title: Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody.
abstract: BACKGROUND
  Sequestration of IgE to prevent its binding to high-affinity IgE receptor FcεRI on basophils and mast cells is an effective therapy for allergic asthma. IgE production requires differentiation of activated IgE(+) B cells into plasma cells upon allergen sensitization. B-cell receptor signaling is suppressed by the inhibitory IgG Fc receptor FcγRIIb; therefore, we reasoned that a therapeutic antibody that coengages FcγRIIb and IgE B-cell receptor would not only sequester IgE but also suppress its production by blocking IgE(+) B-cell activation and differentiation to IgE-secreting plasma cells.
  
  
  OBJECTIVE
  To explore the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcγRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production.
  
  
  METHODS
  By using a murine anti-IgE antibody as a template, we humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcγRIIb. We next compared effects of this antibody (XmAb7195) versus omalizumab on the secretion of IgE and other isotypes in human PBMC cultures and in PBMC-engrafted severe combined immunodeficiency mice.
  
  
  RESULTS
  Relative to omalizumab, XmAb7195 has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcγRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcγRIIb. In PBMC-engrafted mice, XmAb7195 reduced total human IgE (but not IgG or IgM) levels by up to 40-fold relative to omalizumab.
  
  
  CONCLUSIONS
  XmAb7195 acts by IgE sequestration coupled with an FcγRIIb-mediated inhibitory mechanism to suppress the formation of IgE-secreting plasma cells and reduce both free and total IgE levels.
authors.affiliation: Xencor, Inc, Monrovia, CA, USA.
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.forename: Holly M
authors.initials: HM
authors.lastname: Horton
authors.forename: Erik
authors.initials: E
authors.lastname: Pong
authors.forename: Irene W L
authors.initials: IW
authors.lastname: Leung
authors.forename: Hsing
authors.initials: H
authors.lastname: Chen
authors.forename: Duc-Hanh
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Cristina
authors.initials: C
authors.lastname: Bautista
authors.forename: Umesh S
authors.initials: US
authors.lastname: Muchhal
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bernett
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Moore
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D000069444:Omalizumab; D011485:Protein Binding / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018926:Anti-Allergic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; C080571:Fc gamma receptor IIB; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D017455:Receptors, IgE; D017452:Receptors, IgG; C026408:anti-IgE antibodies; D000069444:Omalizumab; D007073:Immunoglobulin E