In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent.
BACKGROUND
Development of neutralising antibodies (NAbs) against recombinant interferon-beta (IFNbeta) is a significant clinical problem in the treatment of multiple sclerosis (MS). Several methods are available to assess NAbs, but there is a lack of consensus on how the different NAb titre levels interfere with the efficacy of the drug, especially in the individual patient.


METHODS
NAb titres were measured with an in vitro MxA induction assay and the in vivo IFNbeta response was assessed by measuring MxA mRNA expression using real-time PCR.


RESULTS
We identified titre levels of NAbs at which the IFNbeta biological activity was reduced or abrogated. Patients with NAb titres of up to 150 TRU/ml (ten times reduction units per ml) still had retained IFNbeta bioactivity, whereas greatly reduced levels of IFNbeta bioactivity were found in patients with NAbs of 150-600 TRU/ml. Titres above 600 TRU/ml were associated with loss of IFNbeta bioactivity. Similar results were obtained when TRAIL mRNA was used as a marker of the in vivo response to IFNbeta.


CONCLUSIONS
There is a stepwise loss of IFNbeta bioactivity with increasing NAb titres and it is possible to identify functionally critical NAb titre levels that are useful to support treatment decisions at the individual patient level.
Sominanda
A
A
Karolinska Institutet, Department of Clinical Neuroscience, Division of Neurology R54, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Hillert
J
J
Fogdell-Hahn
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology*; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D004185:Disability Evaluation; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D064547:Myxovirus Resistance Proteins; D019798:Neopterin / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017186:Titrimetry
D000906:Antibodies; D000998:Antiviral Agents; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019798:Neopterin; D019204:GTP-Binding Proteins