Structure-function analysis of the FCRL5-IgG1 Fc complex reveals an unappreciated pathway for B cell modulation by Fc-attenuated IgG.

Authors

Bart M Herpers, Mo Guo, Sanghwan Ko, George Delidakis, Jin Eyun Kim, Chang-Han Lee, Mohamed I Gadallah, Jennifer S Brodbelt, Y Jessie Zhang, George Georgiou

Published in

Science advances. Volume 12. Issue 35. Pages eaei1233. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

The Fc region of therapeutic IgG antibodies is often engineered to remove or "silence" Fc effector functions, but it remains unclear whether these mutations eliminate all Fc-mediated effector activity. Human Fc receptor-like 5 (FCRL5/FcRH5) is a low-affinity IgG Fc receptor expressed on B cells and is an actively pursued antibody target in multiple myeloma. Here, we show that common Fc function-silencing mutations do not impair FCRL5-mediated activity and therefore attenuate, rather than eliminate, Fc effector function. The crystal structure of the FCRL5-IgG1 Fc complex, solved at 3.4 Å resolution, revealed that FCRL5 binds IgG1 Fc in a 1:1 complex through a binding mode distinct from that of classical Fcγ receptors, explaining why mutations that attenuate Fc effector function spare FCRL5 binding. Fc-engineered antibodies that selectively engage FCRL5 inhibited B cell receptor-induced Ca²⁺ flux in FCRL5-expressing B cells. These findings demonstrate that Fc-attenuated therapeutic IgG retains the ability to engage FCRL5, identifying an unappreciated pathway for B cell modulation.

PMID:
42664341
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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