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Updated: Jun 20, 2025

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Reprogramming human B cells with custom heavy-chain antibodies.

Geoffrey L Rogers1, Chun Huang1, Atishay Mathur1

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Genome editing reprograms human B cells to create custom heavy-chain-only antibodies. This novel approach allows for flexible antibody design and targeted antigen response, advancing antibody engineering.

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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.