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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Targeting to wound is demonstrated with the Tie-1 mAbs. Accordingly, tumor targeting of melanoma is expertized with the same antibodies.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002863:Chromogenic Compounds / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology*; D005697:Galactosides / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D007763:Lac Operon; D008545:Melanoma / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000276:immunology* / Q000502:physiology; D013997:Time Factors; D014018:Tissue Distribution; D014945:Wound Healing; D001616:beta-Galactosidase / Q000378:metabolism
D000911:Antibodies, Monoclonal; D002863:Chromogenic Compounds; D005697:Galactosides; D007211:Indoles; D012333:RNA, Messenger; D042810:Receptor, TIE-1; D001616:beta-Galactosidase; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside