Background

Antibody-drug conjugates (ADCs) offer a powerful strategy for the cell-selective delivery of therapeutics, while minimizing off-target interactions associated with the drug payload. A pertinent exemplar of this approach is the targeted delivery of inhibitors of DNA damage repair processes in tumour cells. However, a limitation associated with existing drugs selectively targeting DNA damage repair defects in cancer cells is their sub-optimal physicochemical properties and off-target cytotoxicity. Therefore, it is critical to develop more effective targeting strategies to deliver drugs to DNA-repair deficient malignancies. ADCs offer a route to address this challenge.

Project Objective

This goal of this PhD project is to develop novel ADCs targeting DNA damage repair deficient cancers and to develop a pipeline of analytical in vitro cell-based assays for the early-stage evaluation of these bioconjugates.

The student will develop synthetic routes to selectively attach cytotoxic payloads to antibodies. In parallel, the student will develop a pipeline of physical, chemical and biological analyses to triage ADCs throughout the course of this project. This will include the use of existing analytical methods such as mass spectrometry, flow field flow fractionation, and hydrophobic interaction chromatography as examples. Comparing traditional sites of conjugation (e.g. cysteine and lysine, via maleimide and active esters, respectively), with the emerging ‘click and stick’ approaches developed in the Burley group will give critical insight into how this variable affects key properties, as outlined below. PARP inhibitors will be used as representative drug entities with associated biological evaluation on DNA damage pathways assessed in DNA repair deficient and proficient cancer cell models.

Further information

Burley Labs