By David N. Leff
Editor's note: Science Scan is a round-up of recently published biotechnology-related research:
In his decades-long campaign to starve tumor cells to death, Harvard Medical School surgeon Judah Folkman has dropped the next shoe -- a gene-therapy attack on the cancers' blood supply.
On Wednesday, April 1, in New Orleans, members of Folkman's laboratory at Children's Hospital, in Boston, told the annual meeting of the American Association for Cancer Research (AACR) that they had transferred and expressed two proteins that block angiogenesis.
The senior author of their presentation was Philippe Leboulch, chief scientific officer of Genetix Pharmaceuticals Inc., of Cambridge, Mass., which collaborated with the Harvard scientists. Their paper's title: "Retrovirus-mediated gene transfer of an angiostatin-endostatin fusion protein with enhanced anti-tumor properties in vivo."
Endostatin and angiostatin are natural inhibitors of the endothelial cells that line the spreading blood vessels of angiogenesis. Both recently were discovered in Folkman's lab (See BioWorld Today, Dec. 2, 1997, p. 1)
Angiostatin comprises the first four kringles (structural sequence domains) of plasminogen, a critical clot-busting molecule. Endostatin matches a fragment of the collagen XVIII protein. Leboulch and his collaborators designed a fusion protein that combined key plasminogen and collagen XVIII gene sequences.
They inserted this package into retroviral vectors, and used it to infect human neuroblastoma cells implanted in nude mice. It strongly inhibited growth of those tumors in the animals. Gene transfer of endostatin and angiostatin separately evoked much weaker responses.
ImClone Monoclonal Antibody Prevents Key Growth Factor From Causing Tumor Angiogenesis
Scientists at New York-based ImClone Systems Inc. reported a different blood-vessel-blocking ploy to the AACR meeting on Monday, March 30.
Their target is the receptor for tumor-derived vascular endothelial growth factor (VEGF), which drives the proliferation of endothelial cells in the proliferating venules, arterioles and capillaries of advancing angiogenesis. This receptor, expressed on tumor-associated capillary blood vessels, is suspected of a major role in supplying growing tumors with oxygen- and nutrient-bearing blood.
ImClone has raised a monoclonal antibody to the human version of this receptor, and reported to the AACR meeting that it bound VEGF and curbed growth of endothelial cells in vitro.
The company's president and CEO, Samuel Waksal, said the findings "provide the underpinning for an IND [investigational new drug] filing anticipated in 1999." *