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Immunotherapy of Folate Receptor Expressing Cancers

By Nimalka Achini Bandara

Abstract

The folate receptor (FR) is a GPI anchored cell surface glycoprotein that functions to facilitate folic acid uptake and mediate signal transduction. With the introduction of multiple folate-targeted drugs into the clinic, the question has arisen regarding how frequently a patient can be dosed with a FR-targeted drug or antibody, and whether dosing frequency exerts any impact on the availability of FR for subsequent rounds of FR-mediated drug uptake. Although the rate of FR recycling has been examined in murine tumor models, little or no information exists on the impact of FR occupancy on its rate of endocytosis. The studies described in chapter two of this thesis quantitates the number of cell surface FR-α and FR-β following exposure to saturating concentrations of a variety of folate-linked molecules and anti-FR antibodies, including the unmodified vitamin, folate-linked drug mimetics, multi-folate derivatized nanoparticles, and monoclonal antibodies to FR. The collected data indicate that FR occupancy has no impact on the rate of FR internalization. The results also demonstrate that multivalent conjugates that bind and cross-link FRs at the cell surface internalize at the same rate as monovalent folate conjugates that have no impact on FR clustering, even though the multivalent conjugates traffic through a different endocytic pathway

Topics: Cancer Immunotherapy, Folate Receptor
Publisher: 'Purdue University (bepress)'
Year: 2015
OAI identifier: oai:docs.lib.purdue.edu:open_access_dissertations-2413
Provided by: Purdue E-Pubs
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