Abstract LB-154: Generation of antagonistic anti-DDR1 monoclonal antibodies as a potential novel cancer therapeutic

Abstract

Abstract Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in diverse cellular roles, including cell adhesion, proliferation, and extracellular matrix remodeling. Multiple tumor types have been shown to overexpress DDR1, including lung, esophageal, breast, ovarian, and pediatric brain cancers, suggesting a potential role for DDR1 in tumor progression. Inhibition of DDR1 signaling may therefore represent a novel therapeutic approach for treating these cancers. Potential therapeutic molecules that modulate human DDR1 activity were identified by screening the AnaptysBio Evolvable Library (ABEL) of fully human germline antibodies. The initial ABEL screen used the soluble DDR-1 extra cellular domain, followed by secondary screening on cell-surface DDR-1. The resulting panel of human antibodies was affinity matured using SHM-XELTM which uses mammalian cell display of human IgG followed by in vitro somatic hypermutation (SHM) as described for a number of other antibodies (Bowers et al., 2014, Methods 65, 44-56). The matured antibodies bound specifically to DDR1 with high affinity (KD<1nM as measured by Biacore), and were able to functionally inhibit collagen triggered DDR1 signaling in multiple cell-based assays. The antibody panel shows selectivity for DDR1 over closely related molecules such as DDR2 and has other properties suitable for preclinical development, including cross-reactivity with the cynomolgus monkey DDR-1 ortholog and good biophysical properties. These antibodies are being further explored for their therapeutic efficacy in tumor types where DDR1 signaling plays a role in disease progression. Citation Format: H. Toni Jun, Brandon Hynes, John L. Macomber, Andrew Lassen, Larry Altobell, Josh MacLaren, David King, Robert A. Horlick. Generation of antagonistic anti-DDR1 monoclonal antibodies as a potential novel cancer therapeutic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-154. doi:10.1158/1538-7445.AM2014-LB-154