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

• Published in: Journal for immunotherapy of cancer 2019-10, Vol.7 (1), p.280-18, Article 280
• Main Authors: 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, Gonzalez, Deyarina
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antibodies; Antibody drug conjugates; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - pharmacokinetics; Antineoplastic Agents, Immunological - therapeutic use; Backup software; Biological products; Biomarkers; Biomarkers, Tumor; Biopharmaceuticals; Biopsy; Brentuximab vedotin; Cancer; Cancer therapies; Cell Line, Tumor; Chemotherapy; Clinical/Translational Cancer Immunotherapy; Cloning; Cytotoxicity; Disease; Disease Models, Animal; Drug therapy; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - mortality; Endometrial Neoplasms - pathology; Endometrium; Estrogens; Female; Gene Expression; Gynecology; Human; Humans; Hyperplasia; Hysterectomy; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Immunoconjugates - pharmacokinetics; Immunoconjugates - therapeutic use; Immunohistochemistry; Immunotherapy; Inotuzumab ozogamicin; Kinases; Ligands; Medical diagnosis; Mice; Middle Aged; Mortality; Novels; Patients; Peptides; Proteins; Radiotherapy; RAGE; Receptor for Advanced Glycation End Products - antagonists & inhibitors; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Research Article; Surgery; Therapeutic; Therapeutics; Tissue Distribution; Toxicity; Tumors; Ultrasonic imaging; Xenograft Model Antitumor Assays
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-019-0765-z

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