In vivo affinity maturation of mouse B cells reprogrammed to express human antibodies.

Publication date: Mar 14, 2024

Mice adoptively transferred with mouse B cells edited via CRISPR to express human antibody variable chains could help evaluate candidate vaccines and develop better antibody therapies. However, current editing strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that these key B-cell functions can be preserved by directly and simultaneously replacing recombined mouse heavy and kappa chains with those of human antibodies, using a single Cas12a-mediated cut at each locus and 5′ homology arms complementary to distal V segments. Cells edited in this way to express the human immunodeficiency virus type 1 (HIV-1) broadly neutralizing antibody 10-1074 or VRC26. 25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated mice. The 10-1074 variants isolated from the mice neutralized a global panel of HIV-1 isolates more efficiently than wild-type 10-1074 while maintaining its low polyreactivity and long half-life. We also used the approach to improve the potency of anti-SARS-CoV-2 antibodies against recent Omicron strains. In vivo affinity maturation of B cells edited at their native loci may facilitate the development of broad, potent and bioavailable antibodies.

Concepts Keywords
Biomed Affinity
Inefficient Antibodies
Mice Antibody
Vaccines Chains
Edited
Express
Heavy
Hiv
Locus
Maturation
Neutralizing
Potent
Reprogrammed
Transferred
Vivo

Semantics

Type Source Name
drug DRUGBANK Tropicamide
disease VO inefficient
disease IDO cell
disease VO vaccinated

Original Article

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