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bioRxiv · 10.64898/2026.03.05.709909

Mechanistic Basis for the Selective Recognition of the Fcγ Receptor IIa by Monoclonal Antibody IV.3

Wang, J.·Novack, S.·Li, J.·Niejadlik, E. G.·Bournazos, S.·Coller, B. S.·Filizola, M.
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Abstract

The monoclonal antibody IV.3 selectively binds the platelet Fc{gamma} receptor IIa (Fc{gamma}RIIa), potently blocking immune complex engagement without cross-reacting with the closely-related Fc{gamma}RIIb. This specificity has made IV.3 invaluable for dissecting Fc{gamma}RIIa-mediated activation in diverse conditions, including infection, autoimmunity, thromboinflammation, and platelet-mediated thrombosis. We combined cryogenic electron microscopy, surface plasmon resonance, alchemical free energy calculations, and molecular dynamics simulations to elucidate IV.3s binding sites on Fc{gamma}RIIa and the mechanistic basis of IV.3 specificity. We find that IV.3 engages a broader Fc{gamma}RIIa epitope than previously recognized, extending beyond residues H/R134 and L135 (R and S in Fc{gamma}RIIb). Simulations of Fc{gamma}IIa-R134 variants bearing either L135 or S135 reveal that IV.3 specificity arises from hydrophobic stabilization mediated by L135 and disruption of an R134-specific interaction network in the presence of S135. These findings provide a mechanistic framework for rational design of Fc{gamma}RIIa-targeted therapeutics.

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Wang, J., Novack, S., Li, J., Niejadlik, E. G., Bournazos, S., Coller, B. S., Filizola, M.. 2026-03-08. Mechanistic Basis for the Selective Recognition of the Fcγ Receptor IIa by Monoclonal Antibody IV.3. https://doi.org/10.64898/2026.03.05.709909

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