title: Tumor Growth Inhibition via Occlusion of Tumor Vasculature Induced by N-Terminally PEGylated Retargeted Tissue Factor tTF-NGR.
abstract: 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.
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Caroline
authors: C
authors: Brand
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Max
authors: M
authors: Fröhlich
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Janine
authors: J
authors: Ring
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Christoph
authors: C
authors: Schliemann
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Torsten
authors: T
authors: Kessler
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Verena
authors: V
authors: Mantke
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Simone
authors: S
authors: König
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Martin
authors: M
authors: Lücke
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Rolf M
authors: RM
authors: Mesters
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Wolfgang E
authors: WE
authors: Berdel
authors: Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
authors: Christian
authors: C
authors: Schwöppe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013925:Thromboplastin / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: C526428:NGR peptide; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D011092:Polyethylene Glycols; D013925:Thromboplastin
keywords: experimental cancer therapy; site-directed PEGylation; vascular infarction; vascular targeted tissue factor