Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study.
BACKGROUND
Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity.


METHODS
In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (< or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b.


RESULTS
Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers > or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6.


CONCLUSIONS
These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.
Pachner
Andrew R
AR
UMDNJ-New Jersey Medical School, 185 South Orange Ave., MSBH506, Newark, NJ 07103, USA. pachner@umdnj.edu
Warth
John D
JD
Pace
Amy
A
Goelz
Susan
S
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000906:Antibodies / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019204:GTP-Binding Proteins / Q000097:blood; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins; D000090123:Viperin Protein
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015415:Biomarkers; D002352:Carrier Proteins; D019204:GTP-Binding Proteins; D007155:Immunologic Factors; D016899:Interferon-beta; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D016601:RNA-Binding Proteins; C484290:IFIT1 protein, human; C579071:MX1 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein