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Cytokine release assays: current practices and future directions
D Finco1, C Grimaldi2, M Fort3
1Pfizer Worldwide Research and Development, Groton, CT, USA.
Abstract:
As a result of the CD28 superagonist biotherapeutic monoclonal antibody (TGN 1412) "cytokine storm" incident, cytokine release assays (CRA) have become hazard identification and prospective risk assessment tools for screening novel biotherapeutics directed against targets having a potential risk for eliciting adverse pro-inflammatory clinical infusion reactions. Different laboratories may have different strategies, assay formats, and approaches to the reporting, interpretation, and use of data for either decision making or risk assessment. Additionally, many independent contract research organizations (CROs), academic and government laboratories are involved in some aspect of CRA work. As a result, while some pharmaceutical companies are providing CRA data as part of the regulatory submissions when necessary, technical and regulatory practices are still evolving to provide data predictive of cytokine release in humans and that are relevant to safety. This manuscript provides an overview of different approaches employed by the pharmaceutical industry and CROs, for the use and application of CRA based upon a survey and post survey follow up conducted by ILSI-Health and Environmental Sciences Institute (HESI) Immunotoxicology Committee CRA Working Group. Also discussed is ongoing research in the academic sector, the regulatory environment, current limitations of the assays, and future directions and recommendations for cytokine release assays.
Insights
Cytokine release assays (CRA) are crucial for assessing biotherapeutic risks post-TGN 1412 incident. This review surveys industry practices, highlighting evolving methods for predicting human cytokine release and ensuring safety.
Area of Science:
- Immunotoxicology
- Biopharmaceutical Safety Assessment
- Drug Development
Background:
- The CD28 superagonist TGN 1412 incident underscored the need for robust cytokine release assays (CRA).
- CRAs are vital for hazard identification and risk assessment of novel biotherapeutics.
- Variability exists in CRA strategies, formats, and data interpretation across laboratories.
Purpose of the Study:
- To provide an overview of diverse CRA approaches used by the pharmaceutical industry and contract research organizations (CROs).
- To discuss ongoing academic research, the regulatory landscape, and current assay limitations.
- To offer recommendations for the future development and application of CRAs.
Main Methods:
- Survey and follow-up conducted by the ILSI-HESI Immunotoxicology Committee CRA Working Group.
- Review of practices employed by pharmaceutical companies, CROs, academic, and government laboratories.
- Analysis of data reporting, interpretation, and decision-making processes.
Main Results:
- Significant variation in CRA methodologies and data utilization exists.
- Practices are evolving to generate data predictive of in vivo human responses.
- Regulatory submissions increasingly incorporate CRA data, though standardization is pending.
Conclusions:
- Standardization of CRA methodologies and data interpretation is needed.
- Further research is essential to enhance the predictive power of CRAs for clinical safety.
- Collaborative efforts are crucial for advancing CRA applications in biotherapeutic development.
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