Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus.
Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.
Yao
Yihong
Y
MedImmune, Translational Sciences, One MedImmune Way, Gaithersburg, MD 20878, USA. YaoY@MedImmune.com
Higgs
Brandon W
BW
Richman
Laura
L
White
Barbara
B
Jallal
Bahija
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology*; D005803:Genes, Immunoglobulin; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000097:blood*; D012216:Rheumatic Diseases / Q000097:blood; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000378:metabolism; D059467:Transcriptome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; D015415:Biomarkers; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; C568334:sifalimumab
Am J Manag Care. 2001 Oct;7(16 Suppl):S480-5
11680779
Viral Immunol. 2003;16(3):291-306
14583145
Ann Rheum Dis. 2007 Aug;66(8):1008-14
17223656
J Exp Med. 2003 Mar 17;197(6):777-88
12642605
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12319-24
14530402
J Immunol. 2005 Mar 1;174(5):2499-506
15728455
Arthritis Rheum. 2004 Nov;50(11):3731-2
15529358
J Interferon Cytokine Res. 2000 Jul;20(7):615-21
10926203
Annu Rev Immunol. 2005;23:307-36
15771573
Curr Opin Immunol. 2004 Dec;16(6):801-7
15511676
N Engl J Med. 2003 Oct 16;349(16):1526-33
14561795
Arthritis Rheum. 2007 May;56(5):1579-88
17469140
Lupus. 2000;9(9):664-71
11199920
N Engl J Med. 2004 Dec 30;351(27):2817-26
15591335
Ann Rheum Dis. 2005 Dec;64(12):1692-7
15843451
Immunity. 2001 Jun;14(6):661-4
11420036
Arthritis Rheum. 2007 Nov;56(11):3784-92
17968926
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2610-5
12604793
J Natl Cancer Inst. 2009 Oct 7;101(19):1308-24
19738166
Arthritis Rheum. 2008 May;58(5):1465-74
18438864
Arthritis Rheum. 2000 Jul;43(7):1431-42
10902743
J Interferon Cytokine Res. 2004 Feb;24(2):131-9
14980077
Arthritis Rheum. 2003 Sep;48(9):2396-401
13130457
Ann Neurol. 2005 May;57(5):664-78
15852401
Hum Mol Genet. 2008 Mar 15;17(6):872-81
18063667
Clin Rheumatol. 2005 Apr;24(2):178-81
15565395
Arthritis Rheum. 1999 Sep;42(9):1785-96
10513791
Arthritis Res Ther. 2003;5(2):68-75
12718746
Nature. 2005 Jun 9;435(7043):834-8
15944708
Arthritis Rheum. 2005 May;52(5):1491-503
15880830
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Jan;107(1):e12-8
19101478
Am J Pathol. 2001 Jul;159(1):237-43
11438470
Arthritis Rheum. 2009 Jun;60(6):1785-96
19479852
Arthritis Rheum. 2005 Apr;52(4):1185-95
15818675
Curr Opin Immunol. 2006 Dec;18(6):676-82
17011763
Arthritis Rheum. 2006 Jun;54(6):1906-16
16736505
Arthritis Rheum. 2004 Dec;50(12):3958-67
15593221
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5294-9
19279210
Lupus. 2008 May;17(5):394-9
18490415
Arthritis Rheum. 2006 Sep;54(9):2951-62
16947629
Genes Immun. 2003 Apr;4(3):177-86
12700592
N Engl J Med. 2009 Feb 19;360(8):790-800
19228622
Hum Genomics Proteomics. 2009 Nov 17;2009:
20948567
Bull NYU Hosp Jt Dis. 2008;66(3):176-83
18937628
Immunity. 2004 May;20(5):539-50
15142523
Lupus. 2001;10(7):484-90
11480846
J Immunol. 2003 Sep 1;171(5):2366-73
12928383
J Exp Med. 2003 Mar 17;197(6):711-23
12642603