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An investigation into the efficacy of novel immuno-oncology Alphamers

Gruchy, Nicole (2016) An investigation into the efficacy of novel immuno-oncology Alphamers. Master of Research (MRes) thesis, University of Kent,. (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:57565)

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Language: English

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Abstract

Centauri Therapeutics are developing antibody recruiting small molecules called Alphamers. Alphamers are formed by an aptamer which is a single stranded oligonucleotide which binds with high affinity and specificity to a target. The aptamer is conjugated via a linker molecule to an oligosaccharide epitope called ?-gal. ?-Gal is not expressed in humans, a characteristic which is exploited by Alphamers. Anti-Gal antibodies are specific for ?-Gal and are the most abundant natural antibody found in human blood. Alphamers recruit anti-Gal antibodies and induce an immune response specific for the target cell. Alphamers investigated throughout this study contain an aptamer which has high affinity and specificity to epidermal growth factor receptor (EGFR). EGFR is over expressed in a range of cancer types, and many anti-EGFR therapies are already on the market. The development of drug resistant cancer has increased therefore a novel targeted drug which is effective in the treatment of drug resistant cancer is needed.

This study focused on the in vitro investigation of the efficacy of EGFR Alphamers. There were three main objectives of the study; determine target binding, investigate downstream effects of Alphamer binding and assess the recruitment of anti-Gal antibodies in response to bound Alphamer. Through use of a competitive ELISA and flow cytometry, results found the aptamer to be highly specific for EGFR, and that aptamer binding was EGFR dependent. Through use of a cell proliferation assay, results showed that the aptamer inhibited EGF binding to EGFR and induced an inhibitory effect on cell growth and proliferation. Western blot analysis suggested that aptamers may have a similar mechanism of action as cetuximab, an anti-EGFR monoclonal antibody currently used in the treatment of colorectal cancer and head and neck cancer. It was found that bound aptamer exerted a stimulatory effect on downstream signalling pathways, as is also seen with cetuximab. Finally, screening of Alphamers found a positive correlation between ?-Gal expression and the recruitment of anti-Gal antibodies.

Item Type: Thesis (Master of Research (MRes))
Uncontrolled keywords: Cancer immunotherapeutics Alphamers In Vitro proof of concept studies
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Users 1 not found.
Date Deposited: 29 Sep 2016 11:00 UTC
Last Modified: 29 May 2019 17:54 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/57565 (The current URI for this page, for reference purposes)
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