Clinical and Quantitative Pharmacology, Adagene, San Diego, California, USA.
Safety Assessment, Genentech, South San Francisco, California, USA.
Clin Transl Sci. 2022 Sep;15(9):2096-2104. doi: 10.1111/cts.13345. Epub 2022 Jun 11.
Biologics are increasingly being co-developed in combination or as novel constructs like bispecific antibodies (BsAbs) with the goal of targeting multiple, non-redundant mechanisms of action. Rational design of combinations and dual-targeting approaches that consider disease complexities have the potential to improve efficacy and safety, to increase duration of clinical benefit, and to minimize clinical resistance mechanisms. Here we summarize examples of BsAbs and biologic combinations that have been approved by health authorities and present drug development considerations when deciding between these two strategies. These include an understanding of target biology, nonclinical safety risks, dose optimization strategies, the regulatory framework, pharmacokinetic, immunogenicity, and bioanalytical assay considerations. The disease biology, target dynamics, and pharmacology objectives were identified as important factors in early drug development to decide between a BsAb versus a combination. Nonclinical safety assessment and dose optimization strategies can also pose challenges for BsAb versus combinations. High unmet medical needs and lack of treatment options are often the common denominators for deciding to develop a BsAb or a combination. Future development of biologic triple combinations and BsAbs combinations with other biologics will further increase drug development complexities and hold promise for more effective treatment options for patients.
生物制剂越来越多地被联合开发，或作为新型构建体（如双特异性抗体），以靶向多种非冗余作用机制。合理设计组合和双重靶向方法，考虑疾病的复杂性，有可能提高疗效和安全性，延长临床获益的持续时间，并最大限度地减少临床耐药机制。在这里，我们总结了已被卫生当局批准的双特异性抗体和生物制剂组合的例子，并在决定这两种策略时介绍了药物开发的考虑因素。这些因素包括对目标生物学、非临床安全性风险、剂量优化策略、监管框架、药代动力学、免疫原性和生物分析检测考虑因素的理解。疾病生物学、目标动力学和药理学目标被确定为早期药物开发中的重要因素，以决定使用双特异性抗体还是组合。非临床安全性评估和剂量优化策略也可能给双特异性抗体与组合带来挑战。高未满足的医疗需求和缺乏治疗选择通常是决定开发双特异性抗体或组合的共同因素。未来生物制剂三联组合和双特异性抗体与其他生物制剂的组合将进一步增加药物开发的复杂性，并为患者提供更有效的治疗选择。
