Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice.
OBJECTIVE
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.


METHODS
A new mouse immunoglobulin G3 monoclonal antibody, 3G4, was raised that binds anionic phospholipids in the presence of serum or beta2-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 H(2)O(2)-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.
Ran
Sophia
S
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 2201 Inwood Road NC7.304, Dallas, TX 75390, USA.
He
Jin
J
Huang
Xianming
X
Soares
Melina
M
Scothorn
Douglas
D
Thorpe
Philip E
PE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D010718:Phosphatidylserines / Q000276:immunology*; D011485:Protein Binding; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D010718:Phosphatidylserines