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

Acta Pharmacologica Sinica volume 44, pages 2322–2330 (2023)Cite this article

Abstract

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.

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Fig. 1: The schematic structure and thermostability analysis of B7-H3×PD-L1 BsAb constructed in IgG1-VHH format.
Fig. 2: The binding activities of B7-H3×PD-L1 BsAb to PD-L1 and B7-H3 fusion proteins.
Fig. 3: Neutralization of PD-1 and PD-L1 interaction by B7-H3×PD-L1 BsAb.
Fig. 4: B7-H3×PD-L1 BsAb showed enhanced abilities to promote T cell proliferation and induce ADCC against tumor cells by human PBMCs.
Fig. 5: B7-H3×PD-L1 BsAb exhibited antitumor activities superior to monotherapies or combination therapies.
Fig. 6: B7-H3×PD-L1 BsAb had a favorable safety profile.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872785), Shanghai Municipal Commission of Science and Technology of China (21S11904500), Major Scientific and Technological Special Project of Zhongshan City (191022172638719 and 210205143867019), CAS Bohai Rim Advanced Research Institute for Drug Discovery Project (LX211005), and the Research & Development Plan in Key Areas of Guangdong Province (2022B1111070007).

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  1. These authors contributed equally: Hua-ying Li, Yi-li Chen, Xiang-nan Deng

Authors and Affiliations

  1. Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China

    Hua-ying Li, Yi-li Chen, Huan-huan Li, Jie Tan & Min Pei

  2. School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Hua-ying Li & Yong-shan Zhao

  3. Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Hua-ying Li, Yu-juan Zheng, Kai-ting Peng, Li-li Yue & Chun-he Wang

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Xiang-nan Deng & Chun-he Wang

  5. Dartsbio Pharmaceuticals, Ltd., Zhongshan, 528400, China

    Guo-jian Liu & Chun-he Wang

  6. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yu-juan Zheng, Kai-ting Peng & Chun-he Wang

  7. Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China

    Min Pei, Xiao-jia Chen & Chun-he Wang

  8. School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China

    Li-li Yue, Yu Liu & Chun-he Wang

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Contributions

CHW and YLC conceived the study and designed the experiments. HYL, XND, JT, YJZ, GJL, HHL, KTP, MP, LLY, XJC, YL, and YSZ conducted the experiments and analyzed the data. HYL and CHW drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yi-li Chen or Chun-he Wang.

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Competing interests

YLC, HYL, JT, HHL and MP are employed by Mabstone Biotechnologies, Ltd.; CHW and GJL are employed by Dartsbio Pharmaceuticals, Ltd. The remaining authors declare no conflicts of interest.

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Li, Hy., Chen, Yl., Deng, Xn. et al. Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities. Acta Pharmacol Sin 44, 2322–2330 (2023). https://doi.org/10.1038/s41401-023-01118-2

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