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Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours. Genmab A/S.

Calcitonin gene-related peptide (CGRP), a 37 amino acid neuropeptide, identified in multiple species, has widespread distribution and expression. CGRP acts through G protein-coupled receptors whose presence and changes in function modulate the peptide′s effects in various tissues. Three receptor subtypes have been identified and CGRP′s signal transduction through the receptors is dependent on two accessory proteins: Receptor activity modifying protein1 (RAMP1) and Receptor component protein (RCP). Several endogenous substances such as glucocorticoids, nitric oxide (NO), nerve growth factors (NGF), and steroid hormones modulate CGRP release and synthesis. Both peptide and non-peptide agonists and antagonists of CGRP receptors are being developed. Also the therapeutic benefits of some antagonists such as BIBN 4096 BS in migraine have been promising. This brief review provides a preliminary understanding of the diverse biological effects of the peptide in various systems. The current status of CGRP and its receptors in many pathophysiological states is not fully explored and future findings are greatly awaited.

Calcitonin gene-related peptide (CGRP), a 37 amino acid neuropeptide, identified in multiple species, has widespread distribution and expression. CGRP acts through G protein-coupled receptors whose presence and changes in function modulate the peptide's effects in various tissues. Three receptor subtypes have been identified and CGRP's signal transduction through the receptors is dependent on two accessory proteins: Receptor activity modifying protein1 (RAMP1) and Receptor component protein (RCP). Several endogenous substances such as glucocorticoids, nitric oxide (NO), nerve growth factors (NGF), and steroid hormones modulate CGRP release and synthesis. Both peptide and non-peptide agonists and antagonists of CGRP receptors are being developed. Also the therapeutic benefits of some antagonists such as BIBN 4096 BS in migraine have been promising. This brief review provides a preliminary understanding of the diverse biological effects of the peptide in various systems. The current status of CGRP and its receptors in many pathophysiological states is not fully explored and future findings are greatly awaited.

This research represents an effort to bridge a critical gap in the knowledge regarding the phenomenon of nitrate tolerance. The first objective was designed to determine if hydrogen peroxide plays a role in the development of nitrate tolerance. Based on current data, one could conclude that nitrate tolerance was associated with decreased endogenous' formation of hydrogen peroxide, which attenuates nitrate tolerance development. Superoxide dismutase mimetics may reduce nitrate tolerance, in part, by increasing the formation of hydrogen peroxide. I have also tested the hypothesis that endogenous calcitonin gene-related peptide (CGRP) affects the process of nitrate tolerance development in blood vessels. The results suggested that nitroglycerin releases CGRP from sensory nerves during the process of desensitization to nitrovasodilators and that interference with either the release or action of endogenous CGRP during this period enhances the extent to which nitrate tolerance occurs. It was further tested whether nitrate tolerance induces a compensatory response involving potassium channels in nitroglycerin-induced smooth muscle relaxation. Findings from these studies provide evidence that (1) an increased expression of large-conductance, calcium-activated potassium channels, BKCa channels may be a mechanism for the NTG-enhanced BKCa current in aortic smooth muscle cells of nitrate-tolerant rats, and (2) the upregulation of BKCa channels in arterial muscle membranes in nitrate tolerance is regarded as a compensatory mechanism for maintaining the vascular relaxation. The results of these studies have definitely improved understanding of the altered cellular mechanisms in nitrate tolerance. Moreover, this information may have important therapeutic implications, inasmuch as the results obtained may suggest new strategies for the development of novel nitrates and like drugs that do not cause tolerance.