title: Inhibition of both the autocrine and the paracrine growth of human leukemia with a fully human antibody directed against vascular endothelial growth factor receptor 2.
abstract: Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. Here we show that certain "liquid" tumors such as acute myeloid leukemia not only produce VEGF but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. In addition, the leukemia-derived VEGF can also stimulate the production of growth factors, including interleukin 6 (IL6) and granulocyte-macrophage colony stimulating factor (GM-CSF), by human endothelial cells, which in turn further promotes the growth of leukemia cells (the paracrine loop). A fully human anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-2C6, strongly blocks KDR/VEGF interaction and neutralizes VEGF-stimulated activation of KDR in endothelial cells. In a system where leukemia cells are co-cultured with endothelial cells, IMC-2C6 inhibits both the production of IL6 and GM-CSF by endothelial cells and the growth of leukemia cells. Finally, IMC-2C6 effectively blocks VEGF-induced migration of KDR+ human leukemia cells, and when administered in vivo, significantly prolonged survival of mice inoculated with KDR+ human leukemia cells. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and certain types of leukemia.
authors.affiliation: Department of Antibody Technology, ImClone Systems Incorporated, New York, New York 10014, USA.
authors.forename: Haifan
authors.initials: H
authors.lastname: Zhang
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Hongli
authors.initials: H
authors.lastname: Li
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bassi
authors.forename: Xenia
authors.initials: X
authors.lastname: Jimenez
authors.forename: Larry
authors.initials: L
authors.lastname: Witte
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Daniel
authors.initials: D
authors.lastname: Hicklin
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D019898:Autocrine Communication / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D019899:Paracrine Communication / Q000187:drug effects*; D014470:Umbilical Cord / Q000276:immunology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D040301:Vascular Endothelial Growth Factor Receptor-2