Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

中文翻译：

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CD3双特异性抗体的临床前和转化安全性评估研讨会的摘要。

当前，在用于治疗液体或实体瘤的临床前和临床开发中，存在许多具有不同分子设计和结合特性的CD3双特异性抗体。CD3双特异性抗体的主要安全隐患是细胞因子的过度释放，这可能会转化为潜在的威胁生命的细胞因子释放综合征（CRS），由于T细胞重定向至表达肿瘤相关抗原（TAA）的正常组织而导致靶器官毒性（肿瘤外/靶细胞毒性），在某些情况下还包括神经毒性。另一个关键挑战是要获得安全的临床起始剂量和有效的递增策略，使处于早期剂量组的患者能够在1期临床试验中获得临床获益。为了扩大治疗指标并为患者带来更多治疗选择，人们正在通过改进分子设计，临床前安全性评估策略和临床管理实践来克服这些挑战。最近在美国食品和药物管理局（FDA）举行了一次由工业，学术和监管机构代表参加的研讨会，讨论了挑战并探讨了可以在CD3双特异性抗体的开发中实现这种改进的地方。在这里，总结了演讲的内容以及在研讨会期间进行的讨论。并召开了监管机构代表会议，讨论挑战，并探讨在哪里可以实施对CD3双特异性抗体开发的此类改进。在这里，总结了演讲的内容以及在研讨会期间进行的讨论。并召开了监管机构代表会议，讨论挑战，并探讨在哪里可以实施对CD3双特异性抗体开发的此类改进。在这里，总结了演讲的内容以及在研讨会期间进行的讨论。