Antibody isotype-specific engagement of Fcgamma 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 (FcgammaR)-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 FcgammaRI, FcgammaRIII, FcgammaRIV, or FcR common gamma chain, or inhibitory FcgammaRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcgammaRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcgammaRIV. The potency of IgG2a/c CD20 mAbs resulted from FcgammaRIV interactions, with potential contributions from high-affinity FcgammaRI. Regardless, FcgammaRIV could mediate IgG2a/b/c CD20 mAb-induced depletion in the absence of FcgammaRI and FcgammaRIII. In contrast, inhibitory FcgammaRIIB deficiency significantly increased CD20 mAb-induced B cell depletion by enhancing monocyte function. Although FcgammaR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcgammaR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcgammaRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.
Hamaguchi
Yasuhito
Y
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Xiu
Yan
Y
Komura
Kazuhiro
K
Nimmerjahn
Falk
F
Tedder
Thomas F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D001402:B-Lymphocytes / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D009000:Monocytes / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007074:Immunoglobulin G; D017452:Receptors, IgG