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In Vivo Effect of Innate Immune Response Modulating Impurities on the Skin Milieu Using a Macaque Model: Impact on
Lydia A Haile1, Montserrat Puig1, Swamy K Polumuri1
1Laboratory of Immunology, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland 20993.
Journal of Pharmaceutical Sciences
|December 8, 2016
Summary
Trace impurities stimulating pattern recognition receptors (PRRs) can trigger immune responses to biologics. This study identified minimal impurity levels causing local inflammation and enhancing therapeutic protein immunogenicity in primates.
Area of Science:
- Biopharmaceutical development
- Immunology
- Drug safety
Background:
- Unwanted immune responses to therapeutic proteins can compromise safety and efficacy.
- Host cell and process-related impurities can stimulate pattern recognition receptors (PRRs), leading to inflammation and increased immunogenicity.
- Identifying minimal levels of innate immune response modulating impurities (IIRMIs) is crucial for biologics development.
Purpose of the Study:
- To determine the minimal levels of individual PRR agonists that activate local immune responses.
- To assess the impact of these minimal impurity levels on the immunogenicity of a model therapeutic protein.
- To establish a link between local mRNA induction, innate immune activation, and antibody development.
Main Methods:
- Purified PRR agonists were used as model impurities.
- Skin studies in rhesus macaques were conducted to assess gene expression changes.
- Spiking studies with rasburicase were performed to evaluate the effect on immunogenicity.
Main Results:
- Specific minimal levels for various PRR agonists (e.g., 10 pg endotoxin, 1 ng PolyI:C, 1 μg flagellin) were identified that induced innate immune gene expression in primate skin.
- These impurity levels were associated with increased immunogenicity of the model therapeutic rasburicase.
- A correlation was observed between local mRNA induction in skin and subsequent antibody development.
Conclusions:
- The study highlights the necessity of testing multiple IIRMIs in biologics.
- It strengthens the understanding of the relationship between local immune activation and antibody responses in primates.
- The findings provide guidance on acceptable levels of IIRMIs in therapeutic products to mitigate immunogenicity risks.
