Inhibition of metastasis of syngeneic murine melanoma in vivo and vasculogenesis in vitro by monoclonal antibody C11C1 targeted to domain 5 of high molecular weight kininogen.
Metastasis of malignant tumors is a major cause of morbidity and mortality. Inhibition of tumor growth in distant organs is of clinical importance. We have demonstrated that C11C1, a murine monoclonal antibody to the light chain region of high molecular weight kininogen (HK), reduces growth of murine multiple myeloma in normal mice and human colon cancer in nude mice. C11C1 inhibits angiogenesis by reducing tumor microvascular density by blocking binding of HK to endothelial cells. We now evaluate the anti-metastatic effect of C11C1 on C57BL/6 mouse lung metastatic model using B16F10 melanoma cells. The tail veins of mice were injected with 0.5 × 10(6) cells of melanoma B16F10. One group received C11C1 and the other received saline (control) intraperitoneally. When mice were killed at 28 days, 6 of 10 control mice had detectable metastatic pulmonary nodules which stained positive with an antibody against S-100 protein, a tumor antigen present in malignant melanoma cells. In the C11C1 groups, none of the mice showed metastatic foci in their lungs. We showed that C11C1 inhibits endothelial cell tube formation in a 3-D collagen fibrinogen gel model by inhibiting the rate of cleavage of HK by plasma kallikrein without changing the binding affinity for HK. These studies demonstrate that a monoclonal antibody to HK has the potential to prevent metastasis with minimal side effects.
Khan
Sabina T
ST
The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 N. Broad Street, OMS 418, Philadelphia, PA 19140, USA.
Pixley
Robin A
RA
Liu
Yuchuan
Y
Bakdash
Nadia
N
Gordon
Brigitte
B
Agelan
Alexis
A
Huang
Yajue
Y
Achary
Mohan P
MP
Colman
Robert W
RW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D017434:Protein Structure, Tertiary
D000911:Antibodies, Monoclonal; D019679:Kininogen, High-Molecular-Weight
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