title: Targeting cell surface β2 -microglobulin by pentameric IgM antibodies.
abstract: Monoclonal antibodies (mAbs) specific for human β(2) -microglobulin (β(2) M) have been shown to induce tumour cell apoptosis in haematological and solid tumours via recruiting major histocompatibility complex (MHC) class I molecules into and excluding cytokine receptors from the lipid rafts. Based on these findings, we hypothesized that IgM anti-β(2) M mAbs might have stronger apoptotic effects because of their pentameric structure. Our results showed that, compared with IgG mAbs, IgM anti-β(2) M mAbs exhibited stronger tumouricidal activity in vitro against different tumour cells, including myeloma, mantle cell lymphoma, and prostate cancer, and in vivo in a human-like xenografted myeloma mouse model without damaging normal tissues. IgM mAb-induced apoptosis is dependent on the pentameric structure of the mAbs. Disrupting pentameric IgM into monomeric IgM significantly reduced their ability to induce cell apoptosis. Monomeric IgM mAbs were less efficient at recruiting MHC class I molecules into and exclusion of cytokine receptors from lipid rafts, and at activating the intrinsic apoptosis cascade. Thus, we developed and validated the efficacy of anti-β(2) M IgM mAbs that may be utilized in the clinical setting and showed that IgM anti-β(2) M mAbs may be more potent than IgG mAbs at inducing tumour apoptosis.
authors.affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Cao
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Lan
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Dongyu
authors.initials: D
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology* / Q000627:therapeutic use; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D001613:beta 2-Microglobulin / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007075:Immunoglobulin M; D019947:Receptors, Interleukin-6; D001613:beta 2-Microglobulin