Poster Presentation The 16th Australian Peptide Conference 2025

Towards the Generation of Glutathione-Sensitive Linkers for Multi-Drug Antibody Drug Conjugates (#131)

Suzie M Chan 1 2 3 , Makhdoom Sarwar 3 4 , William Kelton 3 5 , Stephen M. F. Jamieson 3 6 7 , Iman Kavianinia 1 2 3
  1. School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
  2. School of Biological Sciences, The University of Auckland, Auckland, New Zealand
  3. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
  4. Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
  5. School of Pharmacy and Biomedical Science, University of Waikato, Hamilton, New Zealand
  6. Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
  7. Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

Antibody-drug conjugates (ADCs) are an innovative class of cancer therapeutics, combining the specificity of monoclonal antibodies (mAbs) and cytotoxic activity of small molecule drugs to create an effective treatment whilst minimising off-target adverse effects. A significant challenge in the response to ADC therapies is the development of drug resistance. Clinically, the most effective anticancer treatment options often involve the use of drug combinations which achieves synergistic anticancer effects and overcomes drug resistance. However, all 12 FDA-approved ADCs consist of a single drug-payload attached via a chemical linker to the antibody.1 To address this, there has been rapidly growing interest in the development of multi-drug ADCs whereby different drugs have been conjugated to the antibody generally through either different conjugation sites or a single conjugation site using a linker which carries the different payloads.2

Our group has previously developed a glutathione (GSH)-sensitive cleavable linker designed for the attachment of a single drug-payload to an antibody.3 This work aims to develop a novel platform for the attachment of two mechanistically distinct drug-payloads to a single antibody via the generation of a multi-drug GSH-sensitive linker synthesised on-resin. These linkers would then be conjugated to Mirvetuximab, a folate receptor α (FRα)-targeting mAb. FRα is a glycosylphosphatidylinositol anchored cell-surface glycoprotein and is overexpressed in several cancers including epithelial ovarian (76–80%), endometrial (20–50%), triple-negative breast (35–68%), and non-small-cell lung cancers (14–74%).4 Targeting specificity is being assessed using two FRα-positive ovarian cancer cell lines (SKOV3 and OVCAR8) and an FRα-negative line (A2780). Drug uptake and cytotoxicity are monitored using SYBR Green and crystal violet assays.  This ongoing research aims to establish a versatile and modular ADC platform capable of delivering dual payloads with complementary mechanisms of action. The long-term goal is to overcome resistance pathways and improve therapeutic outcomes in FRα-positive malignancies.

  1. Tong, J. T. W.; Harris, P. W. R.; Brimble, M. A.; Kavianinia, I. An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy. Molecules 2021, 26 (19), 5847.
  2. Journeaux, T.; Bernardes, G. J. L. Homogeneous multi-payload antibody–drug conjugates. Nature Chemistry 2024, 16 (6), 854-870. DOI: 10.1038/s41557-024-01507-y.
  3. Tong, J. T. W.; Sarwar, M.; Ahangarpour, M.; Hume, P. A.; Williams, G. M.; Brimble, M. A.; Kavianinia, I. Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates.
  4. Scaranti, M.; Cojocaru, E.; Banerjee, S.; Banerji, U. Exploiting the folate receptor α in oncology. Nature Reviews Clinical Oncology 2020, 17 (6), 349-359. DOI: 10.1038/s41571-020-0339-5.