Study on the Antirejection Effects of the Dual ICOS and CD28 Antagonist Acazicolcept (ALPN-101) in Mouse Skin and Heart Transplantation Models

BACKGROUND: T cell-mediated rejection significantly constrains the success of organ transplantation. T-cell activation relies on the complementary CD28 and ICOS costimulatory pathways. Thus, this research assessed a new dual CD28/ICOS antagonist, acazicolcept, in rigorous allogeneic transplantation models. METHODS: Mouse models for allogeneic skin transplantation and abdominal heterotopic heart transplantation were developed. Recipients received acazicolcept, PBS, FK506, or single-pathway antagonists (belatacept or prezalumab). Graft viability, histopathological analysis, and T-cell infiltration were evaluated. Flow cytometry assessed spleen and blood lymphocyte subsets and costimulatory molecules. Donor-specific antibodies and graft C4d deposition were assessed to evaluate humoral responses. RESULTS: Acazicolcept significantly extended the median survival time of skin and heart allografts to 31 d and 42.5 d, respectively, substantially surpassing other groups and mitigated histopathological damage. Mechanistic investigations demonstrated that the drug simultaneously downregulated the surface expression of CD28 and ICOS on T cells; effectively inhibited the development of effector memory T cells (Tem); and reduced the expression of PD-1 and CD69, reflecting a profound attenuation of early T-cell activation. Moreover, acazicolcept markedly inhibited humoral immune responses, as demonstrated by diminished C4d deposition in grafts and lowered levels of donor-specific antibody-IgG/IgM in peripheral blood. CONCLUSIONS: Acazicolcept exhibits robust, superior antirejection efficacy compared with single-pathway blockades by concurrently inhibiting CD28 and ICOS signals. This dual mechanism effectively suppresses T-cell activation, effector memory differentiation, and the subsequent antibody-mediated response, offering a robust preclinical justification for its clinical advancement in solid organ transplantation.