Re-engineering CD154 blockade for transplantation: Fc-free design to separate thrombotic risk from therapeutic function

Costimulation blockade of the CD40-CD154 pathway is among the most effective strategies for preventing allograft rejection, yet development of first-generation anti-CD154 antibodies was discontinued after thromboembolic complications. Higher-order immune complexes of soluble CD154 and anti-CD154 immunoglobulin G cross-link Fcγ receptor IIa (FcγRIIa) on platelets and activate them, localizing the liability to the fragment crystallizable region (Fc) rather than to the CD154-binding arm of the antibody. Engineering strategies address this by excluding the Fc altogether or silencing Fc function. Fc-free antagonists structurally preclude FcγRIIa cross-linking but forfeit neonatal Fc receptor (FcRn)-mediated recycling and size protection from glomerular filtration. Such antagonists must therefore recover both functions by other means. Size-based carriers recover only the second: conjugation of polyethylene glycol (PEG) to an anti-CD154 Fab' extends its half-life from hours to weeks, as in dapirolizumab pegol, but leaves FcRn recycling unaddressed, while uncertainties remain regarding long-term PEG exposure. Albumin recovers both through FcRn-dependent recycling and its own molecular size, without engaging Fcγ receptors. Dazodalibep, an Fc-free albumin-fusion CD154 antagonist, was administered with belatacept to kidney transplant recipients in a single-arm phase 2a trial without thrombotic events, but the prespecified composite efficacy endpoint was not met.