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Correspondence: Shannon L. Meeks, smeeks@emory.edu

Author contributions: GB designed and performed the experiments, analyzed the data, and wrote the article. JI, CC, EY, WB, SG, and PL conducted the experiments and acquired the data. PL and SM analyzed the data and edited the article. All authors contributed to the article and approved the submitted version.

Acknowledgements: We would like to acknowledge and thank Curtis Henry, PhD, at Emory University for his helpful input and discussion of this article. Figures 5A, 7A, 8A, D were adapted from “Immunogenicity Assay” by BioRender.com (2022).

Competing interests: GB has received honoraria for advisory board participation from Bayer, Genentech, Octapharma, Kedrion, and Sanofi. PL is an inventor on patents owned by Emory University claiming compositions of matter that include modified FVIII proteins with reduced reactivity with anti-FVIII antibodies. SM has received honoraria for participation in advisory boards from Sanofi, Bayer, Novo Nordisk, CSL Behring, Genentech, HEMA Biologics, Takeda, Spark, Pfizer, Biomarin, and TeraImmune and has received research grants from Octapharma and Genentech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Research Funding:

This research was supported by the Atlanta Pediatric Scholars Program K12 HD072245 (GB), 2016 Hemostasis and Thrombosis Research Society/Novo Nordisk Mentored Research Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society supported by an educational grant from Novo Nordisk Inc. (GB), the Hemophilia of Georgia Clinical Scientist Development Award (GB), NHLBI grant K99HL150595 (GB), NHLBI grant U54HL141981 (SM and PL), and Hemophilia of Georgia, Inc. (SM and PL).

Keywords:

  • B-cell epitope
  • factor VIII
  • hemophilia
  • humoral response
  • immune complex

Factor VIII antibody immune complexes modulate the humoral response to factor VIII in an epitope-dependent manner

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Journal Title:

Frontiers in Immunology

Volume:

Volume 14

Publisher:

, Pages 1233356-None

Type of Work:

Article | Final Publisher PDF

Abstract:

Introduction Soluble antigens complexed with immunoglobulin G (IgG) antibodies can induce robust adaptive immune responses in vitro and in animal models of disease. Factor VIII immune complexes (FVIII-ICs) have been detected in individuals with hemophilia A and severe von Willebrand disease following FVIII infusions. Yet, it is unclear if and how FVIII-ICs affect antibody development over time. Methods In this study, we analyzed internalization of FVIII complexed with epitope-mapped FVIII-specific IgG monoclonal antibodies (MAbs) by murine bone marrow-derived dendritic cells (BMDCs) in vitro and antibody development in hemophilia A (FVIII-/-) mice injected with FVIII-IC over time. Results FVIII complexed with 2-116 (A1 domain MAb), 2-113 (A3 domain MAb), and I55 (C2 domain MAb) significantly increased FVIII uptake by BMDC but only FVIII/2-116 enhanced antibody titers in FVIII-/- mice compared to FVIII alone. FVIII/4A4 (A2 domain MAb) showed similar FVIII uptake by BMDC to that of isolated FVIII yet significantly increased antibody titers when injected in FVIII-/- mice. Enhanced antibody responses observed with FVIII/2-116 and FVIII/4A4 complexes in vivo were abrogated in the absence of the FVIII carrier protein von Willebrand factor. Conclusion These findings suggest that a subset of FVIII-IC modulates the humoral response to FVIII in an epitope-dependent manner, which may provide insight into the antibody response observed in some patients with hemophilia A.

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© 2023 Batsuli, Ito, York, Cox, Baldwin, Gill, Lollar and Meeks

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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