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

Healey, Gareth D., Pan-Castillo, Belen, Garcia-Parra, Jezabel, Davies, Julia, Roberts, Shaun, Jones, Eilir, Dhar, Kalyan, Nandanan, Sarika, Tofazzal, Nasima, Piggott, Luke, Clarkson, Richard, Seaton, Gillian, Frostell, Asa, Fagge, Tim, McKee, Colin, Margarit, Lavinia, Conlan, R. Steven and Gonzalez, Deyarina 2019. Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer. Journal for ImmunoTherapy of Cancer 7 (1) , 280. 10.1186/s40425-019-0765-z

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Abstract

Background The 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. Methods A 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. Results We 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. Conclusions These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
ISSN: 2051-1426
Date of First Compliant Deposit: 11 November 2019
Date of Acceptance: 5 October 2019
Last Modified: 30 May 2020 16:16
URI: http://orca-mwe.cf.ac.uk/id/eprint/126705

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