Reprogramming human B cells with custom heavy chain antibodies

Area of Science:

• Immunology
• Molecular Biology
• Genetic Engineering

Background:

• The immunoglobulin heavy chain (IgH) locus in B cells controls antibody production.
• Reprogramming B cells offers a potential platform for therapeutic molecule generation.

Approach:

• Developed a genome editing strategy to modify the IgH locus in human B cells.
• Created custom heavy chain antibodies (HCAbs) with antigen-recognition domains and Fc domains.
• Enabled differential splicing for B cell receptor (BCR) or secreted antibody expression.

Key Points:

• The HCAb platform is versatile, accepting various antigen-binding domains and Fc modifications.
• Edited B cells expressing anti-HIV Env HCAbs demonstrated regulated BCR and antibody expression.
• Demonstrated B cell response to Env antigen in a tonsil organoid model.

Conclusions:

• Human B cells can be reprogrammed using genome editing to produce customized therapeutic molecules.
• This approach allows for potential in vivo amplification of therapeutic antibodies.
• The engineered HCAbs show promise for targeted immunization responses and therapeutic applications.