Immunogenicity Assessment for Therapeutic Protein Products

Recommendation

7/8 May 2024

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Regulatory Requirements and Practical Implementation

Several scientists worked in the last years on the topic of immunogenicity of therapeutic proteins. As Huub Schellekens stated in his publication in Discovery Medicine on 23 June 2010, "Nearly all therapeutic proteins induce antibodies in patients. However this immunogenicity has been neglected in the use of these products, even though the antibodies may have severe consequences. During the last few years, progress has been made in understanding why patients do not tolerate these protein therapeutic products and also how to manage the problem of immunogenicity."

So immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy. There are risks of immunologically based adverse events, such as anaphylaxis, cytokine release syndrome, and cross-reactive neutralization of endogenous proteins mediating critical functions.

Now, in August 2014, the FDA published a "Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products". The authority indicates: "This guidance is intended to assist manufacturers and clinical investigators involved in the development of therapeutic protein products for human use. In this document, FDA outlines and recommends adoption of a risk-based approach to evaluating and mitigating immune responses to or adverse immunologically related responses associated with therapeutic protein products that affect their safety and efficacy. Any given approach to assessing and mitigating immunogenicity is determined on a case-by-case basis and should take into consideration the risk assessment we describe. For the purposes of this guidance, immunogenicity is defined as the propensity of the therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events."

The document includes

• Clinical Consequences
  A. Consequences for Efficacy
  B. Consequences for Safety
• Recommendations for Immunogenicity Risk Mitigation in the Clinical Phase of Development of the therapeutic Protein Products
• Patient- and Product - Specific factors that Effect immunogenicity
  A. Patient-Specific Factors That Affect Immunogenicity
  B. Product-Specific Factors That Affect Immunogenicity

For more details and the conclusions please see the Guidance "Immunogenicity Assessment for Therapeutic Protein Products".