Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics.

Area of Science:

• Immunology
• Biotechnology
• Drug Development

Background:

• Recombinant human proteins, including monoclonal antibodies, can elicit immune responses in patients.
• Immunogenicity evaluations have historically prioritized humoral responses, underemphasizing T-cell involvement.
• Emerging research underscores the significance of T cells in anti-drug antibody formation.

Purpose of the Study:

• To review the role of T-cell-dependent (Td) immunogenicity assessment in biologic drug development.
• To summarize recent findings on regulatory T-cell epitopes in IgG domains.
• To provide recommendations for Td immunogenicity screening to enhance drug safety.

Main Methods:

• Literature review focusing on T-cell contributions to immunogenicity.
• Analysis of recent publications on effector and regulatory T cells in anti-drug antibody development.
• Examination of data on T-cell epitopes within Fc and CH1 domains of IgG.

Main Results:

• T cells, both effector and regulatory, play a critical role in the development of anti-drug antibodies.
• Specific regulatory T-cell epitopes have been identified in the Fc and CH1 domains of IgG.
• Current preclinical and clinical evaluations may not fully capture T-cell-mediated immunogenicity.

Conclusions:

• T-cell-dependent immunogenicity assessment is vital for evaluating biologic drugs.
• Understanding T-cell epitopes can inform the design of less immunogenic biologics.
• Implementing Td immunogenicity screening can lead to safer protein-based therapeutics.