TY - JOUR
T1 - Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice
AU - Ran, Sophia
AU - He, Jin
AU - Huang, Xianming
AU - Soares, Melina
AU - Scothorn, Douglas
AU - Thorpe, Philip E.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - Purpose: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of viable vascular endothelial cells in tumors, possibly in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a monoclonal antibody directed against anionic phospholipids might exert antitumor effects by causing vascular damage in tumors. Experimental Design: A new mouse immunoglobulin G3 monoclonal antibody, 3G4, was raised that binds anionic phospholipids in the presence of serum or β-glycoprotein I. The antibody was tested for its ability to localize to tumor vessels and exert antitumor effects in mice. Results: 3G4 recognized anionic phospholipids on the external membrane of H2O2-treated endothelial cells and in vitro. It localized specifically to tumor vascular endothelium and to necrotic tumor cells after injection into severe combined immunodeficient mice bearing orthotopic MDA-MB-435 tumors. Treatment with 3G4 retarded the growth of four different tumors in mice. It reduced the growth of established orthotopic MDA-MB-231 and MDA-MB-435 human breast tumors in mice by 75% and 65% respectively, large L540 human Hodgkin's tumors by 50%, and small syngeneic Meth A fibrosarcomas by 90%. Histologic examination revealed vascular damage, a reduction in vascular density, and a reduction in tumor plasma volume. Treatment with 3G4 induced the binding of monocytes to tumor endothelium and infiltration of macrophages into MDA-MB-435 and MDA-MB-231 tumors. No toxicity to the mice was observed. Conclusions: 3G4 localizes specifically to complexes of anionic phospholipids and serum proteins on the surface of vascular endothelial cells in tumors in mice. This results in damage to tumor vasculature and suppression of tumor growth.
AB - Purpose: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of viable vascular endothelial cells in tumors, possibly in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a monoclonal antibody directed against anionic phospholipids might exert antitumor effects by causing vascular damage in tumors. Experimental Design: A new mouse immunoglobulin G3 monoclonal antibody, 3G4, was raised that binds anionic phospholipids in the presence of serum or β-glycoprotein I. The antibody was tested for its ability to localize to tumor vessels and exert antitumor effects in mice. Results: 3G4 recognized anionic phospholipids on the external membrane of H2O2-treated endothelial cells and in vitro. It localized specifically to tumor vascular endothelium and to necrotic tumor cells after injection into severe combined immunodeficient mice bearing orthotopic MDA-MB-435 tumors. Treatment with 3G4 retarded the growth of four different tumors in mice. It reduced the growth of established orthotopic MDA-MB-231 and MDA-MB-435 human breast tumors in mice by 75% and 65% respectively, large L540 human Hodgkin's tumors by 50%, and small syngeneic Meth A fibrosarcomas by 90%. Histologic examination revealed vascular damage, a reduction in vascular density, and a reduction in tumor plasma volume. Treatment with 3G4 induced the binding of monocytes to tumor endothelium and infiltration of macrophages into MDA-MB-435 and MDA-MB-231 tumors. No toxicity to the mice was observed. Conclusions: 3G4 localizes specifically to complexes of anionic phospholipids and serum proteins on the surface of vascular endothelial cells in tumors in mice. This results in damage to tumor vasculature and suppression of tumor growth.
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U2 - 10.1158/1078-0432.CCR-04-1645
DO - 10.1158/1078-0432.CCR-04-1645
M3 - Article
C2 - 15746060
AN - SCOPUS:14644430393
SN - 1078-0432
VL - 11
SP - 1551
EP - 1562
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -