Raludotatug deruxtecan

前言：AnTenGager是德琪自主开发的第二代TCE平台，采用二价结合DAA实现高亲和力，同时采用空间位阻遮蔽CD3实现良好的安全性。TCE作为接棒ADC/双抗的生物药热点，商业价值极高。目前，AnTenGager已孵化10条管线，仅ATG-201就有达成首付款超7亿美元授权的潜力，从现有市值看，相当于再造2个德琪，预期差拉满。TCE是一种双特异性抗体，拥有两种不同的抗原结合域，一种靶向致病细胞表面特异性抗原（TAA，e.g.BCMA、CD19等），另一种靶向T细胞表面受体（e.g.CD3）。不同于传统抗体，TCE无需依赖抗原呈递细胞或MHC分子，能够直接桥接T细胞和致病细胞，形成免疫突触并激活T细胞免疫杀伤功能，在实体瘤、血液瘤、自免疾病领域有治疗潜力。目前，TCE已经发展至第二代。第一代TCE结构通常为「1+1」型，即1个TAA结合臂+1个CD3结合臂，代表药物是Amgen的blinatumomab（CD19×CD3）。第二代TCE结构通常为「2+1」型，即2个TAA结合臂+1个CD3结合臂，代表药物是Roche的glofitamab（CD20xCD3）。相比第一代，第二代TCE通过二价结合提升靶点结合亲和力，并对CD3进行遮蔽处理以降低脱靶和CRS风险。德琪「AnTenGager™」是基于「2+1」结构构建的第二代平台，采用独具一格的空间位阻遮蔽技术，其优势表现为：1.二价结合DAA，亲和力高，可靶向低表达靶点。兼容各种DAA，即插即用，能够开发跨多个治疗领域的TCE。2.利用空间位阻效应实现CD3遮蔽和靶点依赖活性，最大限度减少脱靶因子释放，降低hookeffect和CRS风险。3.CD3序列自主设计，通过与独特构象表位结合（CD3εγ或CD3εσ复合体），具有快上快下的结合动力学，最大程度减少在靶因子释放，并保持强大的T细胞激活作用。4.半衰期更长，小鼠体内半衰期为100-300小时。与其他2+1平台对比，AnTenGager的条件激活逻辑精准、适应症范围广阔、安全性更佳。Roche(Prot-TCB)、Janux(TRACTr)、Xilio的CD3遮蔽需要酶切暴露，依赖肿瘤微环境，只能应用于癌症领域；Xencor(XmAb)、Zymeworks(Azymetric)、信达(Innobody)、维立志博(Leadsbody)的CD3表位保守，使用的是已过专利期的sp34衍生序列，通过下调亲和力降低CRS的策略可能会牺牲T细胞激活强度。另外，研发日上侯冰博士提到，AnTenGager的空间位阻遮蔽是公司自主设计的双抗结构与CD3序列适配的结果，竞对难以复制，技术壁垒较高。基于AnTenGager，德琪开发了10条TCE管线，聚焦实体瘤、血液瘤、自免疾病的治疗，包括2条未披露靶点的三抗，其中「ATG-201」研发进度最为领先。公司对于TCE平台的BD保持开放的态度，平台授权或产品授权都是潜在的合作形式。简单评估已披露靶点TCE管线的价值：1.ATG-201（CD19xCD3，计划26Q4IND）：MSD于2024年8月收购同润临床前CD19xCD3TCECN201，交易对价13亿美元，其中首付款高达7亿美元。临床前模型中，ATG-201显示较CN201具有更深且更持久的体内B细胞清除，同时安全性更佳。ATG-201潜在BD价值可对标CN201，预计首付款超7亿美元，仅首付款就约等于2个德琪的市值。2.ATG-106（CDH6xCD3，计划27Q1IND）：MSD于2023年10月引进第一三共三款ADC（一款为CDH6ADCR-DXd），BD早期付款45亿美元。第一三共对于合约进行拆分，R-DXd对应的早期付款为15亿美元，合同执行后立即支付7.5亿美元。ATG-106与R-DXd同为FIC，且适应症均为卵巢癌+肾癌，BD价值可以相互对标。鉴于ATG-106处于临床前，而R-DXd授权时处于临床I期，保守预估ATG-106首付款不低于R-DXd的40%，即＞3亿美元。3.ATG-112（ALPPL2xCD3，计划26Q1IND）：ALPP/G在除胎盘外的正常组织中不表达，但在子宫内膜、卵巢、膀胱、胃部实体瘤中广泛表达，有望成为晚期实体瘤的治疗靶点。ATG-112是FICALPPL2xCD3TCE，已经展现出较强体内、体外肿瘤抑制活性。在小鼠模型中，ATG-122在不同剂量下（0.1、0.05、0.02mg/kg）均能有效抑制肿瘤生长。目前尚无其他ALPPL2TCE进入临床，仅有一款同靶点CAR-TAB-1015处于临床I期，而且近期由于资源调整暂停开发。在B轮融资阶段，AB-1015是ArsenalBio的核心资产，当时该公司的投后估值为10亿美元左右。4.ATG-110（LY6G5DxCD3，计划27H1IND）：LY6G6D在正常组织中几乎不表达，而在对于IO不敏感的pMMR/MSSmCRC中高表达。pMMR/MSSmCRC在mCRC患者人群中占比超过90%，人群基数大。LY6G6DxCD3TCE在研厂家较多，国外有罗氏、CartographyBiosciences，国内有齐鲁、东阳光药等。Cartography的CBI-1214是该领域的明星项目，计划在26年初启动I期临床。2025年10月，Cartography完成6700万美元B轮投资，由PfizerVentures领投。5.ATG-021（GPRC5DxCD3）：该领域已有商业化先例，强生的Talquetamab于2023年获FDA加速批准上市，官方预测销售峰值50亿+。Talquetamab为传统「1+1」结构，ATG-021为第二代「2+1」结构，后者的靶点结合亲和力显著优于前者。此外，由于Talquetamab并未对CD3进行遮蔽，其CRS发生率高达79%，安全性较差。ATG-021的BD价值可对标Talquetamab，若后续人体数据BIC，总deal至少可达30亿美元+。6.ATG-102（LILRB4xCD3）/ATG-107（FLT3xCD3）：目前LILRB4xCD3、FLT3xCD3均无进入临床产品，两款药物具有成为FIC潜力。LILRB4靶点较新，尚无可对标的商业化或已BD管线；ATG-107的商业化价值可以参考FLT3小分子，代表药物诺华米哚妥林销售峰值预计20亿美元+。$德琪医药-B(06996)$

TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)--The first patient has been dosed in a first-in-human phase 1 trial evaluating DS3610 in patients with advanced, metastatic or unresectable solid tumors. DS3610 is an investigational STING agonist antibody drug conjugate (ADC) containing an immunomodulatory payload discovered by Daiichi Sankyo (TSE:4568). Despite the availability of various cancer immunotherapies, there remains an unmet need for novel treatment options with distinct mechanisms of action that may overcome resistance to current immunotherapy, enhance tumor responses and delay disease progression in solid tumors. “By combining precise tumor targeting with an immunotherapy payload, Daiichi Sankyo is exploring a new way to harness the body’s own defenses to attack cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The initiation of this first-in-human trial of DS3610 represents an important step forward in advancing the next wave of our antibody drug conjugate portfolio and reaffirms our commitment to creating transformative medicines for patients with cancer.” About the Phase 1 Trial The multicenter, open-label, first-in-human phase 1 trial will assess the safety, tolerability, preliminary efficacy and pharmacokinetics of DS3610 in patients with advanced, metastatic or unresectable solid tumors for which no additional standard therapy is available. The dose escalation trial will assess the safety and tolerability of increasing doses of DS3610 to determine the recommended doses for expansion in patients with advanced, metastatic or unresectable solid tumors. The trial will evaluate safety endpoints including dose-limiting toxicities and adverse events. Pharmacokinetic and immunogenicity endpoints will also be assessed, as well as exploratory efficacy endpoints including objective response rate, disease control rate, duration of response, time to response, progression-free survival and overall survival. The trial is expected to enroll patients across multiple sites globally, including Asia, Europe and North America. For more information, please visit ClinicalTrials.gov. About DS3610 DS3610 is an investigational STING agonist ADC consisting of a monoclonal antibody with novel Fc modifications attached to an immunomodulatory payload that acts as an agonist of a stimulator of interferon genes (STING). DS3610 delivers a STING agonist payload directly to tumor environments and induces the immune system in the body to target cancer cells. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of eight ADCs in clinical development crafted from ADC technology discovered in-house by Daiichi Sankyo. The DXd ADC Technology platform of Daiichi Sankyo consists of six ADCs in clinical development where each ADC is comprised of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADCs include ENHERTU® and DATROWAY®, which are being jointly developed and commercialized globally with AstraZeneca, and ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd) and patritumab deruxtecan (HER3-DXd), which are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939 is being developed by Daiichi Sankyo. Additional ADCs being developed by Daiichi Sankyo include DS-9606, which consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload and DS3610, which consists of an antibody attached to a novel immunomodulatory payload that acts as an agonist of STING. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939, DS-9606 and DS3610 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.