Abstract 2615: Preclinical evaluation and mechanistic characterization of M7824 (MSB0011359C), a novel bifunctional fusion protein targeting the PD-L1 and TGFβ pathways

Dual targeting of the programmed death ligand 1 (PD-L1) and transforming growth factor β (TGFβ) pathways, 2 key mediators of tumor immune evasion, may provide synergistic antitumor activity. The novel bifunctional fusion protein M7824 (MSB0011359C) is a fully human IgG1 monoclonal antibody against PD-L1, fused via a glycine-serine linker at the CH3-C terminus to the extracellular domain of human TGFβ receptor II, which functions as a TGFβ “trap.” Thus, M7824 is designed to exert independent and complementary anti-immunosuppressive functions by simultaneously blocking the PD-L1 and TGFβ pathways. The purpose of this study was to evaluate M7824 preclinically. M7824 was efficacious in multiple syngeneic tumor models (EMT-6, MC38, PANC02, 4T1, CT26, and GL261). In orthotopic EMT-6 and intramuscular MC38 models, M7824 showed superior additive antitumor effects compared to anti-PD-L1 antibody or TGFβ trap monotherapy. M7824 also inhibited spontaneous metastases in EMT-6 and 4T1 models. Furthermore, M7824 extended survival and conferred long-term protective antitumor immunity, as demonstrated by protection of cured mice against tumor cell rechallenge. Mechanistically, the dual anti-immunosuppressive activity of M7824 in the MC38 model resulted in unique activation of both the adaptive and innate immune systems, including increased tumor infiltration, proliferation, and cytotoxicity of CD8+ T cells; increased prevalence of splenic tumor antigen-specific CD8+ T cells; increased CD8+ TEM infiltration and CD8+ TEM/naïve ratio; increased tumor-infiltrated natural killer (NK) cells; increased ratio of M1/M2 macrophages; and decreased infiltration of tumor-associated neutrophils and myeloid-derived suppressor cells. Similar immunophenotypic changes were observed in the EMT-6 model. Activation of both the adaptive and innate immune systems contributed to the antitumor activity of M7824 in the MC38 model, as depletion of CD8+ T cells and NK cells led to a substantial decrease in M7824-mediated tumor regression; CD4+ T cells and antibody-dependent cellular cytotoxicity, however, appeared dispensable. Toxicologic evaluation in cynomolgus monkeys indicated M7824 was well tolerated, with only minor hematologic effects observed. Although M7824 is a bifunctional molecule, its antitumor activity can be further improved by combination with standard-of-care therapies: in the MC38 model, combining M7824 with radiotherapy or chemotherapy resulted in more effective inhibition of tumo