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.

Do secondary substances in the thallus of a lichen promote CO2 diffusion and prevent depression of net photosynthesis at high water content?

Many lichens show seriously depressed net photosynthesis (NP) at high thallus water contents due to increased carbon dioxide diffusion resistance through blockage of diffusion pathways by water. The soil lichen Diploschistes muscorum, however, shows no depression and NP is close to maximal even at the highest thallus water content. We investigated whether lichen substances (lecanoric and diploschistesic acids) in the cortex and medulla contributed to this ability to maintain high NP. Dry thalli were extracted with water-free acetone and, after this treatment, were found to be fully viable to the extent of continued growth after replanting in the field. No differences were found in the response of NP to thallus water content between the normal and extracted thalli, in fact the response curves were often nearly identical. Thus, in this species it seems that lichen substances did not maintain the water-free diffusion pathways and some other explanation, possibly structural, needs to be sought.

Sequestration of lichen compounds by lichen-feeding members of the Arctiidae (Lepidoptera).

A survey for the presence of sequestered lichen compounds in 103 wild-caught imagines representing eight different genera and 16 different species of the Arctiidae was conducted. Known lichen compounds were detected for the first time in 24 of the analyzed specimens (representing five different genera and 11 different species) based on their HPLC retention times and on their UV-absorption spectra. The anthraquinone parietin, the depside atranorin, as well as a hydrolytic cleavage product of the latter were among the lichen compounds most frequently detected in wild-caught imagines. The observed variation of sequestered lichen compounds in wild-caught imagines with unknown feeding history may be due to several reasons. Lack of lichen compounds in imagines may have been caused, for example, by larvae feeding on lichens with no or only minute amounts of phenolic products. The age of the specimens analyzed may also influence the results obtained. Avoidance of lichen compounds by selective feeding on those parts of lichen thalli that have no or little lichen products may be another reason for the lack of lichen compounds in imagines. Preliminary feeding experiments conducted with larvae ofEilema complana, for example, indicated that the larvae fed exclusively on the algal layer and cortex of the lichenCladonia pyxidata, whereas the medulla, which is rich in fumarprotocetrarie acid, was avoided. As expected, imagines hatching from the larvae were free of this lichen compound. Any ecological role of the sequestered lichen compounds for the herbivores is unknown. It is possible, however, that sequestered lichen compounds may be utilized for the chemical defense of arctiid moths or against microbial pathogens.

Sequestration of lichen compounds by three species of terrestrial snails.

Three species of lichen-grazing snails,Balea perversa, Chondria clienta, andHelicigona lapicida, all from the Swedish island of Öland, were found to sequester lichen compounds when feeding on the crustous lichen speciesAspicila calcarea, Caloplaca flavovirescens, Lecanora muralis, Physcia adscendens, Tephromela atra, andXanthoria parietina. The lichen compounds detected in the soft bodies of the snail species analyzed included the anthraquinone parietin, the depside atranorin, as well as a presumable degradation product of the latter. Other lichen compounds such as (+)-usnic acid or α-collatolic acid were not found in the soft bodies but were only detected in the feces, suggesting selective uptake of lichen compounds by the snails. In individuals ofC. clienta initially fed on the lichenX. parietina, the amount of sequestered parietin decreased over time on a parietin-free diet but was still detectable in the soft bodies after 28 days. In the ovoviviparous land snail,B. perversa, sequestered parietin was transferred from the mother to the eggs in the reproductive tract.