Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 38, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202208773
Keywords
Bispecific Nanobodies; Cancer Immunotherapy; Fc Biological Functions; Rhamnose; Sortase A
Categories
Funding
- National Natural Science Foundation of China [32000904, 22177040]
- Natural Science Foundation of Jiangsu Province [BK20200601]
- 111 Project [111-2-06]
- Social Development Key Project of Jiangsu Province [BE2019632]
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In this study, we developed a dual-targeting non-IgG format of bispecific antibodies (BsAbs) that can simultaneously target EGFR and HER2 on tumor cells. The BsAbs retained dual-targeting activity and exerted potent anticancer effects through the engagement of endogenous antibodies. The optimized BsAbs also showed improved pharmacokinetics and efficient inhibitory effects against tumor growth. This research provides a general and cost-effective platform for generating new BsAbs for cancer immunotherapy.
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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