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Genmab binned three antibody programmes as part of a pipeline reprioritisation disclosed during the biotech's quarterly earnings call on Wednesday. The culled assets include GEN1047, a CD3/B7H4 bispecific that was in Phase I/II testing for solid tumours; GEN3017, a CD3/CD30 bispecific that had been in a Phase I study for relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma; and GEN1056, a Phase I antibody that was being evaluated for solid tumours in partnership with BioNTech. "These programs simply didn't meet the high bar we have set internally for really having a truly differentiated therapeutic candidate," CEO Jan Van De Winkel said on the call. "We actually intend to focus more on the winners, and expand the breadth of the winners in the future."The company also said it will no longer launch a Phase III trial of Tivdak (tisotumab vedotin) in second and third line squamous cell carcinoma of the head and neck. The antibody-drug conjugate (ADC) won full FDA approval for cervical cancer in April."We continuously evaluate our clinical pipeline to ensure we are prioritising our resources in the best and most effective way possible," Van De Winkel explained. The pruned pipeline "means we are very focussed on maximising the potential of our Phase III programmes," he added, listing cancer assets Tepkinly/Epkinly (epcoritamab), rinatabart sesutecan (Rina-S), and.The former is in five late-stage studies for various cancers, while acasunlimab, a bispecific directed against PD-L1 and 4-1BB, is expected to enter Phase III by year-end for solid tumours. Rina-S is an ADC that targets folate receptor alpha (FRα) and is in development for tumours that express the protein, with a Phase III trial slated to start this quarter. Autoimmunity up next?Despite the slimdown, Van De Winkel assured investors that they "will again see new programmes added to the pipeline."He pointed to the $1.8-billion buyout of ProfoundBio as another source of candidates; Genmab gained Rina-S via the acquisition, along with two other clinical assets. Van De Winkel also commented that, while mainly oncology-focussed now, the biotech has "a very active number of programmes in preclinical development for autoimmune indications… but they are not yet ready for clinical introduction.""The majority of the work at Genmab over the coming years will still be in cancer, where we have our dominant focus, but we are clearly very interested in exploring innovative ways to move towards autoimmune with the T-cell engager programmes, potentially ADCs, and all our next-generation antibody technologies," he said.

关注并星标CPHI制药在线   日前，苏州鑫康合生物医药科技有限公司1类新药「XKH002注射液」在国内首次获得临床试验默示许可，用于治疗晚期实体瘤。       XKH002是鑫康合生物医药自主开发的重组抗B7-H4的阻断性人源化IgG4单克隆抗体，可以有效阻断B7-H4介导的对T细胞增殖和免疫反应的抑制作用，有望治疗对PD-1/PD-L1抗体治疗不响应或者耐药的肿瘤患者。2023年2月，XKH002在美国获批临床。       关于B7-H4及其研究进展       B7-H4，又称B7S1，属于B7家族，是I型跨膜蛋白，由一个信号肽区、一个胞外区、一个跨膜区和一个胞内区组成，2003年首次发现。人类B7-H4 mRNA在多种组织，如肝 脏、骨骼肌、肾脏、胰腺、前列腺、胃、脾、肺等中广泛表达，但B7-H4蛋白却在大多数正常组织中都检测不到。       B7-H4 广泛表达于多种肿瘤和组织，一些炎症因子的微环境能够促进肿瘤细胞及单核细胞、巨噬细胞上B7-H4分子的表达。研究发现，B7-H4在癌症发生和癌症免疫中发挥重要作用，实验证明其调节T细胞的分化，抑制其分化为效应T细胞，介导肿瘤的免疫逃逸。B7-H4阻断效应T细胞的炎症功能，减少IFNγ等细胞因子的产生，并抑制其增殖。相反，B7-H4促进Treg功能，促进IL-10等免疫抑制因子分泌。B7-H4还调节T细胞的分化，抑制其分化为效应T细胞，促进免疫抑制Tregs的产生。       作为抗癌药研发的潜力靶标，目前全球多家药企布局B7-H4靶点，详见下表。在研B7-H4靶向药大多处于1期临床，最快处于2期临床。药物类型上，B7-H4靶向药涉及单抗、双抗、ADC。       在研B7-H4靶向单抗中，NC-762进展较快，2021年7月其针对肺癌、HER2+乳腺癌、卵巢癌或其他潜在肿瘤类型的1/2期临床试验启动。       在研B7-H4靶向ADC中阿斯利康的AZD8205进展最快。AZD8205是首个利用阿斯利康专有linker技术构建的ADC，由新型拓扑异构酶1抑制剂(TOP1i)-linker-B7-H4靶向抗体构成，不但可以直接杀伤B7-H4阳性肿瘤细胞和肿瘤相关巨噬细胞，还可通过旁观者效应杀死周围B7-H4成阴性的癌细胞。       在小鼠的三阴性乳腺癌模型中，AZD8205单次静脉给药就获得了69%的总缓解率，36%达到了完全缓解。在B7-H4高表达和DNA损伤修复缺陷的肿瘤模型中，还表现出更强的抗肿瘤活性。       2023年AACR公布的数据显示：在PARP抑制剂耐药或低B7-H4表达PDX模型中，AZD8205联合AZD5305比单一疗法表现出更高的抗肿瘤活性。而且，AZD8205与抗PD-L1抗体联用时同样增强了抗肿瘤疗效。       Mersana Therapeutics的XMT-1660、豪森药业的HS-20089和Seagen的SGN-B7H4V均处于1期临床。其中XMT-1660是Mersana利用其专有Dolasynthen平台和DolaLock技术开发的ADC，其药物与抗体比率为6，有效载荷是Mersana的DolaLock微管抑制剂，具有可控的旁观者效应。       2022年9月，XMT-1660被FDA授予治疗晚期或转移性三阴性乳腺癌（TNBC）的快速通道认定。       HS-20093是目前进展最快的国产B7-H4靶向ADC，临床前研究中在体外和体内抑制表达B7-H4的肿瘤细胞生长，2021年11月启动1期临床。       在研B7-H4靶向双抗中GEN-1047进展最快，该药是一款利用DuoBody平台设计的靶向CD3/B7-H4的双特异性抗体，目前处于2期临床。       和铂医药开发了两款B7-H4靶向双抗，其中HBM7008是首 个B7-H4/4-1BB双抗，目前处于1期临床。HBM7008由和铂医药创新的免疫细胞衔接器HBICE平台开发，具有独特的肿瘤表达特异性和免疫调控活性，有望在PD-L1阴性或对PD-1/PD-L1免疫治疗药物耐药性的患者中产生更好的疗效。此外，凭借新型生物学作用机制及双抗设计，HBM7008还有望避免4-1BB可能引发的肝毒性风险。       2023年2月，和铂医药与Cullinan Oncology签订授权及合作协议，授予Cullinan Oncology在美国（包括哥伦比亚特区和波多黎各）开发及商业化HBM7008的独家许可权，交易金额达6.25亿美元。       HBM7004是B7-H4/CD3靶向双抗，采取独特的2+1非对称结构设计和更安全的CD3 结合域，目前处于临床前阶段。       总结       与同家族B7-H3靶点相比，B7-H4靶点在研药物数量和进度均较慢，但近年来B7-H4靶向药研发也逐渐火热起来。在研B7-H4靶向药药物类型多样，我国和铂医药、豪森药业、鑫康合生物医药等企业均在积极布局，其中和铂医药的HBM7008已顺利出海。期待未来B7-H4靶点可以有药物早日获批上市，造福广大肿瘤患者。【企业推荐】智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~