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Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy


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.


  1. 1.

    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.

    PubMed  Google Scholar 

  2. 2.

    Kulke MH, Benson AB,3rd, Bergsland E, Berlin JD, Blaszkowsky LS, Choti MA, et al. Neuroendocrine tumors. J Natl Compr Canc Netw. 2012;10:724–64.

    CAS  PubMed  Google Scholar 

  3. 3.

    Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival. J Am Coll Surg. 1998;187:88–92.

    CAS  PubMed  Google Scholar 

  4. 4.

    Norton JA. Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases. Best Pr Res Clin Gastroenterol. 2005;19:577–83.

    Google Scholar 

  5. 5.

    Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010;17:3129–36.

    PubMed  Google Scholar 

  6. 6.

    Adler JT, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS, et al. Pheochromocytoma: current approaches and future directions. Oncologist. 2008;13:779–93.

    PubMed  Google Scholar 

  7. 7.

    Pinchot SN, Pitt SC, Sippel RS, Kunnimalaiyaan M, Chen H. Novel targets for the treatment and palliation of gastrointestinal neuroendocrine tumors. Curr Opin Investig Drugs. 2008;9:576–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Chen H, Pruitt A, Nicol TL, Gorgulu S, Choti MA. Complete hepatic resection of metastases from leiomyosarcoma prolongs survival. J Gastrointest Surg. 1998;2:151–5.

    CAS  PubMed  Google Scholar 

  9. 9.

    Chen H. Therapeutic options for patients with metastatic gastrointestinal carcinoid. J Surg Oncol. 2008;97:203–4.

    PubMed  Google Scholar 

  10. 10.

    Shiba S, Morizane C, Hiraoka N, Sasaki M, Koga F, Sakamoto Y, et al. Pancreatic neuroendocrine tumors: a single-center 20-year experience with 100 patients. Pancreatology. 2016;16:99–105.

    PubMed  Google Scholar 

  11. 11.

    Brown KT, Koh BY, Brody LA, Getrajdman GI, Susman J, Fong Y, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Inter Radiol. 1999;10:397–403.

    CAS  Google Scholar 

  12. 12.

    Isozaki T, Kiba T, Numata K, Saito S, Shimamura T, Kitamura T, et al. Medullary thyroid carcinoma with multiple hepatic metastases: treatment with transcatheter arterial embolization and percutaneous ethanol injection. Intern Med. 1999;38:17–21.

    CAS  PubMed  Google Scholar 

  13. 13.

    Lal A, Chen H. Treatment of advanced carcinoid tumors. Curr Opin Oncol. 2006;18:9–15.

    PubMed  Google Scholar 

  14. 14.

    Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation. 1998;66:1307–12.

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhang R, Straus FH, DeGroot LJ. Effective genetic therapy of established medullary thyroid carcinomas with murine interleukin-2: dissemination and cytotoxicity studies in a rat tumor model. Endocrinology. 1999;140:2152–8.

    CAS  PubMed  Google Scholar 

  16. 16.

    Boudreaux JP, Putty B, Frey DJ, Woltering E, Anthony L, Daly I, et al. Surgical treatment of advanced-stage carcinoid tumors: lessons learned. Ann Surg. 2005;241:839–45.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Nguyen C, Faraggi M, Giraudet AL, de Labriolle-Vaylet C, Aparicio T, Rouzet F, et al. Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy. J Nucl Med. 2004;45:1660–8.

    CAS  PubMed  Google Scholar 

  18. 18.

    Fiorentini G, Rossi S, Bonechi F, Vaira M, De Simone M, Dentico P, et al. Intra-arterial hepatic chemoembolization in liver metastases from neuroendocrine tumors: a phase II study. J Chemother. 2004;16:293–7.

    CAS  PubMed  Google Scholar 

  19. 19.

    Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–73.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hennrich U, Kopka K, Lutathera R. The first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals (Basel). 2019;12:114–21.

    CAS  Google Scholar 

  21. 21.

    Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharm Rev. 2001;53:1–24.

    CAS  PubMed  Google Scholar 

  22. 22.

    Pinchot SN, Holen K, Sippel RS, Chen H. Carcinoid tumors. Oncologist. 2008;13:1255–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Zatelli MC, Tagliati F, Taylor JE, Rossi R, Culler MD, degli Uberti EC, et al. Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt. J Clin Endocrinol Metab. 2001;86:2161–9.

    CAS  PubMed  Google Scholar 

  24. 24.

    Sun LC, Coy DH. Somatostatin receptor-targeted anti-cancer therapy. Curr Drug Deliv. 2011;8:2–10.

    CAS  PubMed  Google Scholar 

  25. 25.

    Leijon H, Remes S, Hagstrom J, Louhimo J, Maenpaa H, Schalin-Jantti C, et al. Variable somatostatin receptor subtype expression in 151 primary pheochromocytomas and paragangliomas. Hum Pathol. 2019;86:66–75.

    CAS  PubMed  Google Scholar 

  26. 26.

    Zhou L, Xu N, Sun Y, Liu XM. Targeted biopharmaceuticals for cancer treatment. Cancer Lett. 2014;352:145–51.

    CAS  PubMed  Google Scholar 

  27. 27.

    Almasbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Dai H, Wang Y, Lu X, Han W. Chimeric antigen receptors modified T-cells for cancer therapy. J Natl Cancer Inst. 2016;108:439–52.

    Google Scholar 

  29. 29.

    Zhang BL, Qin DY, Mo ZM, Li Y, Wei W, Wang YS, et al. Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors. Sci China Life Sci. 2016;59:340–8.

    CAS  PubMed  Google Scholar 

  30. 30.

    Little M, Kipriyanov SM, Le Gall F, Moldenhauer G. Of mice and men: hybridoma and recombinant antibodies. Immunol Today. 2000;21:364–70.

    CAS  PubMed  Google Scholar 

  31. 31.

    Stump B., Steinmann J. Conjugation process development and scale-up. Methods Mol Biol. 2013;1045:235–48.

  32. 32.

    Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7:302ra136.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Pereira DS, Guevara CI, Jin L, Mbong N, Verlinsky A, Hsu SJ, et al. AGS67E, an anti-CD37 monomethyl auristatin E antibody-drug conjugate as a potential therapeutic for B/T-cell malignancies and AML: a new role for CD37 in AML. Mol Cancer Ther. 2015;14:1650–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Whalen KA, White BH, Quinn JM, Kriksciukaite K, Alargova R, Au Yeung TP, et al. Targeting the somatostatin receptor 2 with the miniaturized drug conjugate, PEN-221: a potent and novel therapeutic for the treatment of small cell lung cancer. Mol Cancer Ther. 2019;18:1926–36.

    CAS  PubMed  Google Scholar 

  35. 35.

    Kiaris H, Schally AV, Nagy A, Szepeshazi K, Hebert F, Halmos G, et al. 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 mice. Eur J Cancer. 2001;37:620–8.

    CAS  PubMed  Google Scholar 

  36. 36.

    Sun L, Fuselier JA, Coy DH. Effects of camptothecin conjugated to a somatostatin analog vector on growth of tumor cell lines in culture and related tumors in rodents. Drug Deliv. 2004;11:231–8.

    CAS  PubMed  Google Scholar 

  37. 37.

    Xu N, Ou J, Gilani A-K, Zhou L, Liu M. High-level expression of recombinant IgG1 by CHO K1 platform. Front Chem Sci Eng. 2015;9:376–80.

    CAS  Google Scholar 

  38. 38.

    Ou J, Si Y, Goh K, Yasui N, Guo Y, Song J, et al. Bioprocess development of antibody-drug conjugate production for cancer treatment. PLoS ONE. 2018;13:e0206246.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Xu N, Ou J, Si Y, Goh KY, Flanigan DD, Han X, et al. Proteomics insight into the production of monoclonal antibody. Biochemical Eng J. 2019;145:177–85.

    CAS  Google Scholar 

  40. 40.

    Hasegawa K, Kudoh S, Ito T. Somatostatin receptor staining in FFPE sections using a ligand derivative dye as an alternative to immunostaining. PLoS ONE. 2017;12:e0172030.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Xu N., Liu M., Liu M. Pharmacology, Pharmacokinetics, and Pharmacodynamics of Antibodies. Biosimilairs of Monoclonal Antibodies. John Wiley & Sons, Inc. New Jersey, USA, 2016.

  42. 42.

    Sherbenou DW, Aftab BT, Su Y, Behrens CR, Wiita A, Logan AC, et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest. 2016;126:4640–53.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Si Y, Kim S, Zhang E, Tang Y, Jaskula-Sztul R, Markert JM, et al. Targeted exosomes for drug delivery: biomanufacturing, surface tagging, and validation. Biotechnol J. 2020;15:1900163–74.

    CAS  Google Scholar 

  44. 44.

    Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013;24:499–511.

    CAS  PubMed  Google Scholar 

  45. 45.

    Pozo K, Hillmann A, Augustyn A, Plattner F, Hai T, Singh T, et al. Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget. 2015;6:12080–93.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458–65.

    CAS  PubMed  Google Scholar 

  47. 47.

    Yao H, Jiang F, Lu A., Zhang G. Methods to design and synthesize antibody-drug conjugates (ADCs). Int J Mol Sci. 2016;17:194–209.

    PubMed Central  Google Scholar 

  48. 48.

    Cunningham D, Parajuli KR, Zhang C, Wang G, Mei J, Zhang Q, et al. Monomethyl auristatin E phosphate inhibits human prostate cancer growth. Prostate. 2016;76:1420–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, et al. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016;17:346–54.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Sarikaya I, Sarikaya A, Alnafisi N, Alenezi S. Significance of splenic uptake on somatostatin receptor imaging studies. Nucl Med Rev Cent East Eur. 2018;21:66–70.

    PubMed  Google Scholar 

  51. 51.

    Melis M, Kaemmerer D, de Swart J, Kulkarni HR, Lupp A, Sanger J, et al. Localization of radiolabeled somatostatin analogs in the spleen. Clin Nucl Med. 2016;41:e111–4.

    PubMed  Google Scholar 

  52. 52.

    Reubi JC, Waser B, Horisberger U, Krenning E, Lamberts SW, Gebbers J-O, et al. In vitro autoradiographic and in vivo scintigraphic localization of somatostatin receptors in human lymphatic tissue. Blood. 1993;82:2143–51.

    CAS  PubMed  Google Scholar 

  53. 53.

    Reubi JC, Ursula H, Kappeler A, Laissue JA. Localization of receptors for vasoactive intestinal peptide, somatostatin, and substance P in distinct compartments of human lymphoid organs. Blood. 1998;92:191–7.

    CAS  PubMed  Google Scholar 

  54. 54.

    Fotouhi O, Zedenius J, Hoog A, Juhlin CC. Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors. Neuroendocrinol Lett. 2018;39:305–9.

    CAS  PubMed  Google Scholar 

  55. 55.

    Cakir M, Dworakowska D, Grossman A. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1–molecular pathways. J Cell Mol Med. 2010;14:2570–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Righi L, Volante M, Tavaglione V, Bille A, Daniele L, Angusti T, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol. 2010;21:548–55.

    CAS  PubMed  Google Scholar 

  57. 57.

    Sherman SK, Maxwell JE, Carr JC, Wang D, O'Dorisio MS, O'Dorisio TM, et al. GIPR expression in gastric and duodenal neuroendocrine tumors. J Surg Res. 2014;190:587–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Thies A, Moll I, Berger J, Wagener C, Brummer J, Schulze HJ, et al. CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol. 2002;20:2530–6.

    CAS  PubMed  Google Scholar 

  59. 59.

    Tilki D, Irmak S, Oliveira-Ferrer L, Hauschild J, Miethe K, Atakaya H, et al. CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer. Oncogene. 2006;25:4965–74.

    CAS  PubMed  Google Scholar 

  60. 60.

    Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol. 2002;13:653–68.

    CAS  PubMed  Google Scholar 

  61. 61.

    Yau H, Kinaan M, Quinn SL, Moraitis AG. Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives. Biologics. 2017;11:115–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Guillermet J, Saint-Laurent N, Rochaix P, Cuvillier O, Levade T, Schally AV, et al. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc Natl Acad Sci USA. 2003;100:155–60.

    CAS  PubMed  Google Scholar 

  63. 63.

    Lahlou H, Guillermet J, Hortala M, Vernejoul F, Pyronnet S, Bousquet C, et al. Molecular signaling of somatostatin receptors. Ann N. Y Acad Sci. 2004;1014:121–31.

    CAS  PubMed  Google Scholar 

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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.


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).

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