The outlook for cancer patients who present with evidence of metastasis is best characterized as a precipitous decline in prognosis and overall survival. This dramatic reduction in survival suggests a need to focus on the development of therapeutic and diagnostic reagents that are tailored to cancer in its disseminated form. In pursuit of this goal, a phage display based phenotype screening platform was developed to generate humanized antibodies for use in both circulating tumor cell detection, and therapeutic intervention, using in vivo models of breast cancer metastasis. A broader perspective on this work is that it highlights methods that focus on biologic drug development based on disease phenotype, as opposed to conventional target-based methods. In the context of metastasis, the present work focused on the relevant cancer cell phenotype, termed epithelial to mesenchymal transition, which is believed to be the driver phenotype of cancer dissemination. Phenotype screening approaches do not require prior knowledge of potential targets, and are thus amenable to cancer biomarker discovery, which in turn can lead to innovative, first-in-class approaches to cancer management. A broadly applicable method for deriving humanized antibodies from cell based phenotype screening was developed. Target deconvolution approaches to identify the binding partner of candidate antibodies were also explored. Finally, the fine tuning of antibody binding affinity via affinity maturation methods was also explored through physiologically based pharmacokinetic modelling, in an attempt to establish optimal targeting affinities for both solid tumors and metastases. The work concludes with in vitro and in vivo characterization of two candidate antibodies as therapeutic agents.
University of Minnesota Ph.D. dissertation. July 2016. Major: Pharmaceutics. Advisor: Jayanth Panyam. 1 computer file (PDF); viii, 118 pages.
Humanized antibody development using phage display: applications to solid tumor metastasis.
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