Oct 29, 2018

Reprogramming the antigen specificity of B cells using genome-editing technologies

BioRxiv : the Preprint Server for Biology
James E VossDennis R Burton

Abstract

We have developed a method to introduce novel paratopes into the human antibody repertoire by modifying the immunoglobulin genes of mature B cells directly using genome editing technologies. We used CRISPR-Cas9 in a homology directed repair strategy, to replace the heavy chain (HC) variable region in B cell lines with that from an HIV broadly neutralizing antibody, PG9. Our strategy is designed to function in cells that have undergone VDJ recombination using any combination of variable (V), diversity (D) and joining (J) genes. The modified locus expresses PG9 HC which pairs with native light chains resulting in the cell surface expression of HIV specific B cell receptors (BCRs). Endogenous activation-induced cytidine deaminase (AID) in engineered cells allowed for Ig class switching and generated BCR variants with improved anti-HIV neutralizing activity. Thus, BCRs engineered in this way retain the genetic flexibility normally required for affinity maturation during adaptive immune responses.

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Mentioned in this Paper

Cytidine Deaminase
MRNA Maturation
Genes
Binding Sites, Antibody
SLC3A2 gene
Biologic Development
Antibodies, Neutralizing
Receptors, Cell Surface
HIV Infections
Chemically Induced

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