Tumor Growth Inhibition via Occlusion of Tumor Vasculature Induced by N‑Terminally PEGylated Retargeted Tissue Factor tTF-NGR

• Published in: Molecular pharmaceutics Vol. 12; no. 10; pp. 3749 - 3758
• Main Authors: Brand, Caroline, Fröhlich, Max, Ring, Janine, Schliemann, Christoph, Kessler, Torsten, Mantke, Verena, König, Simone, Lücke, Martin, Mesters, Rolf M, Berdel, Wolfgang E, Schwöppe, Christian
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.10.2015
• Subjects: Animals; Cell Line, Tumor; Cloning, Molecular; Humans; Mass Spectrometry; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization, Pathologic - drug therapy; Oligopeptides - metabolism; Polyethylene Glycols - metabolism; Protein Interaction Domains and Motifs; Recombinant Fusion Proteins - therapeutic use; Thromboplastin - chemistry; Thromboplastin - therapeutic use; experimental cancer therapy; vascular targeted tissue factor; vascular infarction; site-directed PEGylation
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.5b00508

tTF-NGR retargets the extracellular domain of tissue factor via a C-terminal peptide GNGRAHA, a ligand of the surface protein aminopeptidase N (CD13) and upon deamidation of integrin αvβ3, to tumor vasculature. tTF-NGR induces tumor vascular infarction with consecutive antitumor activity against xenografts and selectively inhibits tumor blood flow in cancer patients. Since random PEGylation resulted in favorable pharmacodynamics of tTF-NGR, we performed site-directed PEGylation of PEG units to the N-terminus of tTF-NGR to further improve the antitumor profile of the molecule. Mono-PEGylation to the N-terminus did not change the procoagulatory activity of the tTF-NGR molecule as measured by Factor X activation. Experiments to characterize pharmacokinetics in mice showed a more than 1 log step higher mean area under the curve of PEG20k-tTF-NGR over tTF-NGR. Acute (24 h) tolerability upon intravenous application for the mono-PEGylated versus non-PEGylated tTF-NGR compounds was comparable. PEG20k-tTF-NGR showed clear antitumor efficacy in vivo against human tumor xenografts when systemically applied. However, site-directed mono-PEGylation to the N-terminus does not unequivocally improve the therapeutic profile of tTF-NGR.