TY - JOUR
T1 - Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer
AU - Yeung, Tsz Lun
AU - Leung, Cecilia S.
AU - Yip, Kay Pong
AU - Sheng, Jianting
AU - Vien, Long
AU - Bover, Laura C.
AU - Birrer, Michael J.
AU - Wong, Stephen T.C.
AU - Mok, Samuel C.
N1 - Funding Information:
This study was supported in part by grants RO1CA133057, RO1CA142832, and RC4CA156551; The University of Texas MD Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence grant P50CA083639 from the NIH; the U.S. Department of Health and Human Services; the Gilder Foundation; by grants W81XWH-17-1-0126, W81XWH-17-1-0146, and W81XWH-16-1-0038 from the Ovarian Cancer Research Program, U.S. Department of Defense; Stephanie C. Stelter Professorship of Gynecologic Oncology Center for Ovarian Cancer Research (to S.C. Mok); and funding support from the Mary K. Chapman Foundation and the Ovarian Cancer Research Fund. The Monoclonal Antibodies Core Facility is supported by the Cancer Center Support Grant NCI P30CA016672. We acknowledge the assistance of Dr. Giulio Draetta from the Department of Genomic Medicine and Dr. Anirban Maitra from the Department of Pathology at MD Anderson Cancer Center on pancreatic cancer–related studies.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibrilassociated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models. Experimental Design: MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models. Results: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for in vivo studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. Conclusions: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
AB - Purpose: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibrilassociated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models. Experimental Design: MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models. Results: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for in vivo studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. Conclusions: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
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U2 - 10.1158/1078-0432.CCR-19-0187
DO - 10.1158/1078-0432.CCR-19-0187
M3 - Article
C2 - 31332047
AN - SCOPUS:85074446686
VL - 25
SP - 6417
EP - 6428
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 21
ER -