Early intervention in cancer using monoclonal antibodies and other biological ligands: micropharmacology and the "binding site barrier".

Monoclonal antibodies and other biological ligands tend to distribute nonuniformly in bulky tumors after systemic administration. In part, that observation reflects intrinsic heterogeneity of the tumor; in part, it represents poor percolation through tumor substance. Theoretical considerations led us several years ago to formulate the "binding site barrier" hypothesis, the idea that macromolecular ligands could be prevented from penetrating tumors by the very fact of their successful binding to the target receptor. All else being equal, the higher the density of target moieties (e.g., antigens) and the higher the affinity, the greater the barrier. Experimental evidence for this hypothesis remained circumstantial until we recently obtained direct experimental verification in an animal tumor system. As shown by calculations in the present study, metabolism of ligand in free form or once it has bound to the target can also limit dramatically the extent of penetration. The PERC program package, developed to examine these issues in the case of monoclonal antibodies, has now been applied to other types of ligands as well. We speculate that the same microscopic factors have influenced the evolution of biological ligands, such as the autocrine-paracrine and chemotactic factors. Micropharmacological issues (binding sites, molecular size, and charge) should be taken into account as we design the next generation of biological ligands for systemic administration. The same issues are, perhaps, even more important with respect to molecular design of biological factors to be secreted by genetically modified cells in the treatment of cancer and in cancer vaccines. Since the PERC calculations and experiments relate to aggregates of tumor cells no more than a few hundred micron across, the ideas appear relevant to the problems of early detection and intervention. However, barriers associated with organized epithelial cell layers and basement membrane in the case of early carcinomas and carcinomatous change remain to be understood.