The macroscopic and microscopic pharmacology of monoclonal antibodies.

When monoclonal antibodies directed against tumor-associated antigens are injected intravenously, they sometimes fail to distribute uniformly in the substance of a tumor. To understand the possible reasons, it is necessary to consider both macroscopic and microscopic features of the pharmacology. We have analyzed antibody penetration into microscopic primary tumors and metastases by melding together information on the global pharmacokinetics, convective and diffusive transport across the blood capillary wall, diffusion through the tumor interstitial space, antigen - antibody interaction, metabolism, and lymphatic outflow. This analysis predicts that the very fact of successful binding will decrease the homogeneity of distribution. We believe that this "binding site barrier" constitutes major challenges to the molecular design of next-generation antibodies and also to the design of many other types of ligands for use in treatment of solid tumors.