This Article Full Text 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 Graff, C. P. Articles by Wittrup, K. D. Search for Related Content PubMed PubMed Citation Articles by Graff, C. P. Articles by Wittrup, K. D.

Theoretical Analysis of Antibody Targeting of Tumor Spheroids

Importance of Dosage for Penetration, and Affinity for Retention¹

Department of Chemical Engineering and Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

The interplay among antibody/antigen binding kinetics, antibody diffusion, and antigen metabolic turnover together determines the depth of penetration of antitumor antibodies into prevascular tumor spheroid cell clumps. A sharp boundary between an outer shell of bound high-affinity antibody and an inner antibody-free core has been previously observed and mathematically modeled and was termed the "binding site barrier." We show here that this process is well described by a simplified shrinking core model wherein binding equilibration is much more rapid than diffusion. This analysis provides the following experimentally testable predictions: (a) the binding site barrier is a moving boundary whose velocity is proportional to the time integral of antibody concentration at the spheroid surface (i.e. plasma antibody AUC); (b) the velocity of this moving boundary is independent of binding affinity, if the affinity is sufficiently high to strongly favor antibody/antigen complex formation at prevailing antibody concentrations; and (c) maximum tumor retention is achieved when the antibody/antigen dissociation rate approaches the rate of antigen metabolic turnover. The consistency of these predictions with published experimental results is demonstrated. The shrinking core model provides a simple analytic relationship predicting the effects of altered antibody pharmacokinetics, antibody molecular weight, antigen turnover rate, antigen expression level, and micrometastasis size on antibody penetration and retention. For example, a formula is provided for predicting the bolus dose necessary to accomplish tumor saturation as a function of antibody and tumor properties. Furthermore, this analysis indicates certain attributes necessary for an optimal tumor targeting agent.

This article has been cited by other articles:

				M. M. Schmidt and K. D. Wittrup A modeling analysis of the effects of molecular size and binding affinity on tumor targeting Mol. Cancer Ther., October 1, 2009; 8(10): 2861 - 2871. [Abstract] [Full Text] [PDF]

				K. M. Kim, C. F. McDonagh, L. Westendorf, L. L. Brown, D. Sussman, T. Feist, R. Lyon, S. C. Alley, N. M. Okeley, X. Zhang, et al. Anti-CD30 diabody-drug conjugates with potent antitumor activity Mol. Cancer Ther., August 1, 2008; 7(8): 2486 - 2497. [Abstract] [Full Text] [PDF]

				M. E. Ackerman, D. Pawlowski, and K. D. Wittrup Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids Mol. Cancer Ther., July 1, 2008; 7(7): 2233 - 2240. [Abstract] [Full Text] [PDF]

				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]

				M. Chodorge, L. Fourage, G. Ravot, L. Jermutus, and R. Minter In vitro DNA recombination by L-Shuffling during ribosome display affinity maturation of an anti-Fas antibody increases the population of improved variants Protein Eng. Des. Sel., May 1, 2008; 21(5): 343 - 351. [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]

				G. M. Thurber, S. C. Zajic, and K. D. Wittrup Theoretic Criteria for Antibody Penetration into Solid Tumors and Micrometastases J. Nucl. Med., June 1, 2007; 48(6): 995 - 999. [Abstract] [Full Text] [PDF]

				M. S. Dennis, H. Jin, D. Dugger, R. Yang, L. McFarland, A. Ogasawara, S. Williams, M. J. Cole, S. Ross, and R. Schwall Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent Cancer Res., January 1, 2007; 67(1): 254 - 261. [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]

				J. J. Lammerts van Bueren, W. K. Bleeker, H. O. Bogh, M. Houtkamp, J. Schuurman, J. G.J. van de Winkel, and P. W.H.I. Parren Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action. Cancer Res., August 1, 2006; 66(15): 7630 - 7638. [Abstract] [Full Text] [PDF]

				A. Nguyen, A. E. Reyes II, M. Zhang, P. McDonald, W. L. T. Wong, L. A. Damico, and M. S. Dennis The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin Protein Eng. Des. Sel., July 1, 2006; 19(7): 291 - 297. [Abstract] [Full Text] [PDF]

				L. A. Kunz-Schughart, J. P. Freyer, F. Hofstaedter, and R. Ebner The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model J Biomol Screen, June 1, 2004; 9(4): 273 - 285. [Abstract] [PDF]

				C. P. Graff, K. Chester, R. Begent, and K.D. Wittrup Directed evolution of an anti-carcinoembryonic antigen scFv with a 4-day monovalent dissociation half-time at 37{degrees}C Protein Eng. Des. Sel., April 1, 2004; 17(4): 293 - 304. [Abstract] [Full Text] [PDF]