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

Von Wiley-VCH zur Verfügung gestellt

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.


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.

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