Trastuzumab Pamirtecan

欢迎关注凯莱英要闻7月1日，中国药物临床试验登记与信息公示平台更新了一项第一三共/默沙东登记的B7-H3 ADC药物Ifinatamab Deruxtecan相关III期临床研究，该试验为在前线转移性去势抵抗性前列腺癌（mCRPC）受试者中比较Ifinatamab Deruxtecan与多西他赛的有效性和安全性。Ifinatamab Deruxtecan也成为首个启动前列腺癌适应症III期临床的 B7-H3 ADC。该试验是一项名为 IDeate-Prostate01 的国际多中心、随机、平行、开放性的III期研究，主要终点指标为总生存期（OS）以及影像学无进展生存期（rPFS），次要终点包含TFST、OR、DOR等多项指标。目标入组患者数量为国内216人，国外1440人。Ifinatamab deruxtecan  (I-DXd，DS-7300a)是一款潜在 first-in-class 靶向 B7-H3 的 ADC。该药采用第一三共独有的 DXd ADC 技术设计，由人源化抗 B7-H3 IgG1 单克隆抗体通过可裂解四肽连接子与拓扑异构酶 I 抑制剂有效载荷（一种依喜替康衍生物，DXd）连接组成。目前，Ifinatamab deruxtecan是全球研发进展最快的B7-H3 ADC，在小细胞肺癌、非小细胞肺癌、前列腺癌、食管癌、黑色素瘤等多个热门肿瘤领域均进行探索，其中小细胞肺癌、食管癌、前列腺癌均已进入临床III期试验阶段。数据来源：Insight数据库2023年10月，默沙东与第一三共宣布就三款ADC候选药物：patritumab deruxtecan（HER3-DXd）、ifinatamab deruxtecan（I-DXd）和raludotatug deruxtecan（R-DXd）达成价值220亿美元的全球（除日本外）开发和商业化协议。B7-H3B7-H3（又称CD276）是一种Ⅰ型跨膜糖蛋白，属于B7超家族中的一员，在单核细胞和粒细胞及人体正常组织中均无表达，而在一些树突状细胞、T 细胞、自然杀伤（NK） 细胞和B 细胞上有表达是近年来新发现的免疫检查点。该靶点不仅可通过抑制免疫系统促成肿瘤细胞的免疫逃逸，还可通过一些非免疫途径介导肿瘤的转移、耐药、血管生成从而促进癌症进展。同属于B7家族的还有：B7-1（CD80）、B7-2（CD86）、B7-DC（PD-L2或CD273）、B7-H1（PD-L1或CD274）、B7-H2（ICOSLG）、B7-H4（VTCN1）、B7-H5（VISTA）、B7-H6（NCR3LG1）和 B7-H7（HHLA2）。B7家族被证明为T细胞激活中的共刺激或共抑制分子，其配体和受体在适应性免疫反应和恶性肿瘤中发挥关键作用。B7-H3靶点的研发可谓命途多舛，MacroGenics的B7-H3单抗曾因发生患者死亡而叫停针对头颈鳞癌的III期临床试验。如今也有接近60个项目处于非积极或不活跃状态。但这并没有阻拦各大企业对这一热门靶点的探索。现在，针对B7-H3靶点的单抗、双抗、融合蛋白、CAR-T疗法的开发都在进行中，最火热的仍属ADC。目前在研B7-H3靶点药物超过200个，ADC药物也接近70个，进入临床阶段的有20个。尚无获批上市的产品。国内企业中，翰森制药、宜联生物、映恩生物、信达生物、迈威生物、石药集团、百济神州等知名药业皆有所布局。医药交易方面，针对B7-H3靶点药物的交易达到14项，其中ADC就占11项之多。交易金额最大的属两笔国内企业与MNC巨头的授权许可。· 2023年12月，GSK与翰森制药达成全球独家授权许可协议（除大中华区外），以17.1亿美元引进翰森制药HS-20093。· 2023年4月，BioNTech与映恩生物达成独家许可合作协议，以16.7亿美元引进DB-1303（HER2）及DB-1311（B7-H3）两款药物。PD-(L)1与B7H3 ADC的双抗与联用近年来，PD-1+ADC 联合疗法在多种肿瘤一线治疗中表现十分亮眼。Ifinatamab deruxtecan作为B7-H3研发前列的领头者，在2024年4月，就启动了联合罗氏PD-L1抗体Atezolizumab，在小细胞肺癌患者中开展1/2期临床试验，计划入组总人数为149例。同样，还开展了联合帕博利珠单抗治疗一线局部晚期不可切除/转移性食管癌的I/II期临床试验。今年年初，宜联生物宣布与阿斯利康建立临床研究合作，共同探索YL201（靶向B7H3的抗体偶联药物）与度伐利尤单抗（抗PD-L1免疫检查点抑制剂）联用，治疗多种实体瘤的潜力。双方将共同启动一项多中心、开放性、I/Ib期研究，旨在评估YL201联合度伐利尤单抗在实体肿瘤患者中的安全性、有效性和药代动力学。翰森制药也在2025年正式启动HS-20093和PD-L1抗体Adebrelimab、EGFR抗体Cetuximab、前列腺去势药物恩杂鲁胺(Enzalutamide)等多种药物治疗实体瘤的I期试验。映恩生物与BioNTech达成交易的DB-1311也在2025年登记新的Ib/II期临床研究，联合PDL1/VEGF双抗BNT327用于治疗晚期肺癌。而映恩生物自身的DB-1419作为B7-H3/PD-L1双抗ADC也于陆续在国内外获批临床，用于治疗晚期/转移性实体瘤。感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“queenachuen”。“在看”点一下

The move was influenced by BioNTech’s decision to stop development of its CLDN6-directed CAR-T asset BNT211 in testicular cancer with germ cell tumors, a company spokesperson said. Following a disappointing performance from the company’s CAR-T candidate in an early-stage cancer trial, BioNTech is winding down cell therapy manufacturing at its inaugural U.S. plant.BioNTech will lay off 63 employees at its Gaithersburg, Maryland, cell therapy facility beginning later this summer, according to a Worker Adjustment and Retraining Notification (WARN) alert recently filed with the state.The company has elected to end cell therapy manufacturing at the site—which it acquired from Gilead Sciences’ Kite Pharma in 2021—by the end of the year, a company spokesperson said in an emailed statement.The move, expected to impact members of the Gaithersburg site’s cell therapy technical operations team, was influenced by BioNTech’s decision to stop development of its CLDN6-directed CAR-T asset BNT211 in testicular cancer with germ cell tumors, the spokesperson explained.“Following a thorough assessment of data from a signal-seeking Phase 1 clinical trial on BNT211 in testicular cancer/germ cell tumors, BioNTech has decided to discontinue future investigation of this candidate in this indication,” she said.The discontinuation in testicular cancer won’t affect BioNTech’s ongoing phase 1 BNT211-01 study of the CAR-T prospect in patients with CLDN6-positive relapsed or refractory solid tumors, the spokesperson said.CLDN6 is a protein target expressed on multiple solid tumors, including ovarian cancer, sarcoma, testicular cancer, endometrial cancer and gastric cancer.“We will reassess the clinical development strategy for this asset, including potentially considering evaluating the candidate in other indications,” the spokesperson said, adding that BioNTech “will be realigning Gaithersburg capabilities to support the company’s pipeline” in the coming months. The Gaithersburg cell therapy site became BioNTech’s first U.S. production facility when the German biotech purchased the plant from Gilead’s Kite Pharma unit in July 2021. At the time, BioNTech said it would extend job offers to all 50 Kite staffers who were then working at the facility.While BioNTech will move forward with the development of BNT211 in other oncology indications, this isn’t the first time the company has adjusted its CAR-T priorities this year.Back in March, BioNTech passed on an option to co-develop a dual-targeting CAR-T cell therapy with Autolus Therapeutics, one year after locking down the opportunity to work on the asset.Autolus said that BioNTech declined to exercise its product option for the prospect, coded AUTO1/22, which the biotech attributed to a pipeline prioritization effort BioNTech unveiled earlier that same month.BioNTech picked up the option last February in a $250 million upfront collaboration that also gave it access to Autolus’ manufacturing and clinical site network in the U.K. BioNTech noted at the time that it would use the new infrastructure to continue developing and producing BNT211 for pivotal trials in CLDN6+ tumors. While BioNTech entered the limelight thanks to its Pfizer-partnered mRNA vaccine for COVID-19, the German drugmaker has increasingly turned its attention toward cancer as it seeks to become a “fully integrated immunotherapy powerhouse.”To advance those ambitions, BioNTech executives said in May that the company plans to set up “supply nodes” for the antibody-drug conjugate (ADC) asset BNT323 to help curb its dependence on China suppliers. BioNTech has said it hopes to submit the ADC for FDA review sometime this year.Meanwhile, BioNTech last month telegraphed plans to invest up to 1 billion pounds sterling over the next decade to bolster its R&D operations in the United Kingdom. The project covers the buildout of two new research centers in the country, plus a U.K. headquarters for the company in London.One of the R&D centers, planned for Cambridge, will focus on projects around genomics, oncology, structural biology and regenerative medicine, BioNTech said. And just last week, BioNTech bought out its German mRNA compatriot CureVac in an all-stock transaction worth $1.25 billion. In unveiling the deal, BioNTech glossed over plans to onboard any of CureVac’s mRNA vaccine candidates, instead focusing on the potential of CureVac’s cutting-edge research and manufacturing site in Tübingen, Germany.