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Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy

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.

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Fig. 1: Tissue microarray (TMA) to detect SSTR2 expression in patients.
Fig. 2: Evaluation of the NET-specific targeting of our anti-SSTR2 antibody using IHC of normal human organs.
Fig. 3: Anti-SSTR2 mAb development and production.
Fig. 4: Evaluation of surface binding by anti-SSTR2 mAb.
Fig. 5: ADC construction and in vitro characterization.
Fig. 6: TD and PK studies of ADC.
Fig. 7: Antitumor efficacy study of ADC in NET (BON-Luc) xenografted mouse model.

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Acknowledgements

We would like to thank Dr. J. Bart Rose and Ms. Rachael Guenter and the Tissue-Based Translational Research Lab in the Department of Pathology at University of Alabama at Birmingham (UAB) for the design and construction of the tissue microarray.

Funding

This work was supported by SDHB Pheo Para Coalition (J.A.B.), National Institute of Health (NIH) R21HL 127599A1 (L.Z.), NIH R21CA226491-01A1 (R.J. and X.M.L.), NIH 1R01CA238273-01A1 (X.M.L.), and North American Neuroendocrine Tumor Society (NANETS) Basic/Translational Science Investigator award (R.J.).

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Correspondence to Renata Jaskula-Sztul or Xiaoguang “Margaret” Liu.

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Si, Y., Kim, S., Ou, J. et al. Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-0196-5

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