Factors determining antibody distribution in tumors

Abstract

The development of antibody therapies for cancer is increasing rapidly, primarily owing to their specificity. Antibody distribution in tumors is often extremely uneven, however, leading to some malignant cells being exposed to saturating concentrations of antibody, whereas others are completely untargeted. This is detrimental because large regions of cells escape therapy, whereas other regions might be exposed to suboptimal concentrations that promote a selection of resistant mutants. The distribution of antibody depends on a variety of factors, including dose, affinity, antigens per cell and molecular size. Because these parameters are often known or easily estimated, a quick calculation based on simple modeling considerations can predict the uniformity of targeting within a tumor. Such analyses should enable experimental researchers to identify in a straightforward way the limitations in achieving evenly distributed antibody, and design and test improved antibody therapeutics more rationally.

Figure 1

Poor penetration of trastuzumab (a) and doxorubicin (b) into tumor tissue in xenograft tumor samples. Capillaries are labeled red and the drugs are labeled green. Large zones are essentially free of drug. The scale bar represents 100 μm. Modified, with permission, from Refs. [4] and [6].

Figure 2

Processes of antibody distribution in tumor tissue. (1) Extravasation of antibody across the tumor blood vessel walls is a function of the vessel permeability and occurs slowly. (2) Once in the tumor tissue, the antibodies diffuse freely in the extracellular matrix (a), with their motion retarded by formation of immobile complexes owing to binding (b) and dissociation (c), which are functions of affinity. (3) Antibody administered in the plasma, which supplies free antibody to the tumor, is cleared through several mechanisms, depending on its size, charge and Fc receptor binding. (4) While bound to surface antigens, local clearance of antibodies occurs owing to internalization and degradation at a rate determined by the target antigen.