Antibody–Drug Conjugates Synergize with Agonist Anti-CD137 Monoclonal Antibodies in Solid Tumors

Antibody-drug conjugates (ADCs) show clinical efficacy against several solid malignancies, inducing cytotoxic effects in malignant cells accompanied by changes in the composition of the tumor stroma. The therapeutic effects of some ADCs have been shown to be potentiated by combination with anti-PD(L)1 checkpoint inhibitors, highlighting the potential of combining ADCs and immunotherapy. Here, we investigated the potential of combining ADCs with agonist monoclonal antibodies targeting CD137 (4-1BB), a costimulatory receptor expressed on antigen-primed T lymphocytes and activated NK cells. The combination of MMAE- and deruxtecan-conjugated ADCs towards NECTIN-4 or HER2 with anti-CD137 agonists elicited synergistic effects in mouse tumor models. Treatment with the ADCs increased CD137 expression on intratumor CD8+ and CD4+ T lymphocytes. Moreover, the synergistic antitumor therapeutic efficacy was dependent on cDC1 dendritic cells and CD8+ T cells. ADCs induced features of immunogenic cell death in malignant cells, resulting in cross-presentation and maturation of cDC1 dendritic cells that cross-prime CD8+ T cells to become CD137-positive. Importantly, the anti-CD137 plus ADC synergistic combination attained efficacy against concomitant tumor lesions that failed to express the ADC target. Together, these findings demonstrate that anti-CD137 agonists hold promise for combination strategies with ADCs.