Monovalent Fc receptor blockade by an anti-Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity

Xiaojie Yu, Melissa Menard, József Prechl, Varsha Bhakta, William P. Sheffield, Alan H. Lazarus

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Patients with immune thrombocytopenia (ITP) commonly have antiplatelet antibodies that cause thrombocytopenia through Fcg receptors (FcγRs). Antibodies specific for FcγRs, designed to inhibit antibody-FcγR interaction, had been shown to improve ITP in refractory human patients. However, the development of such FcγR-specific antibodies has stalled because of adverse events, a phenomenon recapitulated in mouse models. One hypothesis behind these adverse events involved the function of the Fc region of the antibody, which engages FcγRs, leading to inflammatory responses. Unfortunately, inhibition of Fc function by deglycosylation failed to prevent this inflammatory response. In this work, we hypothesize that the bivalent antigen-binding fragment regions of immunoglobulinGare sufficient to trigger adverse events and have reasoned that designing amonovalent targeting strategy could circumvent the inflammatory response. To this end, wegenerated a fusion protein comprising amonovalent human FcγRIIIA-specific antibody linked in tandem to human serum albumin, which retained FcγR-binding activity in vitro. To evaluate clinically relevant in vivo FcγR-blocking function and inflammatory effects, we generated a murine version targeting the murine FcγRIII linked to murine albumin in a passive murine ITPmodel. Monovalent blocking of FcγR function dramatically inhibited antibody-dependent murine ITP and successfully circumvented the inflammatory response as assessed by changes in body temperature, basophil activation, and basophil depletion. Consistent with our hypothesis, in vivo crosslinking of the fusion protein induced these inflammatory effects, recapitulating the adverse events of the parent antibody. Thus, monovalent blocking of FcγR function demonstrates a proof of concept to successfully treat FcγR-mediated autoimmune diseases.

Original languageEnglish
Pages (from-to)132-138
Number of pages7
JournalBlood
Volume127
Issue number1
DOIs
Publication statusPublished - Jan 7 2016

Fingerprint

Idiopathic Thrombocytopenic Purpura
Fc Receptors
Toxicity
Albumins
Fusion reactions
Antibodies
Proteins
Basophils
Body Temperature Changes
Serum Albumin
Thrombocytopenia
Crosslinking
Refractory materials
Autoimmune Diseases
Chemical activation
Antigens

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Monovalent Fc receptor blockade by an anti-Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity. / Yu, Xiaojie; Menard, Melissa; Prechl, József; Bhakta, Varsha; Sheffield, William P.; Lazarus, Alan H.

In: Blood, Vol. 127, No. 1, 07.01.2016, p. 132-138.

Research output: Contribution to journalArticle

Yu, Xiaojie ; Menard, Melissa ; Prechl, József ; Bhakta, Varsha ; Sheffield, William P. ; Lazarus, Alan H. / Monovalent Fc receptor blockade by an anti-Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity. In: Blood. 2016 ; Vol. 127, No. 1. pp. 132-138.
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