C Esnault1,2, V Leblond1, C Martin3, A Desgranges3, C B Baltus3, N Aubrey4, Z Lakhrif4, L Lajoie5,6, L Lantier4, B Clémenceau7,8,9, B Sarma2, J Schrama2, R Houben2, D Schrama2, S Hesbacher2, V Gouilleux-Gruart5, Y Feng10, D Dimitrov11, S Guyétant1,12, P Berthon1, M C Viaud-Massuard3,13, M Samimi1,14, A Touzé1, T Kervarrec1,2,12. 1. Team 'Biologie des Infections à Polyomavirus', ISP UMR 1282, INRAE, Université de Tours, Tours, 37200, France. 2. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, 97080, Germany. 3. McSAF, Tours, 37200, France. 4. Team BIOMAP, ISP UMR 1282, INRAE, Université de Tours, Tours, 37200, France. 5. Team FRAME, GICC EA7501, Université de Tours, Tours, 37200, France. 6. Plateforme Scientifique et Technique, Analyse des Systèmes Biologiques Département des Cytométries, Université de Tours, Tours, 37200, France. 7. CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France. 8. LabEx IGO 'Immunotherapy, Graft, Oncology', Nantes, France. 9. CHU de Nantes, Hôtel Dieu, Nantes, F-44000, France. 10. Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, NCI at Frederick, Frederick, MD, 21702, USA. 11. Protein Interactions Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. 12. Department of Pathology, Université de Tours, CHU de Tours, Chambray-les-Tours, 37170, France. 13. Team IMT, GICC EA7501, Université de Tours, Tours, 37200, France. 14. Department of Dermatology, Université de Tours, CHU de Tours, Chambray-les-Tours, 37170, France.
Abstract
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. OBJECTIVES: To produce and evaluate the therapeutic performance of a new antibody-drug conjugate (Adcitmer® ) targeting CD56 in preclinical models of MCC. METHODS: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56-targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56-targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. RESULTS: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56-targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56-mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. CONCLUSIONS: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors.
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. OBJECTIVES: To produce and evaluate the therapeutic performance of a new antibody-drug conjugate (Adcitmer® ) targeting CD56 in preclinical models of MCC. METHODS: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56-targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56-targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. RESULTS: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56-targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56-mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. CONCLUSIONS: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors.
Authors: S Sowparani; P Mahalakshmi; J Pushpa Sweety; Arul Prakash Francis; U M Dhanalekshmi; N Selvasudha Journal: Mol Neurobiol Date: 2022-07-12 Impact factor: 5.682
Authors: Iván Cheng-Sánchez; Federico Moya-Utrera; Cristina Porras-Alcalá; Juan M López-Romero; Francisco Sarabia Journal: Mar Drugs Date: 2022-07-30 Impact factor: 6.085