-碳酸亚丙酯)、聚(丙交酯-共-2-甲基-2-羧基-碳酸亚丙酯)、聚(乙交酯-共聚-2-甲基-2-羧基-碳酸亚丙酯)、聚(丙交酯-共-羟基丁酸酯)、聚(丙交酯-共-3-羟基丁酸酯)、聚(丙交酯-共-4-羟基丁酸酯)、聚(乙交酯-共-羟基丁酸酯)、聚(乙交酯-共-3-羟基丁酸酯)、聚(乙交酯-共-4-羟基丁酸酯)、聚(丙交酯-共-羟基戊酸酯)、聚(丙交酯-共-3-羟基戊酸酯)、聚(丙交酯-共-4-羟基戊酸酯)、聚(乙交酯-共-羟基戊酸酯)、聚(乙交酯-共-3-羟基戊酸酯)、聚(乙交酯-共-4-羟基戊酸酯)、聚(3-羟基丁酸酯-共-4-羟基丁酸酯)、聚(羟基丁酸酯-共-羟基戊酸酯)、聚(3-羟基丁酸酯-共-3-羟基戊酸酯)、聚(3-羟基丁酸酯-共-4-羟基戊酸酯)、聚(4-羟基丁酸酯-共-3-羟基戊酸酯)、(4-羟基丁酸酯-共-4-羟基戊酸酯)、聚(ε-己内酯-共-富马酸酯)，聚(ε-己内酯-共-丙烯富马酸酯)、聚(酯–共-醚)、聚(丙交酯-共-乙二醇)、聚(乙交酯-共-乙二醇)、聚(ε-己内酯-共-乙二醇)、聚(酯-共-酰胺)、聚(DETOSU-1,6HD-共-DETOSU-t-CDM)、聚(丙交酯-共-纤维素酯)、聚(丙交酯-共-乙酸纤维素)、聚(丙交酯-共-丁酸纤维素)、聚(丙交酯-共-乙酸丁酸纤维素)、聚(丙交酯-共-丙酸纤维素)、聚(乙交酯-共-纤维素酯)、聚(乙交酯-共-乙酸纤维素)、聚(乙交酯-共-丁酸纤维素)、聚(乙交酯-共-乙酸丁酸纤维素)、聚(乙交酯-共-纤维素丙酸酯)、聚(丙交酯-共-乙交酯-共-ε-己内酯)、聚(丙交酯-共-乙交酯-共-三亚甲基碳酸酯)、聚(丙交酯-共-ε-己内酯-共-三亚甲基碳酸酯)、聚(乙交酯-共-ε-己内酯-共-三亚甲基碳酸酯)、聚(3-羟基丁酸酯-共-3-羟基戊酸酯-共-4-羟基丁酸酯)、聚(3-羟基丁酸酯-共-4-羟基戊酸酯-共-4-羟基丁酸酯)、胶原蛋白、酪蛋白、多糖、纤维素、纤维素酯、乙酸纤维素、丁酸纤维素、乙酸丁酸纤维素、丙酸纤维素、甲壳质、壳聚糖、葡聚糖、淀粉、改性淀粉，及其共聚物和共混物，其中丙交酯包括L-丙交酯、D-丙交酯和D,L-丙交酯。Non-limiting examples of biodegradable polymers include polyester, poly(alpha-hydroxy acid), polylactide, polyglycolide, poly(epsilon-caprolactone), polydioxanone, poly(hydroxyl alkanoates), poly(hydroxypropionate), poly(3-hydroxypropionate), poly(hydroxybutyrate), poly(3-hydroxybutyrate), poly(4-hydroxybutyrate) ), poly(hydroxyvalerate), poly(3-hydroxyvalerate), poly(hydroxyvalerate), poly(3-hydroxyvalerate), poly(4-hydroxyvalerate), poly( hydroxyoctanoate), poly(2-hydroxyoctanoate), poly(3-hydroxyoctanoate), polysalicylate/polysalicylic acid, polycarbonate, poly(trimethylene carbonate), Poly(ethylene carbonate), poly(propylene carbonate), tyrosine derived polycarbonate, L-tyrosine derived polycarbonate, polyiminocarbonate, poly(DTHiminocarbonate) , poly(bisphenol A iminocarbonate), poly(amino acid), poly(ethyl glutamate), poly(propyl fumarate), polyanhydride, polyorthoester, poly(DETOSU-1, 6HD), poly(DETOSU-t-CDM), polyurethane, polyphosphazene, polyimide, polyamide, nylon, nylon 12, polyoxyethylated castor oil, poly(ethylene glycol), polyvinylpyrrolidone, poly (L-lactide-co-D-lactide), poly(L-lactide-co-D,L-lactide), poly(D-lactide-co-D,L-propane) lactide), poly(lactide-co-glycolide), poly(lactide-co-ε-caprolactone), poly(glycolide-co-ε-caprolactone), poly(lactide-co-ε-caprolactone) lactide-co-dioxanone), poly(glycolide-co-dioxanone), poly(lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylene) carbonate), poly(lactide-co-ethylene carbonate), poly(glycolide-co-ethylene carbonate), poly(lactide-co-propylene carbonate), poly(ethylene carbonate) lactide-co-propylene carbonate), poly(lactide-co-2-methyl-2-carboxy-propylene carbonate), poly(glycolide-co-2-methyl-2-carboxylate) - propylene carbonate), poly(lactide-co-hydroxybutyrate), poly(lactide-co-3-hydroxybutyrate), poly(lactide-co-4-hydroxybutyrate) ester), poly(glycolide-co-hydroxybutyrate), poly(glycolide-co-3-hydroxybutyrate), poly(glycolide-co-4-hydroxybutyrate), poly(glycolide-co-4-hydroxybutyrate) (lactide-co-hydroxyvalerate), poly(lactide-co-3-hydroxyvalerate), poly(lactide-co-4-hydroxyvalerate), poly(glycolide) -co-hydroxyvalerate), poly(glycolide-co-3-hydroxyvalerate), poly(glycolide-co-4-hydroxyvalerate), poly(3-hydroxybutyrate- co-4-hydroxybutyrate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxybutyrate) ester-co-4-hydroxyvalerate), poly(4-hydroxybutyrate-co-3-hydroxyvalerate), (4-hydroxybutyrate-co-4-hydroxy) valerate), poly(ε-caprolactone-co-fumarate), poly(ε-caprolactone-co-propylene fumarate), poly(ester-co-ether), poly(propylene lactide-co-ethylene glycol), poly(glycolide-co-ethylene glycol), poly(ε-caprolactone-co-ethylene glycol), poly(ester-co-amide), poly(DETOSU -1,6HD-co-DETOSU-t-CDM), poly(lactide-co-cellulose ester), poly(lactide-co-cellulose acetate), poly(lactide-co-butyric acid) cellulose), poly(lactide-co-cellulose acetate butyrate), poly(lactide-co-cellulose propionate), poly(glycolide-co-cellulose ester), poly(glycolide) ester-co-cellulose acetate), poly(glycolide-co-cellulose acetate), poly(glycolide-co-cellulose acetate butyrate), poly(glycolide-co-cellulose propionate) ester), poly(lactide-co-glycolide-co-ε-caprolactone), poly(lactide-co-glycolide-co-trimethylene carbonate), poly(lactide) -Co-ε-caprolactone-co-trimethylene carbonate), poly(glycolide-co-ε-caprolactone-co-trimethylene carbonate), poly(3-hydroxybutyrate- Co-3-hydroxyvalerate-co-4-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate-co-4-hydroxybutyrate), collagen, Casein, polysaccharides, cellulose, cellulose esters, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, chitin, chitosan, dextran, starch, modified starch, and Copolymers and blends thereof, wherein lactide includes L-lactide, D-lactide and D,L-lactide.
作为说明性实例，用于注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)的包含一种或多种肽或蛋白质(例如，载脂蛋白模拟物[例如，apoA-I或apoE模拟物]和/或抗体或其片段[例如，抗VEGF抗体或其片段])的缓释组合物可以由一种或多种可生物降解的聚合物(例如己基取代的聚(乳酸)(hexPLA))组成。HexPLA是具有半固体聚集态的疏水性聚酯，其有利于配制。可以将肽/蛋白质微粉化并通过低温研磨掺入液体hexPLA聚合物基质中，形成均匀且可注射的悬浮液。肽/蛋白质可与hexPLA聚合物具有良好的相容性、良好的储存稳定性(例如，在约4℃下的长时间[例如，约3个月或更长])，并且当与周围水介质隔离时聚合物内部具有更好的稳定性。具有hexPLA的肽/蛋白质的制剂可具有例如约1-5％或5-10％的载药量，并且hexPLA可具有例如约1000-2000g/mol、2000-3000g/mol或3000-4000g/mol的分子量(MW)。制剂可在水性介质(例如缓冲液)中形成球形贮库，并将肽/蛋白质释放一段延长的时间(例如，约1、2、3、4、5或6个月)。肽/蛋白质的释放速率可受基于聚合物MW的聚合物粘度的影响和较小程度受载药量的影响，这允许对药物释放曲线进行微调。肽/蛋白质在掺入聚合物基质中时可以保持其结构，并且在从聚合物基质中释放后可以保持其生物活性(例如，对其生物靶标的高亲和力)。As an illustrative example, for injection (e.g., intravitreal, subconjunctival, subretinal, or subtenon's capsule) injections comprising one or more peptides or proteins (e.g., apolipoprotein mimetics [e.g., apoA- I or apoE mimetics] and/or antibodies or fragments thereof [eg, anti-VEGF antibodies or fragments thereof]) may be composed of one or more biodegradable polymers (eg, hexyl-substituted poly(lactic acid). ) (hexPLA)). HexPLA is a hydrophobic polyester with a semi-solid aggregate state, which facilitates formulation. Peptides/proteins can be micronized and incorporated into liquid hexPLA polymer matrices by cryomilling to form homogeneous and injectable suspensions. Peptides/proteins can have good compatibility with hexPLA polymers, good storage stability (eg, at about 4°C for extended periods of time [eg, about 3 months or more]), and when mixed with surrounding aqueous media Better stability inside the polymer during isolation. Formulations of peptide/protein with hexPLA can have, for example, a drug load of about 1-5% or 5-10%, and hexPLA can have, for example, about 1000-2000 g/mol, 2000-3000 g/mol, or 3000-4000 g/mol Molecular Weight (MW). The formulation can form a spherical depot in an aqueous medium (eg, buffer) and release the peptide/protein for an extended period of time (eg, about 1, 2, 3, 4, 5, or 6 months). The release rate of the peptide/protein can be influenced by the viscosity of the polymer based on the MW of the polymer and to a lesser extent by the drug loading, which allows fine-tuning of the drug release profile. The peptide/protein can retain its structure when incorporated into the polymer matrix and retain its biological activity (eg, high affinity for its biological target) after release from the polymer matrix.
作为从聚合物微粒释放的替代方案，固体治疗剂可以以微粒的形式施用，所述微粒主要包含治疗剂或基本上由治疗剂组成。与在施用后基本上完全溶解在水性介质中的试剂相比，这种微粒形式的试剂在施用后将随着时间基本上完全溶解，并从而具有更长的作用持续时间并且需要更少的施用(例如，注射)。此外，这种微粒可以形成用于延长治疗剂递送的贮库。此类微粒可任选地含有相对少量的一种或多种赋形剂。主要包含治疗剂或基本上由治疗剂组成的微粒可以通过例如注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如，玻璃体内、视网膜下或特农氏囊下植入物)局部施用。As an alternative to release from polymeric microparticles, the solid therapeutic agent can be administered in the form of microparticles that contain essentially or consist essentially of the therapeutic agent. Such agents in particulate form will dissolve substantially completely over time after administration and thus have a longer duration of action and require less administration than agents that dissolve substantially completely in the aqueous medium after administration (eg, injection). In addition, such microparticles can form depots for prolonged delivery of therapeutic agents. Such microparticles may optionally contain relatively small amounts of one or more excipients. Microparticles comprising essentially or consisting essentially of a therapeutic agent can be administered, for example, by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon injection), eye drops, or implants (eg, intravitreal, subretinal or subtenon's capsule) topical administration.
在一些实施方案中，缓释组合物在约1周、2周、4周(1个月)、6周、8周(2个月)、10周、3个月、6个月、1年、1.5年、2年、2.5年、3年或更长时间的时期内释放低或相对低但治疗有效的一种或多种治疗剂的剂量。In some embodiments, the extended release composition is at about 1 week, 2 weeks, 4 weeks (1 month), 6 weeks, 8 weeks (2 months), 10 weeks, 3 months, 6 months, 1 year , 1.5 years, 2 years, 2.5 years, 3 years, or longer periods to release a low or relatively low but therapeutically effective dose of one or more therapeutic agents.
缓释聚合物植入物的实例是是一种微管形式的玻璃体内植入物，由聚酰亚胺制成并且一端用硅酮粘合剂密封而另一端用聚乙烯醇密封，并且其持续3年释放出极少量的皮质类固醇氟轻松。缓释聚合物植入物的另一个例子是是一种可生物降解的玻璃体内植入物，其使用固体聚合物递送系统递送延长释放的皮质类固醇地塞米松。可通过缓释的可生物降解的玻璃体内植入物递送的其他治疗剂包括但不限于神经保护剂溴莫尼定。Examples of slow release polymer implants are is an intravitreal implant in the form of microtubules, made of polyimide and sealed with silicone adhesive on one end and polyvinyl alcohol on the other, and it releases very small amounts of corticosteroids for 3 years Fluocinolone. Another example of a slow-release polymer implant is is a biodegradable intravitreal implant that uses The solid polymer delivery system delivers the extended release corticosteroid dexamethasone. Other therapeutic agents that can be delivered by slow-release biodegradable intravitreal implants include, but are not limited to, the neuroprotective agent brimonidine.
缓释眼部药物递送系统的另一个实例是Guo等人的美国专利No.6,375,972中所述的那种。Guo的系统包括含有药物的内药物核心和不能透过药物通过的内管，其中内管具有第一和第二末端并至少覆盖内药物核心的一部分，并且内管由材料确定大小并形成，使得内管尺寸稳定以接受内药物核心而不改变形状。不可渗透的膜定位在内管的第一端并防止药物经内管的第一端通过到内药物核心以外。可渗透膜定位在内管的第二端并允许药物经内管的第二端扩散出内药物核心。例如，可以通过注射或植入玻璃体液、视网膜下或巩膜上应用Guo的缓释系统。Another example of a sustained release ocular drug delivery system is that described in US Patent No. 6,375,972 to Guo et al. Guo's system includes an inner drug core containing a drug and an inner tube that is impermeable to the drug, wherein the inner tube has first and second ends and covers at least a portion of the inner drug core, and the inner tube is sized and formed from a material such that The inner tube is dimensionally stable to receive the inner drug core without changing shape. An impermeable membrane is positioned at the first end of the inner tube and prevents the passage of drug through the first end of the inner tube out of the inner drug core. A permeable membrane is positioned at the second end of the inner tube and allows the drug to diffuse out of the inner drug core through the second end of the inner tube. For example, Guo's sustained release system can be applied by injection or implantation in the vitreous humor, subretinal or scleral.
控释眼用药物递送系统的另一个实例是Yaacobi的美国专利No.6,413,540中所述的那种。Yaacobi的系统包括具有用于放置在巩膜附近的巩膜表面的主体，以及具有通向巩膜表面的开口和含有药物的内核的孔。该系统以受控速率将药物通过巩膜递送到脉络膜和视网膜或通过脉络膜递送到视网膜。Another example of a controlled release ophthalmic drug delivery system is that described in US Patent No. 6,413,540 to Yaacobi. Yaacobi's system includes a body with a scleral surface for placement near the sclera, and a hole with an opening to the scleral surface and a drug-containing inner core. The system delivers drugs at a controlled rate through the sclera to the choroid and retina or through the choroid to the retina.
另一种示例性眼部药物递送装置是渗透泵，例如Ambati等人描述的渗透泵。Ambati的渗透泵分别将IgG和抗ICAM-1单克隆抗体穿过巩膜递送到脉络膜和视网膜，其中全身吸收可忽略不计。J.Ambati et al.,Invest.Opthalmol.Vis.Sci.,41:1186-91(2000)。Another exemplary ocular drug delivery device is an osmotic pump, such as that described by Ambati et al. Ambati's osmotic pumps deliver IgG and anti-ICAM-1 monoclonal antibodies across the sclera to the choroid and retina, respectively, with negligible systemic absorption. J. Ambati et al., Invest. Opthalmol. Vis. Sci., 41: 1186-91 (2000).
药物洗脱隐形眼镜也可用作缓释药物递送系统。这种隐形眼镜可视为可植入装置或用作外用施用的组合物。药物洗脱隐形眼镜的释放持续时间可以通过以下来增加：例如分子印迹、屏障或纳米颗粒/微粒的分散、增加药物与聚合物的结合、或将聚合物[例如，聚(丙交酯-共-乙交酯)]层夹在镜片中，或其任何组合或全部。隐形眼镜可以根据需要提供例如数小时至数天的延长的药物释放，并且由于其易于使用和最小的侵入性可以增加患者的依从性。Drug eluting contact lenses can also be used as sustained release drug delivery systems. Such contact lenses may be considered implantable devices or used as compositions for topical administration. The release duration of drug eluting contact lenses can be increased by, for example, molecular imprinting, barrier or dispersion of nanoparticles/microparticles, increased drug binding to polymers, or incorporation of polymers [eg, poly(lactide-co-) - glycolide)] layer sandwiched in the lens, or any combination or all thereof. Contact lenses can provide extended drug release on demand, eg, hours to days, and can increase patient compliance due to their ease of use and minimal invasiveness.
在一些实施方案中，一种或多种治疗剂(例如，多核苷酸[例如，反义多核苷酸]和/或多肽[例如，载脂蛋白模拟物])独立地包含在具有脂质双层的纳米颗粒、微粒或脂质体中。在一些实施方案中，脂质双层由一种或多种磷脂组成。磷脂的非限制性实例包括磷脂酸(例如，DMPA、DPPA和DSPA)，磷脂酰胆碱(例如，DDPC、DEPC、DLPC、DMPC、DOPC、DPPC、DSPC和POPC)，磷脂酰乙醇胺(例如，DMPE、DOPE、DPPE和DSPE)，磷脂酰甘油(例如，DMPG、DPPG、DSPG和POPG)和磷脂酰丝氨酸(例如，DOPS)。具有由促融合脂质(例如，DPPG)组成的脂质双层的纳米颗粒、微粒或脂质体可以与细胞的质膜融合，并从而将治疗剂递送到那些细胞中。具有脂质双层的纳米颗粒、微粒或脂质体可以经局部或全身施用。In some embodiments, one or more therapeutic agents (eg, polynucleotides [eg, antisense polynucleotides] and/or polypeptides [eg, apolipoprotein mimetics]) are independently contained within a lipid bilayer layers of nanoparticles, microparticles or liposomes. In some embodiments, the lipid bilayer consists of one or more phospholipids. Non-limiting examples of phospholipids include phosphatidic acid (eg, DMPA, DPPA, and DSPA), phosphatidylcholines (eg, DDPC, DEPC, DLPC, DMPC, DOPC, DPPC, DSPC, and POPC), phosphatidylethanolamines (eg, DMPE) , DOPE, DPPE, and DSPE), phosphatidylglycerols (eg, DMPG, DPPG, DSPG, and POPG), and phosphatidylserines (eg, DOPS). Nanoparticles, microparticles or liposomes with lipid bilayers composed of fusogenic lipids (eg, DPPG) can fuse with the plasma membrane of cells and thereby deliver therapeutic agents to those cells. Nanoparticles, microparticles or liposomes with lipid bilayers can be administered topically or systemically.
在一些实施方案中，抗血管生成剂(例如，抗VEGF/VEGFR剂)和抗炎剂(例如，载脂蛋白模拟物[例如，apoA-I模拟物]、CRP抑制剂、补体抑制剂、炎性体抑制剂、皮质类固醇或NSAID，或其任何组合或全部)包含在由可生物降解的聚合物或脂质双层组成的相同或不同的脂质体、纳米颗粒或微粒中，并且为了治疗例如新生血管性AMD(包括1、2和/或3型新生血管形成)而施用。在某些实施方案中，脂质体、纳米颗粒或微粒通过以下局部施用：例如通过滴眼剂或注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)。In some embodiments, anti-angiogenic agents (eg, anti-VEGF/VEGFR agents) and anti-inflammatory agents (eg, apolipoprotein mimetics [eg, apoA-I mimetics], CRP inhibitors, complement inhibitors, inflammatory sex body inhibitors, corticosteroids or NSAIDs, or any combination or all thereof) contained in the same or different liposomes, nanoparticles or microparticles composed of biodegradable polymers or lipid bilayers, and for therapeutic purposes For example, for neovascular AMD (including type 1, 2 and/or 3 neovascularization). In certain embodiments, the liposomes, nanoparticles or microparticles are administered topically, eg, by eye drops or injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule).
包含一种或多种治疗剂的组合物可作为单剂量以单剂量形式存在，其中所有活性和非活性成分在合适的系统中组合，并且不需要将组分混合来形成待施用的组合物。单位剂型可含有一种或多种治疗剂中的每一种的有效剂量或其适当的级分。单位剂型的实例是用于口服施用的片剂、胶囊剂或丸剂。单位剂型的另一个实例是一次性小瓶、安瓿或预填充注射器，所述一次性小瓶、安瓿或预填充注射器含有溶解或悬浮在合适载体(例如水性溶剂)中的一种或多种治疗剂和赋形剂的组合物。小瓶或安瓿可以包括在包含用于施用组合物的器具(例如，注射器、过滤器或过滤针，以及用于注射组合物的注射针)的试剂盒中。该试剂盒还可以包含用于储存和施用组合物的说明书。Compositions containing one or more therapeutic agents may be presented as a single dose in a single dosage form, wherein all active and inactive ingredients are combined in a suitable system, and it is not necessary to mix the components to form the composition to be administered. A unit dosage form may contain an effective dose of each of one or more therapeutic agents, or an appropriate fraction thereof. Examples of unit dosage forms are tablets, capsules or pills for oral administration. Another example of a unit dosage form is a single-use vial, ampoule, or pre-filled syringe containing one or more therapeutic agents dissolved or suspended in a suitable carrier, such as an aqueous solvent, and Composition of excipients. The vial or ampoule can be included in a kit that includes a means for administering the composition (eg, a syringe, filter or filter needle, and an injection needle for injecting the composition). The kit may also contain instructions for storing and administering the composition.
可选地，包含一种或多种治疗剂的组合物可以以试剂盒提供，其中一种或多种治疗剂、赋形剂和载体(例如溶剂)在两个或更多个分开的容器(例如，安瓿、小瓶、管、瓶子或注射器)提供并且需要组合以制备待施用的组合物。在一些实施方案中，两种或更多种治疗剂(例如，apoA-I模拟物和/或apoE模拟物加抗血管生成剂、神经保护剂、抗炎剂、补体抑制剂、抗氧化剂或减少脂质产生的物质)在施用(例如通过注射)制剂之前不久或刚好之前组合到同一制剂。可以以任何合适的形式(例如，在稳定的培养基中或冻干的)提供所述一种或多种治疗剂。该试剂盒可以包含用于施用组合物的器具(例如，注射器，过滤器或过滤针，以及用于注射溶液或悬浮液的注射针)。该试剂盒还可以包含用于储存试剂盒内容物以及用于制备和施用组合物的说明书。Alternatively, a composition comprising one or more therapeutic agents may be provided in a kit wherein the one or more therapeutic agents, excipients and carriers (eg, solvents) are in two or more separate containers ( For example, ampoules, vials, tubes, bottles, or syringes) are provided and required to be combined to prepare the composition to be administered. In some embodiments, two or more therapeutic agents (eg, an apoA-I mimetic and/or an apoE mimetic plus an anti-angiogenic agent, neuroprotective agent, anti-inflammatory agent, complement inhibitor, antioxidant, or reducing agent) lipid-producing substances) are combined into the same formulation shortly before or just before administration (eg, by injection) of the formulation. The one or more therapeutic agents can be provided in any suitable form (eg, in a stable medium or lyophilized). The kit can include means for administering the composition (eg, a syringe, a filter or filter needle, and an injection needle for injecting solutions or suspensions). The kit may also contain instructions for storing the contents of the kit and for preparing and administering the composition.
XII.盐形式XII.Salt Form
化合物/分子(例如，载脂蛋白模拟物，例如L-4F和AEM-28-14)可以以非盐形式存在(例如，游离碱或游离酸，或不具有碱性或酸性原子或官能团)或如果它们可以形成盐则作为盐存在。可以形成盐的化合物可以以非盐形式或以药学上可接受的盐的形式使用。如果化合物具有例如碱性氮原子，则该化合物可与酸形成加成盐(例如，无机酸[如HCl、HBr、HI、硝酸、磷酸或硫酸]或有机酸[例如羧酸或磺酸])。用于制备药学上可接受的盐的合适的酸包括但不限于乙酸、2,2-二氯乙酸、酰化氨基酸、己二酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、环己烷氨基磺酸(cyclohexanesulfamicacid)、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、L-谷氨酸、α-氧代戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(±)-DL-乳酸、(+)-L-乳酸、乳糖酸、月桂酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、高氯酸、磷酸、丙酸、L-焦谷氨酸、丙酮酸、糖酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、单宁酸、(±)-DL-酒石酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸和戊酸。Compounds/molecules (eg, apolipoprotein mimetics such as L-4F and AEM-28-14) may exist in non-salt form (eg, free base or free acid, or have no basic or acidic atoms or functional groups) or They exist as salts if they can form salts. Compounds that can form salts can be used in non-salt form or in the form of a pharmaceutically acceptable salt. If the compound has, for example, a basic nitrogen atom, the compound may form an addition salt with an acid (eg, an inorganic acid [such as HCl, HBr, HI, nitric acid, phosphoric acid, or sulfuric acid] or an organic acid [such as a carboxylic acid or sulfonic acid]) . Suitable acids for preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid , benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, Citric acid, cyclohexanesulfamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid , Galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, Hydrochloric acid, hydroiodic acid, (±)-DL-lactic acid, (+)-L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL - Mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, niacin, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid , Pamoic acid, perchloric acid, phosphoric acid, propionic acid, L-pyroglutamic acid, pyruvic acid, sugar acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid , sulfuric acid, tannic acid, (±)-DL-tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.
如果化合物具有酸性基团(例如，羧基)，则该化合物可与碱形成加成盐。药学上可接受的碱加成盐可以用例如金属(例如碱金属或碱土金属)或胺(例如有机胺)形成。可用作阳离子的金属的非限制性实例包括碱金属(例如锂、钠、钾和铯)、碱土金属(例如镁和钙)、铝和锌。金属阳离子可以通过例如无机碱(例如氢氧化物、碳酸盐和碳酸氢盐)提供。可用于形成碱加成盐的有机胺的非限制性实例包括氯普鲁卡因、胆碱、环己胺、二苄胺、N,N'-二苄基乙二胺、二环己胺、二乙醇胺、乙二胺、N-乙基哌啶、组氨酸、异丙胺、N-甲基葡糖胺、普鲁卡因、吡嗪、三乙胺和三甲胺。药学上可接受的盐在Handbook of Pharmaceutical Salts,Properties,Selection and Use,P.Stahl and C.Wermuth,Eds.,Wiley-VCH(2011)中详细讨论。If the compound has an acidic group (eg, a carboxyl group), the compound can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed, for example, with metals (eg, alkali metals or alkaline earth metals) or amines (eg, organic amines). Non-limiting examples of metals that can be used as cations include alkali metals (eg, lithium, sodium, potassium, and cesium), alkaline earth metals (eg, magnesium and calcium), aluminum, and zinc. Metal cations can be provided, for example, by inorganic bases such as hydroxides, carbonates and bicarbonates. Non-limiting examples of organic amines that can be used to form base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N,N'-dibenzylethylenediamine, dicyclohexylamine, Diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine and trimethylamine. Pharmaceutically acceptable salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011).
XIII.代表性实施方案XIII.Representative Embodiments
仅通过示例的方式提供本公开的以下实施方案：The following embodiments of the present disclosure are provided by way of example only:
1.一种治疗年龄相关性黄斑变性(AMD)的方法，包括向需要治疗的对象施用治疗有效量的载脂蛋白(apo)模拟物，其中所述apo模拟物以每次施用约0.1或0.3mg至约1.5mg的剂量，或者以在约6个月的时间内约0.5或1mg至约10mg的总剂量施用于眼局部、眼内、眼中或眼周。1. A method of treating age-related macular degeneration (AMD), comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimic, wherein the apo mimic is administered at a rate of about 0.1 or 0.3 per administration A dose of mg to about 1.5 mg, or a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months is administered topically, intraocularly, in the eye, or around the eye.
2.实施方案1的方法，其中所述apo模拟物包含apoA-I模拟物，或是apoA-I模拟物。2. The method of embodiment 1, wherein the apo mimetic comprises an apoA-I mimetic, or is an apoA-I mimetic.
3.实施方案2的方法，其中所述apoA-I模拟物包含4F或其变体或盐(例如乙酸盐)，或是4F或其变体或盐(例如乙酸盐)。3. The method of embodiment 2, wherein the apoA-I mimetic comprises 4F or a variant or salt thereof (eg acetate), or 4F or a variant or salt thereof (eg acetate).
4.实施方案3的方法，其中所述apoA-I模拟物包含L-4F或D-4F，或是L-4F或D-4F，各自任选地在N-末端和/或C-末端具有保护基团[例如，Ac-DWFKAFYDKVAEKFKEAF-NH2(SEQ.ID.NO.13)]。4. The method of embodiment 3, wherein the apoA-I mimic comprises L-4F or D-4F, or L-4F or D-4F, each optionally having at the N-terminus and/or the C-terminus Protecting group [eg, Ac-DWFKAFYDKVAEKFKEAF-NH2 (SEQ. ID. NO. 13)].
5.前述实施方案中任一项的方法，其中所述apo模拟物包含apoE模拟物，或是apoE模拟物。5. The method of any of the preceding embodiments, wherein the apo mimetic comprises an apoE mimetic, or is an apoE mimetic.
6.实施方案5的方法，其中所述apoE模拟物包含AEM-28-14或其变体或盐，或是AEM-28-14或其变体或盐。6. The method of embodiment 5, wherein the apoE mimetic comprises AEM-28-14 or a variant or salt thereof, or AEM-28-14 or a variant or salt thereof.
7.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)以每次施用(例如，每次注射)约0.1-0.5mg、0.5-1mg、1-1.5mg、0.1-0.3mg、0.3-0.5mg、0.5-0.75mg、0.75-1mg、1-1.25mg或1.25-1.5mg(例如，约0.1-0.5mg或0.5-1mg)的剂量局部施用。7. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is about 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg per administration (eg, per injection) , 0.1-0.3 mg, 0.3-0.5 mg, 0.5-0.75 mg, 0.75-1 mg, 1-1.25 mg, or 1.25-1.5 mg (eg, about 0.1-0.5 mg or 0.5-1 mg) are administered topically.
8.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)以在约6个月的时间内约0.5或1-5mg、5-10mg、0.5或1-3mg、3-5mg、5-7.5mg或7.5-10mg(例如，约0.5-3mg或3-5mg)的总剂量局部施用。8. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered at about 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg over a period of about 6 months , 3-5 mg, 5-7.5 mg, or 7.5-10 mg (eg, about 0.5-3 mg or 3-5 mg) for topical administration in total doses.
9.前述实施方案中任一项的方法，其中对于整个治疗方案，apo模拟物(例如，L-4F)以约1或2-20mg或5-15mg的总剂量局部施用。9. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered topically at a total dose of about 1 or 2-20 mg or 5-15 mg for the entire treatment regimen.
10.实施方案9的方法，其中对于整个治疗方案，所述apo模拟物(例如，L-4F)以约1-5mg、5-10mg、10-15mg、15-20mg、1-3mg、3-5mg、5-7.5mg、7.5-10mg、10-12.5mg、12.5-15mg、15-17.5mg或17.5-20mg(例如，约1-5mg或5-10mg)的总剂量局部施用。10. The method of embodiment 9, wherein the apo mimetic (eg, L-4F) is administered at about 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 1-3 mg, 3- A total dose of 5 mg, 5-7.5 mg, 7.5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg) is administered topically.
11.前述实施方案中任一项的方法，其中所述每次施用的剂量、所述在约6个月的时间内的总剂量和所述整个治疗方案的总剂量是对于治疗的每只眼睛的。11. The method of any one of the preceding embodiments, wherein the dose per administration, the total dose over a period of about 6 months, and the total dose of the entire treatment regimen are for each eye treated of.
12.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如，玻璃体内、房水内、视网膜下或特农氏囊下植入物)而局部施用。12. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule), eye drops or implants (eg, intravitreal, intra-aqueous, subretinal, or subtenon's capsule) for topical administration.
13.实施方案12的方法，其中所述apo模拟物(例如，L-4F)通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)而局部施用。13. The method of embodiment 12, wherein the apo mimetic (eg, L-4F) is administered topically by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule).
14.实施方案13的方法，其中所述apo模拟物(例如，L-4F)以约1、2、3、4或5mg/mL至约12或15mg/mL的剂量浓度通过注射(例如，玻璃体内注射)而局部施用。14. The method of embodiment 13, wherein the apo mimetic (eg, L-4F) is administered by injection (eg, vitreous) at a dose concentration of about 1, 2, 3, 4, or 5 mg/mL to about 12 or 15 mg/mL. intramuscular injection) for topical administration.
15.实施方案14的方法，其中所述apo模拟物(例如，L-4F)以约1-4mg/mL、4-8mg/mL、8-12mg/mL、1-5mg/mL、5-10mg/mL、10-15mg/mL、1-3mg/mL、3-5mg/mL、5-7.5mg/mL、6-8mg/mL、7.5-10mg/mL、10-12.5mg/mL或12.5-15mg/mL(例如，约1-5mg/mL、5-10mg/mL或6-8mg/mL)的剂量浓度通过注射(例如，玻璃体内注射)而局部施用。15. The method of embodiment 14, wherein the apo mimetic (eg, L-4F) is administered at about 1-4 mg/mL, 4-8 mg/mL, 8-12 mg/mL, 1-5 mg/mL, 5-10 mg /mL, 10-15mg/mL, 1-3mg/mL, 3-5mg/mL, 5-7.5mg/mL, 6-8mg/mL, 7.5-10mg/mL, 10-12.5mg/mL or 12.5-15mg Dosage concentrations per mL (eg, about 1-5 mg/mL, 5-10 mg/mL, or 6-8 mg/mL) are administered locally by injection (eg, intravitreal injection).
16.实施方案13至15中任一项的方法，其中所述apo模拟物(例如，L-4F)以约50-150μL或50-100μL的剂量体积通过注射(例如，玻璃体内注射)而局部施用。16. The method of any one of embodiments 13 to 15, wherein the apo mimetic (eg, L-4F) is administered locally by injection (eg, intravitreal injection) in a dose volume of about 50-150 μL or 50-100 μL apply.
17.实施方案16的方法，其中所述apo模拟物(例如，L-4F)以约50-75μL、75-100μL、100-125μL或125-150μL、或约50μL、75μL、100μL、125μL或150μL(例如约100μL)的剂量体积通过注射(例如，玻璃体内注射)而局部施用。17. The method of embodiment 16, wherein the apo mimetic (eg, L-4F) is administered in about 50-75 μL, 75-100 μL, 100-125 μL, or 125-150 μL, or about 50 μL, 75 μL, 100 μL, 125 μL, or 150 μL A dose volume (eg, about 100 μL) is administered topically by injection (eg, intravitreal injection).
18.实施方案13至17中任一项的方法，其中所述apo模拟物(例如，L-4F)通过每月(4周)或1.5个月(6周)注射(例如，玻璃体内注射)一次而局部施用。18. The method of any one of embodiments 13 to 17, wherein the apo mimetic (eg, L-4F) is injected by monthly (4 weeks) or 1.5 months (6 weeks) injections (eg, intravitreal injections) One time topical application.
19.实施方案13至17中任一项的方法，其中所述apo模拟物(例如，L-4F)通过每2个月(8周)、2.5个月(10周)或3个月(12周)注射(例如，玻璃体内注射)一次而局部施用。19. The method of any one of embodiments 13 to 17, wherein the apo mimetic (eg, L-4F) is administered every 2 months (8 weeks), 2.5 months (10 weeks), or 3 months (12 weeks). Weekly) injection (eg, intravitreal injection) once for topical administration.
20.实施方案13至17中任一项的方法，其中所述apo模拟物(例如，L-4F)通过每4、5或6个月注射(例如，玻璃体内注射)一次而局部施用。20. The method of any one of embodiments 13 to 17, wherein the apo mimetic (eg, L-4F) is administered topically by injection (eg, intravitreal injection) every 4, 5, or 6 months.
21.实施方案13至20中任一项的方法，其中所述apo模拟物(例如，L-4F)以总共约15次或更少、12次或更少、9次或更少、6次或更少、或3次或更少的注射(例如，玻璃体内注射)而局部施用。21. The method of any one of embodiments 13 to 20, wherein the apo mimetic (eg, L-4F) is administered in a total of about 15 times or less, 12 times or less, 9 times or less, 6 times or less, or 3 or less injections (eg, intravitreal injections) for topical administration.
22.实施方案21的方法，其中所述apo模拟物(例如，L-4F)以总共约15次、14次、13次、12次、11次、10次、9次、8次、7次、6次、5次、4次或3次(例如，约3-6或7-10次)的注射(例如，玻璃体内注射)而局部施用。22. The method of embodiment 21, wherein the apo mimetic (eg, L-4F) is administered in a total of about 15, 14, 13, 12, 11, 10, 9, 8, 7 times , 6, 5, 4, or 3 (eg, about 3-6 or 7-10) injections (eg, intravitreal injections) for topical administration.
23.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)在治疗的早期阶段以更高的剂量和/或更频繁地局部施用(例如，通过玻璃体内注射)。23. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is locally administered (eg, by intravitreal injection) at a higher dose and/or more frequently in the early stages of treatment ).
24.前述实施方案中任一项的方法，其中使用所述apo模拟物(例如，L-4F)的所述治疗方案持续约36个月或更短、30个月或更短、24个月或更短、18个月或更短、12个月或更短、或6个月或更短。24. The method of any one of the preceding embodiments, wherein the treatment regimen using the apo mimetic (eg, L-4F) continues for about 36 months or less, 30 months or less, 24 months or less, 18 months or less, 12 months or less, or 6 months or less.
25.实施方案24的方法，其中使用所述apo模拟物(例如，L-4F)的所述治疗方案持续约6-12、12-18、18-24、24-30或30-36个月(例如，约6-12或12-24个月)。25. The method of embodiment 24, wherein the treatment regimen using the apo mimetic (eg, L-4F) continues for about 6-12, 12-18, 18-24, 24-30, or 30-36 months (eg, about 6-12 or 12-24 months).
26.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)至少在AMD的晚期(后期)阶段施用(例如，以治疗中央地图样萎缩[GA]和/或预防或防止新生血管性AMD，和/或治疗新生血管性AMD)。26. The method of any one of the preceding embodiments, wherein the apo mimic (for example, L-4F) is administered (for example, to treat central geographic atrophy [GA] and/or at least in the late (late) stage of AMD prevent or prevent neovascular AMD, and/or treat neovascular AMD).
27.实施方案26的方法，其中所述apo模拟物(例如，L-4F)在AMD后期每约4-8周或4-6周一次，以总共注射约8-12次或更多次注射、每次注射剂量至多约1-1.5mg、或整个治疗方案的总剂量至多约15-20mg，或其任何组合或全部，通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)而局部施用。27. The method of embodiment 26, wherein the apo mimetic (e.g., L-4F) is once every about 4-8 weeks or 4-6 weeks in late AMD for a total of about 8-12 or more injections , up to about 1-1.5 mg per injection, or up to about 15-20 mg in total for the entire treatment regimen, or any combination or all thereof, administered by injection (e.g., intravitreal, subconjunctival, subretinal, or Tenon's capsule) injection) for topical administration.
28.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)至少在AMD的中期阶段施用(例如，以治疗非中央GA和/或预防或防止中央GA和/或新生血管性AMD，或在中期AMD的初始阶段施用以预防或防止非中央GA)。28. The method of any one of the preceding embodiments, wherein the apo mimic (for example, L-4F) is used at least in the mid-stage of AMD (for example, to treat non-central GA and/or prevent or prevent central GA and/ or neovascular AMD, or administered in the initial stages of mid-stage AMD to prevent or prevent non-central GA).
29.实施方案28的方法，其中所述apo模拟物(例如，L-4F)在AMD中期以每约4-8周或4-6周一次、总共注射约8-12次或更多次、每次注射剂量至多约1-1.5mg、或整个治疗方案的总剂量至多约15-20mg，或其任何组合或全部通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)而局部施用。29. The method of embodiment 28, wherein the apo mimetic (e.g., L-4F) is injected every about 4-8 weeks or 4-6 weeks for a total of about 8-12 or more injections in mid-AMD. Dose up to about 1-1.5 mg per injection, or up to about 15-20 mg in total for the entire treatment regimen, or any combination or all by injection (eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule) ) for topical application.
30.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)至少在AMD的早期阶段施用(例如，以预防或防止非中央GA)。30. The method of any of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered at least in the early stages of AMD (eg, to prevent or prevent non-central GA).
31.实施方案30的方法，其中所述apo模拟物(例如，L-4F)在AMD早期以较低频率(例如，每约3、4或6个月注射一次)、较少注射总次数(例如，注射约1、2或3次)或较高每次注射剂量(例如，每次注射约0.5-1mg或1-1.5mg)，或其任何组合或全部通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)而局部施用。31. The method of embodiment 30, wherein the apo mimetic (e.g., L-4F) is early in AMD at a lower frequency (e.g., once every about 3, 4 or 6 months), less total number of injections ( For example, about 1, 2, or 3 injections) or a higher dose per injection (eg, about 0.5-1 mg or 1-1.5 mg per injection), or any combination or all by injection (eg, intravitreal, conjunctival injection) subretinal, subretinal, or subtenon's capsule) for topical administration.
32.前述实施方案中任一项的方法，其中AMD的阶段越晚或AMD病况越严重，则所述apo模拟物(例如，L-4F)更频繁地(其可导致更多的施用总次数)和/或以更高剂量(每次施用的更高剂量和/或更高的完整治疗方案的总剂量)而局部施用(例如，通过玻璃体内注射)。32. The method of any one of the preceding embodiments, wherein the stage of AMD is late or the AMD condition is more severe, then the apo mimic (for example, L-4F) is more frequently (it can cause more total number of applications) ) and/or administered locally (eg, by intravitreal injection) at higher doses (higher dose per administration and/or higher total dose of the complete regimen).
33.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)在固定常规方案、按需方案或治疗和延长方案中局部施用(例如，通过玻璃体内注射)。33. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered locally (eg, by intravitreal injection) in a fixed conventional regimen, an on-demand regimen, or a therapeutic and extended regimen.
34.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)通过组合物局部施用，其中相对于它们合计的量，所述组合物包含以重量计或摩尔浓度计约75-95％(例如，约90％)的apo模拟物和约5-25％(例如，约10％)相应的载脂蛋白(例如，apoA-I)或其活性部分或结构域。34. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered topically by a composition comprising a weight or molar concentration relative to their combined amounts About 75-95% (eg, about 90%) of the apo mimetic and about 5-25% (eg, about 10%) of the corresponding apolipoprotein (eg, apoA-I) or active portion or domain thereof are calculated.
35.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)以包含一种或多种赋形剂的组合物局部施用，所述赋形剂抑制肽/蛋白质聚集、增加肽/蛋白质溶解度、降低溶液粘度或增加肽/蛋白质稳定性，或其任何组合或全部。35. The method of any one of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered topically in a composition comprising one or more excipients that inhibit the peptide/protein Aggregation, increasing peptide/protein solubility, decreasing solution viscosity, or increasing peptide/protein stability, or any combination or all thereof.
36.前述实施方案中任一项的方法，其中所述apo模拟物(例如，L-4F)通过缓释组合物局部施用。36. The method of any of the preceding embodiments, wherein the apo mimetic (eg, L-4F) is administered topically by a sustained release composition.
37.前述实施方案中任一项的方法，所述方法进一步包括施用一种或多种额外的治疗剂。37. The method of any of the preceding embodiments, further comprising administering one or more additional therapeutic agents.
38.实施方案37的方法，其中所述一种或多种额外的治疗剂选自由以下组成的组：抗血脂异常剂、PPAR-α激动剂、PPAR-δ激动剂、PPAR-γ激动剂、抗淀粉样蛋白剂、脂褐素或其组分的抑制剂、抗氧化剂、神经保护剂(神经保护试剂)、细胞凋亡抑制剂、坏死抑制剂、C-反应蛋白(CRP)抑制剂、补体系统或其组分(例如蛋白质)的抑制剂、炎性体抑制剂、抗炎剂、免疫抑制剂、基质金属蛋白酶(MMP)的调节剂、抗血管生成剂和RPE细胞替代疗法。38. The method of embodiment 37, wherein the one or more additional therapeutic agents are selected from the group consisting of anti-dyslipidemic agents, PPAR-alpha agonists, PPAR-delta agonists, PPAR-gamma agonists, Anti-amyloid agents, inhibitors of lipofuscin or components thereof, antioxidants, neuroprotective agents (neuroprotective agents), apoptosis inhibitors, necrosis inhibitors, C-reactive protein (CRP) inhibitors, complement Inhibitors of the system or components thereof (eg, proteins), inflammasome inhibitors, anti-inflammatory agents, immunosuppressants, modulators of matrix metalloproteinases (MMPs), anti-angiogenic agents, and RPE cell replacement therapy.
39.一种预防年龄相关性黄斑变性(AMD)、延迟AMD发作、减缓AMD进展或减轻与AMD相关的视力损害或丧失的程度的方法，包括向需要治疗的对象施用治疗有效量的实施方案1-38中任一个的载脂蛋白(apo)模拟物。39. A method of preventing age-related macular degeneration (AMD), delaying the onset of AMD, slowing the progression of AMD or reducing the degree of visual impairment or loss associated with AMD, comprising administering a therapeutically effective amount of Embodiment 1 to an object in need of treatment - An apolipoprotein (apo) mimetic of any of 38.
40.实施方案39的方法，其中所述AMD是萎缩性AMD(包括非中央和/或中央地图样萎缩)或新生血管性AMD(包括1、2和/或3型新生血管形成)。40. The method of embodiment 39, wherein the AMD is atrophic AMD (including non-central and/or central geographic atrophy) or neovascular AMD (including type 1, 2 and/or 3 neovascularization).
41.一种治疗年龄相关性黄斑变性(AMD)的方法，包括向需要治疗的对象施用治疗有效量的根据实施方案1至38中任一项的载脂蛋白(apo)模拟物和治疗有效量的抗血管生成剂。41. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of antiangiogenic agents.
42.实施方案41的方法，其中所述apo模拟物包含apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)，或是apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)。42. The method of embodiment 41, wherein the apo mimetic comprises an apoA-I mimetic (e.g. L-4F or D-4F) and/or an apoE mimetic (e.g. AEM-28-14), or apoA-I mimetics (eg L-4F or D-4F) and/or apoE mimetics (eg AEM-28-14).
43.实施方案41或42的方法，其中所述抗血管生成剂包含以下或者是以下：抑制血管内皮生长因子作用的物质(抗VEGF剂)和/或抑制血小板衍生生长因子作用的物质(抗PDGF剂)。43. The method of embodiment 41 or 42, wherein the anti-angiogenic agent comprises or is the following: a substance that inhibits the action of vascular endothelial growth factor (anti-VEGF agent) and/or a substance that inhibits the action of platelet-derived growth factor (anti-PDGF). agent).
44.实施方案43的方法，其中所述抗VEGF剂选自由以下组成的组：角鲨胺、PAN-90806、抗VEGF抗体及其片段(例如贝伐单抗雷珠单抗ESBA1008和ESBA903)、抗VEGF适体(例如，哌加他尼(pegaptanib))、抗VEGF设计的锚蛋白重复蛋白(DARPins)(例如，培阿比西帕(abiciparpegol))、VEGF的可溶性受体(例如VEGFR1)、含有一种或多种VEGFR的一个或多个细胞外结构域的可溶性融合蛋白(例如，阿柏西普和康柏西普)，及其组合。44. The method of embodiment 43, wherein the anti-VEGF agent is selected from the group consisting of squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (eg, bevacizumab ranibizumab ESBA1008 and ESBA903), anti-VEGF aptamers (eg, pegaptanib) ), anti-VEGF designed ankyrin repeat proteins (DARPins) (eg, abiciparpegol), soluble receptors for VEGF (eg, VEGFR1), one or more extracellular receptors containing one or more VEGFRs Soluble fusion proteins of the domains (e.g., aflibercept and Compercept), and combinations thereof.
45.实施方案44的方法，其中所述抗VEGF剂包含以下或者是以下：阿柏西普、贝伐单抗或雷珠单抗，或其任何组合或全部。45. The method of embodiment 44, wherein the anti-VEGF agent comprises or is the following: aflibercept, bevacizumab, or ranibizumab, or any combination or all thereof.
46.实施方案41至45中任一项的方法，其中所述抗血管生成剂(例如，抗VEGF剂)以低于常规或推荐给药频率的频率施用，和/或以低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用所述apo模拟物(例如L-4F)治疗的情况下的所述抗血管生成剂的。46. The method of any one of embodiments 41 to 45, wherein the anti-angiogenic agent (eg, an anti-VEGF agent) is administered less frequently than conventional or recommended dosing, and/or less frequently than conventional or recommended Dosages are administered, the usual or recommended dosing frequency or the usual or recommended dose for the anti-angiogenic agent in the absence of treatment with the apo mimetic (eg, L-4F).
47.实施方案46的方法，其中相比于所述抗血管生成剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用所述apo模拟物(例如L-4F)治疗的情况下的，所述抗血管生成剂(例如，抗VEGF剂)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。47. The method of embodiment 46, wherein the conventional or recommended dosing frequency is for in the absence of the apo mimetic (eg L-4F) compared to the conventional or recommended dosing frequency of the anti-angiogenic agent In the case of therapy, the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold less frequently, or 6 times (eg, at least about 2 times).
48.实施方案46或47的方法，其中相比于所述抗血管生成剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用所述apo模拟物(例如L-4F)治疗的情况下的，所述抗血管生成剂(例如，抗VEGF剂)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约10-30％、30-50％或50-70％的剂量施用(例如，通过玻璃体内注射)。48. The method of embodiment 46 or 47, wherein the conventional or recommended dose is compared to the conventional or recommended dose of the anti-angiogenic agent in the absence of treatment with the apo mimetic (eg L-4F). In some cases, the anti-angiogenic agent (eg, anti-VEGF agent) is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% less (eg, at least about about 20%), or about 10-30%, 30-50%, or 50-70% of the dose (eg, by intravitreal injection).
49.实施方案46至48中任一项的方法，其中用所述apo模拟物(例如，L-4F)的治疗减少施用所述抗血管生成剂(例如，抗VEGF剂)的总次数(例如，注射的总次数)。49. The method of any one of embodiments 46 to 48, wherein treatment with the apo mimetic (eg, L-4F) reduces the total number of administrations (eg, the anti-VEGF agent) of the anti-angiogenic agent (eg, anti-VEGF agent) , the total number of injections).
50.实施方案49的方法，其中所述抗血管生成剂(例如，抗VEGF剂)施用(例如，通过玻璃体内注射)不超过约20、18、15、12或10次。50. The method of embodiment 49, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.
51.实施方案46至50中任一项的方法，其中用所述apo模拟物(例如L-4F)和所述抗血管生成剂(例如抗VEGF剂)的治疗具有协同作用。51. The method of any one of embodiments 46 to 50, wherein treatment with the apo mimetic (eg, L-4F) and the anti-angiogenic agent (eg, anti-VEGF agent) is synergistic.
52.实施方案46至51中任一项的方法，其中：52. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含阿柏西普或是阿柏西普和The anti-angiogenic agent comprises aflibercept or aflibercept and
相比于阿柏西普的常规或推荐剂量和给药频率为治疗前3个月以2mg每月施用一次之后以2mg每2个月玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用所述apo模拟物(例如，L-4F)治疗的情况下的，阿柏西普以约1-1.5mg或1.5-2mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约1-1.5mg或1.5-2mg的剂量每月施用一次之后，或者在前1.5或3个月以约1-1.5mg或1.5-2mg的剂量每6周施用一次之后，阿柏西普以约1-1.5mg或1.5-2mg的剂量每3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。Compared to the usual or recommended dose and dosing frequency of aflibercept of 2 mg administered once monthly for the first 3 months of treatment followed by 2 mg administered as an intravitreal injection every 2 months The frequency is for the absence of treatment with the apo mimetic (eg, L-4F), aflibercept at a dose of about 1-1.5 mg or 1.5-2 mg every 3 months, 4 months, 5 Administration (eg, by intravitreal injection) once a month or 6 months, optionally following monthly administration at a dose of about 1-1.5 mg or 1.5-2 mg for the first 1, 2, or 3 months, Or aflibercept at a dose of about 1-1.5 mg or 1.5-2 mg every 3 months, 4 Administration (eg, by intravitreal injection) once a month, 5 months, or 6 months.
53.实施方案46至51中任一项的方法，其中：53. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含阿柏西普，或者是阿柏西普；以及The anti-angiogenic agent comprises aflibercept, or is aflibercept; and
在以与阿柏西普的常规或推荐给药频率基本相似或相同的频率下，所述常规或推荐给药频率是对于没有用所述apo模拟物(例如，L-4F)治疗的情况下的，阿柏西普以约1-1.25mg、1.25-1.5mg或1.5-1.75mg的剂量施用(例如，通过玻璃体内注射)。at substantially similar or the same frequency as the conventional or recommended dosing frequency of aflibercept for the absence of treatment with the apo mimetic (eg, L-4F) Yes, aflibercept is administered (eg, by intravitreal injection) at a dose of about 1-1.25 mg, 1.25-1.5 mg, or 1.5-1.75 mg.
54.实施方案46至51中任一项的方法，其中：54. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含雷珠单抗或者是雷珠单抗并且The anti-angiogenic agent comprises ranibizumab or ranibizumab and
相比于雷珠单抗的常规或推荐剂量和给药频率为以0.5mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用所述apo模拟物(例如L-4F)治疗的情况下的，雷珠单抗以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地前1、2或3个月以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每个月施用一次之后，或者在前1.5或3个月以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每6周施用一次之后，雷珠单抗以约0.2-0.3mg、0.3-0.4mg或0.4-0.5mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。Compared to the usual or recommended dose and dosing frequency of ranibizumab of 0.5 mg administered once a month by intravitreal injection, the usual or recommended dose and dosing frequency are for those without the apo mimetic (e.g. L-4F) treatment, ranibizumab at a dose of about 0.2-0.3 mg, 0.3-0.4 mg, or 0.4-0.5 mg every 2, 3, 4, 5, or 6 months Monthly administration (eg, by intravitreal injection), optionally followed by monthly administration at a dose of about 0.2-0.3 mg, 0.3-0.4 mg, or 0.4-0.5 mg for the first 1, 2, or 3 months, or Ranibizumab is administered at a dose of about 0.2-0.3 mg, 0.3-0.4 mg, or 0.4-0.5 mg every 6 weeks for the first 1.5 or 3 months. A dose of 0.5 mg is administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months.
55.实施方案46至51中任一项的方法，其中：55. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含雷珠单抗或者是雷珠单抗；以及The anti-angiogenic agent comprises or is ranibizumab; and
雷珠单抗以约0.2-0.3mg或0.3-0.4mg的剂量每月施用(例如，通过玻璃体内注射一次)。Ranibizumab is administered monthly (eg, once by intravitreal injection) at a dose of about 0.2-0.3 mg or 0.3-0.4 mg.
56.实施方案46至51中任一项的方法，其中：56. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含贝伐单抗或是贝伐单抗The anti-angiogenic agent comprises bevacizumab or bevacizumab
相比于贝伐单抗用于治疗AMD的常规或推荐剂量和给药频率为以约1.25mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用所述apo模拟物(例如，L-4F)治疗的情况下的，贝伐单抗以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1、2或3个月以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每个月施用一次之后或在前一个1.5或3个月以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每6周施用一次之后，贝伐单抗以约0.5-0.75mg、0.75-1mg或1-1.25mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。Compared to the usual or recommended dose and frequency of administration of bevacizumab for the treatment of AMD of approximately 1.25 mg administered by intravitreal injection once a month, the usual or recommended dose and frequency of administration are In the case of apo mimetic (eg, L-4F) therapy, bevacizumab is administered at a dose of about 0.5-0.75 mg, 0.75-1 mg, or 1-1.25 mg every 2, 3, 4, Administer (eg, by intravitreal injection) once every 5 or 6 months, optionally monthly for the first 1, 2, or 3 months at a dose of about 0.5-0.75 mg, 0.75-1 mg, or 1-1.25 mg Bevacizumab is administered at a dose of about 0.5-0.75 mg, 0.75-1 mg, 0.75-1 mg every 6 weeks after one administration or every 6 weeks for the previous 1.5 or 3 months Or doses of 1-1.25 mg are administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months.
57.实施方案46至51中任一项的方法，其中：57. The method of any one of embodiments 46 to 51, wherein:
所述抗血管生成剂包含贝伐单抗或是贝伐单抗；以及The anti-angiogenic agent comprises bevacizumab or bevacizumab; and
贝伐单抗以约0.5-0.75mg或0.75-1mg的剂量每月施用(例如，通过玻璃体内注射)一次。Bevacizumab is administered (eg, by intravitreal injection) once a month at a dose of about 0.5-0.75 mg or 0.75-1 mg.
58.实施方案46至51中任一项的方法，其中所述抗血管生成剂(例如，抗VEGF剂)每2、3、4、5或6个月施用(例如，通过玻璃体内注射)一次。58. The method of any one of embodiments 46 to 51, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months .
59.实施方案41至58中任一项的方法，其中所述抗血管生成剂(例如，抗VEGF剂)施用于眼局部、眼内、眼中或眼周，例如通过注射(例如，玻璃体内注射、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如玻璃体内、房水内、视网膜下或特农氏囊下植入物)。59. The method of any one of embodiments 41 to 58, wherein the anti-angiogenic agent (eg, an anti-VEGF agent) is administered topically, intraocularly, in the eye, or around the eye, eg, by injection (eg, intravitreal injection) , subconjunctival, subretinal, or subtenon's capsule), eye drops, or implants (eg, intravitreal, intra-aqueous, subretinal, or subtenon's capsule).
60.实施方案41至59中任一项的方法，其中施用所述抗血管生成剂(例如，抗VEGF剂)以治疗或减缓新生血管性(湿性)AMD的进展，所述新生血管性(湿性)AMD包括1、2和3型新生血管形成。60. The method of any one of embodiments 41 to 59, wherein the anti-angiogenic agent (eg, an anti-VEGF agent) is administered to treat or slow the progression of neovascular (wet) AMD, the neovascular (wet) ) AMD includes type 1, 2 and 3 neovascularization.
61.实施方案41至60中任一项的方法，其中所述抗血管生成剂(例如，抗VEGF剂)至少在AMD的晚期(后期)阶段施用以预防新生血管性AMD、延迟新生血管性AMD的发作、或减缓新生血管性AMD的进展。61. The method of any one of embodiments 41 to 60, wherein the anti-angiogenic agent (eg, an anti-VEGF agent) is administered at least in the late (late) stage of AMD to prevent neovascular AMD, delay neovascular AMD onset, or slow the progression of neovascular AMD.
62.实施方案41至61中任一项的方法，其中所述apo模拟物(例如，L-4F)至少在AMD的晚期阶段施用。62. The method of any one of embodiments 41 to 61, wherein the apo mimetic (eg, L-4F) is administered at least in an advanced stage of AMD.
63.实施方案62的方法，其中施用所述apo模拟物(例如，L-4F)以治疗中央地图样萎缩，和/或预防新生血管性AMD、延迟新生血管性AMD的发作或减缓新生血管性AMD的进展，所述新生血管性AMD包括1、2和3型新生血管形成。63. The method of embodiment 62, wherein the apo mimic (for example, L-4F) is used to treat central geographic atrophy, and/or to prevent neovascular AMD, delay the onset of neovascular AMD or slow down neovascularization. Progression of AMD, which includes neovascularization of types 1, 2 and 3.
64.实施方案41至63中任一项的方法，其中所述抗血管生成剂(例如，抗VEGF剂)在固定常规方案、按需方案或治疗和延长方案中施用。64. The method of any one of embodiments 41 to 63, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered on a fixed conventional regimen, an on-demand regimen, or a therapeutic and extended regimen.
65.实施方案41至64中任一项的方法，其中所述apo模拟物(例如L-4F)和所述抗血管生成剂(例如抗VEGF剂)在分开的组合物中施用。65. The method of any one of embodiments 41 to 64, wherein the apo mimetic (eg, L-4F) and the anti-angiogenic agent (eg, anti-VEGF agent) are administered in separate compositions.
66.实施方案41至64中任一项的方法，其中所述apo模拟物(例如L-4F)和所述抗血管生成剂(例如抗VEGF剂)在同一组合物中施用。66. The method of any one of embodiments 41 to 64, wherein the apo mimetic (eg, L-4F) and the anti-angiogenic agent (eg, anti-VEGF agent) are administered in the same composition.
67.治疗年龄相关性黄斑变性(AMD)的方法，包括向需要治疗的对象施用治疗有效量的根据实施方案1至38中任一项的载脂蛋白(apo)模拟物和治疗有效量的补体抑制剂。67. A method of treating age-related macular degeneration (AMD) comprising administering to a subject in need of treatment a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of complement inhibitor.
68.实施方案67的方法，其中所述apo模拟物包含apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)，或是apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)。68. The method of embodiment 67, wherein the apo mimetic comprises an apoA-I mimetic (e.g. L-4F or D-4F) and/or an apoE mimetic (e.g. AEM-28-14), or apoA-I mimetics (eg L-4F or D-4F) and/or apoE mimetics (eg AEM-28-14).
69.实施方案67或68的方法，其中施用所述apo模拟物(例如，L-4F)和所述补体抑制剂以治疗地图样萎缩(GA)。69. The method of embodiment 67 or 68, wherein the apo mimetic (eg, L-4F) and the complement inhibitor are administered to treat geographic atrophy (GA).
70.实施方案69的方法，其中施用所述apo模拟物(例如，L-4F)和所述补体抑制剂以预防中央GA和/或非中央GA、延迟中央GA和/或非中央GA的发作、或减缓中央GA和/或非中央GA的进展。70. The method of embodiment 69, wherein the apo mimetic (eg, L-4F) and the complement inhibitor are administered to prevent central GA and/or non-central GA, delay the onset of central GA and/or non-central GA , or slow the progression of central GA and/or non-central GA.
71.实施方案69或70的方法，其中所述apo模拟物(例如，L-4F)和所述补体抑制剂至少在萎缩性(干性)AMD的晚期(后期)阶段施用以治疗中央GA或减缓中央GA的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。71. The method of embodiment 69 or 70, wherein the apo mimic (for example, L-4F) and the complement inhibitor are administered at least in the late (late) stage of atrophic (dry) AMD to treat central GA or Slow the progression of central GA, and/or prevent neovascular AMD or delay the onset of neovascular AMD.
72.实施方案69至71中任一项的方法，其中至少在AMD的中期阶段施用所述apo模拟物(例如，L-4F)和所述补体抑制剂以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。72. The method of any one of embodiments 69 to 71, wherein the apo mimetic (for example, L-4F) and the complement inhibitor are administered at least in the mid-stage of AMD to treat non-central GA or slow non-central GA progression, and/or prevent central GA and/or neovascular AMD or delay the onset of central GA and/or neovascular AMD.
73.实施方案69至72中任一项的方法，其中至少在AMD的早期阶段或中期AMD的初始阶段施用所述apo模拟物(例如，L-4F)和所述补体抑制剂以预防非中央GA或延迟非中央GA的发作。73. The method of any one of embodiments 69 to 72, wherein at least the apo mimic (for example, L-4F) and the complement inhibitor are used at least in the early stage of AMD or the initial stage of mid-stage AMD to prevent non-central GA or delayed onset of noncentral GA.
74.实施方案67至73中任一项的方法，其中所述补体抑制剂选自由以下组成的组：抗补体因子B(CFB)抗体及其片段(例如TA106)、抗CFD抗体及其片段(例如，兰波利珠单抗)、C3抑制剂(例如，C3补体抑制素及其衍生物[例如，POT-4]、霉酚酸-葡糖胺缀合物和其蛋白质或片段的可溶形式[例如，CR1、衰变加速因子和膜辅因子蛋白])、抗C3b/iC3b抗体及其片段(例如，3E7)、抗C5抗体及其片段(例如，依库珠单抗和LFG316)、抗C5适体(例如，ARC1905)、其他C5抑制剂(例如，Coversin)、C5a受体拮抗剂(例如，JPE-1375、JSM-7717、PMX-025、PMX-53和抗-C5aR抗体及其片段[例如，努哲单抗])、替代补体途径的抑制剂(例如，sCR1、TT30和锌)、经典补体途径的抑制剂(例如，sCR1)、凝集素补体途径的抑制剂(例如，甘露糖相关丝氨酸蛋白酶[MASP]的抑制剂，例如抗MASP抗体及其片段[例如，OMS721])、膜攻击复合物(MAC)形成的抑制剂(例如锌、CD59和具有糖脂锚的修饰的CD59)，及其类似物、衍生物、片段、盐和组合。74. The method of any one of embodiments 67 to 73, wherein the complement inhibitor is selected from the group consisting of: anti-complement factor B (CFB) antibodies and fragments thereof (eg TA106), anti-CFD antibodies and fragments thereof ( For example, lambolizumab), C3 inhibitors (eg, C3 compstatin and its derivatives [eg, POT-4], mycophenolic acid-glucosamine conjugates, and soluble soluble proteins or fragments thereof forms [eg, CR1, decay accelerating factor and membrane cofactor proteins]), anti-C3b/iC3b antibodies and fragments thereof (eg, 3E7), anti-C5 antibodies and fragments thereof (eg, eculizumab and LFG316), anti- C5 aptamer (eg, ARC1905 ), other C5 inhibitors (eg, Coversin), C5a receptor antagonists (eg, JPE-1375, JSM-7717, PMX-025, PMX-53, and anti-C5aR antibodies and fragments thereof [eg, nudezumab ]), inhibitors of the alternative complement pathway (eg, sCR1, TT30, and zinc), inhibitors of the classical complement pathway (eg, sCR1), inhibitors of the lectin complement pathway (eg, mannose-associated serine protease [MASP] Inhibitors, such as anti-MASP antibodies and fragments thereof [eg, OMS721]), inhibitors of membrane attack complex (MAC) formation (eg, zinc, CD59, and modified CD59 with glycolipid anchors), and analogs, derivatives thereof substances, fragments, salts and combinations.
75.实施方案74的方法，其中所述补体抑制剂包含以下或是以下：兰波利珠单抗、LFG316或ARC1905，或其任何组合或全部。75. The method of embodiment 74, wherein the complement inhibitor comprises the following or the following: lambolizumab, LFG316 or ARC1905, or any combination or all thereof.
76.实施方案75的方法，其中所述补体抑制剂包含兰波利珠单抗或是兰波利珠单抗。76. The method of embodiment 75, wherein the complement inhibitor comprises rambolizumab or rambolizumab.
77.实施方案76的方法，其中所述对象在编码补体因子I(CFI)的基因中具有突变。77. The method of embodiment 76, wherein the subject has a mutation in a gene encoding complement factor 1 (CFI).
78.实施方案67至77中任一项的方法，其中用所述apo模拟物(例如，L-4F)和所述补体抑制剂(例如，兰波利珠单抗)的治疗将中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)减缓至少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％或40％)、或约20-40％、40-60％或60-80％。78. The method of any one of embodiments 67 to 77, wherein treatment with the apo mimetic (eg, L-4F) and the complement inhibitor (eg, lambolizumab) alters central GA and and/or the progression of non-central GA (eg, reducing the rate of GA progression, or reducing the size or size of GA lesions) is slowed by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% ( For example, at least about 20% or 40%), or about 20-40%, 40-60%, or 60-80%.
79.实施方案67至78中任一项的方法，其中相比于没有用所述apo模拟物治疗而用所述补体抑制剂治疗的情况下，用所述apo模拟物(例如，L-4F)和所述补体抑制剂(例如，兰波利珠单抗)的治疗减缓中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)比其至少多约10％、20％、30％、50％、100％、150％、200％或300％(例如，至少约20％或30％)、或约10-30％、30-50％、50-100％、100-200％或200-300％(例如，约50-100％)。79. The method of any one of embodiments 67 to 78, wherein the apo mimetic (eg, L-4F is treated with the apo mimetic compared to treatment with the complement inhibitor without the apo mimetic treatment) ) and treatment with the complement inhibitor (eg, lambolizumab) slows the progression of central GA and/or non-central GA (eg, reduces the rate of GA progression, or reduces the area or size of GA lesions) at least more than about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (eg, at least about 20% or 30%), or about 10-30%, 30-50%, 50- 100%, 100-200%, or 200-300% (eg, about 50-100%).
80.实施方案67至79中任一项的方法，其中所述补体抑制剂(例如，兰波利珠单抗)以低于常规或者推荐的给药频率的频率和/或低于常规或推荐剂量的剂量施用，所述常规或推荐给药频率或剂量是对于没有用所述apo模拟物(例如L-4F)治疗的情况下的补体抑制剂的。80. The method of any one of embodiments 67 to 79, wherein the complement inhibitor (eg, lambolizumab) is administered at a frequency lower than conventional or recommended and/or lower than conventional or recommended Dosage is administered at the usual or recommended dosing frequency or dose for a complement inhibitor in the absence of treatment with the apo mimetic (eg, L-4F).
81.实施方案80的方法，其中相比于所述补体抑制剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用所述apo模拟物(例如L-4F)治疗的情况下的，所述补体抑制剂(例如，兰波利珠单抗)的施用(例如，通过玻璃体内注射)频率比其低至少约1.5倍、2倍、3倍、4倍、5倍或6倍(例如，至少约2倍)。81. The method of embodiment 80, wherein the conventional or recommended dosing frequency is for the absence of treatment with the apo mimetic (eg L-4F) compared to the conventional or recommended dosing frequency of the complement inhibitor. In cases where the complement inhibitor (eg, lambolizumab) is administered (eg, by intravitreal injection) at least about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold less frequently or 6 times (eg, at least about 2 times).
82.实施方案80或81的方法，其中相比于所述补体抑制剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用所述apo模拟物(例如，L-4F)治疗的情况下的，所述补体抑制剂(例如，兰波利珠单抗)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％)、或约10-30％、30-50％或50-70％的剂量施用(例如，通过玻璃体内注射)。82. The method of embodiment 80 or 81, wherein the conventional or recommended dose is compared to the conventional or recommended dose of the complement inhibitor for patients without treatment with the apo mimetic (eg, L-4F) In some cases, the complement inhibitor (eg, rambolizumab) is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% less (eg, , at least about 20%), or about 10-30%, 30-50%, or 50-70% of the dose (eg, by intravitreal injection).
83.实施方案80至82中任一项的方法，其中用所述apo模拟物(例如，L-4F)的治疗减少所述补体抑制剂(例如，兰波利珠单抗)施用的总次数(例如，注射的总次数)。83. The method of any one of embodiments 80 to 82, wherein treatment with the apo mimetic (eg, L-4F) reduces the total number of administrations of the complement inhibitor (eg, lambolizumab) (eg, the total number of injections).
84.实施方案83的方法，其中所述补体抑制剂(例如，兰波利珠单抗)施用(例如，通过玻璃体内注射)不超过约20、18、15、12或10次。84. The method of embodiment 83, wherein the complement inhibitor (eg, lambolizumab) is administered (eg, by intravitreal injection) no more than about 20, 18, 15, 12, or 10 times.
85.实施方案80至84中任一项的方法，其中用所述apo模拟物(例如L-4F)和所述补体抑制剂(例如兰波利珠单抗)的治疗具有协同作用。85. The method of any one of embodiments 80 to 84, wherein treatment with the apo mimetic (eg, L-4F) and the complement inhibitor (eg, lambolizumab) is synergistic.
86.实施方案80至85中任一项的方法，其中：86. The method of any one of embodiments 80 to 85, wherein:
补体抑制剂包含兰波利珠单抗或者是兰波利珠单抗；以及Complement inhibitors including rambolizumab or rambolizumab; and
相比于兰波利珠单抗的常规或推荐剂量和给药频率为以约10mg每月通过玻璃体内注射施用一次，所述常规或推荐剂量和给药频率是对于没有用所述apo模拟物(例如L-4F)治疗的情况下的，兰波利珠单抗以约4-6mg、6-8mg或8-10mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次，任选地在前1个月、2个月或3个月以约4-6mg、6-8mg或8-10mg的剂量每月施用一次之后，或在前1.5或3个月以约4-6mg、6-8mg或8-10mg的剂量每6周施用一次之后，兰波利珠单抗以约4-6mg、6-8mg或8-10mg的剂量每2个月、3个月、4个月、5个月或6个月施用(例如，通过玻璃体内注射)一次。Compared to the usual or recommended dose and dosing frequency of lambolizumab, which is administered at about 10 mg once a month by intravitreal injection, the usual or recommended dose and dosing frequency are for the absence of the apo mimetic. (eg L-4F) treatment, lambolizumab at a dose of about 4-6 mg, 6-8 mg or 8-10 mg every 2 months, 3 months, 4 months, 5 months or Administration (eg, by intravitreal injection) once every 6 months, optionally after monthly administration at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg for the first 1, 2, or 3 months , or after administration at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg every 6 weeks for the first 1.5 or 3 months, lambolizumab at a dose of about 4-6 mg, 6-8 mg, or 8-10 mg The doses of ® are administered (eg, by intravitreal injection) once every 2, 3, 4, 5, or 6 months.
87.实施方案80至85中任一项的方法，其中：87. The method of any one of embodiments 80 to 85, wherein:
所述补体抑制剂包含兰波利珠单抗或是兰波利珠单抗；以及The complement inhibitor comprises rambolizumab or rambolizumab; and
兰波利珠单抗以约3-5mg、5-7mg或7-9mg的剂量每月(4周)或1.5个月(6周)施用(例如，通过玻璃体内注射)一次。Lambolizumab is administered (eg, by intravitreal injection) once a month (4 weeks) or 1.5 months (6 weeks) at a dose of about 3-5 mg, 5-7 mg, or 7-9 mg.
88.实施方案80至86中任一项的方法，其中所述补体抑制剂(例如，兰波利珠单抗)每2、3、4、5或6个月(例如，每2个月)施用(例如，通过玻璃体内注射)一次。88. The method of any one of embodiments 80 to 86, wherein the complement inhibitor (eg, lambolizumab) every 2, 3, 4, 5 or 6 months (eg, every 2 months) Administration (eg, by intravitreal injection) once.
89.实施方案67-88中任一项的方法，其中所述补体抑制剂(例如，兰波利珠单抗)施用于眼局部、眼内、眼中或眼周，例如通过注射(例如，玻璃体内、结膜下、视网膜下或特农氏囊下注射)、滴眼剂或植入物(例如玻璃体内、结膜下、视网膜下或特农氏囊下植入物)。89. The method of any one of embodiments 67-88, wherein the complement inhibitor (eg, lambolizumab) is administered topically, intraocularly, in the eye, or around the eye, eg, by injection (eg, vitreous intravitreal, subconjunctival, subretinal or subtenon's capsule injection), eye drops or implants (eg intravitreal, subconjunctival, subretinal or subtenon's capsule implants).
90.实施方案67-89中任一项的方法，其中所述apo模拟物(例如L-4F)和所述补体抑制剂(例如兰波利珠单抗)在分开的组合物中施用。90. The method of any one of embodiments 67-89, wherein the apo mimetic (eg, L-4F) and the complement inhibitor (eg, lambolizumab) are administered in separate compositions.
91.实施方案67-89中任一项的方法，其中所述apo模拟物(例如L-4F)和所述补体抑制剂(例如，兰波利珠单抗)在同一组合物中施用。91. The method of any one of embodiments 67-89, wherein the apo mimetic (eg, L-4F) and the complement inhibitor (eg, lambolizumab) are administered in the same composition.
92.实施方案67至91中任一项的方法，其中至少在AMD的晚期阶段施用所述apo模拟物(例如，L-4F)和所述补体抑制剂以预防新生血管性AMD、延迟新生血管性AMD的发作或减缓新生血管性AMD的进展，所述新生血管性AMD包括1、2和3型新生血管形成。92. The method of any one of embodiments 67 to 91, wherein the apo mimic (for example, L-4F) and the complement inhibitor are used at least in the late stage of AMD to prevent neovascular AMD, delay neovascularization The onset of or slowing the progression of neovascular AMD, which includes type 1, 2 and 3 neovascularization.
93.实施方案92的方法，所述方法进一步包括施用治疗有效量的抗血管生成剂。93. The method of embodiment 92, further comprising administering a therapeutically effective amount of an anti-angiogenic agent.
94.实施方案93的方法，其中所述抗血管生成剂包含以下或是以下：抗VEGF剂(例如，阿比普西普贝伐单抗或雷珠单抗或其任何组合或全部)和/或抗PDGF剂(例如，E10030)。94. The method of embodiment 93, wherein the anti-angiogenic agent comprises or is the following: an anti-VEGF agent (eg, abilipercept Bevacizumab or ranibizumab or any combination or all thereof) and/or an anti-PDGF agent (e.g., E10030 ).
95.实施方案92至94中任一项的方法，其中所述补体抑制剂包含ARC1905或LFG316，或是ARC1905或LFG316。95. The method of any one of embodiments 92 to 94, wherein the complement inhibitor comprises ARC1905 or LFG316, or ARC1905 or LFG316.
96.实施方案67至95中任一项的方法，其中所述补体抑制剂(例如，兰波利珠单抗、ARC1905或LFG316，或其任何组合或全部)在固定常规方案、按需方案或治疗和延长方案中施用。96. The method of any one of embodiments 67 to 95, wherein the complement inhibitor (eg, lambolizumab, ARC1905, or LFG316, or any combination or all thereof) is in a fixed conventional regimen, an on-demand regimen, or Administered in therapeutic and extended regimens.
97.治疗年龄相关性黄斑变性(AMD)的方法，包括向需要治疗的对象施用治疗有效量的根据实施方案1至38中任一项的载脂蛋白(apo)模拟物和治疗有效量的抗氧化剂。97. A method of treating age-related macular degeneration (AMD), comprising administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic according to any one of embodiments 1 to 38 and a therapeutically effective amount of an anti-lipoprotein (apo) mimetic. oxidizing agent.
98.实施方案97的方法，其中所述apo模拟物包含apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)，或是apoA-I模拟物(例如L-4F或D-4F)和/或apoE模拟物(例如AEM-28-14)。98. The method of embodiment 97, wherein the apo mimetic comprises an apoA-I mimetic (e.g. L-4F or D-4F) and/or an apoE mimetic (e.g. AEM-28-14), or apoA-I mimetics (eg L-4F or D-4F) and/or apoE mimetics (eg AEM-28-14).
99.实施方案97或98的方法，其中所述抗氧化剂选自花青素、苯二酚松香烷二萜(例如鼠尾草酸)、肌肽、类胡萝卜素(例如胡萝卜素[例如β-胡萝卜素]、叶黄素类[例如叶黄素、玉米黄质和内消旋玉米黄质]、以及藏红花中的类胡萝卜素[例如，藏红花素和藏红花酸])、类姜黄素(例如姜黄素)、环戊烯酮前列腺素(例如15d-PGJ2)、类黄酮(例如银杏叶中的类黄酮[例如，杨梅素和槲皮素])、异戊二烯类黄酮(如异黄腐醇)、类视黄醇、芪类(如白藜芦醇)、尿酸、维生素A、维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸)、维生素B6(例如，吡哆醛、吡哆胺、4-吡哆酸和吡哆醇)、维生素B9(叶酸)、维生素B12(钴胺素)、维生素C、维生素E(例如，生育酚和生育三烯酚)、硒、锌(例如，锌单半胱氨酸)、脂质过氧化及其副产物的抑制剂和清除剂(例如，维生素E[例如，α-生育酚]、替拉扎特、NXY-059和XJB-5-131)、核因子(红细胞衍生的2)样2(NFE2L2或NRF2)的活化剂(例如OT-551)、超氧化物歧化酶(SOD)模拟物(例如，OT-551)，及其类似物、衍生物、盐和组合。99. The method of embodiment 97 or 98, wherein the antioxidant is selected from the group consisting of anthocyanins, quinol rosinane diterpenes (eg carnosic acid), carnosine, carotenoids (eg carotene [eg beta-carotene] ], luteins [eg, lutein, zeaxanthin, and meso-zeaxanthin], and carotenoids in saffron [eg, crocin and saffron acid]), curcuminoids (eg, curcumin) , cyclopentenone prostaglandins (eg, 15d-PGJ2 ), flavonoids (eg, those in ginkgo biloba [eg, myricetin and quercetin]), isoprene flavonoids (eg, isoflavol) , retinoids, stilbenes (such as resveratrol), uric acid, vitaminA , vitamin B1 (thiamine), vitamin B2( riboflavin), vitaminB3 (niacin), vitaminB6 (eg, pyridoxal, pyridoxamine,4 -pyridoxine, and pyridoxine), vitaminB9 (folic acid), vitamin B12 (cobalamin), vitamin C, vitamin E (eg, tocopherol and tocopherol) Trienol), selenium, zinc (eg, zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its by-products (eg, vitamin E [eg, alpha-tocopherol], tirapaz , NXY-059 and XJB-5-131), activators of nuclear factor (erythrocyte-derived 2)-like 2 (NFE2L2 or NRF2) (e.g. OT-551), superoxide dismutase (SOD) mimetics (e.g. , OT-551), and analogs, derivatives, salts and combinations thereof.
100.实施方案99的方法，其中所述抗氧化剂包含一种或多种维生素(例如，维生素B6、维生素C和维生素E)，一种或多种类胡萝卜素(例如，叶黄素类[例如，叶黄素、玉米黄质和内消旋玉米黄质]和藏红花中的类胡萝卜素[例如，藏红花素和藏红花酸])，或锌，或其任何组合或全部，例如AREDS或AREDS2制剂、制剂、制剂或Saffron 2020TM。100. The method of embodiment 99, wherein the antioxidant comprises one or more vitamins (eg, vitaminB6 , vitamin C, and vitamin E), one or more carotenoids (eg, lutein [eg, , lutein, zeaxanthin and meso-zeaxanthin] and carotenoids in saffron [e.g., crocin and saffron acid]), or zinc, or any combination or all thereof, such as AREDS or AREDS2 formulations, preparation, formulation or Saffron 2020™ .
101.实施方案97至100中任一项的方法，其中所述抗氧化剂(例如，维生素和/或类胡萝卜素)以低于常规或推荐剂量的剂量施用，和/或以低于常规或推荐给药频率的频率施用，所述常规或推荐给药频率或常规或推荐剂量是对于没有用所述apo模拟物(例如L-4F)治疗的情况下的抗氧化剂的。101. The method of any one of embodiments 97 to 100, wherein the antioxidant (eg, vitamins and/or carotenoids) is administered at a dose lower than conventional or recommended doses, and/or at a lower dose than conventional or recommended Administration at the frequency of dosing, the usual or recommended dosing frequency or the usual or recommended dose for the antioxidant in the absence of treatment with the apo mimetic (eg L-4F).
102.实施方案101的方法，其中相比于所述抗氧化剂的常规或推荐剂量，所述常规或推荐剂量是对于在没有用所述apo模拟物(例如，L-4F)治疗的情况下的，所述抗氧化剂(例如，维生素和/或类胡萝卜素)以至少比其少约10％、20％、30％、40％、50％、60％、70％或80％(例如，在至少约20％)、或约10-30％、30-50％或50-70％的剂量施用。102. The method of embodiment 101, wherein the conventional or recommended dose is for in the absence of treatment with the apo mimetic (eg, L-4F) compared to the conventional or recommended dose of the antioxidant , the antioxidants (eg, vitamins and/or carotenoids) are at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% less (eg, at least about 20%), or about 10-30%, 30-50%, or 50-70% of the dose.
103.实施方案101或102的方法，其中相比于所述抗氧化剂的常规或推荐给药频率，所述常规或推荐给药频率是对于在没有用所述apo模拟物(例如L-4F)治疗的情况下的，所述抗氧化剂(例如，维生素和/或类胡萝卜素)的施用(例如，通过玻璃体内注射)频率比其低至少约2、3、5、7或10倍(例如，至少约2倍)。103. The method of embodiment 101 or 102, wherein the usual or recommended dosing frequency of the antioxidant is compared to the usual or recommended dosing frequency of the antioxidant in the absence of the apo mimetic (eg L-4F) In the case of therapy, the antioxidant (eg, vitamin and/or carotenoid) is administered (eg, by intravitreal injection) at least about 2, 3, 5, 7, or 10 times less frequently than it is (eg, at least about 2 times).
104.实施方案103的方法，其中相比于所述抗氧化剂的常规或推荐给药频率为每天至少一次，所述常规或推荐给药频率是对于在没有用所述apo模拟物(例如，L-4F)治疗的情况下的，所述抗氧化剂(例如，维生素和/或类胡萝卜素)每两天或三天施用一次。104. The method of embodiment 103, wherein the usual or recommended frequency of dosing is at least once a day compared to the usual or recommended frequency of dosing of the antioxidant in the absence of the apo mimetic (eg, L -4F) treatment, the antioxidant (eg, vitamins and/or carotenoids) is administered every two or three days.
105.实施方案97至104中任一项的方法，其中所述apo模拟物(例如，L-4F)和所述抗氧化剂(例如，维生素和/或类胡萝卜素)至少在AMD的晚期(后期)阶段施用以治疗中央地图样萎缩(GA)和/或新生血管性AMD(包括1、2和3型NV)或减缓中央地图样萎缩(GA)和/或新生血管性AMD(包括1、2和3型NV)的进展，和/或预防新生血管性AMD或延迟新生血管性AMD的发作。105. The method of any one of embodiments 97 to 104, wherein the apo mimic (for example, L-4F) and the antioxidant (for example, vitamins and/or carotenoids) are at least in the late stage of AMD (late stage) ) phase administration to treat central geographic atrophy (GA) and/or neovascular AMD (including types 1, 2 and 3 NV) or to slow central geographic atrophy (GA) and/or neovascular AMD (including 1, 2 and type 3 NV), and/or prevent neovascular AMD or delay the onset of neovascular AMD.
106.实施方案97至105中任一项的方法，其中所述apo模拟物(例如，L-4F)和所述抗氧化剂(例如，维生素和/或类胡萝卜素)至少在AMD的中期阶段施用以治疗非中央GA或减缓非中央GA的进展，和/或预防中央GA和/或新生血管性AMD或延迟中央GA和/或新生血管性AMD的发作。106. The method of any one of embodiments 97 to 105, wherein the apo mimic (for example, L-4F) and the antioxidant (for example, vitamins and/or carotenoids) are administered at least in the mid-stage of AMD To treat or slow the progression of non-central GA, and/or prevent central GA and/or neovascular AMD or delay the onset of central GA and/or neovascular AMD.
107.实施方案97至106中任一项的方法，其中所述apo模拟物(例如，L-4F)和所述抗氧化剂(例如，维生素和/或类胡萝卜素)至少在AMD的早期阶段或中期AMD的初始阶段施用以预防非中央GA或延迟非中央GA的发作。107. The method of any one of embodiments 97 to 106, wherein the apo mimic (for example, L-4F) and the antioxidant (for example, a vitamin and/or a carotenoid) are at least in the early stages of AMD or Administration in the initial phase of mid-stage AMD to prevent or delay the onset of non-central GA.
108.实施方案97至107中任一项的方法，其中所述抗氧化剂(例如，维生素和/或类胡萝卜素)和任选的所述apo模拟物(例如，L-4F)至少在AMD的早期阶段施用。108. The method of any one of embodiments 97 to 107, wherein the antioxidant (for example, vitamins and/or carotenoids) and optionally the apo mimic (for example, L-4F) are at least in AMD's Early stage administration.
109.实施方案105至108中任一项的方法，其中用所述apo模拟物(例如，L-4F)和所述抗氧化剂(例如，维生素和/或类胡萝卜素)的治疗将中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)减缓至少约10％、20％、30％、40％、50％、60％、70％或80％(例如，至少约20％、或约20-40％、40-60％或60-80％)。109. The method of any one of embodiments 105 to 108, wherein treatment with the apo mimetic (eg, L-4F) and the antioxidant (eg, vitamins and/or carotenoids) treats central GA and and/or the progression of non-central GA (eg, reducing the rate of GA progression, or reducing the size or size of GA lesions) is slowed by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% ( For example, at least about 20%, or about 20-40%, 40-60%, or 60-80%).
110.实施方案105至109中任一项的方法，其中相比于没有用apo模拟物和抗氧化剂治疗，用所述apo模拟物(例如，L-4F)和所述抗氧化剂(例如，维生素和/或类胡萝卜素)的治疗减缓中央GA和/或非中央GA的进展(例如，降低GA进展速率，或减少GA病变面积或大小)比其至少多约10％、20％、30％、50％、100％、150％、200％或300％(例如，在至少约20％或30％)、或约10-30％、30-50％、50-100％、100-200％或200-300％(例如，约50-100％)。110. The method of any one of embodiments 105 to 109, wherein the apo mimetic (eg, L-4F) and the antioxidant (eg, vitamin A) are treated with the apo mimetic (eg, L-4F) compared to no treatment with the apo mimetic and the antioxidant. and/or carotenoids) slows the progression of central GA and/or non-central GA (eg, reduces the rate of GA progression, or reduces the area or size of GA lesions) by at least about 10%, 20%, 30%, 50%, 100%, 150%, 200%, or 300% (eg, at at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200%, or 200% -300% (eg, about 50-100%).
111.实施方案101-110中任一项的方法，其中用所述apo模拟物(例如L-4F)和所述抗氧化剂(例如维生素和/或类胡萝卜素)的治疗具有协同作用。111. The method of any one of embodiments 101-110, wherein treatment with the apo mimetic (eg, L-4F) and the antioxidant (eg, a vitamin and/or a carotenoid) is synergistic.
112.实施方案97-111中任一项的方法，其中所述抗氧化剂(例如，维生素和/或类胡萝卜素)经全身施用(例如，口服)或施用于眼局部、眼内、眼中或眼周(例如，通过注射[例如，玻璃体内，结膜下、视网膜下或特农氏囊下注射]、滴眼剂或植入物[例如玻璃体内、视网膜下或特农氏囊下植入物])。112. The method of any one of embodiments 97-111, wherein the antioxidant (eg, vitamins and/or carotenoids) is administered systemically (eg, orally) or administered topically, intraocularly, in the eye, or in the eye Weekly (eg, by injection [eg, intravitreal, subconjunctival, subretinal, or subtenon's capsule]), eye drops, or implant [eg, intravitreal, subretinal, or subtenon's capsule] ).
113.实施方案97-112中任一项的方法，其中所述apo模拟物(例如L-4F)和所述抗氧化剂(例如维生素和/或类胡萝卜素)在分开的组合物中施用。113. The method of any one of embodiments 97-112, wherein the apo mimetic (eg, L-4F) and the antioxidant (eg, vitamins and/or carotenoids) are administered in separate compositions.
114.实施方案97-112中任一项的方法，其中所述apo模拟物(例如L-4F)和所述抗氧化剂(例如维生素和/或类胡萝卜素)在同一组合物中施用。114. The method of any one of embodiments 97-112, wherein the apo mimetic (eg, L-4F) and the antioxidant (eg, vitamins and/or carotenoids) are administered in the same composition.
XIV.实施例XIV. Examples
以下实施例仅旨在说明本公开。可以可选地适当地使用其他测定、程序、方法、技术、条件和物质，并且可以进行其他研究。The following examples are only intended to illustrate the present disclosure. Other assays, procedures, methods, techniques, conditions and substances may optionally be used as appropriate, and other studies may be performed.
实施例1.通过L-4F减少老年猴中布鲁赫膜的脂质沉积物Example 1. Reduction of Bruch's membrane lipid deposits in aged monkeys by L-4F
根据公认的指南进行猕猴研究。9只患有自然发生的与年龄相关的黄斑病变(表现出与年龄相关的玻璃疣黄斑变化/类似人类早期AMD的黄斑病变)的雌性老年猕猴(Macacafascicularis，均超过20岁)在玻璃体内注射apoA-I模拟物L-4F(Ac-DWFKAFYDKVAEKFKEAF-NH2乙酸盐(SEQ.ID.NO.13))的无菌平衡盐溶液(BSS)(n＝7)，或安慰剂(具有相同的氨基酸但是以无功能的顺序的乱序的L-4F[sL-4F]的无菌BSS)(n＝2)。每只动物的一只眼睛接受6次每月注射50μL体积的相同逐步上升的剂量的L-4F或乱序的L-4F(总共625μg)。每只动物的第二只眼睛没有注射并只观察。注射的眼睛在起始时比每只动物未注射的眼睛表现出更差的玻璃疣变化。表1显示了猕猴研究中使用的给药方案。Macaque studies were conducted according to accepted guidelines. Intravitreal injection of apoA in 9 female aged macaques (Macacafascicularis, all over 20 years old) with naturally occurring age-related macular degeneration (exhibiting age-related drusen macular changes/macular degeneration resembling early AMD in humans) Sterile Balanced Salt Solution (BSS) (n=7) of the I mimetic L-4F (Ac-DWFKAFYDKVAEKFKEAF-NH2 acetate (SEQ. ID. NO. 13)), or placebo (with the same amino acids But sterile BSS of scrambled L-4F [sL-4F] in non-functional order) (n=2). One eye of each animal received 6 monthly injections of the same escalating dose of L-4F or scrambled L-4F (625 μg total) in a volume of 50 μL. The second eye of each animal was not injected and observed only. The injected eyes initially exhibited worse drusen changes than the uninjected eyes of each animal. Table 1 shows the dosing regimen used in the rhesus monkey study.
表1Table 1
进行临床实验室检查(包括血清学、血象和肝酶)，并也进行眼科检查(包括眼底照相术、光学相干断层扫描(OCT)、眼压测试和血液采样)。7个月后，处死所有动物并立即准备眼睛进行组织学检查。将油红O用于中性脂质并将非律平用于酯化的胆固醇来进行组织化学。针对补体因子D(CFD)和膜攻击复合物(MAC，C5b-9)进行免疫组织化学，两者都是替代补体途径活化的标志物。Clinical laboratory tests (including serology, hemogram, and liver enzymes) were performed, and ophthalmologic tests (including fundus photography, optical coherence tomography (OCT), intraocular pressure testing, and blood sampling) were also performed. After 7 months, all animals were sacrificed and eyes were immediately prepared for histological examination. Histochemistry was performed using Oil Red O for neutral lipids and Felippine for esterified cholesterol. Immunohistochemistry was performed for complement factor D (CFD) and membrane attack complex (MAC, C5b-9), both markers of alternative complement pathway activation.
对于用油红O(ORO)染色，将样品用0.3％油红O(Sigma-Aldrich Biochemie GmbH，Hamburg，德国)溶液(在99％异丙醇中)在室温(RT)下处理30分钟然后浸入60％异丙醇溶液中12分钟。用去离子水洗涤样品3分钟后，用苏木精(Carl Roth GmbH，Karlsruhe，德国)进行反染色。然后用封固溶液(来自Merck Millipore，Darmstadt，德国的Aquatex)封固样品，用玻璃盖玻片(Menzel-Graeser GmbH)覆盖，并使用用于生命科学的全自动倒置光显微镜(来自Leica Microsystems Wetzlar，德国的DMI 6000)检查。根据在每个眼睛的两个单独切片中在四个不同区域中评估的定性评估，对布鲁赫膜(BrM)的ORO染色(红色)的强度进行分级来进行图像分析，其中评分范围为0至4(每只眼睛的总共8个不同区域)。BrM和脉络膜的定性ORO染色评分：0＝无染色；1＝+；2＝++；3＝+++；4＝++++。For staining with Oil Red O (ORO), samples were treated with 0.3% Oil Red O (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) solution (in 99% isopropanol) for 30 minutes at room temperature (RT) and then immersed 60% isopropanol solution for 12 minutes. After washing the samples with deionized water for 3 minutes, counterstaining was performed with hematoxylin (Carl Roth GmbH, Karlsruhe, Germany). The samples were then mounted with mounting solution (Aquatex from Merck Millipore, Darmstadt, Germany), covered with glass coverslips (Menzel-Graeser GmbH) and using a fully automated inverted light microscope for life sciences (from Leica Microsystems Wetzlar , Germany's DMI 6000) check. Image analysis was performed by grading the intensity of Bruch's membrane (BrM) ORO staining (red) based on qualitative assessments assessed in four different regions in two separate sections from each eye, where the score ranged from 0 to 4 (total of 8 distinct areas per eye). Qualitative ORO staining scores for BrM and choroid: 0=no staining; 1=+; 2=++; 3=++++; 4=++++.
对于用非律平染色，将样品用去离子水洗涤一次5分钟，并然后用70％乙醇处理45分钟。用去离子水洗涤5分钟后，用在0.1M磷酸钾缓冲液(PPB，pH 7.4)中稀释的胆固醇酯酶(8.12单位/mL)在37℃处理样品3.5小时。然后将样品依次用PPB和磷酸盐缓冲盐水(PBS)两次洗涤3分钟，然后用冷(4℃)PBS洗涤过夜。然后用250pg/mL非律平(Sigma-AldrichBiochemie GmbH，Hamburg，德国)进行非律平染色，在N,N-二甲基甲酰胺(MerckMillipore，Darmstadt，德国)中稀释，在室温下用光屏蔽60分钟。然后用PBS和去离子水依次洗涤样品，用封固溶液(Carl Roth GmbH，Karlsruhe，Germany)封固，用玻璃盖玻片覆盖，并使用倒置荧光显微镜(来自Leica Microsystems,Wetzlar,德国的DMI 6000)检查。使用UV滤光器组(λex/λem＝350nm/455nm)观察非律平荧光。作为阴性对照，用PBS代替胆固醇酯酶，其阻止胆固醇从胆固醇酯中释放并随后通过非律平结合。在来自相同眼睛的三个不同载玻片(来自每只眼睛的总共9个不同区域)上进行BrM的三个独立区域处的非律平荧光强度的半定量分析。For staining with Felipe, the samples were washed once with deionized water for 5 minutes and then treated with 70% ethanol for 45 minutes. After washing with deionized water for 5 minutes, the samples were treated with cholesterol esterase (8.12 units/mL) diluted in 0.1M potassium phosphate buffer (PPB, pH 7.4) at 37°C for 3.5 hours. The samples were then washed sequentially twice with PPB and phosphate buffered saline (PBS) for 3 minutes and then with cold (4°C) PBS overnight. Felipin staining was then performed with 250 pg/mL filpine (Sigma-AldrichBiochemie GmbH, Hamburg, Germany), diluted in N,N-dimethylformamide (MerckMillipore, Darmstadt, Germany), and light shielded at room temperature 60 minutes. The samples were then washed sequentially with PBS and deionized water, followed by a mounting solution ( Carl Roth GmbH, Karlsruhe, Germany) was mounted, covered with a glass coverslip, and examined using an inverted fluorescence microscope (DMI 6000 from Leica Microsystems, Wetzlar, Germany). Non-planar fluorescence was observed using a UV filter set (λex/λem=350nm/455nm). As a negative control, PBS was used instead of cholesterol esterase, which prevents cholesterol release from cholesterol esters and subsequent binding by filpine. Semiquantitative analysis of non-rhythmic fluorescence intensities at three independent areas of BrM was performed on three different slides from the same eye (9 different areas in total from each eye).
除了使用对每种补体组分特异的单克隆抗体外，对膜攻击复合物(MAC，C5b-9)和补体因子D(CFD)的免疫组织化学进行相同的测定。用PBS中的10μg/mL蛋白酶K(Sigma-Aldrich Biochemie GmbH，Hamburg，德国)处理标本，用于在室温下恢复抗原30分钟。随后用山羊血清(5％山羊血清，0.3％Triton X-100的PBS)在室温下封闭切片60分钟。然后使样品与针对C5b-9(在PBS中1:30稀释，小鼠单克隆抗体，Dako Deutschland GmbH，Hamburg，德国)或补体因子D(在PBS中1：200稀释，小鼠单克隆抗体，Santa Cruz Biotechnology，Dallas，Texas，USA)的第一抗体在4℃下反应过夜。在用PBS洗涤后，使样品与第二抗体(在PBS中1：200稀释，抗小鼠的Alexa Fluor 488，Life Technologies Deutschland GmbH，Darmstadt，德国)在37℃下反应1小时。用PBS洗涤样品三次后，用DAPI(1μg/mL，LifeTechnologies GmbH，Darmstadt，德国)进行细胞核染色10分钟。然后将样品用PBS洗涤三次，用抗褪色溶液(Carl Roth GmbH，Karlsruhe，德国)封固，并用玻璃盖玻片覆盖以进行显微镜检查。使用倒置荧光显微镜(来自Leica Microsystems，Wetzlar，德国的DMI 6000)和λex/λem＝470nm/525nm的滤光器组进行荧光显微成像。对于C5b-9的荧光强度的半定量分析，分析来自每只眼睛的3个不同载玻片(每只眼睛的总共9-15个不同区域)的一个载玻片中的3-5个不同区域。对于补体因子D的荧光强度的半定量分析，评估每只眼睛的3个不同区域。The same assays were performed for immunohistochemistry for membrane attack complex (MAC, C5b-9) and complement factor D (CFD), except that monoclonal antibodies specific for each complement component were used. Specimens were treated with 10 μg/mL proteinase K (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) in PBS for antigen retrieval for 30 min at room temperature. Sections were then blocked with goat serum (5% goat serum, 0.3% Triton X-100 in PBS) for 60 minutes at room temperature. The samples were then reacted against C5b-9 (1:30 dilution in PBS, mouse mAb, Dako Deutschland GmbH, Hamburg, Germany) or complement factor D (1:200 dilution in PBS, mouse mAb, The primary antibody of Santa Cruz Biotechnology, Dallas, Texas, USA) was reacted overnight at 4°C. After washing with PBS, the samples were reacted with a secondary antibody (1:200 dilution in PBS, Alexa Fluor 488 anti-mouse, Life Technologies Deutschland GmbH, Darmstadt, Germany) for 1 hour at 37°C. After washing the samples three times with PBS, nuclei were stained with DAPI (1 μg/mL, LifeTechnologies GmbH, Darmstadt, Germany) for 10 minutes. The samples were then washed three times with PBS and treated with anti-fade solution ( Carl Roth GmbH, Karlsruhe, Germany) was mounted and covered with a glass coverslip for microscopy. Fluorescence microscopy imaging was performed using an inverted fluorescence microscope (DMI 6000 from Leica Microsystems, Wetzlar, Germany) and a filter set of λex/λem=470 nm/525 nm. For semi-quantitative analysis of fluorescence intensity of C5b-9, 3-5 different areas in one slide from 3 different slides per eye (total 9-15 different areas per eye) were analyzed . For semi-quantitative analysis of the fluorescence intensity of complement factor D, 3 different regions of each eye were assessed.
用安慰剂(乱序的L-4F)注射的两种对照动物均在两只眼睛中显示布鲁赫膜(BrM)和脉络膜毛细血管的强烈和特异性染色，其中油红O用于中性脂质并且非律平用于酯化的胆固醇。例如，用油红O染色显示在两种对照动物中，BrM中和BrM上存在大量脂质。相比之下，与注射安慰剂的眼睛相比，在用油红O染色时，注射L-4F的眼在6个月后表现出来自BrM的脂质沉积物减少约56％。图2显示了在猕猴注射的眼睛和对应未注射的眼睛中的布鲁赫膜中和布鲁赫膜上中性脂质用油红O(ORO)染色的评分，所述眼睛接受6次每个月在玻璃体内注射L-4F或安慰剂(乱序的L-4F)。非律平荧光的半定量评估显示，与注射安慰剂的眼睛相比，注射L-4F的眼睛中BrM中的酯化的胆固醇降低约68％。图3显示了在猕猴注射的眼睛和对应未注射的眼睛中的布鲁赫膜中的酯化的胆固醇用非律平染色的强度，所述眼睛接受6次每个月在玻璃体内注射L-4F或安慰剂(乱序的L-4F)。Both control animals injected with placebo (scrambled L-4F) showed strong and specific staining of Bruch's membrane (BrM) and choriocapillaris in both eyes with Oil Red O for neutrality Lipids and felipine for esterified cholesterol. For example, staining with Oil Red O showed the presence of large amounts of lipids in and on BrM in both control animals. In contrast, L-4F-injected eyes exhibited approximately 56% reduction in lipid deposits from BrM after 6 months when stained with Oil Red O compared to placebo-injected eyes. Figure 2 shows the scoring of oil red O (ORO) staining of neutral lipids in Bruch's membrane and on Bruch's membrane in rhesus monkey injected eyes and corresponding uninjected eyes that received 6 times each L-4F or placebo (scrambled L-4F) was injected intravitreally. Semi-quantitative assessment of felupine fluorescence showed that esterified cholesterol in BrM was reduced by approximately 68% in L-4F-injected eyes compared to placebo-injected eyes. Figure 3 shows the intensity of Esterified Cholesterol Staining with Felipin in Bruch's membrane in rhesus monkey injected eyes and corresponding non-injected eyes that received 6 monthly intravitreal injections of L- 4F or placebo (scrambled L-4F).
通过对各个特异性抗体的荧光强度的半定量分析，与注射乱序的肽的眼睛相比，注射L-4F的眼睛显示BrM和脉络膜毛细血管中MAC(C5b-9)水平降低约58％并且补体因子D水平降低约为41％。图4显示了在猕猴注射的眼睛和对应未注射的眼睛中的布鲁赫膜的脉络膜毛细血管中的膜攻击复合物(MAC，C5b-9)的染色强度，所述眼睛接受6次每个月在玻璃体内注射L-4F或安慰剂(乱序的L-4F)。图5显示了在猕猴注射的眼睛和对应未注射的眼睛中的补体因子D的染色强度，所述眼睛接受6次每个月在玻璃体内注射L-4F或安慰剂(乱序的L-4F)。By semi-quantitative analysis of the fluorescence intensity of each specific antibody, L-4F-injected eyes showed an approximately 58% reduction in BrM and choriocapillary MAC (C5b-9) levels compared to scrambled peptide-injected eyes and Complement factor D levels were reduced by approximately 41%. Figure 4 shows the staining intensity of membrane attack complex (MAC, C5b-9) in the choriocapillaries of Bruch's membrane corresponding to Bruch's membrane in cynomolgus monkey-injected eyes that received six doses of each L-4F or placebo (scrambled L-4F) was injected intravitreally. Figure 5 shows the staining intensity of complement factor D in macaque injected eyes and corresponding uninjected eyes that received 6 monthly intravitreal injections of L-4F or placebo (scrambled L-4F ).
布鲁赫膜中的脂质沉积使得BrM增厚。尸体解剖后通过电子显微镜检查去核眼的颞外黄斑处来测量布鲁赫膜厚度。与注射安慰剂的眼睛(1.73μm±SE 0.02)相比，注射L-4F的眼睛表现出BrM厚度减少(1.31μm±SE 0.11)约24％。图6显示了在猕猴注射的眼睛和对应未注射的眼睛中的颞外黄斑处测量的布鲁赫膜的厚度，所述眼睛接受6次每个月在玻璃体内注射L-4F或安慰剂(乱序的L-4F)。Lipid deposition in Bruch's membrane thickens BrM. Bruch's membrane thickness was measured by electron microscopy of the extratemporal macula in the enucleated eye after autopsy. L-4F-injected eyes exhibited approximately 24% reduction in BrM thickness (1.31 μm ± SE 0.11) compared to placebo-injected eyes (1.73 μm ± SE 0.02). Figure 6 shows Bruch's membrane thickness measured at the extratemporal macula in macaque injected eyes and corresponding non-injected eyes that received 6 monthly intravitreal injections of L-4F or placebo ( out-of-order L-4F).
在6次每月在玻璃体内注射后，L-4F对对应未注射的眼睛和注射的眼睛具有相似的效果(见图2-6)。不受理论束缚，玻璃体内注射到一只眼睛的L-4F到达BrM，并且从那里可能已进入脉络膜毛细血管并因此进入全身循环并最终进入对应未注射的眼睛。同样不受理论束缚，L-4F在未注射的眼睛中的治疗效果的大小可能部分是由于猕猴的体重相对于眼睛大小相对较小和猕猴的饮食主要为素食使得所述猕猴没有表现出动脉粥样硬化(体循环中L-4F的潜在靶标)。After 6 monthly intravitreal injections, L-4F had similar effects on the corresponding uninjected and injected eyes (see Figures 2-6). Without being bound by theory, L-4F injected intravitreally into one eye reaches the BrM, and from there may have entered the choriocapillaris and thus the systemic circulation and ultimately the corresponding uninjected eye. Again without being bound by theory, the magnitude of the therapeutic effect of L-4F in the uninjected eye may be due in part to the relatively small body weight of the macaques relative to eye size and the macaques' diet that is predominantly vegetarian such that the macaques do not exhibit atherosclerosis like sclerosis (a potential target of L-4F in the systemic circulation).
L-4F在所有猕猴中都具有良好的耐受性，因为玻璃体内注射L-4F的猕猴没有经历任何显著的不良事件或副作用。例如，与第一次注射L-4F前一天hsCRP的血液水平相比，6次每月在玻璃体内注射L-4F并未增加高敏C-反应蛋白(hsCRP)的血液水平。循环hsCRP(主要在肝脏中产生)是全身性炎症的非特异性标志物。L-4F was well tolerated in all macaques, as macaques injected with L-4F did not experience any significant adverse events or side effects. For example, six monthly intravitreal injections of L-4F did not increase blood levels of high-sensitivity C-reactive protein (hsCRP) compared with blood levels of hsCRP the day before the first L-4F injection. Circulating hsCRP (produced mainly in the liver) is a nonspecific marker of systemic inflammation.
总之，apoA-I模拟物L-4F在年龄相关的黄斑病变的猴模型中起到有效的脂质清除剂的作用并从BrM中除去脂质沉积物。通过电子显微镜检查，从BrM去除脂质沉积物恢复了BrM完整性。此外，通过注射L-4F的眼睛中补体激活的显著减少证明了脂质沉积的下游效应(如局部炎症)降低。In conclusion, the apoA-I mimetic L-4F acts as a potent lipid scavenger and removes lipid deposits from BrM in a monkey model of age-related macular degeneration. Removal of lipid deposits from BrM restored BrM integrity by electron microscopy. In addition, a reduction in downstream effects of lipid deposition, such as local inflammation, was demonstrated by a significant reduction in complement activation in L-4F-injected eyes.
实施例2.L-4F单独的I/II期安全性/功效研究Example 2. Phase I/II Safety/Efficacy Study of L-4F Alone
进行随机、开放标记、剂量递增的I/I期研究以评估对患有AMD(例如，中期AMD)的患者施用(例如，通过玻璃体内注射)的L-4F或其变体(例如D-4F)或盐(例如，乙酸盐)的安全性、耐受性、药代动力学和有效剂量。软玻璃疣是AMD进展的高危因素，并且临床上公认是富含脂质的亚RPE-BL沉积物(AMD的标志)。直至玻璃疣减少的L-4F累积剂量以及最大耐受剂量在其他研究中提供了关于最佳L-4F剂量的重要信息，所述其他研究包括其中L-4F(或其变体或盐)与一种或多种其他治疗剂(例如，抗血管生成剂或补体抑制剂)组合施用用于治疗新生血管性(湿性)AMD或萎缩性(干性)AMD。A randomized, open-label, dose-escalation Phase I/I study to evaluate L-4F or a variant thereof (eg, D-4F) administered (eg, by intravitreal injection) to patients with AMD (eg, mid-stage AMD) ) or salt (eg, acetate) safety, tolerability, pharmacokinetics and effective dose. Soft drusen are a high risk factor for AMD progression and are clinically recognized as lipid-rich sub-RPE-BL deposits (a hallmark of AMD). The cumulative dose of L-4F up to drusen reduction and the maximum tolerated dose have provided important information on optimal L-4F doses in other studies including those in which L-4F (or a variant or salt thereof) is combined with One or more other therapeutic agents (eg, anti-angiogenic agents or complement inhibitors) are administered in combination for the treatment of neovascular (wet) AMD or atrophic (dry) AMD.
在I/I期研究中，L-4F或其变体(例如，D-4F)或盐(例如，乙酸盐)在持续一段时间(例如，约6、9或12个月)以特定频率(例如，每月或每两个月)通过玻璃体内以某些剂量(例如，从约0.1mg至约1.5mg的递增剂量)注射施用于一只眼中。另一只眼睛未注射并用作个体内的对照眼。将治疗后评估进行至例如约12个月。主要结果测量标准包括，例如，通过光谱域光学相干断层扫描(SDOCT)和定量眼底自发荧光(qAF)强度的稳定或增加)来量化软玻璃疣的减少(例如，总玻璃疣体积减少约30％)(例如，约15月的时间框架)。次要结果测量标准包括在例如从起始开始的约9和15月的例如视力的稳定性或改善(例如视物变形、暗适应和最佳矫正视力(BCVA))。In Phase I/I studies, L-4F or a variant (eg, D-4F) or salt (eg, acetate) of L-4F or a (eg, monthly or every two months) by intravitreal injection in certain doses (eg, in escalating doses from about 0.1 mg to about 1.5 mg) into one eye. The other eye was left uninjected and served as the in-subject control eye. Post-treatment assessments are conducted, for example, up to about 12 months. Primary outcome measures included, for example, quantification of soft drusen reduction (eg, approximately 30% reduction in total drusen volume) by spectral domain optical coherence tomography (SDOCT) and quantitative fundus autofluorescence (qAF) intensity stabilization or increase ) (for example, about a 15-month time frame). Secondary outcome measures include, eg, stabilization or improvement in vision (eg, visual distortion, dark adaptation, and best-corrected visual acuity (BCVA)), eg, at approximately 9 and 15 months from initiation.
实施例3.L-4F与抗血管生成剂组合的II期功效研究Example 3. Phase II efficacy study of L-4F in combination with anti-angiogenic agents
进行II期研究以评估新生血管性(湿性)AMD患者中L-4F或其变体(例如D-4F)或盐(例如乙酸盐)与抗血管生成剂(例如，抗VEGF剂(如阿柏西普贝伐单抗或雷珠单抗))组合的初步和确认功效。药物以一定频率(例如，每月或每两个月)施用(例如，通过玻璃体内注射)直到新生血管形成(例如，1型、2型或3型新生血管形成)的渗出停止。进行治疗后评估。将药物注射到较差的眼睛中，并且另一只眼睛不注射并用作个体内对照眼睛。目标包括使得用于减少新生血管形成所需的抗VEGF剂的剂量和注射次数减少。A phase II study to evaluate L-4F or a variant thereof (eg D-4F) or a salt (eg acetate) with an anti-angiogenic agent (eg, an anti-VEGF agent (eg, adrenaline) in patients with neovascular (wet) AMD Bersip Bevacizumab or ranibizumab )) preliminary and confirmed efficacy of the combination. The drug is administered (eg, by intravitreal injection) at a frequency (eg, monthly or every two months) until extravasation of neovascularization (eg, type 1, 2, or 3 neovascularization) ceases. Perform post-treatment assessments. Drugs were injected into the inferior eye, and the other eye was left uninjected and served as an in-subject control eye. Goals include reducing the dose and number of injections of anti-VEGF agents required to reduce neovascularization.
实施例4.L-4F与补体抑制剂组合的II期功效研究Example 4. Phase II efficacy study of L-4F in combination with complement inhibitors
进行II期研究以评估患有中期或晚期萎缩性(干性)AMD且表现出非中央或中央地图样萎缩(GA)的患者中L-4F或其变体(例如，D-4F)或盐(例如，乙酸盐)与补体抑制剂(例如，兰波利珠单抗、ARC 1905或LFG316)组合的初步和确认功效。药物以特定频率(例如，每月或每两个月)施用(例如，通过玻璃体内注射)以评估其在减缓非中央或中央GA的进展方面的功效(例如，降低GA进展速率，或减少GA病变面积或大小)。进行治疗后评估。将药物注射到较差的眼睛中，并且另一只眼睛不注射并用作个体内对照眼睛。目标包括使得减缓非中央或中央GA进展所需的补体抑制剂的剂量和注射次数减少。Phase II study to evaluate L-4F or its variants (eg, D-4F) or salts in patients with intermediate or advanced atrophic (dry) AMD who exhibit noncentral or central geographic atrophy (GA) (eg, acetate) and complement inhibitors (eg, lambolizumab, ARC 1905 or LFG316) combination of preliminary and confirmed efficacy. The drug is administered (eg, by intravitreal injection) at a specific frequency (eg, monthly or bimonthly) to assess its efficacy in slowing the progression of non-central or central GA (eg, reducing the rate of GA progression, or reducing the rate of GA progression) lesion area or size). Perform post-treatment assessments. Drugs were injected into the inferior eye, and the other eye was left uninjected and served as an in-subject control eye. Goals include reducing the dose and number of injections of complement inhibitors required to slow the progression of non-central or central GA.
应理解，虽然已经说明和描述了特定实施例，但是可以对其进行多种修改并且在本文预期了多种修改。还应理解，本公开不受本文提供的具体实施例的限制。本文的公开内容的实施方案和实施例的描述和说明不旨在以限制意义解释。还应理解，本公开的所有方面不限于本文所述的具体描述、配置或相对比例，其可取决于各种条件和变量。对于本领域技术人员来说，本公开的实施方案和实施例的形式和细节的多种修改和变化将是显而易见的。因此，预期本公开还涵盖任何和所有这样的修改、变化和等同物。It should be understood that while specific embodiments have been illustrated and described, various modifications may be made thereto and are contemplated herein. It should also be understood that the present disclosure is not limited by the specific examples provided herein. The descriptions and illustrations of the embodiments and examples of the disclosure herein are not intended to be construed in a limiting sense. It is also to be understood that all aspects of the present disclosure are not limited to the specific descriptions, configurations, or relative proportions set forth herein, which may depend upon various conditions and variables. Various modifications and changes in form and detail of the embodiments and examples of the present disclosure will be apparent to those skilled in the art. Accordingly, it is intended that this disclosure also covers any and all such modifications, variations and equivalents.
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| Country | Link |
|---|---|
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| CN (1) | CN110545836A (en) |
| WO (1) | WO2018139991A1 (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494354A (en)* | 2020-04-21 | 2020-08-07 | 复旦大学附属眼耳鼻喉科医院 | Use of ABCA1 agonist in preparation of medicine for treating eye diseases |
| CN113842385A (en)* | 2021-10-26 | 2021-12-28 | 南京北极光生物科技有限公司 | Method for reducing macular degeneration of retina |
| CN118717992A (en)* | 2024-07-17 | 2024-10-01 | 华中科技大学 | Application of complement factor C3 as a therapeutic target for crystalline retinitis pigmentosa |
| CN120093886A (en)* | 2025-05-06 | 2025-06-06 | 成都桥然生物科技有限公司 | Nutritional composition for delaying vision loss based on multimodal targeted delivery and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| KR20250057128A (en) | 2015-12-30 | 2025-04-28 | 코디악 사이언시스 인코포레이티드 | Antibodies and conjugates thereof |
| RS65380B1 (en) | 2017-08-24 | 2024-04-30 | Novo Nordisk As | Glp-1 compositions and uses thereof |
| JP2021514656A (en) | 2018-03-02 | 2021-06-17 | コディアック サイエンシーズ インコーポレイテッドＫｏｄｉａｋ Ｓｃｉｅｎｃｅｓ Ｉｎｃ． | IL-6 antibody and its fusion constructs and conjugates |
| EP3843721A4 (en)* | 2018-08-29 | 2022-10-12 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
| KR20210092754A (en)* | 2018-11-16 | 2021-07-26 | 사이머베이 쎄라퓨틱스, 인코퍼레이티드 | Combination treatment of NAFLD and NASH |
| CA3125605A1 (en)* | 2019-01-04 | 2020-07-09 | The Regents Of The University Of California | Compositions and methods for promoting angiogenesis in the eye |
| AU2020364071A1 (en) | 2019-10-10 | 2022-05-26 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
| IL294520A (en) | 2020-02-18 | 2022-09-01 | Novo Nordisk As | Pharmaceutical formulations |
| EP4504150A1 (en)* | 2022-04-06 | 2025-02-12 | Abionyx Pharma SA | Methods for treating eye diseases using lipid binding protein-based complexes |
| CN120476152A (en)* | 2022-11-28 | 2025-08-12 | 深圳欧科健生物医药科技有限公司 | C5/VEGF bispecific binding molecules |
| CN118986870A (en)* | 2024-08-09 | 2024-11-22 | 山西医科大学 | Eye drop for inhibiting pathological angiogenesis of eyes and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280500A (en)* | 1997-09-29 | 2001-01-17 | 琼-路易斯·达索克斯 | Apolipoprotein A-I agonist and its application in the treatment of dyslipidemia related diseases |
| US20040266663A1 (en)* | 2001-12-07 | 2004-12-30 | Schwartz Daniel M. | Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and bruch's membrane (BM) |
| US20070254832A1 (en)* | 2006-02-17 | 2007-11-01 | Pressler Milton L | Methods for the treatment of macular degeneration and related eye conditions |
| US20100143444A1 (en)* | 2000-08-24 | 2010-06-10 | Anantharamaiah Gattadahalli M | Peptides and peptide mimetics to treat pathologies associated with eye disease |
| WO2016018665A1 (en)* | 2014-07-31 | 2016-02-04 | Uab Research Foundation | Apoe mimetic peptides and higher potency to clear plasma cholesterol |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR200201047T2 (en) | 1999-10-21 | 2002-07-22 | Alcon, Inc. | Medication delivery means. |
| US6375972B1 (en) | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
| WO2012158962A2 (en) | 2011-05-18 | 2012-11-22 | Eumederis Pharmaceuticals, Inc. | Improved peptide pharmaceuticals |
| MX360816B (en) | 2012-11-20 | 2018-11-15 | Mederis Diabetes Llc | Improved peptide pharmaceuticals for insulin resistance. |
| WO2014159813A1 (en) | 2013-03-13 | 2014-10-02 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280500A (en)* | 1997-09-29 | 2001-01-17 | 琼-路易斯·达索克斯 | Apolipoprotein A-I agonist and its application in the treatment of dyslipidemia related diseases |
| US20100143444A1 (en)* | 2000-08-24 | 2010-06-10 | Anantharamaiah Gattadahalli M | Peptides and peptide mimetics to treat pathologies associated with eye disease |
| US20040266663A1 (en)* | 2001-12-07 | 2004-12-30 | Schwartz Daniel M. | Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and bruch's membrane (BM) |
| US20070254832A1 (en)* | 2006-02-17 | 2007-11-01 | Pressler Milton L | Methods for the treatment of macular degeneration and related eye conditions |
| WO2016018665A1 (en)* | 2014-07-31 | 2016-02-04 | Uab Research Foundation | Apoe mimetic peptides and higher potency to clear plasma cholesterol |
| Title |
|---|
| CAPSTONE THERAPEUTICS，: "Capstone Therapeutics Announces That Its Joint Venture, LipimetiX Development, Inc., Has Closed a Series B-1 Preferred Stock Offering", 《CAPSTONE THERAPEUTICS》* |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494354A (en)* | 2020-04-21 | 2020-08-07 | 复旦大学附属眼耳鼻喉科医院 | Use of ABCA1 agonist in preparation of medicine for treating eye diseases |
| CN111494354B (en)* | 2020-04-21 | 2021-06-22 | 复旦大学附属眼耳鼻喉科医院 | Use of ABCA1 agonist in preparing medicine for treating eye diseases |
| CN113842385A (en)* | 2021-10-26 | 2021-12-28 | 南京北极光生物科技有限公司 | Method for reducing macular degeneration of retina |
| CN113842385B (en)* | 2021-10-26 | 2024-08-02 | 南京北极光生物科技有限公司 | Method for reducing macular degeneration of retina |
| CN118717992A (en)* | 2024-07-17 | 2024-10-01 | 华中科技大学 | Application of complement factor C3 as a therapeutic target for crystalline retinitis pigmentosa |
| CN120093886A (en)* | 2025-05-06 | 2025-06-06 | 成都桥然生物科技有限公司 | Nutritional composition for delaying vision loss based on multimodal targeted delivery and preparation method thereof |
| Publication number | Publication date |
|---|---|
| EP3554531A1 (en) | 2019-10-23 |
| WO2018139991A1 (en) | 2018-08-02 |
| KR20190124704A (en) | 2019-11-05 |
| JP2020514407A (en) | 2020-05-21 |
| Publication | Publication Date | Title |
|---|---|---|
| US10905770B2 (en) | Topical delivery of therapeutic agents using cell-penetrating peptides for the treatment of age-related macular degeneration and other eye diseases | |
| CN110545836A (en) | Treating Age-Related Macular Degeneration and Other Eye Diseases with Apolipoprotein Mimics | |
| US20180296525A1 (en) | Treatment of age-related macular degeneration and other eye diseases with one or more therapeutic agents | |
| US10426817B2 (en) | Treatment of age-related macular degeneration and other eye diseases with apolipoprotein mimetics | |
| JP2020528082A5 (en) | ||
| Nowak | AMD ń THE RETINAL DISEASE WITH AN UNPRECISED ETIOPATHOGENE-SIS: IN SEARCH OF EFFECTIVE THERAPEUTICS | |
| AU2009240470B8 (en) | Inhibition of neovascularization by cerium oxide nanoparticles | |
| JP2019034947A (en) | Methods and compositions for preventing or treating ocular diseases | |
| JP2011513229A (en) | Ophthalmic NSAID as an adjuvant | |
| US20120156202A1 (en) | Age related macular degeneration treatment | |
| Himasa et al. | Prospective for diagnosis and treatment of diabetic retinopathy | |
| TW201904610A (en) | Non-antibody vegf antagonists for the treatment of neovascular glaucoma | |
| WO2011097577A2 (en) | Compositions and methods for treating or preventing retinal degeneration | |
| JP2007224030A (en) | Method for treating macular degeneration and related eye symptom | |
| JP6944463B2 (en) | Compositions and Methods for the Treatment of Eye Diseases | |
| HK40011780A (en) | Treatment of age-related degeneration and other eye diseases with apolipoprotein mimetics | |
| JP2005521681A (en) | Method for treating ophthalmic diseases using urea and urea derivatives | |
| US20240000891A1 (en) | Growth and differentiation factor 15 for treatment of proliferative vitreoretinopathy therapy | |
| Zarbin et al. | Review of emerging treatments for age-related macular degeneration | |
| ALKAN | Chorioretinopathy and Management | |
| JP4412554B2 (en) | Retinopathy model animal | |
| Levison | Noninfectious Uveitis: Systemic and Local Corticosteroids | |
| WO2025090106A1 (en) | Compositions and methods for treating neural degeneration in glaucoma and related conditions | |
| Dugel | A new focus on the vitreous and its role in retinal function | |
| JP6764233B2 (en) | Eye disease treatment drug |
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