| Autor: |
Esnault, C., Leblond, V., Martin, C., Desgranges, A., Baltus, C.B., Aubrey, N., Lakhrif, Z., Lajoie, L., Lantier, L., Clémenceau, B., Sarma, B., Schrama, J., Houben, R., Schrama, D., Hesbacher, S., Gouilleux‐Gruart, V., Feng, Y., Dimitrov, D., Guyétant, S., Berthon, P. |
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| Zdroj: |
British Journal of Dermatology; Feb2022, Vol. 186 Issue 2, p295-306, 12p |
| Abstrakt: |
Summary: 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. What is already known about this topic? Merkel cell carcinoma (MCC) is an aggressive skin cancer.While immune checkpoint inhibitors constitute a major advance in treating patients with MCC with advanced disease, new therapeutic options are still urgently required.CD56, which is expressed by most MCC tumours, might constitute a therapeutic target for the development of antibody–drug conjugate therapies. What does this study add? We generated a CD56‐targeting monomethyl auristatin E (MMAE) bioconjugate antibody (Adcitmer®) and demonstrated its optimal biochemical properties, specific binding and cytotoxicity in vitro in MCC cell lines, and its capacity to reduce tumour growth in vivo in a MCC mouse model. What is the translational message? Adcitmer®, a new CD56‐targeting MMAE bioconjugate antibody, may represent a potential therapeutic option to be investigated as an alternative approach or in combination with immune checkpoint inhibitors in patients with inoperable MCC. Linked Comment: L. Leiendecker et al. Br J Dermatol 2022; 186:209–210. Plain language summary available online [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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