FOLR1 x CD16a

▎药明康德内容团队编辑根据中国国家药监局药品审评中心（CDE）官网数据，近期有多款1类新药临床试验申请通过“默示许可”。经过梳理，这些产品包含了多种当下备受关注的新药开发形式，如基因疗法、TIL细胞疗法、CAR-raNK细胞疗法、DNA疫苗、纳米多抗、单/双/三特异性抗体等，针对的靶点包括N3pG淀粉样蛋白、CD70、CD73、EZH2等。本文将挑选其中部分1类新药作介绍，供读者参阅（排名不分先后）。图片来源：123RF辉瑞（Pfizer）：PF-06821497片作用机制：EZH2抑制剂适应症：晚期恶性肿瘤根据辉瑞公司公开资料，PF-06821497片是该公司开发的一款强效、选择性和口服EZH2抑制剂，正在海外处于1期临床试验阶段。EZH2是一种组蛋白甲基转移酶，通过催化组蛋白H3赖氨酸27（H3K27）的甲基化以控制各种基因表达，从而调节细胞的正常生理功能。EZH2过表达或者其功能的过度增强，均会导致相关基因表达过度沉默，最终引起干细胞多向分化潜能障碍和肿瘤的发生。本次PF-06821497片在中国获批临床，针对适应症为晚期恶性肿瘤（包括小细胞肺癌、去势抵抗性前列腺癌、滤泡性淋巴瘤）。杨森公司：aticaprant薄膜包衣片作用机制：KOR拮抗剂适应症：抑郁症公开资料显示，由强生（Johnson ＆ Johnson）旗下杨森公司（Janssen）申报的aticaprant（JNJ-67953964）薄膜包衣片是一种选择性和短效kappa-阿片受体（KOR）拮抗剂，拟开发用于治疗抑郁症或快感缺乏等疾病。公开资料显示，KOR是一种抑制性G蛋白偶联受体（GPCR），广泛分布于中枢神经系统和外周组织，参与痛觉、瘙痒、神经内分泌、情感行为和认知等重要的生理活动。Aticaprant正在海外开展针对成年及老年重度抑郁症的多项3期临床研究。本次该药在中国获批临床，拟开发用于伴中重度快感缺失的成年抑郁症患者的联合治疗。复宏汉霖：HLX23作用机制：抗CD73单抗适应症：实体瘤或淋巴瘤根据复宏汉霖公开资料，HLX23是该公司开发的重组抗CD73全人源单克隆抗体注射液。CD73广泛表达于人体内皮细胞、淋巴细胞等细胞表面，常在多种肿瘤细胞上高表达， HLX23可与癌细胞表面的CD73特异性结合，抑制CD73核苷酸酶功能和促进CD73内吞，抑制肿瘤生长。临床前研究表明该产品在动物体内的耐受性和安全性良好。该药早先已经在美国获批临床，拟用于晚期实体瘤的治疗。本次该药在中国获批临床，拟开发治疗晚期/转移性实体瘤或淋巴瘤。图片来源：123RF普方生物：PRO1184作用机制：靶向FRα的ADC适应症：实体瘤根据普方生物公开资料，PRO1184是该公司在研的一款靶向叶酸受体α（FRα）、以依喜替康作为有效载荷的抗体偶联药物（ADC），采用了普方生物专有的新型亲水性连接子，可以提高药物的活性。FRα是一种位于细胞膜上的叶酸结合蛋白，在多种实体肿瘤中过表达，而在正常人体组织中的表达水平较低，使得其成为ADC治疗FRα表达肿瘤的一个有吸引力的靶点。PRO1184早先已经在美国获批临床，用于治疗晚期癌症患者。本次该药在中国获批临床，拟开发用于局部晚期和/或转移性实体瘤患者。Chinook Therapeutics：BION-1301注射液作用机制：抗APRIL单抗适应症：IgA肾病（IgAN）公开资料显示，BION-1301注射液是Chinook开发的新型抗APRIL单克隆抗体，本次获批临床的适应症为：减少有疾病进展风险的原发性IgAN成人患者的蛋白尿。公开资料显示，阻断APRIL是一种通过降低半乳糖缺陷IgA1（Gd-IgA1）的循环水平来治疗IgA肾病的潜在疾病改善方法。BION-1301正在海外开展治疗IgA肾病患者的1/2期临床试验，中期更新结果显示该产品能够持续降低IgA肾病患者的IgA和Gd-IgA1的水平。厚无生物/天科雅生物：HV-101注射液作用机制：自体TIL细胞治疗产品适应症：实体瘤HV-101注射液为厚无生物和天科雅生物联合申报的全新一代自体TIL细胞治疗产品，本次获批临床的适应症为晚期复发或者转移性实体瘤。肿瘤浸润淋巴细胞（TIL）是机体淋巴细胞侵入到肿瘤组织中，并对肿瘤起识别、抵抗和攻击作用的细胞群体。TIL的作用机制是通过释放细胞毒素直接杀伤肿瘤细胞。此外，TIL还能调节机体免疫功能，提高机体对肿瘤细胞的杀伤能力。公开资料显示，CAR-T细胞疗法在血液瘤中疗效显著，但在实体瘤中则表现欠佳。TIL细胞疗法作为实体瘤的有效解决方案，目前已在全球开展针对多种实体瘤的临床试验，有望在未来成为实体瘤个性化治疗策略。智瓴生物：ZLT-001注射液作用机制：TIL细胞治疗产品适应症：晚期复发或转移性宫颈癌根据智瓴生物新闻稿，ZLT-001注射液是该公司自主开发的TIL细胞治疗新药，本次获批临床针对的适应症为晚期复发或转移性宫颈癌。该疗法是通过从患者的肿瘤组织内分离出TIL，经过智瓴生物独有的技术平台，采用时间轴激活、靶向耦合化、TME抗扰等独特技术对TIL进行纯化，增强TIL的活性与对实体肿瘤杀伤能力，并将数量扩增到十亿甚至是百亿级以上，回输到患者体内实现快速、有效杀伤肿瘤细胞，控制肿瘤生长的目的。烁星生物：SM3321注射液作用机制：纳米多抗药物适应症：急性髓系白血病据烁星生物新闻稿，SM3321注射液是该公司开发的肿瘤双靶点及CD16A激动剂介导的纳米多抗药物。纳米抗体是一类只包含一个重链可变区（VHH）及两个常规的CH2与CH3区的特殊抗体，兼具传统抗体与小分子药物的优势。临床前研究显示，SM3321特有的结合位点能够强力靶向肿瘤细胞，激活免疫细胞功能，减少非特异性毒性反应。SM3321早先已经在美国获批临床，拟用于急性髓系白血病（AML）的治疗。本次该药在中国获批临床，拟开发治疗AML。礼来：remternetug注射液作用机制：N3pG淀粉样蛋白抗体适应症：早期阿尔茨海默病礼来公司（Eli Lilly and Company）的1类新药remternetug注射液在中国获批临床，拟开发治疗早期阿尔茨海默病。公开资料显示，remternetug靶向一种名为N3pG的淀粉样蛋白亚型，目前正在海外进行一项治疗早期阿尔茨海默病患者的3期临床试验。该药采用灵活的给药方案，包括皮下给药，以满足阿尔茨海默病患者的不同需求。图片来源：123RF赛诺菲（Sanofi）：注射用SAR443216作用机制：HER2/CD3/CD28三抗适应症：HER2表达的实体瘤赛诺菲在研的HER2/CD3/CD28三特异性T细胞接合剂注射用SAR443216在中国获批临床，拟开发治疗复发/难治性HER2表达的实体瘤。公开资料显示，SAR443216具有HER2、CD3、CD28三个结合位点，它在临床前研究中显示出对HER2低表达的肿瘤具有较好的T细胞介导的肿瘤细胞杀伤（TDCC）作用，有望为HER2表达的实体瘤（包括HER2低表达实体瘤）患者带来新的治疗选择。该药正在海外开展1期临床研究。华毅乐健：GS1191-0445注射液作用机制：基因治疗药物适应症：血友病A公开资料显示，华毅乐健成立于2019年，由著名生物学家饶毅教授创立。GS1191-0445注射液为该公司研发的基因治疗药物，本次获批临床，拟开发治疗先天性凝血因子VIII缺乏引起的血友病A患者。早先在研究者发起的临床研究（IIT）中，该药物表现出良好的安全和有效性数据，单次给药后观察到长达1年多的良好维持疗效。图片来源：123RF英百瑞生物：IBR854细胞注射液作用机制：CAR-raNK细胞产品适应症：实体瘤根据英百瑞生物公开资料，IBR854细胞注射液是一款同源异体外周血来源的通用现货型CAR-raNK细胞产品，也是一款针对实体肿瘤的非基因修饰方法的CAR-raNK细胞疗法。它的核心构造是将靶向肿瘤抗原5T4的特异性抗体通过linker与同种异体的NK细胞进行共价偶联，能够与表达5T4靶抗原的肿瘤细胞特异性结合，从而达到靶向识别和杀伤肿瘤细胞的目的。本次获批临床，拟用于不可切除的局部晚期或转移性且目前无或不耐受标准治疗的实体瘤患者的治疗。维眸生物：VVN461滴眼液作用机制：小分子免疫调节剂适应症：非感染性前葡萄膜炎VVN461滴眼液是维眸生物研发的一种强效的小分子免疫调节剂，它能高活性抑制多个细胞因子通路，从而减轻和缓解眼部的炎症反应。本次该产品获批临床，针对适应症为非感染性前葡萄膜炎。这是一种自身免疫性疾病，可引起一些严重并发症和后遗症，是主要的致盲原因之一。岸迈生物：EMB-07注射液作用机制：靶向CD3/ROR1双抗适应症：恶性肿瘤EMB-07是岸迈生物研发的靶向CD3和ROR1的双特异性抗体。据岸迈生物新闻稿介绍，该公司通过自主开发CD3抗体，将T细胞定向到ROR1抗原表达肿瘤部位，仅在与肿瘤抗原接合后，促进免疫突触的形成，以选择性靶向杀死ROR1抗原表达肿瘤细胞。本次该产品在中国获批临床，拟开展针对恶性肿瘤患者的1期临床试验。博锐生物：BR108注射液作用机制：靶向CD70单抗适应症：血液系统恶性肿瘤据博锐生物新闻稿，BR108注射液是一款靶向CD70的创新型抗体依赖细胞介导的细胞毒作用（ADCC）增强型单抗，主要用于治疗CD70阳性血液系统恶性肿瘤。此外，BR108还可阻断CD70与其受体CD27的相互作用，解除免疫抑制的肿瘤微环境。本次该产品获批临床的适应症为：复发/难治的血液系统恶性肿瘤。信立泰药业：SAL0119片作用机制：小分子免疫抑制剂适应症：强直性脊柱炎、类风湿关节炎根据信立泰公开资料，SAL0119是该公司研发的口服小分子免疫抑制剂，本次获批临床针对的适应症为活动性强直性脊柱炎及中重度活动性类风湿关节炎。SAL0119具有不同于JAK类的作用机制和广谱的细胞因子抑制作用。在临床前研究中，该药已体现出良好的有效性和安全性。除了上述产品，还有其他1类新药在中国获得临床试验默示许可，如鼎泰海规生物申报的NMM肿瘤治疗性DNA疫苗裸质粒注射液，拟开发治疗晚期实体瘤和复发、难治性淋巴瘤；柯顿生物申报的PD-1基因定制活化T细胞注射液，拟开发治疗肝细胞癌；艾尔普再生医学公司申报的人iPSC来源心肌细胞注射液，拟开发治疗严重慢性缺血性心力衰竭；百力司康的ADC产品注射用BB-1709，拟开发治疗CD73表达的局部晚期/转移性实体瘤等等。限于篇幅，本文不再一一介绍。希望这些创新疗法在临床研究中进展顺利，早日取得突破，为患者带来新的治疗选择。参考资料：[1]中国国家药监局药品审评中心（CDE）官网.Retrieved Feb 3，2023, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]各公司官网及公开资料本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

近日， MAbs期刊发布抗体观察系列文章的第14期“Antibodies to watch in 2023”，介绍了2022年发生的商业抗体治疗药物开发中的关键事件，并预测了2023年可能发生的事件。截至11月中旬，12种抗体治疗药物已在美国或欧盟获得首批批准，包括4种双抗和1种ADC。另有7种于2022年在中国或日本首次获得批准，包括2种双抗。除COVID-19抗体外，后期临床管线药物在过去一年增长了约20%，包括近140种抗体治疗药物，这些药物是使用各种形式和工程技术进行设计的。在那些处于后期开发阶段的药物中，至少有23种药物的上市申请可能会在2023年底前提交。 1COVID-19的抗体疗法 COVID-19大流行的第三个年头结束， SARS-CoV-2依然对全球产生影响，令人担忧的变种如Omicron仍在传播中。截至2022年11月，由约翰霍普金斯大学的调查显示，全球总病例和死亡人数分别超过6.3亿人和660万人。然而，由于公共卫生措施（如使用口罩）、疫苗的广泛接种以及治疗该疾病的药物的开发，目前病例和死亡人数远低于2021年和2022年初的水平。Omicron变种的出现，在2022年极大地改变了SARS-CoV-2抗体的开发格局。由于Omicron变异的频率很高， FDA于2020年和2021年批准的casirivimab 和imdevimab （REGN-COV）、bamlanivimab 和etesevimab以及 sotrovimab的紧急使用授权（EUA）在2020年和2021年期间暂停。此外，许多研究中的SARS-CoV-2抗体的临床开发也被暂停或放弃。目前，只有两个SARS-CoV-2抗体候选产品bebtelovimab和Evushold保留了FDA的EUA。一些不靶向病毒本身，而是靶向与COVID-19症状相关抗原的抗体也正在考虑EUA，例如靶向补体5a的抗体 viloblimab。 2在美欧获得首批的抗体疗法 截至2022年11月中旬，在美国或欧盟首次获得批准的抗体疗法有 (表1) ：tebentafusp（Kimmtrak） 、faricimab（Vabysmo）、sutimlimab（njaymo） 、Relatlimab（Opdualag）、tixagevimab/cilgavimab（Evusheld） 、Mosunetuzumab（Lunsumio）、teclistamab（TECVAYLI）、spesolimab（SPEVIGO）、tremelimumab（Imjuo与Durvalumab联合使用）、Nirsevimab（Beyfortus）、mirvetuximab soravtansine（ELAHERE™）和teplizumab（ZIELD）。这新批准的12种药物中， 6种产品用于癌症，6种产品用于非癌症适应症。从药物类型而言，共有4种双抗（tebentafusp、faricimab、mosunetuzumab 和teclistamab）和1种ADC药物（mirvetuximab soravtansine）。所有4种双抗都是靶向独特的抗原组合。而与目前市场上的抗体疗法相比，ADC 药物mirvetuximab soravtansine和免疫检查点调节性抗体relatlimab也靶向独特的抗原，分别为FRα和LAG3。 3美欧之外获批或审查的抗体疗法 现在，美国或欧盟以外地区首次获得批准的抗体疗法变得越来越普遍，这一趋势在2022年依然持续。有7种于2022年在中国或日本首次获得批准，包括2种双抗。其中，在中国获得了5项的首次批准，包括ormutivimab、serplulimab （HANSIZHUANG）、cadonilimab （开坦尼®）、pucotenlimab （Puyouheng） 和ripertamab （Anpingxi®）；在日本批准了2项为nemolizumab （Mitchga®）和ozoralizumab （Nanozora®）。这7种批准的药物中，nemolizumab靶向的是一种独特的抗原 IL-31Rα；cadonilimab是一种双抗，它靶向的是一种独特的抗原组合（PD-1/CTLA-4）；Ozoralizumab是第一个被批准的双特异性纳米体，靶向TNF/HSA。另外，有其他几种抗体疗法预计将于2023年首次获得批准，中国目前正在审查至少7种候选抗体的上市申请（表2）。 4美欧正进行首次监管审查的抗体疗法 截至2022年11月中旬，16种抗体疗法的BLA或MAA正在接受FDA或EMA的审查（表3）。这些抗体疗法中，2种是靶向CD20和CD3的双抗（glofitamab和epcoritamab），1种是ADC药物（trastuzumab duocarmazine）。此外，FDA正在评估用于治疗早期阿尔茨海默病的两种候选产品的BLA，分别是lecanemab和donanemab。 5后期临床管线的抗体疗法 自从2010年发表的第一期Antibodies to Watch以来，后期临床研究中的抗体疗法的数量急剧增加，从2010年中的26种药物增加到现在的近140种（图1）。2013-2017年间，非癌症适应症的增长速度超过了癌症适应症。这一趋势在2018年发生了逆转，一个关键区别是应用了增强抗体生物活性的新形式。2010年至今，ADC和双特异性等增强抗体在两组中的使用都有所增加，但在癌症抗体中的增加幅度更大。从2017年到现在，在任何一年的后期临床抗体疗法研究中，大约一半的靶向癌症的抗体不是常规的全长分子，而非癌症适应症的抗体基本都是全长分子。图1. 2010-2023年后期临床研究中抗体疗法的形式和数量在非癌症和癌症适应症的后期临床试验中，大多数抗体都基于全长的IgG1骨架。约三分之一的抗体骨架为免疫活性较低的IgG2和IgG4（图2a和2b ）。另外数据显示，超过三分之二的分子被设计以某种方式改善其治疗效果（图2c和2d）。例如，改造Fc结构域以增加与FcRn的结合，从而增加血清半衰期，其更多地用于非癌症适应症，特别是抗SARS-CoV-2、金黄色葡萄球菌和RSV等病原体引起的传染病的抗体。通过增加Fc受体亲和力的工程，例如通过糖基化改善ADCC，通常用于癌症适应症。ADC和免疫偶联物利用抗体的特异性将另一个功能部分，如有毒药物、细胞因子或细胞因子结合域直接递送到靶标。这种工程化改造在癌症适应症中更为常见。通过在Fc结构域中引入突变来降低免疫效应器的功能，既可用于癌症适应症，如检查点抑制剂，也用于非癌症适应症，如阻断不想要的配体-受体相互作用。图2. 后期临床研究中的抗体形式和工程策略后期临床研究中的抗体疗法，主要作用机制（MOA）也是多样化的（图3）。大多数用于非癌症适应症的抗体是封闭抗体，另外有11种和4种抗体分别通过抗原清除和细胞耗竭特性发挥作用（图3a）。具体来看，4种抗体bentracimab、ligelizumab、birtamimab和E2814分别靶向tricagrelor、IgE、amyloid和tau，具有阻断和抗原清除双重特性。靶向OX40和BLyS/BAFF/TACI/BCMA受体的2种抗体rocatinlimab和inalumab分别具有阻断和细胞耗竭的特性。图3. 后期临床研究中的抗体疗法的主要作用机制（MOA）在癌症适应症的抗体中，MOA的多样性更大（图3b）。阻断靶标的抗体也占多数。有16种抗体用于有效载荷递送，11种通过清除抗原发挥作用，7种是细胞结合因子，7种通过CDC、ADCC和ADCP发挥作用。在具有阻断作用的43种抗体中，31种具有免疫调节作用，9种靶向肿瘤，另外3种靶向肿瘤微环境。具有阻断作用的43种抗体中，只有2种抗体是激动型的，分别是靶向DR5和OX40的INBRX-109和ivuxolimab。通过细胞毒性或放射性有效载荷递送的16个抗体偶联物中，有13个是ADC，其中6个是微管蛋白抑制剂，4个是DNA结合剂，3个是拓扑异构酶I抑制剂。剩余的3个偶联物中有2个偶联物是放射免疫偶联物，1个是免疫细胞因子偶联物。在7种免疫细胞结合抗体中，6种旨在通过CD3招募T细胞，1种名为AFM13旨在通过CD16A结合NK细胞。除了tarlatamab通过 DLL3将T细胞重定向到实体肿瘤外，大多数是通过CD20、BCMA、GPCR5D或CD30将T细胞或NK细胞重定向到血液瘤。与具有单一作用机制的细胞结合抗体不同，其他癌症适应症抗体可以通过多种机制发挥作用。telisotuzumab vedotin和zilovertamab vedotin，通过细胞毒性有效载荷传递和阻断受体信号（分别为cMET和ROR1）发挥作用。7种抗体具有双重作用机制，既能阻断抗体，又能促进抗原清除。这其中，1个是靶向EGFR非重叠表位的两个抗体的混合物，1个是靶向CD73的抗体，5个是双抗（2个靶向PD-L1和TGF-β，2个靶向VEGF和DLL3，1个靶向VEGF和PD-1）。靶向FGFR2b和IL1RAP的2种抗体bemarituzumab和nadunolimab，均可以通过CDC、ADCC、ADCP和作为阻断剂发挥双重作用。在目前处于晚期临床研究的近140种抗体疗法中，至少有23种已经取得了巨大的进展，这些很可能会在2023年底之前提交上市申请。 6受挫而停止开发的抗体疗法 医药公司每年都会通过停止某些药物开发来优化管线，其原因包括缺乏足够的疗效或存在安全信号，以及商业考虑，如其他资产的优先顺序、竞争格局变化以及进一步开发的资金可用性。在排除SARS-CoV-2抗体疗法的情况下，2022年在开发后期停止使用的抗体疗法的数量很少，与过去几年的数量相似。例如，Regeneron停止了fasinumab 和REGN1908-1909的临床开发，其都已进入III期研究，但由于安全性或疗效不足而停止了开发。在向监管机构提交上市申请后而停止的抗体治疗是罕见的，在过去的20年里只发生了不到6例。Oportuzumab monatox是一种免疫毒素，由人源化的抗上皮细胞黏附分子ScFv连接到ETA（252-608）假单胞菌外毒素，Sesen Bio分别向FDA和EMA提交了BLA和MAA以用于治疗卡介苗反应不敏感的非肌肉浸润性膀胱癌。然而，在2021年8月，该公司收到了FDA的一封完整的回复信，建议提供更多的临床/统计数据和分析，然后其撤回MAA。2022年，Sesen Bio宣布自愿暂停进一步开发该药物，然后与开发细胞和基因疗法的Carisma治疗公司进行了合并重组。 7抗体市场的未来展望 抗体疗法的商业临床管线在过去一年中依然显示出大幅增长，尽管与2022年年增长率相比，速度略有放缓。美国或欧盟地区首次获得批准的抗体疗法已达12款，在年底前有望达到或超过之前的纪录（13个）。美国和欧盟以外地区的年度批准药物数量也正在逐步增加。值得注意的是，这一年工程化抗体疗法（例如双抗）和抗体偶联药物（例如，ADC）取得了重大进展，在通过后期临床研究和监管审查后，其有望很快进入市场。然而，在过去的几年里，一些抗体疗法的BLA需要进行第二轮审查，这推迟了它们的批准，但不一定会影响其获批。FDA最近开始更加重视旨在加速批准的药物的验证性临床研究，尤其是抗癌药物。加速审批途径允许FDA根据药物对替代终点的影响批准用于严重或危及生命的疾病的产品，该终点可以合理的预测患者的临床益处，但需要进行必要的批准后验证试验来确认该药物是否提供了预期的临床益处。如果没有确认任何益处，则制药公司或FDA可能会将该产品从市场上撤掉。2022年10月20日发表在《新英格兰医学杂志》上的一篇文章阐述了FDA目前对加速批准抗癌药物的想法，在这篇文章中，作者提出一些观点，认为可以使用一些方法来缩短从加速批准到确认药物是否提供益处的时间。数据显示，如果正在进行验证性研究，停药时间的中位数是3.8年，而如果没有开始这样的研究，当药物获得加速批准时，停药时间的中位数是7.3年。在此期间，患者暴露在药物的风险中，但没有获得预期的益处。在抗体治疗领域，getuzumab ozogamicin（Mylotarg）提供了一个很好的例子。Mylotarg于2000年获得FDA的加速批准，在上市十多年后，由于验证试验未能验证预期的临床益处并表现出安全性问题后自愿撤回。随后的研究最终使该药物于2017年重返美国市场。在最近的一个例子中，应FDA的请求，GSK于2022年11月自愿从美国市场上撤回Blenrep（belantamab mafodotin-blmf），因为确证的III期DREAMM-3试验不符合加速批准规定的要求。然而其他正在进行的潜在确证试验（DREAMM-7，DREAMM-8）可能允许该药物未来重返美国市场。 参考文献：Antibodies to watch in 2023. MAbs

AFM13: Secured access to commercially viable natural killer (NK) cell product to accelerate clinical development of AFM13 and address the high unmet need of CD30-positive lymphoma patients through a collaboration with Artiva Biotherapeutics; an Investigational New Drug (IND) application filing is expected in H1 2023 AFM13 combination with NK cells: As of July 31, 2022 in 24 patients with CD30-positive lymphoma treated at the highest dose level of the combination treatment of AFM13 with allogeneic cord-blood derived NK cells continues to achieve a 100% overall response rate (ORR) and an improved 70.8% complete response rate (CR) AFM13 monotherapy: On track to report topline data of the registration-directed REDIRECT trial in mid-December 2022 AFM24: Updated data from AFM24-101 and AFM24-102 presented at the Society for Immunotherapy of Cancer (SITC) show first partial response to AFM24 in combination with atezolizumab; data updates from the three ongoing studies are expected at major scientific conferences in Q2 and Q3 of 2023 AFM28: Clinical trial applications (CTA) have been filed in European countries and initiation of phase 1 study is expected in the H1 of 2023 Net cash used in operating activities for the quarter ended September 30, 2022, was €19.0 million Cash and cash equivalents as of September 30, 2022, were approximately €222.9 million with anticipated cash runway into mid-2024 Conference call and webcast scheduled for November 15, 2022, at 8:30 a.m. EST / 14:30 CET HEIDELBERG, Germany, Nov. 15, 2022 (GLOBE NEWSWIRE) -- Affimed N.V. (Nasdaq: AFMD) (“Affimed” or the “Company”), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, today reported financial results for the third quarter ended September 30, 2022 and provided an update on clinical and corporate progress. “We are excited to have secured a partner that is able to provide a commercially viable NK cell product that enables us to start a registration directed, multicenter clinical trial in order to bring this promising treatment to patients in need as fast as possible. This collaboration builds on the foundation of the exceptional data of AFM13 in combination with NK cells that will be presented at ASH,” said Dr. Adi Hoess, CEO of Affimed. “The progress we are making across our pipeline has laid the foundation for the next steps of development. We are looking forward to sharing key clinical milestones before the end of this year, including topline data from the REDIRECT study and data from the combination of AFM13 with NK cells.” Clinical Stage Program Updates AFM13 (CD30/CD16A) Affimed expects to report topline data from the phase 2 REDIRECT study (AFM13-202) of AFM13 monotherapy in patients with relapsed / refractory (r/r) CD30-positive peripheral T-cell lymphoma (PTCL) in mid-December. REDIRECT is a phase 2, registration-directed study of AFM13 monotherapy that has completed enrollment of more than 100 r/r PTCL patients. The focus of the topline data will be the overall response rate and preliminary assessment of response duration. A clinical update from the ongoing phase 1/2 trial with Affimed’s lead innate cell engager (ICE®) AFM13 precomplexed with cord blood-derived NK cells followed by three weekly infusions of AFM13 in patients with CD30-positive r/r Hodgkin and non-Hodgkin lymphomas will be provided at the upcoming ASH conference in an oral presentation by Dr. Yago Nieto, M.D., Ph.D., Professor of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center and principal investigator of the study, on Saturday, December 10, 2022 at 1:15 p.m. CST / 2:15 p.m. EST. Since the last study update in April 2022 until July 31, 2022 an additional 11 patients were enrolled, resulting in 24 patients treated at the recommended phase 2 dose (RP2D) with up to 4 cycles; a total of 30 patients have been enrolled in the study. The combination treatment continues to show a 100% ORR at the highest dose level and a further improvement in the CR rate, from the previously reported 61.5% to 70.8%. The safety pro AFM13 is consistent with previously reported data of infusion related reactions being manageable, with the main treatment-related side-effect being infusion-related reactions. The side effects observed in the trial were transient and did not lead to treatment delays or discontinuations. Affimed plans to host an in-person investor meeting and webcast in conjunction with the American Society of Hematology (ASH) Annual Meeting and Exposition on Saturday, Dec. 10, 2022. Partnership with Artiva In November 2022, Affimed announced a strategic partnership with Artiva Biotherapeutics to jointly develop, manufacture and commercialize a combination therapy of AFM13 and Artiva’s cord blood-derived, cryopreserved/off-the-shelf, allogeneic NK cell product candidate, AB-101 in CD30-positive lymphomas. Affimed submitted a pre-IND meeting request for the AFM13 and AB-101 co-administered combination therapy to the U.S. Food and Drug Administration (FDA) requesting feedback on the clinical trial design in relapsed/refractory (r/r) Hodgkin lymphoma with an exploratory arm evaluating the combination in r/r CD30-positive peripheral T-cell lymphoma and potential path to registration. The FDA is expected to provide feedback by Q1 2023. The companies expect to submit an Investigational New Drug (IND) application to the FDA in H1 2023. AFM24 (EGFR/CD16A) AFM24-101: Affimed continues to enroll patients in the expansion phase of the AFM24 monotherapy study at the RP2D. The expansion cohorts include patients with renal cell carcinoma (clear cell), non-small cell lung cancer (EFGR mutant) and colorectal cancer. Comprehensive correlative science findings of the AFM24-101 study presented in a poster at the 37th SITC Annual Meeting showed that starting at low doses of AFM24, NK cell activation was seen in peripheral blood. CD16A receptor occupancy leveled off at doses of 320mg and above, indicating receptor saturation. Activation of the adaptive immune system was also seen at higher doses of AFM24. When tissue biopsies were analyzed, AFM24-treated patients had an increase in NK cells and cytotoxic T cells in the tumor, suggesting that treatment with AFM24 activates both the innate and adaptive immune system in the periphery of the tumor as well as the tumor microenvironment. AFM24-102: Enrollment continues in the phase 1/2a combination study of AFM24 with the anti-PD-L1 checkpoint inhibitor atezolizumab (Tecentriq®) in patients with advanced epidermal growth factor receptor-expressing solid tumors. AFM24-102 includes patients with non-small cell lung cancer (EGFR wildtype), gastric and gastroesophageal junction adenocarcinoma and pancreatic/hepatocellular/biliary tract cancer. Patients being enrolled in the study are required to have progressed or relapsed on standard of care therapies. The first cohort (160 mg) was completed successfully with no reports of dose-limiting toxicities (DLTs). Enrollment is ongoing in the second dose escalation cohort treating patients with a weekly AFM24 dose of 480 mg. No DLTs were observed in the first three patients treated in this cohort and three additional patients are being enrolled at this dose level to confirm 480 mg as the RP2D. Data from the first cohort of the phase 1 dose escalation study presented at SITC showed that clinical activity was observed in two patients at the 160 mg dose level. A patient with gastric cancer and skin metastases who had rapidly progressed following four prior lines of therapy, including a PD-1 inhibitor, achieved a partial response (PR). The second patient with pancreatic adenocarcinoma showed stable disease (SD) beyond four months. AFM24-103: In the phase 1/2a combination study of AFM24 with SNK01, NKGen Biotech’s ex vivo expanded and activated autologous NK cell therapy, enrollment has been completed in the first dose cohort (160 mg AFM24 weekly), with no DLTs observed. The Company is currently enrolling patients at the 480 mg dose level. AFM24-103 is focused on the treatment of patients with non-small cell lung cancer (NSCLC, EGFR-wildtype), squamous cell carcinoma of the head and neck, and colorectal cancer. Affimed expects to provide data updates from the three ongoing studies at major scientific conferences in Q2 and Q3 of 2023. Preclinical Programs AFM28 (CD123/CD16A) Affimed’s AFM28 ICE® targets CD16A on NK cells and macrophages, and CD123 on leukemic blasts and leukemic stem cells that are prevalent in acute myeloid leukemia (AML). Pre-clinical data from a collaboration between Affimed and the Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University will be presented at the ASH conference. The study evaluated the efficacy of AFM28 in preclinical AML models. In a panel of AML cell lines, AFM28 successfully engaged allogeneic NK cells to destroy CD132-positive tumor cells through antibody-dependent cytotoxicity (ADCC). ADCC induced by AFM28 was independent of leukemic cell mutational profiles and was also effective in targeting cells with low levels of CD123 surface expression. Residual leukemic stem cells are a frequent cause for relapse and associated with poor prognosis. Patient-derived AML cell cultures incubated with AFM28 and allogeneic NK cells showed significantly reduced numbers of outgrowing colonies compared to controls. That indicates that LSCs and progenitor cells were eliminated. These results were confirmed in an AML mouse model demonstrating complete inhibition of tumor growth throughout a 42-day treatment period in comparison to untreated control mice who all developed systemic disease. The Company anticipates initiating the phase 1 clinical study for AFM28 in the first half of 2023. Partnerships and Collaborations Partnered programs with Genentech and Roivant continue to progress. Roivant presented a poster at SITC that AFVT-2101/AFM32 represents a novel approach to treating folate receptor alpha (FRα) expressing tumors by engaging the innate immune response for safe and effective tumor cell killing. The company announced that it is expecting to enter phase 1 clinical trial in 2023. Affimed is eligible for additional proceeds including pre-clinical milestones as well as milestones based on early regulatory achievements. Third Quarter 2022 Financial Highlights Affimed's consolidated financial statements are prepared in accordance with International Financial Reporting Standards (IFRS) as issued by the International Accounting Standard Board (IASB). The consolidated financial statements are presented in Euros (€), the Company's functional and presentation currency. As of September 30, 2022, cash and cash equivalents totaled €222.9 million compared to €197.6 million on December 31, 2021. Based on the Company’s current operating plan and assumptions, cash and cash equivalents are expected to support operations into mid-2024. Net cash used in operating activities for the quarter ended September 30, 2022, was €19.0 million compared to €25.6 million for the quarter ended September 30, 2021. Total revenue for the quarter ended September 30, 2022, was €14.9 million compared with €8.7 million for the quarter ended September 30, 2021. Revenue predominately relates to the Genentech and Roivant collaborations. Research and development expenses for the quarter ended September 30, 2022, increased by 27% from €20.6 million to €26.1 million compared to the quarter ended September 30, 2021. Research and development expenses increased primarily due to higher expenses associated with the development of the AFM13 and AFM24 programs and included costs to produce clinical trial material, clinical patient trial costs and manufacturing, an increase in costs associated with other early-stage programs and infrastructure, and an increase in share-based payment expenses. General and administrative expenses increased 19% from €6.8 million in the quarter ended September 30, 2021 to €8.1 million in the quarter ended September 30, 2022. The increase predominately relates to an increase in headcount, higher share-based payment expenses, an increase in insurance premiums and higher consulting costs. Net finance income for the quarter ended September 30, 2022 increased by 84% from €1.5 million in the quarter ended September 30, 2021, to €2.7 million. Net finance income is largely the result of foreign exchange gains related to assets denominated in U.S. dollars as a result of currency fluctuations between the U.S. dollar and the Euro during the year. Net loss for the quarter ended September 30, 2022, was €16.5 million, or €0.11 loss per common share compared with a net loss of €17.1 million, or €0.14 loss per common share, for the quarter ended September 30, 2021. The weighted number of common shares outstanding for the quarter ended September 30, 2022 was 149.3 million. Additional information regarding these results is included in the notes to the consolidated financial statements as of September 30, 2022, which will be included in Affimed’s filings with the U.S. Securities and Exchange Commission (SEC). Note on International Financial Reporting Standards (IFRS) Affimed prepares and reports consolidated financial statements and financial information in accordance with IFRS as issued by the IASB. None of the financial statements were prepared in accordance with Generally Accepted Accounting Principles in the United States. Affimed maintains its books and records in Euro. Conference Call and Webcast Information Affimed will host a conference call and webcast November 15, 2022, at 8:30 a.m. EST / 14:30 CET to discuss third quarter 2022 financial results and corporate developments. The conference call will be available via phone and webcast. The live audio webcast of the call will be available in the “Webcasts” section on the “Investors” page of the Affimed website at . To access the call by phone, please use link , and you will be provided with dial-in details and a pin number. Notes: To avoid delays, we encourage participants to dial into the conference call 15 minutes ahead of the scheduled start time. A replay of the webcast will be accessible at the same link for 30 days following the call. About Affimed N.V. Affimed (Nasdaq: AFMD) is a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer by actualizing the untapped potential of the innate immune system. The Company’s proprietary ROCK® platform enables a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors, enabling a broad pipeline of wholly-owned and partnered single agent and combination therapy programs. The ROCK® platform predictably generates customized innate cell engager (ICE®) molecules, which use patients’ immune cells to destroy tumor cells. This innovative approach enabled Affimed to become the first company with a clinical-stage ICE®. Headquartered in Heidelberg, Germany, with offices in New York, NY, Affimed is led by an experienced team of biotechnology and pharmaceutical leaders united by a bold vision to stop cancer from ever derailing patients’ lives. For more about the Company’s people, pipeline and partners, please visit: . Forward-Looking Statements This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. Forward-looking statements appear in a number of places throughout this release and include statements regarding the Company’s intentions, beliefs, projections, outlook, analyses and current expectations concerning, among other things, the potential of AFM13, AFM24, AFM28 and the Company’s other product candidates, the value of its ROCK® platform, its ongoing and planned preclinical development and clinical trials, its collaborations and development of its products in combination with other therapies, the timing of and its ability to make regulatory filings and obtain and maintain regulatory approvals for its product candidates, its intellectual property position, its collaboration activities, its ability to develop commercial functions, clinical trial data, its results of operations, cash needs, financial condition, liquidity, prospects, future transactions, growth and strategies, the industry in which it operates, the trends that may affect the industry or the Company, impacts of the COVID-19 pandemic, the benefits to Affimed of orphan drug designation, the impact on its business by political events, war, terrorism, business interruptions and other geopolitical events and uncertainties, such as the Russia-Ukraine conflict, the fact that the current clinical data of AFM13 in combination with NK cell therapy is based on AFM13 precomplexed with fresh allogeneic cord blood-derived NK cells from The University of Texas MD Anderson Cancer Center, as opposed to Artiva’s AB-101 and other uncertainties and factors described under the heading “Risk Factors” in Affimed’s filings with the SEC. Given these risks, uncertainties, and other factors, you should not place undue reliance on these forward-looking statements, and the Company assumes no obligation to update these forward-looking statements, even if new information becomes available in the future. Investor Relations Contact Alexander Fudukidis Director, Investor Relations E-Mail: a.fudukidis@affimed.com Tel.: +1 (917) 436-8102 Unaudited consolidated interim statements of comprehensive income / (loss) (in € thousand) For the three months ended September For the nine months ended September 2022 2021 2022 2021 Revenue 14,888 8,662 30,195 30,028 Other income – net 118 231 642 710 Research and development expenses (26,126) (20,621) (65,333) (53,826) General and administrative expenses (8,089) (6,841) (23,509) (16,766) Operating loss (19,209) (18,569) (58,005) (39,854) Finance income / (costs) – net 2,719 1,474 5,443 5,421 Loss before tax (16,490) (17,095) (52,562) (34,433) Income taxes 0 0 (2) (2) Loss for the period (16,490) (17,095) (52,564) (34,435) Other comprehensive income / (loss) Items that will not be reclassified to profit or loss Equity investments at fair value OCI – net change in fair value (73) (3,489) (6,846) (8,838) Other comprehensive income / (loss) (73) (3,489) (6,846) (8,838) Total comprehensive income / (loss) (16,563) (20,584) (59,410) (43,273) Basic and diluted earnings / (loss) per share in € per share (undiluted = diluted) (0.11) (0.14) (0.38) (0.29) Weighted number of common shares outstanding 149,339,335 119,786,695 140,036,614 118,545,453 Consolidated interim statements of financial position (in € thousand) September 30, 2022 December 31, 2021 (unaudited) ASSETS Non-current assets Intangible assets 1,555 1,607 Leasehold improvements and equipment 3,584 3,814 Long-term financial assets 0 12,348 Right-of-use assets 710 972 5,849 18,741 Current assets Cash and cash equivalents 222,895 197,630 Trade and other receivables 1,691 4,809 Inventories 673 421 Assets held for sale 1,731 0 Other assets and prepaid expenses 3,560 3,534 230,550 206,394 TOTAL ASSETS 236,399 225,135 EQUITY AND LIABILITIES Equity Issued capital 1,493 1,234 Capital reserves 578,390 474,087 Fair value reserves (5,954) (5,973) Accumulated deficit (392,826) (333,397) Total equity 181,103 135,951 Non current liabilities Borrowings 13,027 17,060 Contract liabilities 1,238 7,209 Lease liabilities 203 368 Total non-current liabilities 14,468 24,637 Current liabilities Trade and other payables 15,078 18,860 Borrowings 4,957 580 Lease liabilities 541 683 Contract liabilities 20,252 44,424 Total current liabilities 40,828 64,547 TOTAL EQUITY AND LIABILITIES 236,399 225,135 Unaudited consolidated interim statements of cash flows (in € thousand) For the nine months ended September 30, 2022 2021 Cash flow from operating activities Income / (loss) for the period (52,564) (34,435) Adjustments for the period: - Income taxes 2 2 - Depreciation and amortization 1,066 935 - Net gain / loss from disposal of leasehold improvements and equipment 0 (2) - Share-based payments 14,779 8,117 - Finance income / costs – net (5,443) (5,421) (42,160) (30,804) Change in trade and other receivables 3,118 (1,320) Change in inventories (252) (446) Change in other assets and prepaid expenses (26) 1,064 Change in trade, other payables, provisions and contract liabilities (33,888) (26,802) (73,208) (58,308) Interest received 228 0 Paid interest (950) (647) Paid income tax (2) (2) Net cash used in operating activities (73,932) (58,957) Cash flow from investing activities Purchase of intangible assets (30) (5) Purchase of leasehold improvements and equipment (263) (1,527) Cash received from the sale of financial assets 3,772 0 Net cash used for investing activities 3,479 (1,532) Cash flow from financing activities Proceeds from issue of common shares, including exercise of share-based payment awards 95,907 103,379 Transaction costs related to issue of common shares (6,159) (6,548) Proceeds from borrowings 0 10,000 Transaction costs related to borrowings 0 (236) Repayment of lease liabilities (538) (372) Repayment of borrowings (70) (69) Cash flow from financing activities 89,140 106,154 Exchange-rate related changes of cash and cash equivalents 6,578 6,223 Net changes to cash and cash equivalents 18,687 45,665 Cash and cash equivalents at the beginning of the period 197,630 146,854 Cash and cash equivalents at the end of the period 222,895 198,742 Unaudited consolidated interim statements of changes in equity (in € thousand) Issued capital Capital reserves Fair Value reserves Accumulated deficit Total equity Balance as of January 1, 2021 983 345,164 1,720 (275,874) 71,993 Issue of common shares 205 94,138 94,343 Exercise of share-based payment awards 10 2,667 2,677 Equity-settled share-based payment awards 8,117 8,117 Loss for the period (34,435) (34,435) Other comprehensive loss (8,838) (8,838) Balance as of September 30, 2021 1,198 450,086 (7,118) (310,309) 133,857 Balance as of January 1, 2022 1,234 474,087 (5,973) (333,397) 135,951 Issue of common shares 259 89,423 89,682 Exercise of share-based payment awards 101 101 Equity-settled share-based payment awards 14,779 14,779 Transfer of cumulative loss on sale of financial assets 6,865 (6,865) 0 Loss for the period (52,564) (52,564) Other comprehensive loss (6,846) (6,846) Balance as of September 30, 2022 1,493 578,390 (5,954) (392,826) 181,103