The Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, 310024, China.
Angew Chem Int Ed Engl. 2022 Sep 19;61(38):e202208773. doi: 10.1002/anie.202208773. Epub 2022 Aug 17.
Bispecific antibodies (BsAbs) are next-generation therapeutics for complex cancer treatment. Herein, we developed a dual-targeting non-IgG format of bsAbs by using a bispecific nanobody (bsNb) that can simultaneously target EGFR and HER2 on tumor cells. Site-specific modification of the anti-EGFR-HER2 bsNb was conducted using the rhamnose (Rha) hapten via sortase A-mediated ligation to reconstitute the missing crystallizable fragment (Fc) effector biological functions. Functionally similar to bsAbs, bsNb-Rha conjugates retained dual-targeting activity and exerted potent anticancer effects via the Fc-domain-mediated engagement of endogenous anti-Rha antibodies. Further, an optimized bsNb-Rha conjugate exhibited markedly improved pharmacokinetics and efficient inhibitory effects against xenograft tumor growth in vivo. Our strategy provides a general and cost-effective platform to generate a new bsAb format for cancer immunotherapy.
双特异性抗体（BsAbs）是用于复杂癌症治疗的下一代治疗药物。在此，我们通过使用能够同时针对肿瘤细胞上的 EGFR 和 HER2 的双特异性纳米抗体（bsNb）开发了一种双靶向非 IgG 格式的 bsAb。通过使用甘露糖（Rha）半抗原通过 Sortase A 介导的连接对抗 EGFR-HER2 bsNb 进行了位点特异性修饰，以重新构建缺失的可结晶片段（Fc）效应生物功能。与 bsAbs 具有相似功能的 bsNb-Rha 缀合物保留了双重靶向活性，并通过 Fc 结构域介导的内源性抗 Rha 抗体的参与发挥强大的抗癌作用。此外，优化的 bsNb-Rha 缀合物表现出明显改善的药代动力学特性，并在体内有效地抑制异种移植肿瘤的生长。我们的策略为癌症免疫治疗提供了一种通用且经济有效的生成新型 bsAb 格式的平台。
