2. Academic Validation
  3. Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug Conjugates (ADCs)

Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug Conjugates (ADCs)

  • Sci Rep. 2020 Jun 1;10(1):8869. doi: 10.1038/s41598-020-65860-x.
Ricarda M Hoffmann 1 2,  Silvia Mele 1,  Anthony Cheung 1 3,  Daniel Larcombe-Young 3,  Gintare Bucaite 4 5,  Eirini Sachouli 1,  Iva Zlatareva 1,  Hassan O J Morad 1,  Rebecca Marlow 3 6,  James M McDonnell 4 5,  Mariangela Figini 7,  Katie E Lacy 1,  Andrew J N Tutt 3 6,  James F Spicer 8,  David E Thurston 9 10,  Sophia N Karagiannis 1 2 3,  Silvia Crescioli 11 12
Affiliations

Affiliations

  • 1 St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, 9th Floor, Guy's Hospital, London, SE1 9RT, United Kingdom.
  • 2 NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London, London, United Kingdom.
  • 3 Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom.
  • 4 Randall Centre for Cell and Molecular Biophysics, King's College London, London, SE1 1UL, United Kingdom.
  • 5 Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, SE1 1UL, United Kingdom.
  • 6 Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom.
  • 7 Biomarker Unit, Department of Applied Research and Technology Development, Fondazione, IRCCS Istituto Nazionale dei Tumouri Milano, 20133, Milan, Italy.
  • 8 School of Cancer & Pharmaceutical Sciences, King's College London, 3rd Floor, Guy's Hospital, London, United Kingdom.
  • 9 Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King's College London, London, SE1 9NH, United Kingdom.
  • 10 Femtogenix Ltd, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire, AL5 2JQ, United Kingdom.
  • 11 St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, 9th Floor, Guy's Hospital, London, SE1 9RT, United Kingdom. silvia.crescioli@kcl.ac.uk.
  • 12 NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London, London, United Kingdom. silvia.crescioli@kcl.ac.uk.
PMID: 32483228 DOI: 10.1038/s41598-020-65860-x
Abstract

Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to Cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked Antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to Antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast Cancer cell survival in vitro and in growth restriction of orthotopic breast Cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development.

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