Semester

Fall

Date of Graduation

2021

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Mark McLaughlin

Committee Co-Chair

Gregory Dudley

Committee Member

Justin Legleiter

Committee Member

Brian Popp

Committee Member

Werner Geldenhuys

Abstract

The therapeutic monoclonal antibodies are very important tools to fight against the diseases especially in the field of cancer immunotherapy. Many immunotherapeutic antibodies are being used to treat cancer that target multiple different components of the cancer microenvironment. Cells with extracellular juxtacrine ligands [JL-cells] and extracellular juxtacrine receptors [JR-cells] form JL-cell-JR-cell interfaces that produce juxtacrine signals inside JR-cells. [76] Juxtacrine signaling unlike endocrine or paracrine signaling requires no release or cellular uptake of ligands. [76] Immune checkpoint inhibitors are soluble IgG antibodies that block juxtacrine ligand engagements with juxtacrine receptors on tumor or other immune cells. [77] Rapid Nobel Prize recognition of immune checkpoint inhibitor discoveries shows juxtacrine signal modulation can have great significance in immunotherapy. We hypothesize the lack of juxtacrine ligand release and the lack of ligand cellular uptake enables juxtacrine ligand mimics mounted to non-living surfaces to activate juxtacrine receptors on adjacent infiltrating adaptive immune cells. IgG agonistic antibodies that are never released into solution can modulate the immune response of cells that infiltrate adjacent to the beads and interact with the displayed IgG agonistic antibodies. We have designed a linker molecule labeled with lanthanides which we characterized by common organic characterization techniques as well as by ICP-MS technique analogous to the Cy-TOF analytical techniques. Then we devised the technique for installing linker molecule labeled antibodies to Macrobead which are also tagged with linker molecule of different metals and then characterized the metal contents by ICP-MS technique to measure potentially multiple antibodies on the bead surface. We have also developed a non-aqueous synthetic route to make metallated DOTA-based system that we verified by a model molecule system

Embargo Reason

Patent Pending

Available for download on Friday, December 09, 2022

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