Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities

Hua-ying Li1,2,3, Yi-li Chen1, Xiang-nan Deng4, Huan-huan Li1, Jie Tan1, Guo-jian Liu5, Yu-juan Zheng3,6, Min Pei1,7, Kai-ting Peng3,6, Li-li Yue3,8, Xiao-jia Chen7, Yu Liu8, Yong-shan Zhao2, Chun-he Wang3,4,5,6,7,8
1 Shanghai Mabstone Biotechnologies, Ltd., Shanghai 201203, China
2 School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
3 Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
5 Dartsbio Pharmaceuticals, Ltd., Zhongshan 528400, China
6 University of Chinese Academy of Sciences, Beijing 100049, China
7 Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
8 School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
Correspondence to: Yi-li Chen:, Chun-he Wang:,
DOI: 10.1038/s41401-023-01118-2
Received: 6 March 2023
Accepted: 28 May 2023
Advance online: 16 June 2023


Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.
Keywords: cancer immunotherapy; B7-H3; PD-L1; bispecific antibodies; VHH; antibody-dependent cell-mediated cytotoxicity (ADCC)

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