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
| Autor: | Ninfa L. Straubinger, Stephen Caddick, Daniel B. Longley, James F Burrows, Darren K.W. Chan, Charlene Minx, Michelle K. Greene, Jun Wang, Robert M. Straubinger, Sandra Van Schaeybroeck, James R. Baker, Vijay Chudasama, Eifion Robinson, Ting Chen, Christopher J. Scott, Donald E. Mager |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Antibody-drug conjugate Immunoconjugates medicine.medical_treatment Cetuximab Mice Transgenic Mice SCID medicine.disease_cause Article Targeted therapy Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences Targeted therapies 0302 clinical medicine SDG 3 - Good Health and Well-being Growth factor receptor Antigen In vivo Cell Line Tumor Pancreatic cancer Animals Humans Medicine Aminobenzoates Molecular Targeted Therapy business.industry Drugs Investigational medicine.disease Xenograft Model Antitumor Assays ErbB Receptors Gene Expression Regulation Neoplastic Mice Inbred C57BL Pancreatic Neoplasms body regions Cell Transformation Neoplastic Oncology 030220 oncology & carcinogenesis Mutation Cancer research KRAS business Oligopeptides Chemical modification medicine.drug |
| Zdroj: | Greene, M K, Chen, T, Robinson, E, Straubinger, N L, Minx, C, Chan, D K W, Wang, J, Burrows, J F, Van Schaeybroeck, S, Baker, J R, Caddick, S, Longley, D B, Mager, D E, Straubinger, R M, Chudasama, V & Scott, C J 2020, ' 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 ', British Journal of Cancer . https://doi.org/10.1038/s41416-020-01046-6 British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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