更新于：2024-11-01

CD59

更新于：2024-11-01

基本信息

别名

16.3A5、1F5 antigen、20 kDa homologous restriction factor

+ [27]

简介

Potent inhibitor of the complement membrane attack complex (MAC) action. Acts by binding to the C8 and/or C9 complements of the assembling MAC, thereby preventing incorporation of the multiple copies of C9 required for complete formation of the osmolytic pore. This inhibitor appears to be species-specific. Involved in signal transduction for T-cell activation complexed to a protein tyrosine kinase. The soluble form from urine retains its specific complement binding activity, but exhibits greatly reduced ability to inhibit MAC assembly on cell membranes.

关联

项与 CD59 相关的药物

HMR-59

靶点

CD59

作用机制

CD59激动剂

在研机构

Janssen Research & Development LLC [+2]

原研机构

Tufts University

在研适应症

年龄相关性黄斑变性 [+1]

非在研适应症

糖尿病性视网膜病变 [+4]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

rCD59-APT542

靶点

CD59

作用机制

CD59拮抗剂

在研机构

University of Arkansas for Medical Sciences

原研机构

University of Arkansas for Medical Sciences

在研适应症

脉络膜新生血管

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WO2024005250

专利挖掘

靶点

CD59

作用机制-

在研机构

SillaJen, Inc.

原研机构

SillaJen, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

项与 CD59 相关的临床试验

NCT06635148 / Recruiting临床2期

Long-term Extension Study for Participants With Geographic Atrophy (GA) Secondary to Age-related Macular Degeneration (AMD) in JNJ-81201887 Parent Clinical Studies

The purpose of this study is to assess the long-term safety and tolerability after an intravitreal injection (a shot of medicine into the eye) of JNJ-81201887 administered in parent clinical studies.

开始日期2024-09-19

申办/合作机构

Janssen Research & Development LLC

CTR20233305 / Recruiting临床1期

一项在患有继发于年龄相关性黄斑变性的地图样萎缩的中国患者中评价JNJ-81201887（AAVCAGsCD59）玻璃体内给药的安全性和耐受性的I期、开放性、多中心、剂量递增研究

本试验的目的为评估眼部给予单侧单次JNJ-81201887注射的安全性和耐受性

开始日期2023-12-13

申办/合作机构

强生（中国）投资有限公司

[+3]

ISRCTN38641780 / Recruiting临床2期

A phase IIb, randomized, double-masked, multicenter, dose-ranging, sham-controlled clinical trial to evaluate intravitreal JNJ-81201887 (AAVCAGsCD59) compared to sham procedure for the treatment of geographic atrophy secondary to age-related macular degeneration

开始日期2023-03-06

申办/合作机构

Janssen Global Services, LLC

100 项与 CD59 相关的临床结果

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100 项与 CD59 相关的转化医学

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0 项与 CD59 相关的专利（医药）

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2,315

项与 CD59 相关的文献（医药）

2024-12-31·Emerging Microbes & Infections

SARS-CoV-2 hijacks host CD55, CD59 and factor H to impair antibody-dependent complement-mediated lysis

Article

作者: Prantl, Lena ; Tajti, Gabor ; Stoiber, Heribert ; Mueller, André ; Malekshahi, Zahra ; Ohradanova-Repic, Anna ; Fontaine, Frédéric ; Stockinger, Hannes ; Teutsch, Aron ; Gebetsberger, Laura ; Marella, Nara

The complement system is a vital anti-microbial defence mechanism against circulating pathogens. Excessive complement activation can have deleterious outcomes for the host and is consequently tightly modulated by a set of membrane-associated and fluid-phase regulators of complement activation (RCAs). Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks host cellular RCA members CD55 and CD59 and serum-derived Factor H (FH) to resist antibody-dependent complement-mediated lysis triggered by immunized human sera. Blockage of the biological functions of virion-associated CD55 and CD59 and competition of FH recruitment with functionally inactive recombinant FH-derived short consensus repeats SCR18-20 restore SARS-CoV-2 complement sensitivity in a synergistic manner. Moreover, complement-mediated virolysis is dependent on classical pathway activation and does not occur in the absence of virus-specific antibodies. Altogether, our findings present an intriguing immune escape mechanism that provides novel insights into the immunopathology observed in severe coronavirus disease 2019 (COVID-19).

2024-12-31·Cancer Biology & Therapy

CD46 and CD59 inhibitors enhance complement-dependent cytotoxicity of anti-CD38 monoclonal antibodies daratumumab and isatuximab in multiple myeloma and other B-cell malignancy cells

Article

作者: Gopal, Ajay ; Fromm, Jonathan R ; Carter, Darrick ; Lieber, André ; Koob, Theo ; Wang, Hongjie

Multiple myeloma (MM) is an incurable malignancy of the B-cell lineage. Remarkable progress has been made in the treatment of MM with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM. Daratumumab and isatuximab treatment of MM lines (without Ad35K++ or rILYd4) resulted in the upregulation of CD46/CD59 and/or survival of CD46^high/CD59^high MM cells that escaped the second round of daratumumab and isatuximab treatment. The escape in the second treatment cycle was prevented by the pretreatment of cells with Ad35K++. Overall, our data demonstrate that Ad35K++ and rILYd4 are efficient co-therapeutics of daratumumab and isatuximab, specifically in multi-cycle treatment regimens, and could be used to improve treatment of multiple myeloma.

2024-10-01·Clinical and Molecular Hepatology

DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease

Article

作者: Kang, Keon Wook ; Jung, Hyo-Jung ; Lee, Jun Min ; Kim, Hee-Jin ; Sohn, Hyun Ahm ; Haam, Keeok ; Kim, Won ; Yoo, Taekyeong ; Go, Hanyong ; Lee, Dong Hyeon ; Kwon, Eun-Soo ; Choi, Murim ; Kim, Mirang ; Magdy, Amal ; Park, Jong-Lyul

Background/Aims: Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.Methods: Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.Results: Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.Conclusions: Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.

项与 CD59 相关的新闻（医药）

2024-09-08

·生物探索

Immunity | 抗体和补体是血栓形成的关键驱动因素

引言抗体是体液免疫防御的主要组成部分，用以清除衰老细胞，维持机体稳态【1】。除此之外，抗体还可以用于治疗恶性和炎症性疾病【2】。一些临床证据表明，抗体，无论其来源 (内源性/外源性) 或特异性 (多克隆/抗原特异性) 如何，都可促使血栓形成。抗体治疗，包括且不限于抗胸腺细胞球蛋白、抗表皮生长因子受体 (EGFR)，抗血管内皮生长因子受体 (EGFR) 以及静脉注射免疫球蛋白 (IVIG)【3】，都与高凝状态和血栓并发症有关。这些发现是否与抗体的特定作用模式有关 (也就是它们的抗原特异性)，或者抗体本身是否具有血栓性尚不清楚【4-7】。不仅是输入人体的外源性治疗性抗体，而且内源性抗体的产生失调也与血栓形成风险增加有关，比如最近报道了多例疫苗诱导的免疫性血栓性血小板减少症、肝素诱导的血小板减少症、抗磷脂综合征、多发性骨髓瘤，以及目前病因不明的单克隆免疫球蛋白病。尽管上述病例还没有找到共性，但是这些内源性抗体的血栓前作用似乎与靶抗原有关，且潜在机制仍不清楚。与抗体类似，补体系统 (抗体的主要效应臂) 也与血栓形成有关:正常人群补体C3浓度升高与静脉血栓栓塞的风险增加有关。在包括COVID-19在内的传染病中，补体也与血栓形成事件有关。此外，补体活化与血栓性血小板减少性紫癜的血栓前状态有关。在系统性红斑狼疮或原发性自身免疫性溶血性贫血患者中，广泛的自身抗体驱动的补体激活与深静脉血栓形成和补体因子在血小板上沉积的高风险相关。除了抗体触发的补体激活外，抗体非依赖性补体激活也与血栓形成前状态相关：突发性夜间血红蛋白尿 (CD55和CD59) 或非典型溶血性尿毒症综合征 (如因子H) 中补体调节蛋白的基因突变也与血栓形成有关。靶向补体药物在治疗上述这些疾病的同时，也能降低血栓形成的风险。但是，抗体和补体驱动血栓形成的关键机制仍没有研究透彻。 2024年9月2日，来自德国慕尼黑大学的Konstantin Stark等人在Immunity上发表了文章Antibodies and complement are key drivers of thrombosis，发现抗体和补体是小鼠静脉血栓形成的关键驱动因素，治疗性补体抑制可以防止血栓形成，而不会对止血产生负面影响。静脉血栓栓塞 (VTE) 是一种常见的致命疾病，尽管采取了预防措施，但发病率仍在增加。临床观察表明抗体浓度升高或基于抗体的治疗与血栓事件有关。然而，抗体如何促成血栓形成尚不清楚。在这里，作者揭示了抗体和补体如何共同作为体内血栓形成的中枢介质。作者发现，抗体的作用独立于它们的抗原结合功能，并且发生在两个阶段，每个阶段都由不同种类的抗体主导。首先是第一阶段，深静脉血栓形成期间的血流减少，允许IgM结合内皮细胞，从而形成Toso和聚合免疫球蛋白受体介导的内皮细胞活化，并启动内皮细胞暴露血管性血友病因子和选择素P所诱导的血小板和白细胞募集。其次是第二阶段，血小板活化之后，可以提供促凝剂表面，促进纤维蛋白依赖性和硫酸软骨素A依赖性的IgG沉积，且这一阶段无需考虑抗体的抗原特异性以及Fc受体参与与否。上述两个阶段启动了补体驱动的血小板激活和髓系白细胞募集的恶性循环，最终导致血栓形成。另外，作者还确定，静脉停滞和covid -19免疫血栓失调的人类中存在上述机制。并且，这种抗体驱动的血栓形成可以通过药物靶向补体来预防。综上所述，作者的研究结果揭示了一种抗体驱动血栓形成途径，该途径通过IgM受体和聚合免疫球蛋白受体介导的内皮细胞活化，以及随后的IgG介导的补体激活启动血栓形成恶性循环。作者的工作表明，靶向这一血栓形成前轴为血栓形成提供了一种创新的预防和治疗选择，重要的是，它规避了与传统抗凝治疗相关的出血风险，为靶向血栓形成而不影响止血开辟了创新途径。参考文献 1. Ehrenstein, M.R., and Notley, C.A. (2010). The importance of natural IgM: scavenger, protector and regulator. Nat. Rev. Immunol. 10, 778–786. https://doi.org/10.1038/nri2849. 2. Elvin, J.G., Couston, R.G., and van der Walle, C.F. (2013). Therapeutic antibodies: market considerations, disease targets and bioprocessing. Int. J. Pharm. 440, 83–98. https://doi.org/10.1016/j.ijpharm.2011.12.039. 3. Aggarwal, R., Charles-Schoeman, C., Schessl, J., Bata-Cso ̈rgo}, Z., Dimachkie, M.M., Griger, Z., Moiseev, S., Oddis, C., Schiopu, E., Vencovsky ́, J., et al. (2022). Trial of Intravenous Immune Globulin in Dermatomyositis. N. Engl. J. Med. 387, 1264–1278. https://doi.org/10. 1056/NEJMoa2117912. 4. Alahmari, A.K., Almalki, Z.S., Alahmari, A.K., and Guo, J.J. (2016). Thromboembolic Events Associated with Bevacizumab plus Chemotherapy for Patients with Colorectal Cancer: A Meta-Analysis of Randomized Controlled Trials. Am. Health Drug Benefits 9, 221–232. 5. Ammann, E.M., Jones, M.P., Link, B.K., Carnahan, R.M., Winiecki, S.K., Torner, J.C., McDowell, B.D., Fireman, B.H., and Chrischilles, E.A. (2016). Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood 127, 200–207. https://doi.org/10.1182/blood-2015-05-647552. 6. Cumpelik, A., Gerossier, E., Jin, J., Tsakiris, D., Dickenmann, M., Sadallah, S., Schifferli, J.A., and Zecher, D. (2015). Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG). Am. J. Transplant. 15, 2588–2601. https://doi.org/10.1111/ ajt.13316. 7. Daniel, G.W., Menis, M., Sridhar, G., Scott, D., Wallace, A.E., Ovanesov, M.V., Golding, B., Anderson, S.A., Epstein, J., Martin, D., et al. (2012). Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion 52, 2113– 2121. https://doi.org/10.1111/j.1537-2995.2012.03589.x. 8. Gupta, D., Shukla, P., Bisht, S.S., Bhatt, M.L., Pant, M.C., and Srivastava, K. (2011). Deep vein and artery thrombosis associated with cetuximab- based chemoradiotherapy. Indian J. Pharmacol. 43, 478–480. https:// doi.org/10.4103/0253-7613.83135. https://doi.org/10.1016/j.immuni.2024.08.007 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

疫苗

2024-08-08

·微信

诺华：有望形成IgAN“三驾马车”！首款针对替代补体通路的创新疗法再批重磅适应症

欢迎关注凯莱英药闻今日，诺华宣布，美国食品药品监督管理局 (FDA)已加速批准iptacopan（商品名：Fabhalta）的新适应症，用于降低成人IgA肾病（IgAN）患者的蛋白尿水平，这些患者有疾病迅速进展的风险。 Iptacopan是一款同类首创的补体因子B（FB）抑制剂，最早于2023年12月获FDA批准作为口服单一疗法，治疗成人阵发性睡眠性血红蛋白尿 (PNH)；2024年6月，iptacopan（伊普可泮）用于成人PNH患者的上市申请获NMPA批准，距离FDA批准仅间隔四个月。除伊普可泮外，诺华正在推进另外两种具有高度差异化作用机制的 IgAN 疗法的后期开发：1、atrasentan（阿曲生坦），一种在研口服内皮素 A 受体拮抗剂，已于 2024 年第二季度向FDA提交上市申请；2、zigakibart，一种在研皮下注射抗 APRIL 单克隆抗体，目前正处于 III 期开发阶段。关于伊普可泮 Iptacopan是一款口服、强效、选择性、小分子FB抑制剂，通过作用于补体系统C5末端通路的上游；它可能在治疗多种替代通路功能异常导致的疾病同时，不影响其它补体通路介导的对微生物入侵的免疫反应，降低患者受到感染的风险。该药物在IgAN适应症的获批，主要基于III期APPLAUSE-IgAN研究数据；在这项多中心、随机、双盲、安慰剂对照、平行组、III期研究中，将470例成人原发性IgAN患者，1：1分配至iptacopan 200mg组和安慰剂组。中期研究终点为第9个月时IgAN患者的24h尿蛋白肌酐比（UPCR）相对于基线的变化。结果显示：在第9个月时，iptacopan在蛋白尿减少方面优于安慰剂，可显著降低lgAN患者蛋白尿高达44%，而安慰剂组仅为 9%，证实iptacopan可在支持性治疗的基础上提供了具有临床意义和显著统计学意义的蛋白尿减少。在安全性上，iptacopan最常见的不良反应（≥5%）是上呼吸道感染、脂质紊乱和腹痛，可能导致由荚膜细菌引起的严重感染。对延缓肾功能下降的评估，需要测量超过24个月的年化肾小球滤过率（eGFR）斜率，预计将于2025年完成。除了 IgAN，公司还在开发iptacopan用于其他罕见疾病，包括 C3 肾小球病 (C3G)、非典型溶血性尿毒症综合征 (aHUS)、免疫复合物膜增生性肾小球肾炎 (IC-MPGN) 和狼疮性肾炎 (LN)。此外，公司计划在年底前向 FDA 和 EMA 提交用于治疗C3G 的申请。关于FB抑制剂补体系统是先天免疫系统的一部分，补体由经典通路、替代通路和凝集素通路三种途径之一激活，产生一系列蛋白水解裂解，以增强免疫反应或形成膜攻击复合体(MAC)。C1处于经典通路的上游，C3属于三条通路的汇集点，而C5则位于通路末端。在正常情况下，血管内溶血由CD59阻断，CD59能阻止补体反应的最后一步，即阻止在靶细胞上形成孔的MAC。倘若患者红细胞缺乏，将CD59连接至其表面的GPI锚而导致血管内溶血；靶向末端补体C5能阻止MAC复合物的形成，阻断血管内溶血。补体因子B是一种丝氨酸蛋白酶，是调节补体旁路途径级联反应的必需蛋白，在此过程中，补体因子B 被补体因子D分解为两个亚基 Ba 和 Bb。Bb 与C3b 一起形成了替代途径的C3 转化酶 C3bBb，然后形成C5 转化酶（C3bBbC3b），最终形成膜攻击复合物。据不完全统计，目前针对补体因子B开发的在研药物近30种，研究类型涵盖小分子抑制剂、单抗、反义疗法、RNAi等。关于IgAN 免疫球蛋白A肾病（即IgA肾病/IgAN）是一种免疫复合物引起的肾小球肾炎，通常表现为血尿、蛋白尿及进展型肾衰竭。IgAN虽然被认为属罕见病，但却是全球原发性肾脏疾病的最常见原因。IgAN与肾脏炎症、血尿及蛋白尿有关。患者最终会进展为肾衰竭或终末期肾脏疾病（ESRD）；在整个疾病过程中，多达50%的患者需要进行透析或肾脏移植。全球及中国IgAN患者人数未来预计保持相对稳定。根据弗若斯特沙利文报告，全球IgAN患者人数由2016年的887.64万人增加至2020年的926.69万人（包括中国的220万人）。预计全球IgAN患者总数将于2025年达到973.06万人（包括中国230万人），并于2030年达到1,016.52万人（包括中国237万人）。目前IgAN的治疗方案仍以支持治疗以及缓解症状为主，支持治疗主要以血管紧张素转化酶抑制剂（ACEI）和血管紧张素受体拮抗剂（ARB）控制血压以降低尿蛋白，糖皮质激素、免疫抑制剂等也被用于长期的治疗。当前治疗方案可能伴随较多的副作用，并且临床效果有限。除伊普可泮外，全球范围内共有两款药物获批治疗IgAN：Nefecon以Sparsentan，后续在研产品主要集中在B细胞信号通路（如BLyS、APRIL）、补体信号通路（如CFB、MASP-2）。 Nefecon是一种布地奈德的缓释制剂，也是第一款获FDA及EMA批准上市，用于治疗IgAN的药品，通过在回肠派尔集合淋巴结处释放布地奈德进行治疗。该药物于2023年11月在国内获批，云顶新耀拥有在大中华区的开发权。 Sparsentan是一种双重内皮素血管紧张素受体拮抗剂(DEARA)，靶向阻断内皮素A受体和血管紧张素II亚型1受体通路，能够保护肾小球足细胞，防止肾小球硬化和系膜细胞增生，并减少蛋白尿产生；它是首个获批的IgA肾病非免疫抑制疗法。参考资料 1、公司官网 2、国信证券、华创证券感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

临床3期临床结果上市批准申请上市临床2期

2024-05-10

·GlobeNewswire-Health Care

Apertura Gene Therapy Showcases Advancements in Capsid Engineering Platform in Presentations at ASGCT Annual Meeting

– Significant advancements in engineering neutralizing antibody (NAb) evasion properties into receptor-targeted capsids, including novel TfR1-binding capsids, demonstrate increased opportunities to treat AAV seropositive patients – Disclosed multiple families of capsids targeting two novel proteins – CA4 and CD59; capsids binding human CA4 cross the blood-brain barrier in humanized mice, while capsids that cross react with human and non-human primate CD59 demonstrate enhanced tropism for the Central Nervous System (CNS) and skeletal muscle NEW YORK, May 10, 2024 (GLOBE NEWSWIRE) -- Apertura Gene Therapy, a biotechnology company widening the aperture of gene therapy opportunities for treating debilitating diseases, showcased significant advancements in its capsid engineering platform during several presentations at the 27th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). Scientists from the lab of academic collaborator and scientific co-founder, Ben Deverman, Ph.D., Senior Director of Vector Engineering and Institute Scientist at the Broad Institute of MIT and Harvard, presented new data showcasing the progress made in engineering neutralizing antibody (NAb) evasion attributes into the company’s novel, human-receptor targeted capsids and disclosed two newly identified families of capsids targeting human CA4 and CD59. “The progress regarding human CA4, CD59 and NAb-evading capsids presented by the lab of Apertura collaborator and scientific co-founder, Dr. Ben Deverman, support our position as the leader in receptor-mediated capsid engineering and validate our strategy to advance our internal CNS programs utilizing better gene therapy delivery vehicles that are human-centric blood brain barrier crossing capsids. We look forward to advancing our first program toward an IND submission next year,” said Joseph La Barge, Chief Executive Officer of Apertura. “Our proven ability to engineer NAb-evading attributes into our TfR1 and other receptor targeting capsids opens new opportunities to treat more patients who otherwise would not be eligible for gene therapy clinical trials or treatments.” The presence of anti-AAV NAbs at even low levels has been repeatedly shown to lower therapeutic levels of transgene expression and has long been a challenge in the gene therapy field. The presence of pre-existing NAbs across the population has limited the eligible patient population for clinical trials and addressable patient population for commercial products. Apertura’s capsid engine has yielded novel capsids that have demonstrated NAb-evading properties while maintaining the full engineered tropism of the capsid. Specifically, the data show that the latest TfR1-binding capsids are not neutralized below 50% activity (when diluted at 1:4) in a subset of sera that are neutralizing to AAV9, AAV5 and the TfR1 binding capsids without antibody evading mutations. Data from the company’s ongoing preclinical studies support the premise that subsets of patients with pre-existing NAbs, who would otherwise be excluded from treatment, could be dosed with its novel, NAb-evading capsids. The CD59 receptor is a GPI-anchored protein and member of the Ly6 family that is broadly expressed across the human body. Apertura’s novel capsids, engineered with the company’s proprietary, mechanism-of-action focused engine, have demonstrated through in-vitro and in-vivo studies efficient gene delivery to the brain, spinal cord and skeletal muscle, while de-targeting the liver, opening up significant opportunities for addressing neuromuscular and lysosomal storage disorders. These capsids have also shown to cross react with non-human primate CD59. Carbonic anhydrase IV (CA4) is a GPI-anchored enzyme highly expressed on endothelial cells across the blood-brain barrier. These proprietary, engineered capsids effectively cross the blood brain barrier in mice modified to express the human receptor and transduce multiple cell types across the CNS with high efficiency. The oral presentations and posters presented at ASGCT can be viewed here. Presentation details Presentation: Second Generation AAV Capsids Reprogrammed to Bind Human Transferrin Receptor are Targeted to the Brain and De-targeted from the Liver in human TFRC Knock-in Mice (#120)Presenter: Ken Chan, PhD, Broad Institute of MIT and Harvard Presentation: An AAV Capsid Programmed to Bind a Broadly Expressed Human Receptor Mediates Enhanced Gene Delivery to the CNS and Skeletal Muscle in vivo (#217)Presenter: Jason Wu, PhD, Broad Institute of MIT and Harvard Poster: Human CA4-Targeting AAV Capsids Efficiently Transduce the CNS in Humanized Mice (#991)Presenters: Nuria Roxana Botticello-Romero, Jason Wu, Qin Huang, Thomas Beddow, Ken Y. Chan, Pamela Brauer, Fatma Elzahraa Eid, Alina Chan, Benjamin E. Deverman Poster: Engineering Human CNS Receptor-Targeted Capsids for Improved Antibody Evasion (#1551)Presenters: Simon Pacouret, William Donahoe, John W. Harvey, Pamela P. Brauer, Qingxia Zheng, Chin-Yen Lin, Binhui Zhao, Gabrielle Clouse, Qin Huang, Jencilin Johnson, Casey Keyes, Catherine P. Pirtle, Jarrett Rios, Albert T. Chen, Fatma Elzahraa Eid, Andrew J. Barry, Yujia A. Chan, Ken Y. Chan, Benjamin E. Deverman, Poster: Benchmarking natural and synthetic AAV capsids for neutralizing antibody evasion (#1553)Presenters: William Donahoe, Simon Pacouret, Pamela P. Brauer, John W. Harvey, Catherine P. Pirtle, Ken Y. Chan, Yujia A. Chan, Benjamin E. Deverman About Apertura Gene TherapyApertura Gene Therapy is a biotechnology company unlocking new opportunities for treating currently intractable diseases. The company is uniquely positioned to develop genetic medicines by simultaneously engineering AAV capsids, genetic regulatory elements and payloads to overcome limitations in cellular access, gene expression, pre-existing immunity and manufacturability. Apertura is advancing an internal pipeline of programs targeting undisclosed central nervous system disorders utilizing its novel capsids and plans to submit an Investigational New Drug (IND) application for its first product candidate in 2025. Founded in 2021 on technologies from the Broad Institute and Harvard Medical School, and with support from Deerfield Management Company, the company is based in New York City. For more information, please visit our website at www.aperturagtx.com and follow us on LinkedIn. Contacts: Investorsinvestors@aperturatx.com Mediamedia@aperturatx.com

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