Blood cytokines as biomarkers of in vivo toxicity in preclinical safety assessment: considerations for their use.
In the drive to develop drugs with well-characterized and clinically monitorable safety profiles, there is incentive to expand the repertoire of safety biomarkers for toxicities without routine markers or premonitory detection. Biomarkers in blood are pursued because of specimen accessibility, opportunity for serial monitoring, quantitative measurement, and the availability of assay platforms. Cytokines, chemokines, and growth factors (here referred to collectively as cytokines) show robust modulation in proximal events of inflammation, immune response, and repair. These are key general processes in many toxicities; therefore, cytokines are commonly identified during biomarker discovery studies. In addition, multiplexed cytokine immunoassays are easily applied to biomarker discovery and routine toxicity studies to measure blood cytokines. However, cytokines pose several challenges as safety biomarkers because of a short serum half-life; low to undetectable baseline levels; lack of tissue-specific or toxicity-specific expression; complexities related to cytokine expression with multiorgan involvement; and species, strain, and interindividual differences. Additional challenges to their application are caused by analytical, methodological, and study design-related variables. A final consideration is the strength of the relationship between changes in cytokine levels and the development of phenotypic or functional manifestations of toxicity. These factors should inform the integrated judgment-based qualification of novel biomarkers in preclinical, and potentially clinical, risk assessment. The dearth of robust, predictive cytokine biomarkers for specific toxicities is an indication of the significant complexity of these challenges. This review will consider the current state of the science and recommendations for appropriate application of cytokines in preclinical safety assessment.
Tarrant
Jacqueline M
JM
Safety Assessment, Genentech, Inc., South San Francisco, California 94080, USA. tarrant.jacqueline@gene.com
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D018570:Risk Assessment; D018675:Toxicity Tests
D015415:Biomarkers; D016207:Cytokines
J Clin Pharmacol. 2005 Oct;45(10):1165-71
16172181
J Immunol Methods. 2009 Jan 1;340(1):55-64
18983846
Exp Hematol. 2002 Nov;30(11):1227-37
12423675
Arch Dermatol Res. 2000 Aug;292(8):391-6
10994773
Methods. 2006 Apr;38(4):294-303
16481197
Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1186-92
15321784
N Engl J Med. 2006 Sep 7;355(10):1018-28
16908486
Ann Intern Med. 1998 Jan 15;128(2):127-37
9441573
Cytometry B Clin Cytom. 2009 May;76(3):159-68
18823005
J Clin Periodontol. 2003 Dec;30(12):1046-52
15002890
Clin Pharmacol Ther. 2001 Mar;69(3):89-95
11240971
PLoS One. 2007 Jul 18;2(7):e621
17637837
Blood. 1997 Oct 1;90(7):2541-8
9326219
Toxicology. 2008 Mar 20;245(3):219-23
18280028
Nat Immunol. 2009 Apr;10(4):333-9
19295629
Cytokine Growth Factor Rev. 2009 Feb;20(1):61-75
19213592
J Immunol. 2004 Mar 1;172(5):2731-8
14978070
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 May 1;877(13):1259-71
19038585
Cytokine. 2002 Sep 7;19(5):228-35
12393169
Biomarkers. 2010 Mar;15(2):140-8
19848603
Nature. 2008 Jul 24;454(7203):428-35
18650913
Eur J Obstet Gynecol Reprod Biol. 1999 Apr;83(2):213-7
10391535
Toxicol Pathol. 2008 Oct;36(6):840-9
18776166
Cytokine Growth Factor Rev. 2009 Feb;20(1):43-59
19038572
J Immunol Methods. 2009 Oct 31;350(1-2):161-70
19732777
Transfus Med. 2001 Dec;11(6):403-17
11851938
Cardiovasc Res. 2007 May 1;74(2):213-22
17382916
Toxicol Pathol. 2006;34(1):39-51
16507543
Clin Pharmacol Ther. 1999 Jun;65(6):615-29
10391667
Cancer Biomark. 2005;1(1):29-39
17192030
Shock. 2007 Mar;27(3):238-41
17304103
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4265-73
16857801
Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3450-6
19064561
J Immunotoxicol. 2009 Mar;6(1):1-10
19519157
Clin Vaccine Immunol. 2008 Jan;15(1):42-8
18003817
Nat Rev Immunol. 2009 Oct;9(10):692-703
19859064
FEBS Lett. 2007 May 15;581(10):2017-21
17470370
Annu Rev Med. 2008;59:1-12
18186700
Shock. 2002 Apr;17(4):322-8
11954835
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21407-12
19955445
Cytometry B Clin Cytom. 2004 Sep;61(1):35-9
15351980
J Clin Invest. 2008 Apr;118(4):1405-16
18357346
Front Biosci (Landmark Ed). 2009 Jan 01;14:540-51
19273084
Expert Opin Drug Metab Toxicol. 2007 Apr;3(2):209-34
17428152
J Transl Med. 2004 Jun 2;2(1):17
15175100
Cell. 2008 Jan 25;132(2):259-72
18243101
Biochem Biophys Res Commun. 2002 Oct 4;297(4):700-13
12359210
News Physiol Sci. 2000 Dec;15:298-303
11390930
Mol Biol Evol. 1999 Feb;16(2):180-93
10028286
Pharm Res. 2005 Apr;22(4):499-511
15846456
Clin Pharmacol Ther. 2009 Mar;85(3):247-58
19177065
Nat Immunol. 2008 Apr;9(4):353-9
18349815
Transpl Immunol. 2005 Jun;14(2):77-82
15935297
Toxicol Appl Pharmacol. 2005 Feb 15;203(1):62-87
15694465
J Pharm Biomed Anal. 2005 Jan 4;36(5):1037-44
15620530
Clin Chem. 2009 Jun;55(6):1092-9
19372187