Distribution and metabolism of antibodies and macromolecules in tumor tissue
Author(s)Thurber, Greg M
Massachusetts Institute of Technology. Dept. of Chemical Engineering.
K. Dane Wittrup.
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Tumor targeting drugs that selectively treat cancerous tissue are promising agents for lowering the morbidity and mortality of cancer. Within this field, antibody treatments for cancer are currently being developed for both imaging and therapeutic applications. A major limitation with this class of drugs is the poor distribution and low uptake in tumor tissue. Poor distribution leaves some cells completely devoid of treatment, while others experience marginally toxic concentrations that could foster drug resistance. The low overall uptake in vascularized tumors constrains the therapeutic index and lowers signal to noise ratios for imaging applications. Since antibody therapies are currently used to treat both bulk tumors and residual disease, an understanding of the limitations in targeting prevascular metastases and vascularized tumors is required. In order to circumvent the current limitations with antibody therapies, the underlying causes must first be determined. In this thesis, the various steps in tumor localization of antibodies are analyzed in order to determine which steps are limiting uptake and distribution. Mathematical models are developed that indicate the distance antibodies and other binding macromolecules will penetrate into tumors and micrometastases. These models can also estimate the maximum uptake and time course of antibody concentration in tumors. The experimental distribution of a CEA binding antibody is measured in tumor spheroids and a mouse xenograft system to validate the model predictions. Using dimensional analysis of the fundamental transport rates that occur in tumors and micrometastases, two main groups determine the distance antibodies will penetrate in tumor tissue.(cont.) The clearance modulus indicates whether antibody persistence in the blood is sufficient to allow the drug to reach all cells in the micrometastasis or vascularized tumor. The Thiele modulus, defined for antibody transport in tumors, relates the internalization and catabolism of bound antibodies on cancer cells to the maximum distance the antibodies will reach in the tissue. These groups are related to the overall time course and maximum uptake in tumors, indicating when all cells will be targeted, and what factors determine this limit. These models can aid in experimental design, data interpretation, and strategies to improve uptake.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.Vita.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Dept. of Chemical Engineering.; Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology