Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity.

Antibody-drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efficacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FcγR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~30% of the PBS group at day 14. The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efficacy, including for the treatment of immunologically cold tumors.