Infarction of solid Hodgkin's tumors in mice by antibody-directed targeting of tissue factor to tumor vasculature.
We demonstrated previously that selective thrombosis of the blood vessels of solid tumors in mice can be achieved by targeting the extracellular domain of tissue factor by means of an antibody to an experimentally induced marker on tumor vascular endothelium. In the present study, we extend this finding to a naturally occurring marker of tumor vascular endothelium, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is expressed by vascular endothelial cells in Hodgkin's disease and various solid tumors in mice and humans. It is absent from vascular endothelial cells in normal tissues in mice, with the exception of the heart and lungs, where it is present on venules. A monoclonal antibody to murine VCAM-1 was covalently linked to the extracellular domain of human tissue factor to create a "coaguligand." After i.v. administration to severe combined immunodeficient mice bearing human Hodgkin's tumors, the coaguligand localized selectively to VCAM-1-expressing vessels, caused thrombosis of those vessels, and retarded tumor growth. The coaguligand also localized to VCAM-1-expressing vessels in the heart and lungs of the mice but did not induce thrombosis in these sites. An immunohistochemical evaluation of the distribution of a monoclonal anti-phosphatidylserine (PS) antibody in the mice showed that the VCAM-1-expressing vessels in the tumor expressed PS, whereas the VCAM-1-expressing vessels in the heart and lungs lacked PS. The lack of thrombotic effect of the coaguligand on heart and lung vessels may be because PS is needed to provide the procoagulant surface upon which coagulation complexes can assemble. The requirement for coincident expression of the targeted marker and PS on tumor endothelium probably contributes to the selectivity of thrombotic action and the safety of coaguligands.
Ran
S
S
Hamon Center for Therapeutic Oncology Research and the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Gao
B
B
Duffy
S
S
Watkins
L
L
Rote
N
N
Thorpe
P E
PE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005165:Factor V / Q000378:metabolism; D006689:Hodgkin Disease / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010718:Phosphatidylserines / Q000032:analysis; D051381:Rats; D013925:Thromboplastin / Q000008:administration & dosage*; D013927:Thrombosis / Q000209:etiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D010718:Phosphatidylserines; D019010:Vascular Cell Adhesion Molecule-1; D005165:Factor V; D013925:Thromboplastin