This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Behr, T. M. Articles by Goldenberg, D. M. Search for Related Content PubMed PubMed Citation Articles by Behr, T. M. Articles by Goldenberg, D. M.

Reduction of the Renal Uptake of Radiolabeled Monoclonal Antibody Fragments by Cationic Amino Acids and Their Derivatives¹

Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, New Jersey 07103-2763 [T. M. B., R. M. S., M. E. J., R. D. B., R. M. D., D. M. G.], Immunomedics, Inc., Morris Plains, New Jersey 07950 [G. L. G.], and Department of Nuclear Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, D-91054 Erlangen, Germany [T. M. B., H. J. B., F. G. W., W. S. B.]

The renal uptake of radiolabeled antibody fragments and peptides is a problem in radioimmunodetection and radioimmunotherapy, especially with intracellularly retained radiometals. The aim of this study was to develop suitable methods to reduce this kidney uptake. BALB/c mice or nude mice bearing the human GW-39 colon carcinoma xenograft were given i.p. injections of basic amino acids or a range of different basic amino acid derivatives, amino sugars, as well as cationic peptides. The effect of these agents on the biodistribution of Fab' and F(ab')₂ fragments of different mAbs radiolabeled with ^99mTc, ¹⁸⁸Re, ¹¹¹In, ⁸⁸Y, or ¹²⁵I was studied. Tumor and organ uptake was determined and compared to untreated mice. The kidney uptake of Fab' fragments was reduced 5–6-fold in a dose-dependent manner as compared to untreated controls. The uptake in all other organs, as well as the tumor, was unaffected. A similar reduction in renal retention was seen for all other intracellularly retained isotopes, as well as for F(ab')₂ fragments. D- and L-isomers of lysine were equally effective whether given i.p. or p.o. D-glucosamine was effective, but its N-acetyl derivative was not. Basic polypeptides (e.g., poly-L-lysine) were also effective; their potency increased with increasing molecular weight. HPLC of the urine taken from treated animals showed the excretion of intact Fab', in contrast to mostly low-molecular-weight metabolites in the control group. These studies indicate that a variety of basic compounds is capable of inhibiting the tubular reabsorption of peptides and proteins, thus lowering the kidney uptake of antibody fragments significantly. On a molecular basis, the effect seems to essentially rely on the presence of a positively charged amino group. By reducing renal retention of antibody fragments, their role as imaging and therapeutic agents may be expanded.

¹ Supported in part by United States Public Health Service Outstanding Investigator Grant CA39841 from the NIH (D. M. G.).

² Recipient of Deutsche Forschungsgemeinschaft fellowship grant DFG Be 1689/1-1.

³ To whom requests for reprints should be addressed, at Center for Molecular Medicine and Immunology, 1 Bruce Street, Newark, NJ 07103.

Received 4/21/95. Accepted 7/ 5/95.

This article has been cited by other articles:

				S. R. Kumar and S. L. Deutscher 111In-Labeled Galectin-3-Targeting Peptide as a SPECT Agent for Imaging Breast Tumors J. Nucl. Med., May 1, 2008; 49(5): 796 - 803. [Abstract] [Full Text] [PDF]

				S. R. Kumar, T. P. Quinn, and S. L. Deutscher Evaluation of an 111In-Radiolabeled Peptide as a Targeting and Imaging Agent for ErbB-2 Receptor Expressing Breast Carcinomas Clin. Cancer Res., October 15, 2007; 13(20): 6070 - 6079. [Abstract] [Full Text] [PDF]

				R. M. Sharkey, H. Karacay, W. J. McBride, E. A. Rossi, C.-H. Chang, and D. M. Goldenberg Bispecific Antibody Pretargeting of Radionuclides for Immuno Single-Photon Emission Computed Tomography and Immuno Positron Emission Tomography Molecular Imaging: An Update Clin. Cancer Res., September 15, 2007; 13(18): 5577s - 5585s. [Abstract] [Full Text] [PDF]

				E. Dadachova, R. A. Bryan, X. Huang, G. Ortiz, T. Moadel, and A. Casadevall Comparative Evaluation of Capsular Polysaccharide-Specific IgM and IgG Antibodies and F(ab')2 and Fab Fragments as Delivery Vehicles for Radioimmunotherapy of Fungal Infection Clin. Cancer Res., September 15, 2007; 13(18): 5629s - 5635s. [Abstract] [Full Text] [PDF]

				M. Gotthardt, J. van Eerd-Vismale, W. J.G. Oyen, M. de Jong, H. Zhang, E. Rolleman, H. R. Maecke, M. Behe, and O. Boerman Indication for Different Mechanisms of Kidney Uptake of Radiolabeled Peptides J. Nucl. Med., April 1, 2007; 48(4): 596 - 601. [Abstract] [Full Text] [PDF]

				E. Vegt, J. F.M. Wetzels, F. G.M. Russel, R. Masereeuw, O. C. Boerman, J. E. van Eerd, F. H.M. Corstens, and W. J.G. Oyen Renal Uptake of Radiolabeled Octreotide in Human Subjects Is Efficiently Inhibited by Succinylated Gelatin J. Nucl. Med., March 1, 2006; 47(3): 432 - 436. [Abstract] [Full Text] [PDF]

				S. M. Verwijnen, E. P. Krenning, R. Valkema, J. G.M. Huijmans, and M. de Jong Oral Versus Intravenous Administration of Lysine: Equal Effectiveness in Reduction of Renal Uptake of [111In-DTPA]Octreotide J. Nucl. Med., December 1, 2005; 46(12): 2057 - 2060. [Abstract] [Full Text] [PDF]

				R. M. Sharkey, H. Karacay, T. M. Cardillo, C.-H. Chang, W. J. McBride, E. A. Rossi, I. D. Horak, and D. M. Goldenberg Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods Clin. Cancer Res., October 1, 2005; 11(19): 7109s - 7121s. [Abstract] [Full Text] [PDF]

				M. Behe, G. Kluge, W. Becker, M. Gotthardt, and T. M. Behr Use of Polyglutamic Acids to Reduce Uptake of Radiometal-Labeled Minigastrin in the Kidneys J. Nucl. Med., June 1, 2005; 46(6): 1012 - 1015. [Abstract] [Full Text] [PDF]

				R. M. Sharkey and D. M. Goldenberg Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies J. Nucl. Med., January 1, 2005; 46(1_suppl): 115S - 127S. [Abstract] [Full Text] [PDF]

				E. Dadachova, J. D. Nosanchuk, L. Shi, A. D. Schweitzer, A. Frenkel, J. S. Nosanchuk, and A. Casadevall Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin PNAS, October 12, 2004; 101(41): 14865 - 14870. [Abstract] [Full Text] [PDF]

				E. A. Rossi, R. M. Sharkey, W. McBride, H. Karacay, L. Zeng, H. J. Hansen, D. M. Goldenberg, and C.-H. Chang Development of New Multivalent-bispecific Agents for Pretargeting Tumor Localization and Therapy Clin. Cancer Res., September 1, 2003; 9(10): 3886S - 3896. [Abstract] [Full Text] [PDF]

				T. M. Behr, R. D. Blumenthal, S. Memtsoudis, R. M. Sharkey, S. Gratz, W. Becker, and D. M. Goldenberg Cure of Metastatic Human Colonic Cancer in Mice with Radiolabeled Monoclonal Antibody Fragments Clin. Cancer Res., December 1, 2000; 6(12): 4900 - 4907. [Abstract] [Full Text]

				C. F. Foulon, C. J. Reist, D. D. Bigner, and M. R. Zalutsky Radioiodination via D-Amino Acid Peptide Enhances Cellular Retention and Tumor Xenograft Targeting of an Internalizing Anti-Epidermal Growth Factor Receptor Variant III Monoclonal Antibody Cancer Res., August 1, 2000; 60(16): 4453 - 4460. [Abstract] [Full Text]

				T. M. Behr, M. Behe, M. G. Stabin, E. Wehrmann, C. Apostolidis, R. Molinet, F. Strutz, A. Fayyazi, E. Wieland, S. Gratz, et al. High-Linear Energy Transfer (LET) {{alpha}} versus Low-LET {beta} Emitters in Radioimmunotherapy of Solid Tumors: Therapeutic Efficacy and Dose-limiting Toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab' Fragments in a Human Colonic Cancer Model Cancer Res., June 1, 1999; 59(11): 2635 - 2643. [Abstract] [Full Text] [PDF]

				Y. Arano, Y. Fujioka, H. Akizawa, M. Ono, T. Uehara, K. Wakisaka, M. Nakayama, H. Sakahara, J. Konishi, and H. Saji Chemical Design of Radiolabeled Antibody Fragments for Low Renal Radioactivity Levels Cancer Res., January 1, 1999; 59(1): 128 - 134. [Abstract] [Full Text] [PDF]

				H. Kobayashi, N. Le, I.-s. Kim, M.-K. Kim, J.-E. Pie, D. Drumm, D. S. Paik, T. A. Waldmann, C. H. Paik, and J. A. Carrasquillo The Pharmacokinetic Characteristics of Glycolated Humanized Anti-Tac Fabs Are Determined by Their Isoelectric Points Cancer Res., January 1, 1999; 59(2): 422 - 430. [Abstract] [Full Text] [PDF]