VISTA-targeted antibody-drug conjugates exhibit potent antitumor effects on malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a malignant tumor of the pulmonary pleural tissue for which there is a lack of effective targeted therapy. In this study, moderate to high V-domain immunoglobulin T-cell activation suppressor (VISTA) expression levels were observed in most MPM clinical tumor samples. We prepared two high-affinity anti-VISTA monoclonal antibodies (mAbs) and generated two novel VISTA-targeted antibody-drug conjugates (ADCs) by conjugating anti-VISTA mAbs with the potent cytotoxic drug monomethyl auristatin E (MMAE). αV1-MMAE and αV2-MMAE showed potent killing effects to VISTA-positive cell lines in vitro, with half-maximal inhibitory concentration (IC₅₀) of nanomolar levels. αV1-MMAE and αV2-MMAE were also able to significantly induce apoptosis and cause G2/M phase arrest in VISTA-positive cells. In the VISTA-positive human MPM xenograft model, both αV1-MMAE and αV2-MMAE showed significant antitumor activity, led to a significant survival advantage compared to mice in the control group, and effectively induced apoptosis in the tumor tissues of mice. In conclusion, we demonstrated that the novel VISTA-targeted ADCs (αV1-MMAE and αV2-MMAE), especially αV1-MMAE, had potent killing effects against VISTA-positive MPM cells both in vitro and in vivo. Therefore, through further development, they may have the potential to become new drugs for the treatment of MPM.

Keywords

antibody-drug conjugate / malignant pleural mesothelioma / monoclonal antibody / monomethyl auristatin E / V-domain immunoglobulin suppressor of T cell activation

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2024 The Authors. MedComm - Oncology published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).