Thesis

The development of a modular and convergent approach to the synthesis of antibody drug conjugates

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2023
Thesis identifier
  • T17541
Person Identifier (Local)
  • 201978299
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Antibody-Drug conjugates (ADCs) are a promising class of pharmaceutical that exploit the highly selective binding affinity of the antibody to deliver a payload, typically cytotoxic, to a target cell. As a result, many ADCs are used in oncology to target and destroy cancerous cells. However, the generation of ADCs can be a long and linear process to synthesise highly complex molecules that are then conjugated to the antibody, with little opportunity for variation within the synthetic route. By taking a modular approach to ADCs, libraries of analogues could be generated in a high throughput manner that allow for hit screening where a range of properties can be investigated, such as the average drug to antibody ratio (aDAR), conjugation site, and linker length/cleavage mechanism. This modular strategy focuses on a series of variables, including antibody, linker (cleavable or non-cleavable), and payload. The current study describes the process and synthesis of reagents that can be brought together in this more convergent manner. In addition to this, work has been undertaken to investigate the use of alternative conjugation residues, beyond those traditionally used, such as lysine and cysteine, to further increase the diversity of a product library and to understand how targeting different residues affect the stability and efficacy of the product ADC. This approach employs the use of “click chemistry” through the reaction of azides and strained-alkynes to join the linker-payload fragment to a functionalised antibody. The products of this modular approach were analysed by mass spectroscopy to determine the drug-to-antibody ratio and the effectiveness of the click chemistry. A subset of these was also analysed in an SPR binding assay enabling an effective comparison between a series of conjugation methods and their impact on the ADC. Finally, a series of improvements and expansions of the modular approach was applied to further highlight the breadth of this methodology.
Advisor / supervisor
  • Jones, Gavin
  • Jamieson, Craig
  • Nicolle, Simon
Resource Type
Note
  • The confidentiality statement on each page of this thesis DOES NOT apply.
DOI
Funder
Embargo Note
  • Previously held under moratorium in Chemistry department (GSK) from 15/09/2023 until 25/11/2025. The digital version of this thesis is restricted to Strathclyde users only until 15/09/2028.

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