Effect of andecaliximab (anti-MMP9) on proteolysis of IL-7 in vitro, TCR diversity in mice, and serum IL-7 in gastric cancer patients in combination with chemotherapy.

101Background: Andecaliximab (andeca) is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9). IL-7 selectively enhances the proliferation and survival of naive, memory, and effector T-cells (but not regulatory T-cells) in the periphery. Previous clinical trials with systemic recombinant IL-7 therapy increased TCR diversity. In the disease setting, elevated circulating IL-7 may be due to a compensatory increase in IL-7 production as demonstrated in mice upon inhibition of IL-7 signaling. Methods: An in vitro screen, in which recombinant active human MMP9 was incubated with > 140 human recombinant folded proteins, identified IL-7 as the most efficient substrate of MMP9. Results: IL-7 proteolysis occurred between A128:L129. IL-7 proteolysis altered the global protein structure, evidenced by a loss of cooperative unfolding observed with intact IL-7 (intrinsic fluorescence, Tm = 59.3o C). Mouse MMP9 proteolyzed mouse IL-7 in vitro. In the orthotopic syngeneic NeuT mouse model, MMP...