Reprogramming human B cells with custom heavy chain antibodies

Rogers, G. L.; Huang, C.; Mathur, A.; Huang, X.; Chen, H.-Y.; Stanten, K.; Morales, H.; Chang, C.-H.; Kezirian, E. J.; Cannon, P. M.

doi:10.1101/2023.06.28.546944

bioRxiv · 10.1101/2023.06.28.546944

Reprogramming human B cells with custom heavy chain antibodies

Rogers, G. L.·Huang, C.·Mathur, A.·Huang, X.·Chen, H.-Y.·Stanten, K.·Morales, H.·Chang, C.-H.·Kezirian, E. J.·Cannon, P. M.

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Abstract

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

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Rogers, G. L., Huang, C., Mathur, A., Huang, X., Chen, H.-Y., Stanten, K., Morales, H., Chang, C.-H., Kezirian, E. J., Cannon, P. M.. 2023-06-30. Reprogramming human B cells with custom heavy chain antibodies. https://doi.org/10.1101/2023.06.28.546944

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