ABBV-303 Is an NK-cell Engager Specific for c-Met-Expressing Tumors.

Abstract

NK cell-redirecting therapies are emerging as promising "off the shelf" cancer treatments with fewer safety issues compared with T cell-directed therapies. In this study, we developed ABBV-303, a c-Met-targeted multispecific NK-cell engager. ABBV-303 included three functional arms: (i) a c-Met-binding single-chain variable fragment; (ii) a Fab that binds NKG2D, a stimulatory receptor on NK cells, and activated CD8+ T cells; and (iii) a heterodimeric IgG1 Fc that binds FcγRIIIa on NK cells. ABBV-303 binding to NKG2D and FcγRIIIa redirected NK cells to lyse c-Met-expressing tumor cells and induced CD8+ T-cell activation. The treatment of peripheral blood mononuclear cells with ABBV-303 in the presence of c-Met+ tumor cells stimulated NK and CD8+ T cells as demonstrated by modulation of activation-associated surface proteins and release of soluble factors. ABBV-303 drove subnanomolar redirected killing potency against tumor cells from different solid tumor indications expressing a range of c-Met levels. ABBV-303 demonstrated antitumor activity against established xenografts in CD34-humanized, IL15 transgenic NOD/SCID-gamma mice and in a c-Met+ tumor explant. When compared with a CD3 bispecific with the same c-Met binder, ABBV-303 drove lower levels of inflammatory cytokines at equivalent levels of tumor cell killing and enhanced tolerance of normal cells expressing c-Met, consistent with the natural tendency of NK cells to preferentially react with stressed or cancer cells as compared with normal, healthy tissue. Together, this study showed that ABBV-303 is effective at driving antitumor immunity against a wide range of c-Met-expressing tumors. ABBV-303 is a biologic that engages and potently redirects NK cells and costimulates CD8+ T cells in c-Met expressing tumors while demonstrating relative tolerance of normal tissue-derived cells.