• Institution: LOCKSS

Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus

  1. Yihong Yao yaoy{at}medimmune.com1
  2. Brandon W. Higgs higgsb{at}medimmune.com1
  3. Chris Morehouse morehousec{at}medimmune.com1
  4. Melissa de los Reyes delosreyesm{at}medimmune.com1
  5. Wendy Trigona trigonaw{at}medimmune.com1
  6. Philip Brohawn brohawnp{at}medimmune.com1
  7. Wendy White whitew{at}medimmune.com1
  8. Jianliang Zhang zhangj{at}medimmune.com1
  9. Barbara White whiteb{at}medimmune.com1
  10. Anthony J. Coyle coylea{at}medimmune.com1
  11. Peter A. Kiener kienerp{at}medimmune.com1
  12. Bahija Jallal jallalb{at}medimmune.com1
  1. 1MedImmune, LLC., One MedImmune Way, Gaithersburg, MD 20878, USA


To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.

  • Received June 19, 2008.
  • Revision received October 20, 2008.
  • Accepted November 5, 2008.

This Article

  1. doi: 10.4061/2009/374312 Hum Genomics Proteomics 374312