title: A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.
abstract: Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Bushey
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Nicely
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rex C
authors.initials: RC
authors.lastname: Bentley
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kingshuk
authors.initials: K
authors.lastname: Roy Choudhury
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Gottlin
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campa
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: hliao@duke.edu.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: patz0002@mc.duke.edu.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Patz
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003001:Cloning, Molecular; D017242:Complement Factor H / Q000737:chemistry / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D018360:Crystallography, X-Ray; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D008958:Models, Molecular; D016296:Mutagenesis / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; C493495:CFH protein, human; D000939:Epitopes; D010455:Peptides; D017242:Complement Factor H; D003165:Complement System Proteins; D000409:Alanine