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

作　　者：Hua-ying Li Yi-li Chen Xiang-nan Deng Huan-huan Li Jie Tan Guo-jian Liu Yu-juan Zheng Min Pei Kai-ting Peng Li-li Yue Xiao-jia Chen Yu Liu Yong-shan Zhao Chun-he Wang 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2023年第11期2322-2330,共9页中国药理学报（英文版）

基　　金：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);the Research&Development Plan in Key Areas of Guangdong Province(2022B1111070007).

摘　　要：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.

关 键 词：cancer immunotherapy B7-H3 PD-L1 bispecific antibodies VHH antibody-dependent cell-mediated cytotoxicity(ADCC) 

分 类 号：R285.5[医药卫生—中药学]