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http://dx.doi.org/10.5483/BMBRep.2018.51.11.076

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)
Publication Information
BMB Reports / v.51, no.11, 2018 , pp. 572-577 More about this Journal
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
Antitumor efficacy; Melanoma; MMP-2/9; PD-1/PD-L1; Targeting protein;
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1 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   DOI
2 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   DOI
3 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   DOI
4 Simon S and Labarriere N (2017) PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunology 7, e1364828
5 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
6 Mittendorf EA, Philips AV, Meric-Bernstam F et al (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2, 361-370   DOI
7 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   DOI
8 Masugi Y, Nishihara R, Yang J et al (2017) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut 66, 1463-1473   DOI
9 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   DOI
10 Kaunitz GJ, Cottrell TR, Lilo M et al (2017) Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest 97, 1063-1071   DOI
11 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   DOI
12 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   DOI
13 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   DOI
14 Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369, 122-133   DOI
15 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   DOI
16 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
17 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   DOI
18 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   DOI
19 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   DOI
20 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   DOI
21 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   DOI
22 Postow MA, Chesney J, Pavlick AC et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372, 2006-2017   DOI
23 Karam A and Dorigo O (2012) MMPs in ovarian cancer as therapeutic targets. Anticancer Agents Med Chem 12, 764-772   DOI
24 Kessenbrock K, Plaks V and Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52-67   DOI
25 Egeblad M and Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161-174   DOI
26 John A and Tuszynski G (2001) The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 7, 14-23   DOI
27 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   DOI
28 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   DOI
29 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   DOI
30 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   DOI
31 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   DOI
32 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
33 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   DOI
34 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   DOI
35 Holliger P and Hudson PJ (2005) Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23, 1126-1136   DOI
36 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   DOI
37 Hidalgo M and Eckhardt SG (2001) Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93, 178-193   DOI
38 Zucker S, Cao J and Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19, 6642-6650   DOI
39 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
40 Kleffel S, Posch C, Barthel SR et al (2015) Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242-1256   DOI
41 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   DOI
42 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   DOI