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. 2020 Jan;18(1):201-216.
doi: 10.1111/jth.14647.

Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

Vincent P Diego  1   2 , Bernadette W Luu  1   2   3 , Marco Hofmann  4 , Long V Dinh  3 , Marcio Almeida  1   2 , Jerry S Powell  5 , Raja Rajalingam  6 , Juan M Peralta  1   2 , Satish Kumar  1   2 , Joanne E Curran  1   2 , Zuben E Sauna  7 , Roberta Kellerman  8 , Yara Park  9 , Nigel S Key  8   9 , Miguel A Escobar  10 , Huy Huynh  11 , Anne M Verhagen  11 , Sarah Williams-Blangero  1   2 , Paul V Lehmann  12   13   14 , Eugene Maraskovsky  11 , John Blangero  1   2 , Tom E Howard  1   2   3   15
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Free article

Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

Vincent P Diego et al. J Thromb Haemost. 2020 Jan.
Free article

Abstract

Background: Plasma-derived (pd) or recombinant (r) therapeutic factor VIII proteins (FVIIIs) are infused to arrest/prevent bleeding in patients with hemophilia A (PWHA). However, FVIIIs are neutralized if anti-FVIII-antibodies (inhibitors) develop. Accumulating evidence suggests that pdFVIIIs with von Willebrand factor (VWF) are less immunogenic than rFVIIIs and that distinct rFVIIIs are differentially immunogenic. Since inhibitor development is T-helper-cell-dependent, human leukocyte antigen (HLA)-class-II (HLAcII) molecules constitute an important early determinant.

Objectives: Use dendritic cell (DC)-protein processing/presentation assays with mass-spectrometric and peptide-proteomic analyses to quantify the DP-bound, DQ-bound, and DR-bound FVIII-derived peptides in individual HLAcII repertoires and compare the immunogenic potential of six distinct FVIIIs based on their measured peptide counts.

Patients/methods: Monocyte-derived DCs from normal donors and/or PWHA were cultured with either: Mix-rFVIII, a VWF-free equimolar mixture of a full-length (FL)-rFVIII [Advate® (Takeda)] and four distinct B-domain-deleted (BDD)-rFVIIIs [Xyntha® (Pfizer), NovoEight® (Novo-Nordisk), Nuwiq® (Octapharma), and Afstyla® (CSL Behring GmBH)]; a pdFVIII + pdVWF [Beriate® (CSL Behring GmBH)]; Advate ± pdVWF; Afstyla ± pdVWF; and Xyntha + pdVWF.

Results: We showed that (i) Beriate had a significantly lower immunogenic potential than Advate ± pdVWF, Afstyla - pdVWF, and Mix-rFVIII; (ii) distinct FVIIIs differed significantly in their immunogenic potential in that, in addition to (i), Afstyla + pdVWF had a significantly lower immunogenic potential than Beriate, while the immunogenic potential of Beriate was not significantly different from that of Xyntha + pdVWF; and (iii) rFVIIIs with pdVWF had significantly lower immunogenic potentials than the same rFVIIIs without pdVWF.

Conclusions: Our results provide HLAcII peptidomic level explanations for several important clinical observations/issues including the differential immunogenicity of distinct FVIIIs and the role of HLAcII genetics in inhibitor development.

Keywords: blood coagulation factor inhibitors; factor VIII; hemophilia A; histocompatibility antigens class II; peptide; quantitative peptidomics; sequence analysis.

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References

REFERENCES

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