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Polymorphisms in the F8 Gene and MHC-II Variants as Risk Factors for the Development of Inhibitory Anti-Factor VIII Antibodies during the Treatment of Hemophilia A: A Computational Assessment

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  • Gouri Shankar Pandey
  • Chen Yanover
  • Tom E Howard
  • Zuben E Sauna

Abstract

The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs) in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6) of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II) molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants). Using a computational binding predictor, we were able to expand our analysis to (a) include all wild type peptides spanning each polymorphic position; and (b) consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population). Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes and thus could explain the increased incidence of anti-drug antibodies in hemophilia A patients with haplotypes H3 and H4.Author Summary: The development of anti-drug antibodies to therapeutic proteins is a significant impediment to development and licensure of therapeutic proteins and limits their clinical utility. The development of such antibodies requires CD4+ T-cell activation, which is mediated by the recognition of epitopes presented by MHC class-II (MHC-II) molecules. Here, we use experimental measurements and computational predictions of peptide-MHC-II affinities to study the clinical observation that African-American hemophilia A patients have a higher incidence of anti-drug antibodies to Factor VIII than Caucasian patients. Specifically, we used the experimental data to select and validate a computational prediction method which, in turn, allowed us to expand our analysis to a larger repertoire of peptide-MHC-II complexes. We showed that wild type peptides spanning haplotype polymorphisms common in the African American population bind MHC-II proteins significantly more than a negative control, thus providing a mechanistic explanation of the phenomenon in this population.

Suggested Citation

  • Gouri Shankar Pandey & Chen Yanover & Tom E Howard & Zuben E Sauna, 2013. "Polymorphisms in the F8 Gene and MHC-II Variants as Risk Factors for the Development of Inhibitory Anti-Factor VIII Antibodies during the Treatment of Hemophilia A: A Computational Assessment," PLOS Computational Biology, Public Library of Science, vol. 9(5), pages 1-11, May.
  • Handle: RePEc:plo:pcbi00:1003066
    DOI: 10.1371/journal.pcbi.1003066
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    1. Morten Nielsen & Claus Lundegaard & Thomas Blicher & Bjoern Peters & Alessandro Sette & Sune Justesen & Søren Buus & Ole Lund, 2008. "Quantitative Predictions of Peptide Binding to Any HLA-DR Molecule of Known Sequence: NetMHCIIpan," PLOS Computational Biology, Public Library of Science, vol. 4(7), pages 1-10, July.
    2. Peng Wang & John Sidney & Courtney Dow & Bianca Mothé & Alessandro Sette & Bjoern Peters, 2008. "A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach," PLOS Computational Biology, Public Library of Science, vol. 4(4), pages 1-10, April.
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