Adcitmer® , a new CD56-targeting monomethyl auristatin E-conjugated antibody, is a potential therapeutic approach in Merkel cell carcinoma.

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.

Magnetic nanocarriers for the specific delivery of siRNA: Contribution of breast cancer cells active targeting for down-regulation efficiency.

The association between superparamagnetic iron oxide nanoparticles (SPION), carrying small interfering RNA (siRNA) as therapeutic agents and humanized anti- human epidermal growth factor receptor-2 (HER2) single-chain antibody fragments (scFv) for the active delivery into HER2-overexpressing cells appears as an interesting approach for patients with HER2-overexpressing advanced breast cancer. The obtained Targeted Stealth Magnetic siRNA Nanovectors (TS-MSN) are formulated by combining: (i) the synthesis protocol of Targeted Stealth Fluorescent Particles (T-SFP) which form the core of TS-MSN and (ii) the formulation protocol allowing the loading of T-SFP with polyplexes (siRNA and cationic polymers). TS-MSN have suitable physico-chemical characteristics for intravenous administration and protect siRNA against enzymatic degradation up to 24 h. The presence of HER2-targeting scFv on TS-MSN allowed an improved internalization (3-4 times more compared to untargeted S-MSN) in HER2-overexpressing breast cancer cells (BT-474). Furthermore, anti-survivin siRNA delivered by TS-MSN in HER2-negative breast-cancer control cells (MDA-MB-231) allowed significant down-regulation of the targeted anti-apoptotic protein of about 70%. This protein down-regulation increased in HER2+ cells to about 90% (compared to 70% with S-MSN in both cell lines) indicating the contribution of the HER2-active targeting. In conclusion, TS-MSN are promising nanocarriers for the specific and efficient delivery of siRNA to HER2-overexpressing breast cancer cells.