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Predicted and Observed Effects of Antibody Affinity and Antigen Density on Monoclonal Antibody Uptake in Solid Tumors

Chemical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources, NIH, Bethesda, Maryland 20892 [C. S., P. F. M., R. L. D.]; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [T. R. S.]; Department of Pathology, Beth Israel Hospital and Harvard Medical School and the Charles A. Dana Research Institute, Boston, Massachusetts 02215 [H. F. D.]; and Department of Chemical and Biochemical Engineering and the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854 and Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02215 [M. L. Y.]

The uptake and binding of monoclonal antibodies (MAbs) in solid tumors after a bolus i.v. injection are described using a compartmental pharmacokinetic model. The model assumes that MAb permeates into tumor unidirectionally from plasma across capillaries and clears from tumor by interstitial fluid flow and that interstitial antibody-antigen interactions are characterized by the Langmuir isotherm for reversible, saturable binding. Typical values for plasma clearance and tumor capillary permeability of a MAb and for interstitial fluid flow and interstitial volume fraction of a solid tumor were used to simulate the uptake of MAbs at various values of the binding affinity or antigen density for a range of MAb doses. The model indicates that at low doses, an increase in binding affinity may lead to an increase in MAb uptake. On the other hand, at doses approaching saturation of antigen or when uptake is permeation limited, an increase in the binding affinity from moderate to high affinity will have only a small effect on increasing MAb uptake. The model also predicts that an increase in antigen density will greatly increase MAb uptake when uptake is not permeation limited. Our experiments on MAb uptake in melanoma tumors in athymic mice after injection of 20 µg MAb (initial plasma concentration, about 120 nM) are consistent with these model-based conclusions. Two MAbs differing in affinity by more than 2 orders of magnitude (3.8 x 10⁸ M^-1 and 5 x 10¹⁰ M^-1) but with similar in vivo antigen densities in M21 melanoma attained similar concentrations in the tumor. Two MAbs of similar affinity but having a 3-fold difference in in vivo antigen density in SK-MEL-2 melanoma showed that the MAb targeted to the more highly expressed antigen attained a higher MAb concentration. We also discuss the model predictions in relation to other experiments reported in the literature. The theoretical and experimental findings suggest that, for high dose applications, efforts to increase MAb uptake in a tumor should emphasize the identification of an abundantly expressed antigen on tumor cells more than the selection of a very high affinity MAb.

¹ To whom requests for reprints should be addressed, at Building 13, Room 3W13.

² Present address: Baxter Healthcare Corp., Round Lake, IL 60073.

Received 6/19/91. Accepted 11/ 1/91.

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