Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy
- 20 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Gene Therapy
- Vol. 28 (7-8), 799-812
- https://doi.org/10.1038/s41417-020-0196-5
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (NIH R21CA226491-01A1)
- North American Neuroendocrine Tumor Society
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R21HL 127599A1)
This publication has 65 references indexed in Scilit:
- Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathwaysJournal of Cellular and Molecular Medicine, 2010
- Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ casesAnnals of Oncology, 2010
- Carcinoid TumorsThe Oncologist, 2008
- Pheochromocytoma: Current Approaches and Future DirectionsThe Oncologist, 2008
- One Hundred Years After “Carcinoid”: Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United StatesJournal of Clinical Oncology, 2008
- Therapeutic options for patients with metastatic gastrointestinal carcinoidJournal of Surgical Oncology, 2008
- Effects of Camptothecin Conjugated to a Somatostatin Analog Vector on Growth of Tumor Cell Lines in Culture and Related Tumors in RodentsDrug Delivery, 2004
- cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activityBlood, 2003
- A targeted cytotoxic somatostatin (SST) analogue, AN-238, inhibits the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC in nude miceEuropean Journal of Cancer, 2001
- Medullary Thyroid Carcinoma with Multiple Hepatic Metastases: Treatment with Transcatheter Arterial Embolization and Percutaneous Ethanol Injection.Internal Medicine, 1999