Abstract

Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as “inhibitors,” which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was “Immune Tolerance Induction,” consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ~30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to “bypass” the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

Highlights

  • Factor VIII (FVIII) is an essential blood coagulation cofactor

  • This review focuses on mechanisms of factor VIII immunogenicity and novel approaches to promote immune tolerance to this important protein drug

  • We focus on recent advances, some of which are being tested in current clinical trials, and others that have the potential for future clinical translation, e.g., animal model studies and in vitro experiments utilizing donated human blood samples

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Summary

INTRODUCTION

Factor VIII (FVIII) is an essential blood coagulation cofactor. Recombinant or plasma-derived FVIII is a lifesaving protein drug for hemophilia A (HA) patients, whose F8 gene mutations result in either a complete lack of endogenous FVIII or in a circulating dysfunctional FVIII. Analysis of the T-cell receptor (TCR) repertoire of these FVIII-specific cells showed cells that stained most strongly for this tetramer (likely indicating high-avidity binding) had a very narrow, oligoclonal TCR repertoire Together, these results are consistent with a role for clonal deletion and anergy, and perhaps regulatory T cells, as important components of the functional “peripheral tolerance” that most HA patients achieve, whereas clones that escape this elimination or down-regulation following exposure to infused FVIII (including high-intensity FVIII treatment as part of ITI therapy) can persist and continue to provide help to B cells leading to antibody secretion. The roles of FVIII-specific T-effector cells in patients with a persistent inhibitor require further clarification; are these cells essential for maintenance of longstanding inhibitor responses, which are primarily driven by memory B cells?

ROLES OF COMPLEMENT AND OXIDATION IN FVIII IMMUNOGENICITY
GLYCAN INFLUENCES ON FVIII IMMUNOGENICITY
GUT MICROBIOME INFLUENCES ON FVIII IMMUNOGENICITY
ORAL TOLERANCE
Findings
DISCUSSION
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