In silico calculated affinity of FVIII‐derived peptides for HLA class II alleles predicts inhibitor development in haemophilia A patients with missense mutations in the F8 gene

Abstract

Forty per cent of haemophilia A (HA) patients have missense mutations in the F8 gene. Yet, all patients with identical mutations are not at the same risk of developing factor VIII (FVIII) inhibitors. In severe HA patients, human leucocyte antigen (HLA) haplotype was identified as a risk factor for onset of FVIII inhibitors. We hypothesized that missense mutations in endogenous FVIII alter the affinity of the mutated peptides for HLA class II, thus skewing FVIII-specific T-cell tolerance and increasing the risk that the corresponding wild-type FVIII-derived peptides induce an anti-FVIII immune response during replacement therapy. Here, we investigated whether affinity for HLA class II of wild-type FVIII-derived peptides that correspond to missense mutations described in the Haemophilia A Mutation, Structure, Test and Resource database is associated with inhibitor development. We predicted the mean affinity for 10 major HLA class II alleles of wild-type FVIII-derived peptides that corresponded to 1456 reported cases of missense mutations. Linear regression analysis confirmed a significant association between the predicted mean peptide affinity and the mutation inhibitory status (P = 0.006). Significance was lost after adjustment on mutation position on FVIII domains. Although analysis of the A1-A2-A3-C1 domains yielded a positive correlation between predicted HLA-binding affinity and inhibitory status (OR = 0.29 [95% CI: 0.14-0.60] for the high affinity tertile, P = 0.002), the C2 domain-restricted analysis indicated an inverse correlation (OR = 3.56 [1.10-11.52], P = 0.03). Our data validate the importance of the affinity of FVIII peptides for HLA alleles to the immunogenicity of therapeutic FVIII in patients with missense mutations.

HLA-DRB1–factor VIII binding is a risk factor for inhibitor development in nonsevere hemophilia: a case-control study

“…Previous investigations of the association of FVIII peptide affinity for class II alleles with inhibitor development have used missense mutations and inhibitor status listed in databases and HLA-DRB1 alleles reported to be common in European populations. 14 The study by Pashov et al evaluated patients with hemophilia A of any severity, although .92% of their mutations were associated with nonsevere hemophilia A. They used a binding score that aggregated the affinity of each possible peptide containing the missense mutation with all 10 HLA alleles; thus, 15-mer peptide binding to each of 10 HLA alleles (15 3 10 matrix) was aggregated using the lowest percentile rank of each HLA allele and averaging across the 10 alleles.…”

FVIII inhibitors: pathogenesis and avoidance

“…Recently, using computer-based in silico methods, the FVIII-specific T-cell tolerance and inhibitor risk was suggested to correlate with the binding affinity of the oligopeptides to the HLA alleles in subjects with point mutations. 37 Computerized models for determining the role of the HLA class II alleles have become frequently used over the years, recently in the context of FVIII polymorphisms and inhibitor risk in patients with the H3/H4 haplotypes. 38 Indeed, this approach may be a useful tool for further elucidating the complex immune response, but more data and relationship to the clinical setting are required to confirm the findings.…”

Recent Advances in Application of Pharmacogenomics for Biotherapeutics

“…Recently, this approach has been applied to understand genetic basis of immunogenicity to recombinant Factor VIII, a BT used for treatment of hemophilia A (66)(67)(68)(69)(70). A growing body of literature points to influence of human genetic variability on efficacy as well as tolerability/ adverse effects of a number of vaccines (reviewed in ref.…”