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Effects of protein aggregates: an immunologic perspective
1Food and Drug Administration, Center for Drug Evaluation and Research, Building 29A, Room 2D-16, 8800 Rockville Pike, Bethesda, MD 20892, USA. amy.rosenberg@fda.hhs.gov
The AAPS Journal
|October 10, 2006
Summary
Protein aggregates can boost immune responses, leading to adverse events with therapeutic proteins. Understanding aggregate structures is key to assessing immunogenicity risks and improving product safety.
Area of Science:
- Immunology
- Protein Biochemistry
- Pharmaceutical Sciences
Background:
- Protein aggregates are known to enhance immune responses to therapeutic proteins.
- Adverse events linked to protein aggregates have been observed with early protein therapies like IVIG.
- The specific aggregate species responsible for these immunogenic effects remain poorly understood.
Purpose of the Study:
- To provide a framework for understanding how protein aggregates interact with the immune system.
- To explore the role of aggregate structure in B-cell activation and antibody production.
- To discuss the implications of protein aggregates for immunogenicity risk assessment and product development.
Main Methods:
- Review of basic immunologic research on antigen presentation and B-cell activation.
- Analysis of how highly arrayed protein structures influence immune responses.
- Discussion of factors influencing aggregate formation during manufacture and packaging.
Main Results:
- Highly arrayed protein aggregates can potently induce antibody responses, even without T-cell help.
- Multivalent protein species may enhance immune responses by cross-linking B-cell receptors.
- This cross-linking activates B cells and facilitates efficient T-cell help for antibody production.
Conclusions:
- Protein aggregate structure is critical for their immunogenicity.
- Understanding these interactions is essential for assessing and mitigating immunogenicity risks in protein therapeutics.
- Further research into aggregate species and their effects is needed for safer product development.
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