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Theoretic Criteria for Antibody Penetration into Solid Tumors and Micrometastases

¹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ² Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts

Correspondence: For correspondence or reprints contact: K. Dane Wittrup, PhD, Department of Chemical Engineering and Biological Engineering Division, Massachusetts Institute of Technology, Building E19-551, 77 Massachusetts Ave., Cambridge, MA 02139. E-mail: wittrup{at}mit.edu

Targeting tumors with antibody-based therapeutics is a complex task presenting multiple kinetic barriers. Antibody internalization and clearance inhibit uptake both in solid tumors, limited by tumor vascular permeability, and in micrometastases, limited by diffusion. Methods: A modeling exercise is used to introduce 2 simple criteria that must be less than unity for saturation of both tumors and micrometastases. The clearance modulus and the Thiele modulus are ratios of the plasma clearance rate and antibody catabolism, respectively, to the tumor tissue penetration rate. Results: Even low rates of antigen internalization from constitutive membrane turnover can significantly retard antibody penetration. Rapid clearance of single-chain variable fragments also hinders uptake, often more than counterbalancing their more rapid extravasation and diffusion. Conclusion: The model illustrates that with the large resistance from the tumor capillary, antibodies may be more suitable for targeting micrometastases than vascularized tumors.

Key Words: molecular imaging • monoclonal antibodies • radionuclide therapy • biodistribution • penetration • pharmacokinetics

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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