Chemoenzymatic Synthesis of a Rhamnose‐Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy. Issue 38 (17th August 2022)

• Record Type: Journal Article
• Authors: Hong, Haofei; Lin, Han; Li, Dan; Gong, Liang; Zhou, Kun; Li, Yanchun; Yu, Hangyan; Zhao, Kai; Shi, Jie; Zhou, Zhifang; Huang, Zhaohui; Wu, Zhimeng
• Is Part Of: Angewandte Chemie international edition. Volume 61:Issue 38(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-17
• Subjects: Bispecific Nanobodies -- Cancer Immunotherapy -- Fc Biological Functions -- Rhamnose -- Sortase A; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202208773
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Rhamnosylation of a bispecific nanobody (bsNb‐Rha), as a mimic of the full‐length bispecific antibody, was developed for cancer immunotherapy. The bsNb‐Rha conjugate simultaneously targeted EGFR and HER2 antigens expressed on tumor cells, followed by the engagement of endogenous anti‐Rha antibodies to trigger an efficient Fc‐domain‐mediated immune response, leading to enhanced activity in vitro and in vivo against the dual‐positive cancer cells.