Reprogramming human B cells with custom heavy-chain antibodies.

Area of Science:

• Immunology
• Molecular Biology
• Genetic Engineering

Background:

• Current genome editing strategies for antibody reprogramming are complex and limit customization of the antibody's constant region.
• The immunoglobulin locus in B cells offers potential for engineering custom antibodies not achievable through traditional immunization.

Purpose of the Study:

• To develop a novel genome editing strategy for human B cells to create heavy-chain-only antibodies with customizable antigen-binding and effector functions.
• To demonstrate the feasibility of this approach using the human immunodeficiency virus envelope protein as a model antigen.

Main Methods:

• Editing the immunoglobulin heavy-chain locus in human B cells to express heavy-chain-only antibodies.
• Utilizing alternative splicing for regulated expression of B cell receptors and antibodies.
• Testing the engineered B cells in a tonsil organoid model with human immunodeficiency virus envelope protein antigen.

Main Results:

• Successfully generated human B cells expressing heavy-chain-only antibodies targeting the HIV Env protein.
• Demonstrated regulated expression of engineered antibodies via alternative splicing.
• Observed antigen-specific responses in a tonsil organoid model, indicating successful immunization mimicry.

Conclusions:

• This genome editing strategy enables the reprogramming of human B cells to produce novel heavy-chain-only antibodies with enhanced compositional flexibility.
• The engineered cells retain in vivo amplification potential and respond to specific antigens, offering a versatile platform for antibody-based therapeutics and research.