Abstract C099: Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer

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 monoclonal antibody targeting microfibril associated protein 5 (MFAP5), which is secreted predominately by cancer associated fibroblasts (CAFs), in ovarian and pancreatic cancer models.MFAP5-targeting monoclonal antibodies were developed using purified full-length human MFAP5 recombinant protein as an antigen in mice and antibodies from hybridoma clones were evaluated for their toxicity, and 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 vitroassays. 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. The results demonstrated that antibody clone 130A recognized a common epitope shared between human and murine MFAP5 protein. Kinetic assays showed that the dissociation constant (Kd) of clone 130A for human and mouse MFAP5 protein were at 1.93nM and 2.51nM respectively, suggesting that clone 130A has high binding affinity to both human MFAP5 and mouse MFAP5 protein. Toxicity studies of clone 130A showed that mice treated with MAbs had no adverse effects in complete blood counts, serum ALT, AST, alkaline phosphatase and urea nitrogen levels, and major organ histology. In vitrofunctional studies showed that clone 130A suppressed ovarian and pancreatic cancer cell, and endothelial cell motility. In vivostudies showed that clone 130A suppressed tumor growth in ovarian and pancreatic cancer-bearing mice, down-regulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. 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 in treating these diseases. Citation Format: Tsz-Lun Yeung, Cecilia Leung, Sammy Ferri-Borgogno, Kay-Pong Yip, Jianting Sheng, Long Vein, Laura Bover, Michael Birrer, Stephen Wong, Samuel C Mok. Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C099. doi:10.1158/1535-7163.TARG-19-C099