Chemoenzymatic Synthesis of a Rhamnose-Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy

被引：25

作者：

Hong, Haofei ^{[1
]}

Lin, Han ^{[1
]}

Li, Dan ^{[1
]}

Gong, Liang ^{[1
]}

Zhou, Kun ^{[1
]}

Li, Yanchun ^{[1
]}

Yu, Hangyan ^{[1
]}

Zhao, Kai ^{[2
]}

Shi, Jie ^{[1
]}

Zhou, Zhifang ^{[1
]}

Huang, Zhaohui ^{[3
,4
]}

Wu, Zhimeng ^{[1
]}

机构：

[1] Jiangnan Univ, Sch Biotechnol, Minist Educ, Key Lab Carbohydrate Chem & Biotechnol, Wuxi 214122, Jiangsu, Peoples R China

[2] Westlake Univ, Sch Life Sci, Key Lab Struct Biol Zhejiang Prov, Hangzhou 310024, Peoples R China

[3] Jiangnan Univ, Affiliated Hosp, Wuxi Canc Inst, Wuxi 214062, Jiangsu, Peoples R China

[4] Jiangnan Univ, Lab Canc Epigenet, Sch Med, Wuxi 214122, Jiangsu, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2022年 / 61卷 / 38期

基金：

中国国家自然科学基金;

关键词：

Bispecific Nanobodies; Cancer Immunotherapy; Fc Biological Functions; Rhamnose; Sortase A; ENDOGENOUS ANTIBODIES; IMMUNE-RESPONSE; EGFR; OVEREXPRESSION; CONJUGATE; BINDING; HER2;

D O I：

10.1002/anie.202208773

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：9

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