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Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer

Authors
  • Healey, Gareth D.1
  • Pan-Castillo, Belen1
  • Garcia-Parra, Jezabel1
  • Davies, Julia1
  • Roberts, Shaun2
  • Jones, Eilir2
  • Dhar, Kalyan3
  • Nandanan, Sarika4
  • Tofazzal, Nasima2
  • Piggott, Luke5
  • Clarkson, Richard6
  • Seaton, Gillian6
  • Frostell, Asa7
  • Fagge, Tim8
  • McKee, Colin9
  • Margarit, Lavinia1, 4
  • Conlan, R. Steven1
  • Gonzalez, Deyarina1
  • 1 Swansea University Medical School, Swansea University, Reproductive Biology and Gynaecological Oncology Group, Singleton Park, Swansea, SA2 8PP, UK , Swansea (United Kingdom)
  • 2 Swansea Bay University Health Board, Singleton Hospital, Cellular Pathology Department, Sketty Lane, Swansea, SA2 8QA, UK , Swansea (United Kingdom)
  • 3 Swansea Bay University Health Board, Singleton Hospital, Gynecology Oncology Department, Sketty Lane, Swansea, SA2 8QA, UK , Swansea (United Kingdom)
  • 4 Cwm Taf Morgannwg University Health Board, Obstetrics & Gynecology Department Princess of Wales Hospital, Coity Road, Bridgend, CF31 1RQ, UK , Bridgend (United Kingdom)
  • 5 Cardiff University, University Hospital of Wales, Welsh Cancer Research Centre, Institute of Cancer & Genetics, School of Medicine, Heath Park, Cardiff, CF14 4XN, UK , Cardiff (United Kingdom)
  • 6 Cardiff University, European Cancer Stem Cell Research Institute, School of Biosciences, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK , Cardiff (United Kingdom)
  • 7 GE Healthcare Bio-Sciences, Uppsala, SE-751 84, Sweden , Uppsala (Sweden)
  • 8 GE Healthcare, Little Chalfont, Buckinghamshire, HP7 9NA, UK , Little Chalfont (United Kingdom)
  • 9 ADC Biotechnology Ltd, OpTIC Technium, Ffordd William Morgan, St Asaph Business Park, St Asaph, Denbighshire, LL17 0JD, UK , St Asaph (United Kingdom)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Oct 29, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0765-z
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundThe treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required.MethodsA cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease.ResultsWe have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman’s Rank Order Correlation: ρ = − 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease.ConclusionsThese data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.

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