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; Bernadette W. Luu; Marco Hofmann; Long V. Dinh; Marcio Almeida; Jerry S. Powell; Raja Rajalingam; Juan M. Peralta; Satish Kumar; Joanne E. Curran; Zuben E. Sauna; Roberta Kellerman; Yara Park; Nigel S. Key; Miguel A. Escobar; Huy Huynh; Anne M. Verhagen; Sarah Williams-Blangero; Paul V. Lehmann; Eugene Maraskovsky; John Blangero; Tom E. Howard

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, Bernadette W. Luu, Marco Hofmann, Long V. Dinh, Marcio Almeida, Jerry S. Powell, Raja Rajalingam, Juan M. Peralta, Satish Kumar, Joanne E. Curran, Zuben E. Sauna, Roberta Kellerman, Yara Park, Nigel S. Key, Miguel A. Escobar, Huy Huynh, Anne M. Verhagen, Sarah Williams-Blangero, Paul V. Lehmann, Eugene MaraskovskyJohn Blangero, Tom E. Howard

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	201-216
Number of pages	16
Journal	Journal of Thrombosis and Haemostasis
Volume	18
Issue number	1
DOIs	https://doi.org/10.1111/jth.14647
State	Published - Jan 1 2020
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Hematology

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Diego, V. P., Luu, B. W., Hofmann, M., Dinh, L. V., Almeida, M., Powell, J. S., Rajalingam, R., Peralta, J. M., Kumar, S., Curran, J. E., Sauna, Z. E., Kellerman, R., Park, Y., Key, N. S., Escobar, M. A., Huynh, H., Verhagen, A. M., Williams-Blangero, S., Lehmann, P. V., ... Howard, T. E. (2020). Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A. Journal of Thrombosis and Haemostasis, 18(1), 201-216. https://doi.org/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. / Diego, Vincent P.; Luu, Bernadette W.; Hofmann, Marco; Dinh, Long V.; Almeida, Marcio; Powell, Jerry S.; Rajalingam, Raja; Peralta, Juan M.; Kumar, Satish; Curran, Joanne E.; Sauna, Zuben E.; Kellerman, Roberta; Park, Yara; Key, Nigel S.; Escobar, Miguel A.; Huynh, Huy; Verhagen, Anne M.; Williams-Blangero, Sarah; Lehmann, Paul V.; Maraskovsky, Eugene; Blangero, John; Howard, Tom E.

In: Journal of Thrombosis and Haemostasis, Vol. 18, No. 1, 01.01.2020, p. 201-216.

Research output: Contribution to journal › Article › peer-review

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 2020, 'Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A', Journal of Thrombosis and Haemostasis, vol. 18, no. 1, pp. 201-216. https://doi.org/10.1111/jth.14647

Diego, Vincent P. ; Luu, Bernadette W. ; Hofmann, Marco ; Dinh, Long V. ; Almeida, Marcio ; Powell, Jerry S. ; Rajalingam, Raja ; Peralta, Juan M. ; Kumar, Satish ; Curran, Joanne E. ; Sauna, Zuben E. ; Kellerman, Roberta ; Park, Yara ; Key, Nigel S. ; Escobar, Miguel A. ; Huynh, Huy ; Verhagen, Anne M. ; Williams-Blangero, Sarah ; Lehmann, Paul V. ; Maraskovsky, Eugene ; Blangero, John ; Howard, Tom E. / Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A. In: Journal of Thrombosis and Haemostasis. 2020 ; Vol. 18, No. 1. pp. 201-216.

@article{fc52e0397a2c4330bb83ab393d0de882,

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

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{\textregistered} (Takeda)] and four distinct B-domain-deleted (BDD)-rFVIIIs [Xyntha{\textregistered} (Pfizer), NovoEight{\textregistered} (Novo-Nordisk), Nuwiq{\textregistered} (Octapharma), and Afstyla{\textregistered} (CSL Behring GmBH)]; a pdFVIII + pdVWF [Beriate{\textregistered} (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",

author = "Diego, {Vincent P.} and Luu, {Bernadette W.} and Marco Hofmann and Dinh, {Long V.} and Marcio Almeida and Powell, {Jerry S.} and Raja Rajalingam and Peralta, {Juan M.} and Satish Kumar and Curran, {Joanne E.} and Sauna, {Zuben E.} and Roberta Kellerman and Yara Park and Key, {Nigel S.} and Escobar, {Miguel A.} and Huy Huynh and Verhagen, {Anne M.} and Sarah Williams-Blangero and Lehmann, {Paul V.} and Eugene Maraskovsky and John Blangero and Howard, {Tom E.}",

year = "2020",

month = jan,

day = "1",

doi = "10.1111/jth.14647",

language = "English (US)",

volume = "18",

pages = "201--216",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley-Blackwell",

number = "1",

}

TY - JOUR

T1 - Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

AU - Diego, Vincent P.

AU - Luu, Bernadette W.

AU - Hofmann, Marco

AU - Dinh, Long V.

AU - Almeida, Marcio

AU - Powell, Jerry S.

AU - Rajalingam, Raja

AU - Peralta, Juan M.

AU - Kumar, Satish

AU - Curran, Joanne E.

AU - Sauna, Zuben E.

AU - Kellerman, Roberta

AU - Park, Yara

AU - Key, Nigel S.

AU - Escobar, Miguel A.

AU - Huynh, Huy

AU - Verhagen, Anne M.

AU - Williams-Blangero, Sarah

AU - Lehmann, Paul V.

AU - Maraskovsky, Eugene

AU - Blangero, John

AU - Howard, Tom E.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - blood coagulation factor inhibitors

KW - factor VIII

KW - hemophilia A

KW - histocompatibility antigens class II

KW - peptide

KW - quantitative peptidomics

KW - sequence analysis

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