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J Thromb Haemost 2020 Jan;18(1):201-16

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

Diego VP, Luu BW, Hofmann M, Dinh LV, Almeida M, Powell JS, Rajalingam R, Peralta JM, Kumar S, Curran JE, Sauna ZE, Kellerman R, Park Y, Key NS, Escobar MA, Huynh H, Verhagen AM, Williams-Blangero S, Lehmann PV, Maraskovsky E, Blangero J, Howard TE


BACKGROUND: Plasma-derived (pd) or recombinant (r) therapeutic FVIII 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, HLA-class-II (HLAcII) molecules comprise an important early determinant. OBJECTIVES: Use dendritic cell (DC)-protein processing/presentation assays with mass-spectrometric and peptide-proteomic analyses to quantify the DP-, DQ-, 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(R)) and four distinct B-domain-deleted (BDD)-rFVIIIs (Xyntha(R), Novoeight(R), Nuwiq(R), and Afstyla(R)); a pdFVIII + pdVWF (Beriate(R)); 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 Xyntha + pdVWF; and (iii) rFVIIIs with pdVWF had a significantly lower immunogenic potential 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.

Category: Journal Article
PubMed ID: #31556206 DOI: 10.1111/jth.14647
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2019-09-15 Entry Last Modified: 2020-01-19