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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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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: 20 Oct 2021 01:20

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