Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice.

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in embryogenesis and the vascularization of solid tumors. At the present time there are two well-characterized receptors for VEGF that are selectively expressed on endothelium. VEGF receptor 2 [VEGFR2 (KDR/Flk-1)] mediates endothelial cell mitogenesis and permeability increases, whereas the role of VEGF receptor 1 [VEGFR1 (Flt-1)] has not been clearly defined. In the present study, a monoclonal antibody, 2C3, is shown to block the interaction of VEGF with VEGFR2 but not with VEGFR1 through ELISA, receptor binding assays, and receptor activation assays. 2C3 blocks the VEGF-induced vascular permeability increase in guinea pig skin. 2C3 has potent antitumor activity, inhibiting the growth of newly injected and established human tumor xenografts in mice. These findings demonstrate the usefulness of 2C3 in dissecting the pathways that are activated by VEGF in cells that express both VEGFR1 and VEGFR2, as well as highlighting the dominant role of VEGFR2 in mediating VEGF-induced vascular permeability increase and tumor angiogenesis.

Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice.

BACKGROUND: Pancreatic carcinoma is associated with a poor prognosis, and treatment options for patients with this disease are limited. The epidermal growth factor (EGF) receptor and its ligands are overexpressed in human pancreatic carcinoma and may contribute to the pathophysiology of these tumors. METHODS: The anti-EGF receptor monoclonal antibody IMC-C225 was used to determine the effects of EGF receptor blockade on the growth of human pancreatic carcinoma BxPC-3 cells in vitro. Athymic mice bearing established (200 mm(3)) subcutaneous BxPC-3 xenografts were treated with IMC-C225 (17 or 33 mg/kg every 3 days) alone or in combination with 5-fluorouracil (17 mg/kg twice weekly). RESULTS: IMC-C225 inhibited exogenous ligand-stimulated tyrosine phosphorylation of the EGF receptor on BxPC-3 tumor cells. Treatment of BxPC-3 cells with IMC-C225 inhibited DNA synthesis (23.8%) and colony formation in soft agar (45.6%). IMC-C225 treatment significantly suppressed the growth of BxPC-3 tumors compared with treatment with vehicle alone (P = 0.003). Combination therapy with IMC-C225 and the chemotherapeutic agent 5-fluorouracil enhanced the antitumor effects compared with either agent alone and resulted in regression of pancreatic tumors in several animals. Histologic examination of pancreatic tumors from mice treated with IMC-C225 showed extensive tumor necrosis that coincided with a substantial decrease in tumor cell proliferation and an increase in tumor cell apoptosis. CONCLUSIONS: These data suggest that IMC-C225 affects the growth of pancreatic tumors by inhibiting EGF receptor-dependent proliferation and survival, and demonstrates the potential for therapeutic application of IMC-C225 antibody in the treatment of human pancreatic carcinoma.

Potent antitumor effects of an antitumor endothelial cell immunotoxin in a murine vascular targeting model.

Immunotoxins and other antibody-based therapeutic reagents have proved effective agonist lymphomas and leukemias, but results with carcinomas and other solid tumors have thus far been less impressive. A major reason for this difference is that macromolecules penetrate poorly and unevenly into solid tumors. A solution to this problem would be to attack the endothelial cells of the tumor vascular bed rather than the tumor cells themselves. We have developed a murine model of this vascular targeting approach where transfection of the tumor cells with a cytokine gene causes them to induce the expression of an experimental marker (MHC Class II) on tumor endothelium. In this report we show that an anti-Class II-deglycosylated Ricin A-chain immunotoxin kills IFN-gamma-activated endothelial cells in culture and, when injected into tumor-bearing Balb/c nude mice, causes complete thrombosis of the tumor vasculature, widespread infarction, and dramatic regressions of large solid tumors. These findings suggest that immunoconjugates prepared with recently described antibodies against human tumor endothelium could provide a broad-based therapy for variety of solid cancers in humans.