(22a) Novel Anti-SSTR2 Antibody-Targeted Therapy for Neuroendocrine Cancers

Neuroendocrine cancer encompasses a group of complex malignancies that arise throughout the body from neuroendocrine cells. Surgery is often curative for patients with localized disease, but there are limited beneficial therapeutic options for patients with metastatic disease. To address the lack of effective treatments for patients with unresectable neuroendocrine tumors (NETs), we have developed a targeted therapy, an antibody drug conjugate (ADC) that uses a novel, engineered monoclonal antibody (mAb) to target a known NET surface marker named somatostatin receptor subtype 2 (SSTR2). Specifically, SSTR2 was confirmed as an appropriate target using immunohistochemistry and in vitro analyses. We developed a new anti-SSTR2 mAb using hybridoma technology and further designed a humanized mAb. A stable mAb producing CHO DG44 cell line and fed-batch production process in a stirred tank bioreactor were also developed. The newly designed anti-SSTR2 mAb was conjugated with antimitotic monomenthyl auristatin E to generate the ADC. Furthermore, the ADC was evaluated through in vitro experiments including flow cytometry, confocal microscopy, immunoblotting, and toxicity assays. Finally, the therapeutic values of the ADC was assessed in vivo using NET xenograft mouse models. Both in vitro and in vivo experiments successfully demonstrated that the engineered mAb had highly specific binding to SSTR2 on NET cells and the engineered mAb-based ADC effectively killed cancer cells and inhibited tumor growth. In conclusion, this study has generated a novel targeted therapy for treatment of neuroendocrine cancer. The results from this study could lead to the development of new, effective treatments for patients with neuroendocrine cancer.