The Design and Synthesis of Dual Loaded 4-Vinylpyridine Derived Antibody-Drug Conjugates

Sharpe, James (2022) The Design and Synthesis of Dual Loaded 4-Vinylpyridine Derived Antibody-Drug Conjugates. Doctoral thesis, University of East Anglia.

[thumbnail of 2022SharpeJPhD.pdf] PDF
Restricted to Repository staff only until 31 March 2027.

Request a copy


ADCs are a growing field within cancer treatment, and 11 have been approved by the FDA to date. Commonly, ADCs comprise a N-substituted maleimide conjugation chemistry that couples a potent cytotoxin (via a linker moiety to the nitrogen) to a highly selective antibody (via conjugation to a thiol) that targets a tumour associated antigen. Maleimide based conjugation chemistries are prone to retro-Michael reactions, that uncouple the cytotoxin from the antibody.

The use of a 4-vinylpyridine derivative (PermaLink®) as an alternative to maleimide has been shown by Iksuda Therapeutics to form a more stable ADC via irreversible formation of a thioether. With the development of ADCs moving towards the use of more potent warheads, the stability of the conjugation chemistry is paramount. The use of multiple, different drugs attached to one antibody has also been shown to overcome the problems of antigen expression heterogeneity, and multidrug resistance.

The design, synthesis, evaluation, and bioconjugation of dual-loaded ADC linker-toxins is described herein. 16 derivatives of dual-loadable 4-vinylpyridine were assessed for their ability to undergo conjugation with a thiol, and the rates determined. From these, three were PEGylated and loaded with a potent cytotoxin, and conjugated to the antibody Herceptin®.

Cell kill analysis of one of the ADCs generated, revealed that the complete ADC was more potent than the unconjugated cytotoxin, suggesting that antibody binding was functional, as was the payload release mechanism.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: James Tweddle
Date Deposited: 09 Dec 2022 15:48
Last Modified: 09 Dec 2022 15:48

Actions (login required)

View Item View Item