Subcutaneous ANtibody-conjugated microGel platform enabling combination immunotherapy for refractory solid tumors

Background: Drug delivery systems (DDSs) are increasingly utilized to enhance the precision and durability of biologics in oncology. However, current cancer immunotherapies show limited efficacy in solid tumors due to profoundly immunosuppressive tumor microenvironments, underscoring the need for innovative delivery platforms. We developed the ANtibody-conjugated microGel (ANGel), a deformable hydrogel-based submicron particle engineered to deliver combination monoclonal antibodies (mAbs) targeting both the PD-1/PD-L1 axis and co-stimulatory pathways. Methods: ANGel formulations were generated by surface affinity loading of multiple mAb types. In vitro studies assessed therapeutic synergy between two anti-PD-1/PD-L1 mAbs and two co-stimulatory mAbs when formulated with ANGel. Lead combinations were evaluated in vivo using triple-negative breast cancer (TNBC) mouse models. Subcutaneous administration was performed at peritumoral sites to assess local delivery, antitumor activity, and survival. Dose sensitivity and formulation parameters were fine-tuned to identify optimal therapeutic regimens. Results: ANGel significantly enhanced in vitro synergy between PD-1/PD-L1-targeting and co-stimulatory mAbs compared with free-antibody mixtures. In TNBC models, subcutaneous peritumoral delivery of combination ANGel (dANGel) formulations produced marked tumor-growth delay relative to free-combination mAbs, including combinations with hyaluronidase. Antitumor efficacy of dANGel formulations demonstrated strong dose-dependent and regimen-dependent sensitivity, enabling optimization for maximal therapeutic output. Notably, dANGel treatment extended progression-free survival to 204 days, compared with 23 days achieved by anti-PD-L1 plus anti-CTLA-4 mAbs formulated with hyaluronidase. Conclusions: These results demonstrate ANGel as a potent local delivery platform capable of overcoming key barriers to solid-tumor immunotherapy. By enabling subcutaneous peritumoral administration of synergistic mAb combinations, ANGel provides a novel therapeutic strategy with the potential to substantially improve outcomes in refractory solid tumors. Preclinical findings support dANGel as a strong candidate for clinical translation.