title: Inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight kininogen.
abstract: We have shown that human high molecular weight kininogen is proangiogenic due to release of bradykinin. We now determined the ability of a murine monoclonal antibody to the light chain of high molecular weight kininogen, C11C1, to inhibit tumor growth compared to isotype-matched murine IgG. Monoclonal antibody C11C1 efficiently blocks binding of high molecular weight kininogen to endothelial cells in a concentration-dependent manner. The antibody significantly inhibited growth of human colon carcinoma cells in a nude mouse xenograft assay and was accompanied by a significant reduction in the mean microvascular density compared to the IgG control group. We also showed that a hybridoma producing monoclonal antibody C11C1 injected intramuscularly exhibited markedly smaller tumor mass in a syngeneic host compared to a hybridoma producing a monoclonal antibody to the high molecular weight kininogen heavy chain or to an unrelated plasma protein. In addition, tumor inhibition by purified monoclonal antibody C11C1 was not due to direct antitumor effect because there was no decrease of tumor cell growth in vitro in contrast to the in vivo inhibition. Our results indicate that monoclonal antibody C11C1 inhibits angiogenesis and human tumor cell growth in vivo and has therapeutic potential for treatment of human cancer.
authors.affiliation: Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Song
authors.forename: Irma M
authors.initials: IM
authors.lastname: Sainz
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Irma
authors.initials: I
authors.lastname: Isordia-Salas
authors.forename: Abdel
authors.initials: A
authors.lastname: Bior
authors.forename: Harlan N
authors.initials: HN
authors.lastname: Bradford
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: Guo
authors.forename: Robin A
authors.initials: RA
authors.lastname: Pixley
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Robert W
authors.initials: RW
authors.lastname: Colman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D017209:Apoptosis; D001920:Bradykinin / Q000737:chemistry*; D002455:Cell Division; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005174:Factor XII / Q000378:metabolism; D006531:HEPES / Q000737:chemistry; D006801:Humans; D006825:Hybridomas / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000737:chemistry; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D019679:Kininogen, High-Molecular-Weight / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D019679:Kininogen, High-Molecular-Weight; D005174:Factor XII; D006531:HEPES; D001920:Bradykinin