Chemoenzymatic Synthesis of a Rhamnose-Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy
Chemoenzymatic Synthesis of a Rhamnose-Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy
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DOI：
10.1002/anie.202208773
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发表时间：
2022-08-17
影响因子：
16.6
通讯作者：
Wu, Zhimeng
中科院分区：
文献类型：
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作者：
Hong, Haofei;Lin, Han;Wu, Zhimeng
双特异性抗体 (BsAb) 是复杂癌症治疗的下一代疗法。在此，我们通过使用双特异性纳米抗体（bsNb）开发了一种双靶向非 IgG 形式的 bsAb，该双特异性纳米抗体可以同时靶向肿瘤细胞上的 EGFR 和 HER2。使用鼠李糖 (Rha) 半抗原通过分选酶 A 介导的连接对抗 EGFR-HER2 bsNb 进行位点特异性修饰，以重建缺失的可结晶片段 (Fc) 效应子生物学功能。与 bsAb 功能相似，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 抗体的结合发挥了有效的抗癌作用。此外，优化的 bsNb-Rha 缀合物表现出显着改善的药代动力学和对体内异种移植肿瘤生长的有效抑制作用。我们的策略提供了一个通用且具有成本效益的平台来生成用于癌症免疫治疗的新bsAb形式。
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.