ABBV-303 is a Natural Killer Cell Engager Specific for c-Met-Expressing Tumors

Abstract Natural killer (NK) cell redirecting therapies are emerging as promising “off the shelf” cancer treatments with fewer safety issues compared to T cell directed therapies. Here, we developed ABBV-303, a c-Met targeted multispecific NK cell engager. ABBV-303 included three functional arms: (1) a c-Met binding scFv; (2) a Fab that binds NKG2D, a stimulatory receptor on NK cells and activated CD8+ T cells; and (3) a heterodimeric IgG1 Fc which 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. 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 sub-nanomolar redirected killing potency against tumor cells from different solid tumor indications expressing a range of c-Met levels. ABBV-303 demonstrated anti-tumor activity against established xenografts in CD34-humanized, IL-15 transgenic NSG mice and in a c-Met+ tumor explant. When compared to 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 to normal, healthy tissue. Together, this study showed that ABBV-303 is effective at driving anti-tumor immunity against a wide range of c-Met expressing tumors.