6–8 Thus, alternative approaches to modulate this important target are warranted. 1–3 Based on a strong mechanistic rationale and robust preclinical proof of concept, 4 5 CD137 has been recognized for its potential as a promising target in cancer, but this promise has not been realized for patients due to hepatic toxicity and limited efficacy observed in the initial therapies evaluated, including the agonistic CD137 antibodies, urelumab and utomilumab. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists.ĬD137 (4-1BB/TNFRSF9) is an inducible costimulatory receptor belonging to the tumor necrosis factor (TNF) receptor superfamily involved in the activation of T cells, natural killer (NK) cells, and other immune cells. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 induces complete tumor regressions and resistance to tumor re-challenge.
Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes.
In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist.
BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. Results Transcriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells.