Article Dans Une Revue Scientific Reports Année : 2024

Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens

Jérôme Moreaux

Résumé

T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. We designed a single-chain Ig-encoding cassette ("scFull-Ig") that redirects antigen specificity when inserted at a single position of the IgH locus. This design, which places combined IgH and IgL variable genes downstream of a pVH promoter, nevertheless preserves all Ig functional domains and the intrinsic mechanisms that regulate expression from the IgM B cell receptor (BCR) expression to Ig secretion, somatic hypermutation and class switching. This single-locus editing provides an efficient and safe strategy to both disrupt endogenous Ig expression and encode a new Ig paratope. As a proof of concept, the functionality of scFull BCR and/or secreted Ig was validated against two different classical human tumor antigens, HER2 and hCD20. Once validated in cell lines, the strategy was extended to primary B cells, confirming the successful engineering of BCR and Ig expression and the ability of scFull-Ig to undergo further class switching. These results further pave the way for future B cell-based adoptive immunotherapy and strategies to express a therapeutic mAb with a variety of switched H-chains that provide complementary functions.

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hal-04723581 , version 1 (07-10-2024)

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Natsuko Ueda, Marine Cahen, Jenny Leonard, Laurent Deleurme, Stéphane Dreano, et al.. Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens. Scientific Reports, 2024, 14 (1), pp.22432. ⟨10.1038/s41598-024-74005-3⟩. ⟨hal-04723581⟩
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