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A Comparative Analysis of Acute-phase Proteins as Inflammatory Biomarkers in Preclinical Toxicology Studies: Implications for Preclinical to Clinical Translation
1 AstraZeneca, Alderley Park, United Kingdom Correspondence: Anne Lanevschi. 19F58 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom; e-mail: anne .pietersma{at}astrazeneca.com. Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.
Key Words: biomarkers • preclinical safety assessment–risk management • inflammation Abbreviations: A1AG, alpha-1-acid glycoprotein • A2MG, alpha-2-macroglobulin • AP, Alderley Park • APP, acute-phase protein • CARS, counter-inflammatory response syndrome • CRP, C-reactive protein • DIC, disseminated intravascular coagulation • FDPs, fibrin or fibrinogen degradation products • FIB, fibrinogen • HAPT, haptoglobin • HMGB1, high-mobility group B1 protein • ICAM-1, intercellular adhesion molecule-1 • ICH, International Conference for Harmonization • IFN
This version was published on January
1, 2009 Toxicologic Pathology, Vol. 37, No. 1,
28-33 (2009) |
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2a, interferon-alpha 2a • IL-1, interleukin-1 • IL-2, interleukin-2 • IL-6, interleukin-6 • LPS, bacterial lipopolysaccharide • PAI-1, plasminogen activator inhibitor type 1 • SAA, serum amyloid A • SIRS, systemic inflammatory response syndrome • TAFI, thrombin activatable fibrinoly-sis inhibitor • TAT, thrombin-antithrombin • TEG, thromboelastography • TF, tissue factor • TG, thrombin generation • TGN1412, TeGenero1412 drug candidate • TNF