HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Fujimori, K. Articles by Weinstein, J. N. Search for Related Content PubMed PubMed Citation Articles by Fujimori, K. Articles by Weinstein, J. N.

A Modeling Analysis of Monoclonal Antibody Percolation Through Tumors: A Binding-Site Barrier

Laboratory of Mathematical Biology, Division of Cancer Biology and Diagnosis, National Cancer Institute
Laboratory of Applied Studies, Division of Computer Research and Technology, National Institutes of Health, Bethesda, Maryland

Correspondence: For reprints contact: Kenji Fujimori, MD, Building 10, Room 4B-56, NIH, The Laboratory of Mathematical Biology, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892.

ABSTRACT

For successful use of radiolabeled monoclonal antibodies (MAbs) for diagnosis and therapy, it is helpful to understand both global and microscopic aspects of antibody biodistribution. In this study, antibody distribution in a tumor is simulated by splicing together information on global pharmacokinetics: transport across the capillary wall, diffusive penetration through the tumor interstitial space, and antigen-antibody interaction. The geometry simulated corresponds to spherical nodules of densely packed tumor cells. This modeling analysis demonstrates that: 1) antigen-antibody binding in tumors can retard antibody percolation; 2) high antibody affinity at a given dose tends to decrease antibody percolation because there are fewer free antibody molecules. The result is a more heterogeneous distribution; 3) the average antibody concentration in the tumor does not increase linearly with affinity; and 4) increasing antibody dose leads to better percolation and more uniform distribution. This mathematical model and the general principles developed here can be applied as well to other biologic ligands.

FOOTNOTES

^* Permanent address: Department of Nuclear Medicine, School of Medicine, Hokkaido University, Sapporo, Japan.

This article has been cited by other articles:

				G. M. Thurber and K. D. Wittrup Quantitative Spatiotemporal Analysis of Antibody Fragment Diffusion and Endocytic Consumption in Tumor Spheroids Cancer Res., May 1, 2008; 68(9): 3334 - 3341. [Abstract] [Full Text] [PDF]

				J. L. Martinez-Torrecuadrada, L. H. Cheung, P. Lopez-Serra, R. Barderas, M. Canamero, S. Ferreiro, M. G. Rosenblum, and J. I. Casal Antitumor activity of fibroblast growth factor receptor 3-specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis Mol. Cancer Ther., April 1, 2008; 7(4): 862 - 873. [Abstract] [Full Text] [PDF]

				E. El Emir, U. Qureshi, J. L.J. Dearling, G. M. Boxer, I. Clatworthy, A. A. Folarin, M. P. Robson, S. Nagl, M. A. Konerding, and R. B. Pedley Predicting Response to Radioimmunotherapy from the Tumor Microenvironment of Colorectal Carcinomas Cancer Res., December 15, 2007; 67(24): 11896 - 11905. [Abstract] [Full Text] [PDF]

				O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]

				M. R. Dreher and A. Chilkoti Toward a Systems Engineering Approach to Cancer Drug Delivery J Natl Cancer Inst, July 4, 2007; 99(13): 983 - 985. [Full Text] [PDF]

				V. Tolmachev, A. Orlova, R. Pehrson, J. Galli, B. Baastrup, K. Andersson, M. Sandstrom, D. Rosik, J. Carlsson, H. Lundqvist, et al. Radionuclide Therapy of HER2-Positive Microxenografts Using a 177Lu-Labeled HER2-Specific Affibody Molecule Cancer Res., March 15, 2007; 67(6): 2773 - 2782. [Abstract] [Full Text] [PDF]

				S. Kubetzko, E. Balic, R. Waibel, U. Zangemeister-Wittke, and A. Pluckthun PEGylation and Multimerization of the Anti-p185HER-2 Single Chain Fv Fragment 4D5: EFFECTS ON TUMOR TARGETING J. Biol. Chem., November 17, 2006; 281(46): 35186 - 35201. [Abstract] [Full Text] [PDF]

				R. M. Sharkey Radioimmunotherapy Against the Tumor Vasculature: A New Target? J. Nucl. Med., July 1, 2006; 47(7): 1070 - 1074. [Full Text] [PDF]

				R. M. Sharkey and D. M. Goldenberg Targeted Therapy of Cancer: New Prospects for Antibodies and Immunoconjugates CA Cancer J Clin, July 1, 2006; 56(4): 226 - 243. [Abstract] [Full Text] [PDF]

				M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst, March 1, 2006; 98(5): 335 - 344. [Abstract] [Full Text] [PDF]

				R. M. Reilly Radioimmunotherapy of Solid Tumors: The Promise of Pretargeting Strategies Using Bispecific Antibodies and Radiolabeled Haptens J. Nucl. Med., February 1, 2006; 47(2): 196 - 199. [Full Text] [PDF]

				T. Nakahara, S. M. Norberg, D. R. Shalinsky, D. D. Hu-Lowe, and D. M. McDonald Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors Cancer Res., February 1, 2006; 66(3): 1434 - 1445. [Abstract] [Full Text] [PDF]

				R. M. Sharkey The Direct Route May Not Be the Best Way to Home J. Nucl. Med., March 1, 2005; 46(3): 391 - 394. [Full Text] [PDF]

				G. P. Adams, R. Schier, A. M. McCall, H. H. Simmons, E. M. Horak, R. K. Alpaugh, J. D. Marks, and L. M. Weiner High Affinity Restricts the Localization and Tumor Penetration of Single-Chain Fv Antibody Molecules Cancer Res., June 1, 2001; 61(12): 4750 - 4755. [Abstract] [Full Text] [PDF]

				A. M. Ballangrud, W.-H. Yang, D. E. Charlton, M. R. McDevitt, K. A. Hamacher, K. S. Panageas, D. Ma, N. H. Bander, D. A. Scheinberg, and G. Sgouros Response of LNCaP Spheroids after Treatment with an {{alpha}}-Particle Emitter (213Bi)-labeled Anti-Prostate-specific Membrane Antigen Antibody (J591) Cancer Res., March 1, 2001; 61(5): 2008 - 2014. [Abstract] [Full Text]

				J. W. G. Stroomer, J. C. Roos, M. Sproll, J. J. Quak, K.-H. Heider, B. J. Wilhelm, J. A. Castelijns, R. Meyer, M. O. Kwakkelstein, G. B. Snow, et al. Safety and Biodistribution of 99mTechnetium-labeled Anti-CD44v6 Monoclonal Antibody BIWA 1 in Head and Neck Cancer Patients Clin. Cancer Res., August 1, 2000; 6(8): 3046 - 3055. [Abstract] [Full Text]

				L. H. Pai-Scherf, J. A. Carrasquillo, C. Paik, O. Gansow, M. Whatley, D. Pearson, K. Webber, M. Hamilton, C. Allegra, M. Brechbiel, et al. Imaging and Phase I Study of 111In- and 90Y-labeled Anti-LewisY Monoclonal Antibody B3 Clin. Cancer Res., May 1, 2000; 6(5): 1720 - 1730. [Abstract] [Full Text]

				M. F. Flessner, J. Lofthouse, and E. R. Zakaria In vivo diffusion of immunoglobulin G in muscle: effects of binding, solute exclusion, and lymphatic removal Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2783 - H2793. [Abstract] [Full Text] [PDF]

				Y. Mano, H. Suzuki, T. Terasaki, T. Iwahashi, K.-I. Ono, M. Naito, T. Tsuruo, and Y. Sugiyama Kinetic Analysis of the Disposition of MRK16, an Anti-P-glycoprotein Monoclonal Antibody, in Tumors: Comparison Between in Vitro and in Vivo Disposition J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 391 - 401. [Abstract] [Full Text]