Binding and Neutralising antibodies

Fox E, Green B, Markowitz C, Murray R, Goodman AD, Glenski SJ, Loupe P, Cogburn JN.The effect of scheduled antibody testing on treatment patterns in interferon-treated patients withmultiple sclerosis. BMC Neurol. 2014 Apr;14(1):73. [Epub ahead of print]

BACKGROUND:Many patients with relapsing-remitting multiple sclerosis (MS) treated with high-dose interferon-beta (IFNbeta) develop serum binding antibodies (BAb) and neutralizing antibodies (NAb). NAb reduces the biological activity of IFNbeta, which contributes to clinical failure in these patients. We investigated whether access to antibody (Ab) test results would alter usual care of (IFNbeta)-treated patients and whether BAb could predict NAb.
METHODS:This was a randomized, controlled, open-label, parallel-group, multicenter study in patients with multiple sclerosis. Subjects (n = 1358) were randomly assigned to Ab testing or usual care. BAb and NAb titres were measured using standard assays. Primary and secondary outcomes were the proportion of patients whose IFNbeta therapy changed and the type of and reasons for therapy changes.
RESULTS:Therapy changes differed between the Ab testing and usual care arms (19.6% and 14.0%, respectively; p = 0 . 004). Results from Ab testing were more frequently reported as the reason for therapy change in the Ab testing arm than in the usual care arm (p < 0.0001). NAb and BAb positivity significantly increased the likelihood of therapy change and reduced IFNbeta-associated adverse events. BAb titres were a significant predictor of NAb positivity (p = 0.0012). Initial BAb-positive and NAb-positive status in both study arms had a significant impact on the overall number of patients with a therapy change (p < 0.05).
CONCLUSION: Access to Ab test results impacted therapy management. BAb titres can predict NAb positivity in patients on high-dose IFNbeta.

Núñez C, Cénit MC, Alvarez-Lafuente R, Río J, Fernández-Arquero M, Arroyo R, Montalbán X, Fernández O, Oliver-Martos B, Leyva L, Comabella M, Urcelay E. HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis. J Med Genet. 2014 Apr 19. doi: 10.1136/jmedgenet-2014-102348. [Epub ahead of print]

BACKGROUND: Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe.
METHODS: Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives.
RESULTS: The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)).
CONCLUSIONS: 50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.

Binding antibodies (BAbs) bind to any part of the molecule but neutralizing antibodies (NAbs) bind to the active site of the molecule and stop it working. If you make alot of BAbs you may make more NAbs, if you make NAbs you need to change treatments.

Can we predict who will make Nabs. This study suggests that if you express certain HLA types then this is more likely upto four times more likely. We have talked about what is HLA (Click here). If you express these HLA types you are likely to recognise certain proteins and they probably increase the chances that you can see beta interferons and react against it. Are these tests definitive not usually.

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