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Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo

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Summary

Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3+ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.

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References

  1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30

    Article  Google Scholar 

  2. Dillman RO, CornforthAN DC, McClay EF, Amatruda TT, de Leon C, Ellis RE, Mayorga C, Carbonell D, Cubellis JM (2012) Tumor stem cell antigens as consolidative active specific immunotherapy: a randomized phase II trial of dendritic cells versus tumor cells in patients with metastatic melanoma. J Immunother 35(8):641–649

    Article  CAS  PubMed  Google Scholar 

  3. Ullenhag GJ, Sadeghi AM, Carlsson B, Ahlström H, Mosavi F, Wagenius G, Tötterman TH (2012) Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy. Cancer Immunol Immunother 61 (5):725–732

    Article  PubMed  Google Scholar 

  4. Larkin J, Chiarion-Sileni V, Gonzaler R, Grob JJ, Cowey CL, Lao CD, Schadedof D, Dummer R, Smylie M, Rutkowki P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horek C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Steinberger P, Majdic O, Derdak SV, Pfistershammer K, Kirchberger S, Klauser C, Zlabinger G, Pickl WF, Stöckl J, Knapp W (2004) Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains. J Immunol 172(4):2352–2359

    Article  CAS  PubMed  Google Scholar 

  6. Leitner J, Klauser C, Pickl WF, Stöckl J, Majdic O, Bardet AF, Kreil DP, Dong C, Yamazaki T, Zlabinger G, Pfistershammer K, Steinberger P (2009) B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction. Eur J Immunol 39(7):1754–1764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang L, Kang FB, Shan BE (2014) B7-H3-mediated tumor immunology: Friend or foe? Int J Cancer 134(12):2764–2771

    Article  CAS  PubMed  Google Scholar 

  8. Picarda E, Ohaegbulam KC, Zan g X (2016) Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res 22(14):3425–3431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, Asuthkar S (2017) B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol 6(4):66–75

    PubMed  PubMed Central  Google Scholar 

  10. Wang J, Chong KK, Nakamura Y, Nguyen L, Huang SK, Kuo C, Zhang W, Yu H, Morton DL, Hoon DS (2013) B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. J Invest Dermatol 133(8):2050–2058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM, Fodstad O (2012) B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer 130(10):2282–2290

    Article  CAS  PubMed  Google Scholar 

  12. Flem-Karlsen K, Tekle C, Andersson Y, Flatmark K, Fodstad Ø, Nunes-Xavier CE (2017) Immunoregulatory protein B7-H3 promotes growth and decreases sensitivity to therapy in metastatic melanoma cells. Pigment Cell Melanoma Res 30(5):467–476

    Article  CAS  PubMed  Google Scholar 

  13. Lee YH, Martin-Orozco N, Zheng P, Li J, Zhang P, Tan H, Park HJ, Jeong M, Chang SH, Kim BS, Xiong W, Zang W, Guo L, Liu Y, Dong ZJ, Overwijk WW, Hwu P, Yi Q, Kwak L, Yang Z, Mak TW, Li W, Radvanyi LG, Ni L, Liu D, Dong C (2017) Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res 27(8):1034–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, Burke S, Ciccarone V, Li H, Yang Y, Son T, Chen Y, Easton AN, Li JC, Rillema JR, Licea M, Fieger C, Liang TW, Mather JP, Koenig S, Stewart SJ, Johnson S, Bonvini E, Moore PA (2012) Development of an Fc-enhanced anti–B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res 18(14):3834–3845

    Article  CAS  PubMed  Google Scholar 

  15. Kramer K, Kushner BH, Modak S, Pandit-Taskar N, Smith-Jones P, Zanzonico P, Humm JL, Xu H, Wolden SL, Souweidane MM, Larson SM, Cheung NK (2010) Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neuro-Oncol 97(3):409–418

    Article  Google Scholar 

  16. Lum LG, Thakur A (2011) Targeting T cells with bispecific antibodies for cancer therapy. BioDrugs 25(6):365–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhutani D, Lum LG (2015) Activated T cells armed with bispecific antibodies kill tumor targets. Curr Opin Hematol 22(6):476–483

    Article  CAS  PubMed  Google Scholar 

  18. Ma J, Ma P, Zhao C, Xue X, Han H, Liu C, Tao H, Xiu W, Cai J, Zhang M (2016) B7-H3 as a promising target for cytotoxicity T cell in human cancer therapy. Oncotarget 7(20):29480–29491

    PubMed  PubMed Central  Google Scholar 

  19. Ma J, Han H, Liu D, Li W, Feng H, Xue X, Wu X, Niu G, Zhang G, Zhao Y, Liu C, Tao H, Gao B (2013) HER2 as a promising target for cytotoxicity T cells in human melanoma therapy. PLoS One 8(8):e73261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fousek K, Ahmed N (2015) The evolution of T-cell therapies for solid malignancies. Clin Cancer Res 21(15):3384–3392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, Pestell RG, Han X, Wu K (2017) Recent advances of bispeicific antibodies in solid tumors. J Hematol Oncol 10(1):15

    Article  Google Scholar 

  22. Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R (2015) Targeted T-cell therapy in stage IV breast cancer: a phase I clinical trial. Clin Cancer Res 21(10):2305–2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG (2015) Phase I Study of Anti-CD3 x anti-Her2 bispecific antibody in metastatic castrate resistant prostate cancer patients. Prostate Cancer 2015:285193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tiffen JC, Bailey CG, Ng C, Rasko JE, Holst J (2010) Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo. MolCancer 9:299

    CAS  Google Scholar 

  25. Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, Bickham KL, Lerner H, Goldstein M, Sykes M, Kato T, Farber DL (2013) Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38(1):187–197

    Article  CAS  Google Scholar 

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Funding

This work is funded by grants from the National Nature Science Foundation of China (No.31400754) and Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150701).

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Authors and Affiliations

  1. Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyi Road, Haidian District, Beijing, 100038, China

    Juan Ma, Xin Sun, Jin Zhao, Ximing Sun & Man Zhang

  2. Clinical Laboratory Medicine, Peking University Ninth School of Clinical Medicine, Beijing, 100038, China

    Juan Ma, Jin Zhao, Ximing Sun & Man Zhang

  3. Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, 100038, China

    Juan Ma, Xin Sun, Jin Zhao & Man Zhang

  4. Medical Experimental Centre, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Tengfei Shang

  5. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Pan Ma

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  1. Juan Ma
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  3. Pan Ma
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  4. Xin Sun
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  5. Jin Zhao
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Correspondence to Juan Ma or Man Zhang.

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Juan Ma, Tengfei Shang, Pan Ma, Xin Sun, Jin Zhao, Ximing Sun, and Man Zhang declare that they have no conflicts of interest.

Ethical approval

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee. The animal study complied with the Guide for the Care and Use of Laboratory Animals of the Ministry of Health, and the protocol was approved by the Ethics Committee of Beijing Shijitan Hospital of Capital Medical University.

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Ma, J., Shang, T., Ma, P. et al. Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo. Invest New Drugs 37, 1036–1043 (2019). https://doi.org/10.1007/s10637-018-00719-7

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  • DOI: https://doi.org/10.1007/s10637-018-00719-7

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