Roche Pharma Research and Early Development (pRED), Large Molecule Research (LMR), Roche Innovation Center Munich, Penzberg, Germany.
Veraxa Biotech, Heidelberg, Germany.
Nat Commun. 2024 Oct 31;15(1):9406. doi: 10.1038/s41467-024-53730-3.
The generation of antibody-drug conjugates with optimal functionality depends on many parameters. These include binder epitope, antibody format, linker composition, conjugation site(s), drug-to-antibody ratio, and conjugation method. The production of matrices that cover all possible parameters is a major challenge in identifying optimal antibody-drug conjugates. To address this bottleneck, we adapted our Format Chain Exchange technology (FORCE), originally established for bispecific antibodies, toward the generation of binder-format-payload matrices (pair-FORCE). Antibody derivatives with exchange-enabled Fc-heterodimers are combined with payload-conjugated Fc donors, and subsequent chain-exchange transfers payloads to antibody derivatives in different formats. The resulting binder-format-conjugate matrices can be generated with cytotoxic payloads, dyes, haptens, and large molecules, resulting in versatile tools for ADC screening campaigns. We show the relevance of pair-FORCE for identifying optimal HER2-targeting antibody-drug conjugates. Analysis of this matrix reveals that the notion of format-defines-function applies not only to bispecific antibodies, but also to antibody-drug conjugates.
抗体药物偶联物的最佳功能的产生取决于许多参数。这些参数包括结合物表位、抗体形式、连接子组成、连接部位、药物抗体比和连接方法。生产涵盖所有可能参数的基质是确定最佳抗体药物偶联物的主要挑战。为了解决这一瓶颈，我们改编了我们的格式链交换技术（FORCE），最初用于双特异性抗体，以生成结合物-形式-有效载荷矩阵（pair-FORCE）。具有可交换 Fc-杂二聚体的抗体衍生物与缀合有效载荷的 Fc 供体结合，随后链交换将有效载荷转移到不同形式的抗体衍生物上。可以用细胞毒性有效载荷、染料、半抗原和大分子生成由此产生的结合物-形式-缀合物基质，从而为 ADC 筛选活动提供多功能工具。我们展示了 pair-FORCE 对于鉴定最佳 HER2 靶向抗体药物偶联物的相关性。对该矩阵的分析表明，格式定义功能的概念不仅适用于双特异性抗体，也适用于抗体药物偶联物。
