Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy

Yingnan Si, Seulhee Kim, Jianfa Ou, Yun Lu, Patrick Ernst, Kai Chen, Jason Whitt, Angela M. Carter, James M. Markert, James A. Bibb, Herbert Chen, Lufang Zhou, Renata Jaskula-Sztul, Xiaoguang “Margaret” Liu

Research output: Contribution to journalArticle

Abstract

Neuroendocrine (NE) tumors include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo- and radio-therapies have marginal curative benefits. The goal of this study was to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). First, we confirmed that somatostatin receptor 2 (SSTR2) is an ideal cancer cell surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and three NET cell lines. Then, we developed a new monoclonal antibody (mAb, IgG1, and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells. Finally, the ADC was evaluated in vivo using a NET xenograft mouse model to assess cancer-specific targeting, tolerated dosage, pharmacokinetics, and antitumor efficacy. The anti-SSTR2 ADC exclusively targeted and killed NET cells with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 ADC has a high-therapeutic potential for NET therapy.

Original languageEnglish (US)
JournalCancer Gene Therapy
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy'. Together they form a unique fingerprint.

  • Cite this

    Si, Y., Kim, S., Ou, J., Lu, Y., Ernst, P., Chen, K., Whitt, J., Carter, A. M., Markert, J. M., Bibb, J. A., Chen, H., Zhou, L., Jaskula-Sztul, R., & Liu, X. M. (Accepted/In press). Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy. Cancer Gene Therapy. https://doi.org/10.1038/s41417-020-0196-5