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.

Synthesis of naphthyridin-2(1H)-one derivatives via ring expansion of 3-substituted-1H-pyrrolo[2,3-b]pyridin-2(3H)-one derivatives.

The reaction of 3-substituted 1H-pyrrolo[2,3-b]pyridin-2(3H)-one derivatives with sodium azide or azidotrimethylsilane under microwave irradiation provided 3- and 4-amino-naphthyridin-2(1H)-one derivatives through cycloaddition-ring expansion. The insertion of the azide into the α,ß unsaturated carbonyl of 3-substituted pyrrolo[2,3-b]pyridin-2(3H)-one derivatives proceeded via an unusual rearrangement. This methodology provided 39 ring expansion examples in moderate to good yields.

An ion-pairing, reversed-phase liquid chromatography method to assess the cross-contamination of cancer chemotherapy infusions prepared in a dual-operator aseptic isolator.

UNLABELLED: Cytotoxics are usually prepared in a centralized pharmacy unit in a controlled hospital environment. Despite the rigorous operating procedures used for such preparations, contamination is theoretically possible - for example due to vial switches. Therefore products ought to be checked in order to determine whether quality control measures are adequate. Numerous strategies have been applied locally to ensure the safety of both patients and operators but the efficacy of these methodologies has not previously been examined. The aim of this study was to develop an analytical method sensitive enough to detect traces of anti-cancer drugs, in order to evaluate cross-contamination between infusions prepared in a dual-operator isolator in the dedicated pharmacy unit. We developed a high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection to identify and quantify the following seven drugs: 5-Fluorouracil, Cytarabine, Gemcitabine, Irinotecan, Doxorubicin, Epirubicin, and Daunorubicin. We assessed the levels of cross-contamination in 20 random preparations. We achieved separation of the seven drugs in less than 28 min, with a lower limit of quantification capable of detecting cross-contamination. An assessment of 20 preparations revealed no cross-contamination. We developed a reproducible and sensitive HPLC method which could be a potentially useful tool for use in practice. We checked the level of cross-contamination in anti-cancer drug infusions and confirmed that the process in current use was safe. This study is the first to assess cross-contamination in anti-cancer preparations. This work is the first step in an extensive programme of quality control, whose aim is to ensure the safety of both patients and operators. Copyright © 2015 John Wiley & Sons, Ltd. KEY FINDINGS: Development of a reproducible and sensitive HPLC method capable of detecting seven anticancer drugs. This method could be used alongside MS detection, to check for biological contamination of nursing and pharmacy staff with anticancer drugs. No cross-contamination was detected in cancer chemotherapy infusions prepared in a dual-operator aseptic isolator.

Implementation study of patient-ready syringes containing 25 mg/mL methotrexate solution for use in treating ectopic pregnancy.

BACKGROUND: Ectopic pregnancy (EP) is a significant cause of morbidity and mortality during the first trimester of pregnancy. Small unruptured tubal pregnancies can be treated medically with a single dose of methotrexate (MTX). OBJECTIVE: The aim of this study was to evaluate the stability of a 25 mg/mL solution of MTX to devise a secure delivery circuit for the preparation and use of this medication in the management of EP. METHOD: MTX solutions were packaged in polypropylene syringes, stored over an 84-day period, and protected from light either at +2 to +8°C or at 23°C. We assessed the physical and chemical stability of the solutions at various time points over the storage period. A pharmaceutical delivery circuit was implemented that involved the batch preparation of MTX syringes. RESULTS: We show that 25 mg/mL MTX solutions remain stable over an 84-day period under the storage conditions tested. Standard doses were prepared, ranging from 50 mg to 100 mg. The results of this study suggest that MTX syringes can be prepared in advance by the pharmacy, ready to be dispensed at any time that a diagnosis of EP is made. CONCLUSION: The high stability of a 25 mg/mL MTX solution in polypropylene syringes makes it possible to implement a flexible and cost-effective delivery circuit for ready-to-use preparations of this drug, providing 24-hour access and preventing treatment delays.

A stability-indicating, ion-pairing, reversed-phase liquid chromatography method for studies of daunorubicin degradation in i.v. infusion fluids.

A new stability-indicating method based on high-performance liquid chromatography coupled to ultraviolet and evaporative light scattering detection (HPLC-UV-ELSD) was developed for the quantification of daunorubicin. This is an ion-pairing, reversed-phase method. The column was a Synergi MAX-RP C12 4 µm (150 mm × 4.6 mm). The mobile phase was 6.2mM nonafluoropentanoic acid in aqueous solution and acetonitrile under isocratic elution mode. The drug was subjected to oxidation, basic and acid hydrolysis to apply stress conditions. Good resolution was achieved between daunorubicin, related products and all degradation products in an overall analytical run time of approximately 16 min with the parent compound daunorubicin eluting at approximately 8 min. The method was fully validated according to ICH guidelines and SFSTP protocols in terms of accuracy, precision, specificity and linearity. For daunorubicin, the decision criteria selected consisted of the acceptability limits (±3%) and the proportion of results within the calculated tolerance intervals (95%). In conclusion, the proposed analytical procedures were validated over the selected validation domains daunorubicin (0.25-0.45 mg/mL) and shown to provide a very effective method. Physical and chemical stability study was carried out on daunorubicin preparation in our hospital centralized pharmacy unit.

First Mariner Mos1 transposase inhibitors.

We described chemical inhibitors of Mos1 transposition. Some were already known to affect a related prokaryotic transposase (Tn5) or HIV-1 integrase, whereas the other were new compounds in this field. The new compounds were all organized around a bis-(heteroaryl)maleimides scaffold. Their mechanism of action depended on the chemical substitutions on the scaffold. The cross-activity, between HIV-1 integrase and Mos1 transposase, of the new group of inhibitors showed that Mos1 transposase could constitute an excellent surrogate HIV-1 inhibitor screen.