Targeting CD56 with an antibody–drug conjugate in Merkel cell carcinoma
Authors: L. Leiendecker, P.S. Jung, A.C. Obenauf
Journal: British Journal of Dermatology (2021)

Linked Article: Esnault et al. Br J Dermatol 2022; 186:295–306. Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with 5-year survival rates of 50%. The pathogenesis of MCC is associated with either the clonal integration of the Merkel cell polyomavirus (MCV) or ultraviolet radiation-induced genomic alterations. MCV-associated MCCs exhibit a low mutational burden and no recurring oncogenic alterations besides the viral integration in the tumour genome, whereas MCV-negative, ultraviolet radiation-associated MCCs show ˜100-fold higher mutational load with recurrent inactivating mutations in RB1 and TP53.1 However, the mechanisms driving these two independent oncogenic processes are unknown, hindering mechanism-based therapeutic strategies. Conventional treatments such as radio- or chemotherapy have limited and short-lived clinical efficacy.2 Immunotherapy with checkpoint inhibitors, such as anti-programmed death 1 (pembrolizumab) or anti-programmed death ligand 1 (avelumab), has been shown to be effective for MCC treatment, with objective responses rates of 46–56%.3, 4 However, new therapeutic targets are needed for patients who do not respond to, who progress under, or who are not eligible for immunotherapy. In this issue of the BJD, Esnault and colleagues5 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.6 Nine ADCs are currently approved as cancer treatments, including trastuzumab deruxtecan, which reduced the risk of disease progression or death by 72% in patients with HER2-positive breast cancer, demonstrating the great potential of this class of therapies.7 ADCs consist of three main components – an antibody, a linker and a payload – all three influencing the clinical properties.6 Esnault et al. synthesized a novel ADC by linking an already established CD56-specific antibody with a monomethyl auristatin E (MMAE) payload through an innovative bioconjugation process. MMAE is a potent antineoplastic agent that binds to tubulin dimers, thereby inhibiting tubulin polymerization and disrupting mitosis.6 CD56, also known as neural cell adhesion molecule 1 (NCAM1), encodes a cell-surface adhesion protein, expressed primarily in neuronal and haematopoietic lineages.8 Esnault and colleagues report that 66% of their MCC tumours express CD56, independently of MCV integration. They found that cytotoxicity is mediated via cell cycle arrest and cell death in their in vitro models, and observed strongly reduced tumour outgrowth in an in vivo MCC xenograft mouse model. Taking the results together, Adcitmer® is an interesting addition to the growing list of targeted therapies, including inhibitors of mammalian target of rapamycin,9 phosphoinositide 3-kinase9 and lysine-specific demethylase 1,10 that are effective in preclinical MCC models. Given these encouraging results, further studies are needed to evaluate the drug-safety profile of Adcitmer®, particularly its effects on normal, CD56-expressing cell populations, especially natural killer cells and neuronal cell types. Reduced natural killer cell function might influence antitumour and antiviral responses,8 and peripheral neuropathy is a common side-effect in patients treated with MMAE.6 With a favourable drug-safety profile, Adcitmer® should also be considered as a treatment option for other CD56-expressing tumours, such as blastic plasmacytoid dendritic cell neoplasms. As combination therapies are likely to be more effective, it is of interest whether Adcitmer® can stimulate the immune system (e.g. by releasing tumour antigens) to enhance the efficacy of immune checkpoint inhibitors. Lukas Leiendecker: Writing-original draft (equal); Writing-review & editing (equal). Pauline Sophie Jung: Writing-original draft (equal); Writing-review & editing (equal). Anna Christina Obenauf: Writing-original draft (equal); Writing-review & editing (equal).