title: Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma.
abstract: Reduced uninvolved immunoglobulin (Ig) levels are a hallmark of multiple myeloma. We previously showed that B-cell maturation antigen (BCMA) is solubilized and at high levels in multiple myeloma patient serum. We hypothesize that soluble BCMA binds B-cell-activating factor (BAFF) preventing its function to stimulate late B cells, and would result in lower polyclonal antibody levels in these patients.
  
  
  
  Mice were dosed with recombinant human BCMA (rhBCMA) and BCMA-BAFF complexes were analyzed in plasma, and its effects on antibody and Ig heavy chain mRNA levels determined. Using flow cytometry, BAFF binding to B cells was examined in the presence of rhBCMA and sera from multiple myeloma patients. In multiple myeloma sera, BCMA-BAFF complex formation and BCMA, IgA, IgG levels, and heavy-light chain isoform pair levels were determined.
  
  
  
  rhBCMA-BAFF complexes formed in immune-competent and deficient mice. Mice with human multiple myeloma xenografts, which contain plasma hBCMA and hBCMA-BAFF complexes, showed reduced plasma-free BAFF levels. rhBCMA administered to immune competent mice markedly reduced plasma IgA, IgG, and IgM levels and splenic Ig heavy chain mRNA levels. In serum from multiple myeloma patients, BCMA-BAFF complexes were detected and BAFF levels were reduced. Multiple myeloma patient sera containing BCMA prevented binding of BAFF to B cells. There is an inverse correlation between serum BCMA and uninvolved polyclonal Ig level in multiple myeloma patients.
  
  
  
  Our results show that soluble BCMA sequesters circulating BAFF, thereby preventing it from performing its signaling to stimulate normal B-cell and plasma cell development, resulting in reduced polyclonal antibody levels in multiple myeloma patients. Clin Cancer Res; 22(13); 3383-97. ©2016 AACR.
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Abigail
authors.initials: A
authors.lastname: Gillespie
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: George
authors.initials: G
authors.lastname: Tang
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Morgan
authors.initials: M
authors.lastname: Ferros
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Nika Manik
authors.initials: NM
authors.lastname: Harutyunyan
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Suzie
authors.initials: S
authors.lastname: Vardanyan
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Jillian
authors.initials: J
authors.lastname: Gottlieb
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Wang
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California.
authors.forename: Haiming
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, California. jberenson@imbcr.org.
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism*; D053301:B-Cell Maturation Antigen / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood*; D007074:Immunoglobulin G / Q000097:blood*; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000097:blood / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D046912:Multiprotein Complexes / Q000097:blood / Q000235:genetics; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D046912:Multiprotein Complexes; D020033:Protein Isoforms; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human