Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy. (1st January 2021)

• Record Type: Journal Article
• Authors: Yuan, Qingyun; Liang, Qiaoyan; Sun, Zujun; Yuan, Xingxing; Hou, Weihua; Wang, Yuxiong; Wang, Huijie; Yu, Min
• Is Part Of: Oncoimmunology. Volume 10:Number 1(2021)
• Publication Date: 2021-01-01
• Subjects: PD-1 -- c-Met -- bispecific antibodies -- diabodies -- immunotherapy -- solid tumor; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2021.1914954
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Although the blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has become a promising treatment strategy for several types of cancers, the constitutive activation of c-Met in tumors may cause a low overall response rate to PD-1 inhibitors. Increasing evidence indicates that the dual inhibition of c-Met and PD-1 could improve the efficacy of anti-PD-1/PD-L1 monoclonal antibodies for tumor immunotherapy. In this study, we developed two bispecific single-chain diabodies targeting c-Met and PD-1 for the treatment of solid tumors based on protein homology modeling, and we identified that the binding affinity of diabody-mp to c-Met was 50-folds higher than that of diabody-pm. The results of in vitro studies revealed that both diabodies suppressed HGF-induced proliferation, migration, and invasion of tumor cells, inhibiting the activation of c-Met signaling by antagonizing HGF binding to c-Met. Moreover, they promoted T cell activation by blocking the PD-1 pathway, mediating tumor cellular cytotoxicity through T cell engagement. In vivo studies with mice models demonstrated that diabody-mp exhibited higher therapeutic efficacy than other structural antibodies, greatly enhancing the survival of c-Met-positive tumor-bearing mice compared to single or combined c-Met and PD-1 blockade therapy. Furthermore, diabody-mp, which had a higher c-Met binding affinity, showed better anti-tumoral activity than diabody-pm, which had a lower c-Met binding affinity. In conclusion, bispecific anti-PD-1/c-Met diabody-mp, with high c-Met-associated affinity, inhibited tumor growth by activating T cells, suggesting its therapeutic potential for c-Met-positive solid tumors.