Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy

CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti–mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcγR)-dependent pathways with a hierarchy of IgG2a...

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Main Authors:	Hamaguchi, Yasuhito, Xiu, Yan, Komura, Kazuhiro, Nimmerjahn, Falk, Tedder, Thomas F.
Format:	Online
Language:	English
Published:	The Rockefeller University Press 2006
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118227/

id	pubmed-2118227
recordtype	oai_dc
spelling	pubmed-21182272007-12-13 Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy Hamaguchi, Yasuhito Xiu, Yan Komura, Kazuhiro Nimmerjahn, Falk Tedder, Thomas F. Articles CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti–mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcγR)-dependent pathways with a hierarchy of IgG2a/c>IgG1/IgG2b>IgG3. To understand the molecular basis for these CD20 mAb subclass differences, B cell depletion was assessed in mice deficient or blocked for stimulatory FcγRI, FcγRIII, FcγRIV, or FcR common γ chain, or inhibitory FcγRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcγRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcγRIV. The potency of IgG2a/c CD20 mAbs resulted from FcγRIV interactions, with potential contributions from high-affinity FcγRI. Regardless, FcγRIV could mediate IgG2a/b/c CD20 mAb–induced depletion in the absence of FcγRI and FcγRIII. In contrast, inhibitory FcγRIIB deficiency significantly increased CD20 mAb–induced B cell depletion by enhancing monocyte function. Although FcγR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcγR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcγRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies. The Rockefeller University Press 2006-03-20 /pmc/articles/PMC2118227/ /pubmed/16520392 http://dx.doi.org/10.1084/jem.20052283 Text en Copyright © 2006, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hamaguchi, Yasuhito Xiu, Yan Komura, Kazuhiro Nimmerjahn, Falk Tedder, Thomas F.
spellingShingle	Hamaguchi, Yasuhito Xiu, Yan Komura, Kazuhiro Nimmerjahn, Falk Tedder, Thomas F. Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
author_facet	Hamaguchi, Yasuhito Xiu, Yan Komura, Kazuhiro Nimmerjahn, Falk Tedder, Thomas F.
author_sort	Hamaguchi, Yasuhito
title	Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
title_short	Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
title_full	Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
title_fullStr	Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
title_full_unstemmed	Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy
title_sort	antibody isotype-specific engagement of fcγ receptors regulates b lymphocyte depletion during cd20 immunotherapy
description	CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti–mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcγR)-dependent pathways with a hierarchy of IgG2a/c>IgG1/IgG2b>IgG3. To understand the molecular basis for these CD20 mAb subclass differences, B cell depletion was assessed in mice deficient or blocked for stimulatory FcγRI, FcγRIII, FcγRIV, or FcR common γ chain, or inhibitory FcγRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcγRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcγRIV. The potency of IgG2a/c CD20 mAbs resulted from FcγRIV interactions, with potential contributions from high-affinity FcγRI. Regardless, FcγRIV could mediate IgG2a/b/c CD20 mAb–induced depletion in the absence of FcγRI and FcγRIII. In contrast, inhibitory FcγRIIB deficiency significantly increased CD20 mAb–induced B cell depletion by enhancing monocyte function. Although FcγR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcγR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcγRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.
publisher	The Rockefeller University Press
publishDate	2006
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118227/
_version_	1611414635809865728

Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy

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