title: Penetratin improves tumor retention of single-chain antibodies: a novel step toward optimization of radioimmunotherapy of solid tumors.
abstract: Single-chain Fv (scFv) antibody fragments exhibit improved pharmacokinetics and biodistribution compared with intact IgG. The tumor uptake of scFvs is rapid, and the serum half-life is shorter than IgG. However, scFvs exhibit lower net dose deposition in the tumor due to a shorter residence time that limits their use in radioimmunotherapy. To improve the tumor uptake and retention of scFvs, we investigated the utility of cell-penetrating peptides, penetratin and transactivator of transcription (TAT). Biodistribution studies were done in LS174T tumor-bearing mice with divalent scFv derived from anti-tumor-associated glycoprotein 72 monoclonal antibody (mAb) CC49. Penetratin increased the tumor retention of scFvs without affecting the peak dose accumulation. The percentage of doses retained in tumors at 24 hours post-administration with a control (no peptide), penetratin, and TAT were 27.25%, 79.84%, and 48.55%, respectively, of that accumulated at 8 hours postinjection. The tumor-to-blood ratios at 24 hours postadministration were 7.14, 19.53, and 16.48 with control, penetratin, and TAT treatment, respectively, whereas the pharmacokinetics were unaltered. Coinjection with TAT, however, resulted in increased uptake of the radioconjugate by the lungs. Autoradiography of the excised tumors indicated a more homogenous distribution of the radiolabeled scFv with both penetratin and TAT in comparison with the control treatment. Real-time whole-body imaging of the live animals confirmed improved tumor localization with penetratin without any increase in the uptake by normal tissues. In conclusion, a significant improvement in the tumor retention of sc(Fv)2 was achieved by administration of penetratin. Therefore, the combination of penetratin and scFvs has the potential of improving the utility of mAb-based radiopharmaceuticals.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Jain
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
authors.forename: David
authors.initials: D
authors.lastname: Colcher
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000912:Antibodies, Neoplasm / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D057846:Cell-Penetrating Peptides; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005260:Female; D015696:Gene Products, tat / Q000494:pharmacology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D000922:Immunotoxins / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling; D051379:Mice; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; C091202:B72.3 antibody; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; C414409:penetratin