Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer

  • Br J Cancer. 2020 Nov;123(10):1502-1512. doi: 10.1038/s41416-020-01046-6.
Michelle K Greene  1 ,  Ting Chen  2 ,  Eifion Robinson  3 ,  Ninfa L Straubinger  2 ,  Charlene Minx  2 ,  Darren K W Chan  2 ,  Jun Wang  2 ,  James F Burrows  4 ,  Sandra Van Schaeybroeck  1 ,  James R Baker  3 ,  Stephen Caddick  3 ,  Daniel B Longley  1 ,  Donald E Mager  2 ,  Robert M Straubinger  5  6 ,  Vijay Chudasama  7 ,  Christopher J Scott  8
Affiliations
  • 1. The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
  • 2. Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
  • 3. Department of Chemistry, University College London, London, UK.
  • 4. School of Pharmacy, Queen's University Belfast, Belfast, UK.
  • 5. Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA. [email protected].
  • 6. Department of Pharmacology & Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA. [email protected].
  • 7. Department of Chemistry, University College London, London, UK. [email protected].
  • 8. The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. [email protected].
PMID: 32913288 DOI: 10.1038/s41416-020-01046-6
Abstract

Background: Antibody-drug conjugate (ADC) construction poses numerous challenges that limit clinical progress. In particular, common bioconjugation methods afford minimal control over the site of drug coupling to antibodies. Here, such difficulties are overcome through re-bridging of the inter-chain disulfides of cetuximab (CTX) with auristatin-bearing pyridazinediones, to yield a highly refined anti-epidermal growth factor receptor (EGFR) ADC.

Methods: In vitro and in vivo assessment of ADC activity was performed in KRAS mutant Pancreatic Cancer (PaCa) models with known resistance to CTX therapy. Computational modelling was employed for quantitative prediction of tumour response to various ADC dosing regimens.

Results: Site-selective coupling of an Auristatin to CTX yielded an ADC with an average drug:antibody ratio (DAR) of 3.9, which elicited concentration- and EGFR-dependent cytotoxicity at sub-nanomolar potency in vitro. In human xenografts, the ADC inhibited tumour growth and prolonged survival, with no overt signs of toxicity. Key insights into factors governing ADC efficacy were obtained through a robust mathematical framework, including target-mediated dispositional effects relating to antigen density on tumour cells.

Conclusions: Together, our findings offer renewed hope for CTX in PaCa therapy, demonstrating that it may be reformatted as a next-generation ADC and combined with a predictive modelling tool to guide successful translation.

Products