Targeting endothelial growth with monoclonal antibodies against Tie-1 kinase in mouse models.

Abstract

Tie-1 is a transmembrane tyrosine kinase expressed in vascular endothelial cells during angiogenic processes and vasculogenesis. Here we evaluate targeting of rebuilding endothelium with (125)I-labeled Tie-1 monoclonal antibodies (mAbs) in mice. At first, activity of Tie-1 kinase during reforming of blood vessels was evaluated in melanoma allografts in transgenic mice with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining of the Tie-1 promoter gene. Subsequently, in vivo targeting of the healing wound was evaluated with iodinated Tie-1 mAbs in mice, and finally, after confirming the specificities for targeting, we evaluated the biodistribution of Tie-1 mAbs in a melanoma model. Tie-1 mAbs target epithelial skin wounds in mice. Biokinetics of (125)I-Tie-1 mAbs demonstrate a stabilized equilibrium between the blood and wound over 3 days. The accumulation in wound is 21% injected dose/gram (ID/g) and 17% ID/g at 48 h with the two clones of Tie-1 mAbs, 3c4c7 and 10f11g6. Tie-1 promoter is active in the melanoma model in mice. In melanomas, the tumor accumulation is 5% and 4.4% ID/g, and the tumor:liver values are 2.7 and 4.4, respectively, for the two clones of Tie-1 mAbs, 3c4c7 and 10f11g6. The clearance of (125)I-Tie-1 antibodies is slow when compared with that of the iodinated control antibody. Targeting to wound is demonstrated with the Tie-1 mAbs. Accordingly, tumor targeting of melanoma is expertized with the same antibodies.