title: Structure and cancer immunotherapy of the B7 family member B7x.
abstract: B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vigdorovich
authors.affiliation: Department of Biochemistry, Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Garrett-Thomson
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Janakiram
authors.affiliation: Department of Biochemistry, Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Udupi A
authors.initials: UA
authors.lastname: Ramagopal
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yael M
authors.initials: YM
authors.lastname: Abadi
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Scandiuzzi
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Kim C
authors.initials: KC
authors.lastname: Ohaegbulam
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Chinai
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: Department of Biochemistry, Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: steve.almo@einstein.yu.edu.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA. Electronic address: xing-xing.zang@einstein.yu.edu.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1