For those who aren't familiar with the work, a recent abstract is appended. I have doubts about the practicality of inducing localized thrombosis in humans.
Davis.... thanks! I remember Thorpe from collaborations with Vitetta and attempts to commercialize deglycosylated ricin A chain. This is not his first brush with industry. I also had a chance to work with a student from Taylor's lab when I was Director of the Hybridoma Facility at USC School of Medicine..... way back when monoclonals were hot out of Cambridge. Dr. Taylor has also had other interactions with industry. I have a slightly different view of TCLN than you do. Hope they do well, however, and am very interested to see how this project progresses. Abstract follows. Rick
Cancer Res 1998 Oct 15;58(20):4646-53
Infarction of solid Hodgkin's tumors in mice by antibody-directed targeting
of tissue factor to tumor vasculature.
Ran S, Gao B, Duffy S, Watkins L, Rote N, Thorpe PE
Hamon Center for Therapeutic Oncology Research and the Department of Pharmacology, University of Texas Southwestern
Medical Center, Dallas 75235, USA.
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. |
