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Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia

Authors
  • Blumberg, Richard S.1, 2
  • Lillicrap, David3
  • 1 Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA;
  • 2 Harvard Digestive Diseases Center, Boston, MA; and
  • 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 17, 2018
Volume
131
Issue
20
Pages
2205–2214
Identifiers
DOI: 10.1182/blood-2017-12-822908
PMID: 29588277
PMCID: PMC5958656
Source
PubMed Central
License
Unknown

Abstract

Hemophilia, or inherited genetic deficiencies in coagulation factors, results in uncontrolled bleeding requiring replacement therapy with recombinant proteins given preventively or on demand. However, a major problem with these approaches is the potential for development of immune responses to the administered proteins due to the underlying genetic deficiency of the factor(s) throughout life. As such, there is great interest in developing strategies that avoid immunogenicity and induce immune tolerance. Recently, recombinant factor VIII (rFVIII) and rFIX fused to the crystallizable fragment (Fc) domain of immunoglobulin G (IgG) have been developed as therapeutic agents for hemophilia A and B, respectively. Although it is well known that the possession of an Fc domain confers IgG’s longer-lasting circulating half-life, it is not generally appreciated that the Fc domain also confers immunoregulatory properties that are associated with the induction of tolerance. Here, we review some of the latest advances in our understanding of the tolerogenic abilities of IgG Fc and the impact of Fc-fusion proteins of rFVIII on the treatment of hemophilia.

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