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Anti-CD154 domain antibodies are engineered monoclonal antibodies that target the CD154 molecule (also known as CD40 ligand), a key costimulatory protein involved in T cell-mediated immune responses. CD154 is expressed on activated T cells, especially CD4^+ T follicular helper cells, and its engagement with CD40 on antigen-presenting cells (such as B cells and dendritic cells) is critical for processes like B cell maturation, antibody class switching, and the formation of regulatory T cells. Anti-CD154 therapies, including domain antibodies (dAbs) that are Fc-silent, block this interaction to suppress alloreactive immune responses, offering strong potential in organ transplantation and autoimmune diseases. Preclinical studies demonstrate that anti-CD154 domain antibodies can prolong graft survival, suppress alloreactive T and B cell expansion, diminish cytokine production, and promote regulatory T cell differentiation, with reduced risk of Fc-mediated adverse effects compared to traditional antibodies. Development has been hampered by thromboembolic events in early clinical trials of Fc-intact anti-CD154 antibodies, but Fc-silent domain antibodies may offer enhanced safety profiles[3][5][6].
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