Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids

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Abstract
Poor tissue penetration is a significant obstacle to the development of successful antibody drugs for immunotherapy of solid tumors, and diverse alterations to the properties of antibody drugs have been made to improve penetration and homogeneity of exposure. However, in addition to properties of the antibody drug, mathematical models of antibody transport predict that the antigen expression level and turnover rate significantly influence penetration. As intrinsic antigen properties are likely to be difficult to modify, they may set inherent limits to penetration. Accordingly, in this study, we assess their contribution by evaluating the distance to which antibodies penetrate spheroids when these antigen properties are systematically varied. Additionally, the penetration profiles of antibodies against carcinoembryonic antigen and A33, two targets of clinical interest, are compared. The results agree well with the quantitative predictions of the model and show that localizing antibody to distal regions of tumors is best achieved by selecting slowly internalized targets that are not expressed above the level necessary for recruiting a toxic dose of therapeutic. Each antibody-bound antigen molecule that is turned over or present in excess incurs a real cost in terms of penetration depth—a limiting factor in the development of effective therapies for treating solid tumors. [Mol Cancer Ther 2008;7(7):2233–40]