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

Abstract

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.

Antibody–Drug Conjugates as an Emerging Therapy in Oncodermatology

“…Recently, a new CD56-targeting MMAE-conjugated ADC, Adcitmer ® , using a new bioconjugation approach has shown the control of MCC tumor growth in a mouse preclinical model [115].…”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…Then, after ligation of the linker-drug derivative 54 , based on the monomethyl auristatin E ( 3 ) , with the reduced anti-CD30 chimeric immunoglobulin G subclass cAC10 mAb, furnished ADC 55 , whose characterization led to a stable and homogeneous DAR distribution of 4, and excellent stability in the presence of thiol-containing proteins, such as human serum albumin (HSA), and a similar efficacy profile to Adcetris in a Karpas 299 xenograft model of CD30-positive lymphoma, with complete tumor regression in all mice when treated once at 1 mg/kg of 55 [ 112 ] . Encouraged by these results, the authors extended their technology to other antibodies such as trastuzumab (ADC 56 ) and a CD56-targeting antibody (ADC 57 ), which was called Adcitmer [ 113 ]. In the case of 56 , the in vivo evaluation in a BT-474 xenograft mice model of HER2 + breast cancer confirmed its efficacy with complete tumor regression in all mice treated only twice at 5 mg/kg, resulting in more efficacy than the ADC ado-trastuzumab emtansine (T-DM1), which only cured three out of eight mice.…”

Targeting CD56 with an antibody–drug conjugate in Merkel cell carcinoma

“…In this issue of the BJD , Esnault and colleagues 5 investigated a new antibody–drug conjugate (ADC) targeting CD56, named Adcitmer ® , in preclinical MCC models. ADCs enable the delivery of antineoplastic agents to cancer cells by exploiting the expression of cell‐surface antigens specific to cancer cells.…”