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

Abstract：

:Patients with immune thrombocytopenia (ITP) commonly have antiplatelet antibodies that cause thrombocytopenia through Fcγ 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 immunoglobulin G are sufficient to trigger adverse events and have reasoned that designing a monovalent targeting strategy could circumvent the inflammatory response. To this end, we generated a fusion protein comprising a monovalent 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 ITP model. 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 cross-linking 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.

journal_name

Blood

journal_title

Blood

authors

Yu X,Menard M,Prechl J,Bhakta V,Sheffield WP,Lazarus AH

doi

10.1182/blood-2015-08-664656

subject

Has Abstract

pub_date

2016-01-07 00:00:00

pages

132-8

issue

eissn

0006-4971

issn

1528-0020

pii

blood-2015-08-664656

journal_volume

127

pub_type

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