1. A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy
- Author
-
Xinyuan Liu, Yue Cui, Mei-Qing Feng, Lei Tang, Yi-Li Chen, Liu Guojian, Xingchen Dong, Chunhe Wang, and Yifeng Hung
- Subjects
Receptor, ErbB-2 ,Programmed Cell Death 1 Receptor ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,Mice ,ADCC, antibody-dependent cell-mediated cytotoxicity ,DC, dendritic cell ,Antineoplastic Agents, Immunological ,human epidermal growth factor receptor 2 (HER2) ,Antibodies, Bispecific ,BLI, biolayer interferometry ,HER2, human epidermal growth factor receptor 2 ,skin and connective tissue diseases ,Cytotoxicity ,SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis ,Antibody-dependent cell-mediated cytotoxicity ,GEJC, gastroesophageal junction cancer ,biology ,Chemistry ,PD-1/PD-L1, programmed cell death protein 1 and programmed cell death ligand 1 ,BTC, biliary tract cancer ,CRC, colorectal cancer ,GC, gastric cancer ,VH, variable heavy ,Signal transduction ,mAbs, monoclonal antibodies ,Research Article ,PBMC, peripheral blood mononuclear cell ,BC, breast cancer ,medicine.drug_class ,antibody-dependent cell-mediated cytotoxicity ,NSCLC, non-small-cell lung cancer ,DSF, differential scanning fluorimetry ,Monoclonal antibody ,Peripheral blood mononuclear cell ,MLR, mixed lymphocyte reaction ,breast cancer ,In vivo ,Cell Line, Tumor ,PD-L1 ,medicine ,Animals ,Humans ,CDC, complement-dependent cytotoxicity ,Molecular Biology ,Antibody-Dependent Cell Cytotoxicity ,VL, variable light ,Neoplasms, Experimental ,Cell Biology ,Xenograft Model Antitumor Assays ,MOA, mechanisms of action ,In vitro ,BsAbs, bispecific antibodies ,programmed death ligand 1 ,Cancer research ,biology.protein ,SEC, size exclusion chromatography - Abstract
Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses towards HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared to monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced anti-tumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells.
- Published
- 2021
- Full Text
- View/download PDF