title: Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus.
abstract: Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.
authors.affiliation: Xencor, Inc., Monrovia, CA 91016, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Horton
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Ortiz
authors.forename: Erik
authors.initials: E
authors.lastname: Pong
authors.forename: Saso
authors.initials: S
authors.lastname: Cemerski
authors.forename: Irene W L
authors.initials: IW
authors.lastname: Leung
authors.forename: Noam
authors.initials: N
authors.lastname: Jacob
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zalevsky
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001666:Binding Sites, Antibody; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005784:Gene Amplification / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017452:Receptors, IgG / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology
chemical_list: D018941:Antigens, CD19; C080571:Fc gamma receptor IIB; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG