title: Cytokine release assays: current practices and future directions.
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.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT, USA. Electronic address: Deborah.finco@pfizer.com.
authors.forename: D
authors.initials: D
authors.lastname: Finco
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Grimaldi
authors.affiliation: Discovery Toxicology, Amgen Inc., Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fort
authors.affiliation: Janssen Research and Development, Spring House, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Kiessling
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Wolf
authors.affiliation: Immunotoxicology, Bristol-Myers Squibb, New Brunswick, NJ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Salcedo
authors.affiliation: Clinical Pharmacology & DMPK, MedImmune, LLC, Hayward, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Faggioni
authors.affiliation: Clinical Pharmacology & DMPK, MedImmune, LLC, Hayward, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ibraghimov
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Scesney
authors.affiliation: AbbVie Bioresearch Center, Worcester, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Serna
authors.affiliation: Genentech Inc., South San Francisco, USA.
authors.forename: R
authors.initials: R
authors.lastname: Prell
authors.affiliation: National Institute for Biological Standards & Control, Potters Bar, UK.
authors.forename: R
authors.initials: R
authors.lastname: Stebbings
authors.affiliation: Discovery Toxicology, Amgen Inc., Seattle, WA, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Narayanan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized; D001681:Biological Assay / Q000379:methods*; D018106:CD28 Antigens / Q000276:immunology; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology; D009102:Multiple Organ Failure / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; C509303:TGN-1412
keywords: Cytokine release assay; Cytokine storm; Monoclonal antibody; TGN 1412