Inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight kininogen.
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.
Song
James S
JS
Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Sainz
Irma M
IM
Cosenza
Stephen C
SC
Isordia-Salas
Irma
I
Bior
Abdel
A
Bradford
Harlan N
HN
Guo
Yan-Lin
YL
Pixley
Robin A
RA
Reddy
E Premkumar
EP
Colman
Robert W
RW
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
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D019679:Kininogen, High-Molecular-Weight; D005174:Factor XII; D006531:HEPES; D001920:Bradykinin