ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 948

Dual Neutralization Of TNF and IL-17 Provides Greater Efficacy In Collagen Induced Arthritis Through Regulation Of a Gene Transcription Program That Includes CXCL1 and CXCL5

Carolyn Cuff1, Chung-Ming Hsieh2, Suzanne Mathieu3, Anwar Murtaza4, Margaret Hugunin3, Shaughn Bryant3, Robert O'brien3, Lisa Olson5 and Jeffrey Voss3, 1Immunology, AbbVie, Inc, Worcester, MA, 2Biologics, AbbVie Pharmaceuticals, Worcester, MA, 3Immunology, AbbVie Pharmaceuticals, Worcester, MA, 4Broad Institute, Cambridge, MA, 5AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , , , ,

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Dual neutralization of TNF and IL-17 is hypothesized to provide greater efficacy in rheumatoid arthritis (RA) and inflammatory diseases compared to either monotherapy as these cytokines cooperatively up-regulate cytokines and metalloproteinases.  Moreover, dual blockade has been reported to provide greater efficacy in mouse collagen induced arthritis (CIA) compared to either monotherapy.  To better understand the mechanism of this apparent cooperativity, we conducted a series of experiments utilizing the mouse CIA model.

Methods:

CIA was induced in DBA/1 mice according to standard method and animals were treated with vehicle, anti-TNF antibody (8C11, 12 mg/kg), anti-IL-17 (MAB421, 12 mg/kg), or both antibodies twice a week for 3 weeks beginning at the onset of disease.  Affymetrix gene chips were used to measure RNA expression in the paw.  PCR was used to analyze chemokine expression in fibroblast like synoviocyte (FLS) culture.  ELISA and MSD were utilized to measure chemokines in paw homogenate on day 7 of disease.

Results:

Neutralization of mouse TNF or IL‑17 alone with antibodies resulted in a significant but partial inhibition of arthritic score (36% and 43% inhibition, respectively, p < 0.05).  However, when the 2 cytokines were neutralized by administration of anti-TNF and anti-IL-17 mAbs, arthritic score was significantly reduced to a greater extent (60%; p < 0.05).  Combination treatment was also more effective at preventing bone destruction vs anti-TNF alone as determined by micro-CT analysis (80% vs 42%, p < 0.05).  Microarray analysis of paw RNA from mono or dual cytokine inhibition identified pathways that could account for the enhanced efficacy. Consistent with cooperative gene regulation observed in vitro, these data demonstrated that combination treatment regulated a unique subset of disease related genes that were not regulated by monotherapy.  Among other molecules, the protein level of the chemokines CXCL1 and CXCL5 were inhibited in paw homogenates by the combination treatment (73% and 70% respectively, p < 0.05) whereas monotherapies had little effect.  TNF and IL-17 concordantly regulated CXCL1 and CXCL5 mRNA expression in both mouse and human FLS cultures, indicating the cooperative regulation of mediators of arthritis by TNF and IL-17 may translate to human tissues.

Conclusion:

These data provide a mechanistic basis for the increased efficacy achieved by dual blockade of TNF and IL-17 in mouse CIA and support the rationale for testing dual TNF/IL-17 blockade in the treatment of RA.

Disclosure:

C. Cuff,

AbbVie,

3,

AbbVie,

1;

C. M. Hsieh,

AbbVie,

3,

AbbVie,

1;

S. Mathieu,

AbbVie,

3,

AbbVie,

1;

A. Murtaza,
None;

M. Hugunin,

abbvie,

3,

abbvie,

1;

S. Bryant,

AbbVie,

1,

AbbVie,

3;

R. O’brien,

AbbVie,

3;

L. Olson,

Abbott Immunology Pharmaceuticals,

3;

J. Voss,

Abbott Immunology Pharmaceuticals,

3.

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