Humanized antibody-drug conjugates for SSTR2-positive tumor treatment

Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and meningiomas. The objective of this study was to develop an SSTR2-targeted therapy to treat both tumor types. We engineered and humanized an anti-SSTR2 monoclonal antibody (mAb) demonstrating strong cancer cell binding, internalization in cancer cells, and tumor specificity, as evidenced by flow cytometry, confocal microscopy, and live-animal imaging. Antibody-drug conjugates (ADCs) were generated by conjugating the SSTR2 mAb with potent payloads, including monomethyl auristatin F (MMAF) or mertansine (DM1). In vitro assessments revealed high cytotoxicity across diverse NET subtypes and meningioma cell lines. In vivo efficacy was confirmed in two mouse models, i.e. subcutaneous NET xenografts and intracranial meningioma xenografts, where treatment inhibited proliferation, induced apoptosis and cell death, exhibited minimal toxicity, and extended survival. The mechanism of action was further elucidated through bulk RNA sequencing post-treatment. These findings highlight the therapeutic potential of our humanized SSTR2 mAb for targeted payload delivery in NETs and meningiomas.