Abstract 182: Superior targeting of tumor-stromal interactions and endothelial migration with a bispecific antibody to α5 and αv integrins

Introduction: The integrin α5β1 has been implicated in the adhesive and migratory response of prostate cancer cells induced by fibronectin fragments secreted by human bone-marrow derived mesenchymal stromal cells (hBM-MSCs) [Joshi, Cell Adh and Migr 2016). Genetic inactivation of integrin α5 in PC-3 cells downregulated the bcl-2 family of proteins and induced programmed cell death (Ren, Mol Cell Res 2017) - linking hBM-MSCs to a putative bone marrow niche survival program for prostate cancer cells. We hypothesized that the fibronectin-binding integrins α5β1 and integrin αv collaborate in broader tumor-stromal interactions and sought to examine the impact of combinatorial inactivation of these integrins. Methods: Monospecific antibodies to α5 (or its obligate α5β1 heterodimer) and to integrin alpha v (or the αvβ3 heterodimer) were utilized to assess the efficacy of a combinatorial neutralization approach over either single agent in α5/αv co-expressing cells from diverse tumor types including prostate, breast, glioma, cervix and uterine cancer. Assays included adhesion, migration, cell survival and the induction of endothelial migration in co-culture with stromal cells. To address the hypothesis that a bispecific integrin targeting antibody would be superior to a combinatorial approach with monospecific integrin antibodies, a bispecific antibody prototype that simultaneously targets the α5β1 and αv integrins [Bsα5β1/αvAb] was constructed and deployed in comparative assays. Results: Combined α5 and av neutralization with dual monospecific antibodies was superior to individual single agents in blocking adhesion, migration and the induction of endothelial chemotaxis across diverse tumor types that co-expressed α5 and αv integrins. However, a significant superiority of the Bsα5β1/αvAb was noted over the combinatorial approach with monospecific antibodies in these assays. In addition, a significant reduction in cell survival was noted in selected tumor types with the Bsα5β1/αvAb. Strikingly, the Bsα5β1/αvAb was significantly more potent than bevacizumab in the inhibition of endothelial migration induced by tumor-stromal cell interactions Conclusions: Combinatorial α5 and av integrin targeting in tumor cells that co-express α5 and av integrins effectively abrogates tumor-stromal interactions and the resultant endothelial migratory response. A Bsα5β1/αvAb demonstrates a significant improvement over combinatorial monospecific antibodies likely through diverse mechanisms including cross-priming. Targeting tumor, stromal and endothelial cells simultaneously with a Bsα5β1/αvAb approach represents a potentially effective therapeutic strategy for targeting diverse mechanisms of progressive disease in the tumor microenvironment. Citation Format: Raghav Joshi, Wenying Ren, Paul Mathew. Superior targeting of tumor-stromal interactions and endothelial migration with a bispecific antibody to α5 and αv integrins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 182.