title: Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL.
abstract: In 10-20% of the cases of chronic lymphocytic leukemia of B-cell phenotype (B-CLL), the IGHV1-69 germline is utilized as VH gene of the B cell receptor (BCR). Mouse G6 (MuG6) is an anti-idiotypic monoclonal antibody discovered in a screen against rheumatoid factors (RFs) that binds with high affinity to an idiotope expressed on the 51p1 alleles of IGHV1-69 germline gene encoded antibodies (G6-id(+)). The finding that unmutated IGHV1-69 encoded BCRs are frequently expressed on B-CLL cells provides an opportunity for anti-idiotype monoclonal antibody immunotherapy. In this study, we first showed that MuG6 can deplete B cells encoding IGHV1-69 BCRs using a novel humanized GTL mouse model. Next, we humanized MuG6 and demonstrated that the humanized antibodies (HuG6s), especially HuG6.3, displayed ∼2-fold higher binding affinity for G6-id(+) antibody compared to the parental MuG6. Additional studies showed that HuG6.3 was able to kill G6-id(+) BCR expressing cells and patient B-CLL cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, both MuG6 and HuG6.3 mediate in vivo depletion of B-CLL cells in NSG mice. These data suggest that HuG6.3 may provide a new precision medicine to selectively kill IGHV1-69-encoding G6-id(+) B-CLL cells.
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: De-Kuan
authors.initials: DK
authors.lastname: Chang
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Vinodh B
authors.initials: VB
authors.lastname: Kurella
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Biswas
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Avnir
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Wang
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Madhura
authors.initials: M
authors.lastname: Panditrao
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Peterson
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Tallarico
authors.affiliation: c Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: d Division of Immunity and Infection, University of Birmingham, School of Medicine , Edgbaston, Birmingham , UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Goodall
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: c Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: d Division of Immunity and Infection, University of Birmingham, School of Medicine , Edgbaston, Birmingham , UK.
authors.forename: Roy
authors.initials: R
authors.lastname: Jefferis
authors.affiliation: a Department of Cancer Immunology and Virology , Dana-Farber Cancer Institute , Boston , MA , USA.|b Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000096:biosynthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000598276:IGHV1-69 protein, human; D011947:Receptors, Antigen, B-Cell
keywords: B-cell chronic lymphocytic leukemia; GTL mice; cytotoxicity; humanization; immunotherapy; monoclonal antibody; precision medicine