Abstract
Genome editing within the constant region of the immunoglobulin Heavy chain locus (IGH) can reprogram B cells to express heavy-chain-only antibodies (HCAbs) containing custom antigen-recognition domains. HCAb-engineered cells express both surface B cell receptor (BCR) and secreted antibody isoforms and respond to antigen. Here, we extend this approach to also allow customization of the constant (Fc) domain of the Heavy chain by selecting alternate editing sites within IGH, producing HCAbs with enhanced effector functions or containing mutations to extend antibody half-life. We also introduced mutations to force obligate HCAb homodimers and prevent unwanted pairing with endogenous antibody chains. Finally, we showed that additional domains could be accommodated at the HCAb C-terminus and preferentially expressed in the secreted isoform. Together, these data demonstrate the flexibility of the HCAb editing platform to express fully customized molecules that take advantage of the properties of B cells.
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P.M.C. discloses support for the research of this work from National Institutes of Health grants U19 HL156247, UM1 AI164561, P01 HL183483 and R01 AI167003. A.M. discloses support for the research of this work from National Institutes of Health grant F30 AI186662. Tonsil tissue was collected and processed by the Norris Comprehensive Cancer Center Translational Pathology Core, supported by National Cancer Institute grant P30 CA014089. The remaining authors declare no relevant funding.
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Intellectual property discussed in this paper has been licensed by Be Biopharma from the University of Southern California. P.M.C. is a compensated member of Be Biopharma’s Scientific Advisory Board. The remaining authors declare no competing interests.
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Huang, C., Mathur, A., Chang, CH. et al. Engineering B cells to express fully customizable antibodies with enhanced Fc functions. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72991-8
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DOI: https://doi.org/10.1038/s41467-026-72991-8
