THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES AND OTHER BIOLOGICAL LIGANDS

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Before a monoclonal antibody (or other biological ligand) can label or kill a tumor cell, it must generally reach that cell. For portions of a tumor more than a few microns from the nearest blood vessel, access may be limited by the rate at which the molecule can "percolate" through the extracellular space. We are investigating the spatial and temporal profiles of immunoglobulin (Ig) distribution generated by diffusion and convection through tumors, taking into account specific binding, nonspecific binding, and metabolism. For this purpose, we developed theoretical models that splice together the global pharmacology and the microscopic percolation process. Significant predictions: (1) Antibody molecules may be prevented from penetrating a tumor by the very fact of their successful binding to antigen (the "binding site barrier"). Thus, lower affinity might sometimes be preferable. (2) Even with saturable binding (but not metabolism), the "C times T" exposure of tumor cells to antibody will be the same throughout the mass. (3) Metabolism will decrease the relative "C times T" exposure of cells farther from the blood vessel. This may be a major barrier to effective treatment of solid tumors with ligand molecules. Predictions of the model have been tested using subcutaneous tumors and micrometastases in guinea pigs. We used a combination of double-label autoradiography and double-chromophore immunohistochemistry to determine simultaneously the microscopic distribution of antibody, isotype matched control IgG, antigen, and blood vessels. The result in both S.C. tumors and micrometastases was direct experimental validation of our "binding site barrier" hypothesis. We have speculated that the "binding site barrier" is a factor in the evolution of physiological autocrine/paracrine and endocrine molecules. As a corollary, we think that the micropharmacology should be taken into account as we design the next generation of such molecules for exogenous administration or for secretion by genetically modified cells.