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Design, prototype development and testing of an antibody-drug conjugate using a novel colchicine derivative

Antonio Vitale

Design, prototype development and testing of an antibody-drug conjugate using a novel colchicine derivative.

Rel. Jacek Adam Tuszynski. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2020

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From the Paul Ehrlich’s idea of the “magic bullet”, developed more than 100 years ago, outstanding findings pushed many researchers and companies to getting into the ADCs technology. The modular structure of the ADCs based on three major constituents, a monoclonal antibody (mAb), a linker molecule and a cytotoxic payload, theoretically allows the appropriate efficacy and controlled therapeutic toxicity for the treatment of many cancers and not only. Nowadays, many other diseases are also treated with this strategy. Today, seven ADCs are marketed and several hundred are advancing through different preclinical and clinical stages of development. The purpose of this Master’s thesis work was to design, synthetize and test in-vitro an novel antibody-drug conjugate (ADC) using Panitumumab as a biological molecule and a new produced colchicine derivative named CCI-001 as a payload. First, several reactions have been carried out in order to obtain the chemical conjugation between the CCI-001 with a heterobifunctional pegylated linker, taking advantages of two different strategies. The obtained products, CCI-NH2 and L+D_1, were then deeply characterized by several analytical methods. The therapeutic index of the obtained new chemically conjugated molecules was found improved when compared to the CCI-001. Particularly, showing a tremendous increase in hydrophilicity compared to the standard one. Moreover, the cytotoxicity of these new molecules as well as for the final ADC was assessed in three different cell lines, finding a preserved cytotoxicity in a nanomolar concentration range. On the other hand, none of the ADC treated cell lines reached the 50 % of the cell viability. In order to explain this behaviour, the uptake of the standard antibody was monitored through the conjugation with a fluorescence dye. EGFR receptor dependent attitude was confirmed, leading to final thoughts to explain the unexpected ADC lack in cytotoxicity.

Relators: Jacek Adam Tuszynski
Academic year: 2020/21
Publication type: Electronic
Number of Pages: 114
Corso di laurea: Corso di laurea magistrale in Ingegneria Biomedica
Classe di laurea: New organization > Master science > LM-21 - BIOMEDICAL ENGINEERING
Ente in cotutela: Università of Alberta (CANADA)
Aziende collaboratrici: UNSPECIFIED
URI: http://webthesis.biblio.polito.it/id/eprint/15829
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