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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma

  • Wei, Mulan (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Liu, Xujie (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Cao, Chunyu (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Yang, Jianlin (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Lv, Yafeng (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Huang, Jiaojiao (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Wang, Yanlin (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College) ;
  • Qin, Ye (Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University Medical College)
  • Received : 2018.04.10
  • Accepted : 2018.06.11
  • Published : 2018.11.30
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Abstract

Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma-binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy.

Keywords

References

  1. Ostrand-Rosenberg S, Horn LA and Haile ST (2014) The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol 193, 3835-3841 https://doi.org/10.4049/jimmunol.1401572
  2. Simon S and Labarriere N (2017) PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunology 7, e1364828
  3. van de Ven R, Niemeijer AN, Stam AGM et al (2017) High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes. ERJ Open Res 3, 1-9
  4. Mittendorf EA, Philips AV, Meric-Bernstam F et al (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2, 361-370 https://doi.org/10.1158/2326-6066.CIR-13-0127
  5. Brody R, Zhang Y, Ballas M et al (2017) PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer 112, 200-215 https://doi.org/10.1016/j.lungcan.2017.08.005
  6. Masugi Y, Nishihara R, Yang J et al (2017) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut 66, 1463-1473 https://doi.org/10.1136/gutjnl-2016-311421
  7. Howitt BE, Strickland KC, Sholl LM et al (2017) Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology 6, e1277308 https://doi.org/10.1080/2162402X.2016.1277308
  8. Kaunitz GJ, Cottrell TR, Lilo M et al (2017) Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest 97, 1063-1071 https://doi.org/10.1038/labinvest.2017.64
  9. Chemnitz JM, Parry RV, Nichols KE, June CH and Riley JL (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173, 945-954 https://doi.org/10.4049/jimmunol.173.2.945
  10. Keir ME, Butte MJ, Freeman GJ and Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26, 677-704 https://doi.org/10.1146/annurev.immunol.26.021607.090331
  11. Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369, 122-133 https://doi.org/10.1056/NEJMoa1302369
  12. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366, 2443-2454 https://doi.org/10.1056/NEJMoa1200690
  13. Cho DC, Sosman JA, Sznol M et al (2013) Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 31, 4505-4505
  14. Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563-567 https://doi.org/10.1038/nature14011
  15. Audrito V, Serra S, Stingi A et al (2017) PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p. Oncotarget 8, 15894-15911 https://doi.org/10.18632/oncotarget.15213
  16. Obeid JM, Erdag G, Smolkin ME et al (2016) PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 5, e1235107 https://doi.org/10.1080/2162402X.2016.1235107
  17. Ribas A and Tumeh PC (2014) The future of cancer therapy: selecting patients likely to respond to PD1/L1 blockade. Clin Cancer Res 20, 4982-4984 https://doi.org/10.1158/1078-0432.CCR-14-0933
  18. Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16, 908-918 https://doi.org/10.1016/S1470-2045(15)00083-2
  19. Weber JS, D'Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16, 375-384 https://doi.org/10.1016/S1470-2045(15)70076-8
  20. Postow MA, Chesney J, Pavlick AC et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372, 2006-2017 https://doi.org/10.1056/NEJMoa1414428
  21. Kessenbrock K, Plaks V and Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52-67 https://doi.org/10.1016/j.cell.2010.03.015
  22. Egeblad M and Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161-174 https://doi.org/10.1038/nrc745
  23. John A and Tuszynski G (2001) The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 7, 14-23 https://doi.org/10.1007/BF03032599
  24. Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ and Kosma VM (2004) Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 10, 7621-7628 https://doi.org/10.1158/1078-0432.CCR-04-1061
  25. Liu Z, Li L, Yang Z et al (2010) Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer 10, 270 https://doi.org/10.1186/1471-2407-10-270
  26. Karam A and Dorigo O (2012) MMPs in ovarian cancer as therapeutic targets. Anticancer Agents Med Chem 12, 764-772 https://doi.org/10.2174/187152012802650174
  27. Roy R, Yang J and Moses MA (2009) Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 27, 5287-5297 https://doi.org/10.1200/JCO.2009.23.5556
  28. Beckman RA, Weiner LM and Davis HM (2007) Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer 109, 170-179 https://doi.org/10.1002/cncr.22402
  29. Li L, Huang YH, Li Y, Wang FQ, Shang BY and Zhen YS (2005) Antitumor activity of anti-type IV collagenase monoclonal antibody and its lidamycin conjugate against colon carcinoma. World J Gastroenterol 11, 4478-4483 https://doi.org/10.3748/wjg.v11.i29.4478
  30. Wang FQ, Shang BY and Zhen YS (2003) [Antitumor effects of the immunoconjugate composed of lidamycin and monoclonal antibody 3G11]. Yao Xue Xue Bao 38, 515-519
  31. Qin Y, Liu XJ, Li L et al (2014) MMP-2/9-oriented combinations enhance antitumor efficacy of EGFR/HER2-targeting fusion proteins and gemcitabine. Oncol Rep 32, 121-130 https://doi.org/10.3892/or.2014.3169
  32. Holliger P and Hudson PJ (2005) Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126-1136 https://doi.org/10.1038/nbt1142
  33. Zhong G, Zhang S, Li Y et al (2010) A tandem scFv-based fusion protein and its enediyne-energized analogue show intensified therapeutic efficacy against lung carcinoma xenograft in athymic mice. Cancer Lett 295, 124-133 https://doi.org/10.1016/j.canlet.2010.02.020
  34. Hidalgo M and Eckhardt SG (2001) Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93, 178-193 https://doi.org/10.1093/jnci/93.3.178
  35. Zucker S, Cao J and Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19, 6642-6650 https://doi.org/10.1038/sj.onc.1204097
  36. Liu XJ, Li L, Liu XJ et al (2017) Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma. Int J Nanomedicine 12, 5255-5269 https://doi.org/10.2147/IJN.S139507
  37. Vanella V, Festino L, Strudel M, Simeone E, Grimaldi AM and Ascierto PA (2017) PD-L1 inhibitors in the pipeline: Promise and progress. Oncoimmunology 7, e1365209
  38. Kleffel S, Posch C, Barthel SR et al (2015) Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242-1256 https://doi.org/10.1016/j.cell.2015.08.052
  39. Clark CA, Gupta HB, Sareddy G et al (2016) Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 76, 6964-6974 https://doi.org/10.1158/0008-5472.CAN-16-0258
  40. Almozyan S, Colak D, Mansour F et al (2017) PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer 141, 1402-1412 https://doi.org/10.1002/ijc.30834
  41. Godefroy E, Manches O, Dreno B et al (2011) Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell 19, 333-346 https://doi.org/10.1016/j.ccr.2011.01.037
  42. Zhou J, Jin B, Jin Y, Liu Y and Pan J (2017) The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo. Theranostics 7, 1447-1462 https://doi.org/10.7150/thno.17451