HLA-Fc fusion proteins for antigen-specific humoral suppression

Diverse human leukocyte antigens (HLA) play a crucial role in adaptive immune responses via peptide presentation. Unrelated to this role, alloimmunization to mismatched HLA represents a significant barrier to allogeneic transplantation. Despite the complexity of HLA structures and the diversity of alleles, advancements in recombinant HLA protein production have enabled their use in diagnostics and are paving the way for therapeutic applications. HLA-Fc fusion proteins, combining the extracellular domains of HLA molecules with the Fc region of immunoglobulins, offer a promising approach for antigen-specific immunotherapy. This review examines the engineering challenges and therapeutic potential of HLA-Fc fusion proteins in mitigating unwanted HLA alloimmunization and antibody-mediated rejection (AMR) following transplantation. HLA-Fc fusion proteins provide enhanced stability and effector functions, enabling the selective targeting and depletion of anti-HLA antibody-producing cells. Preclinical studies demonstrate their efficacy in neutralizing anti-HLA antibodies and depleting cognate antibody-producing cells, highlighting their potential to improve transplant outcomes and reduce AMR. Future research may focus on optimizing these fusion proteins, understanding their effects on primary B cells and long-lived plasma cells, and exploring combination therapies to enhance their clinical efficacy.