Daratumumab infusion reaction rates pre- and post-addition of montelukast to pre-medications

Daratumumab, a CD38-directed monoclonal antibody indicated for multiple myeloma treatment in adult patients, is associated with a high incidence of infusion-related reactions (IRRs). Due to CD38 receptor presence in the lungs, many reactions present similarly to asthma or allergic rhinitis. Montelukast, a leukotriene receptor antagonist, has been hypothesized to reduce daratumumab IRRs due to its efficacy in treating allergic rhinitis and asthma and the presence of leukotriene receptors in the lungs. Recently published data reported daratumumab can be safely administered via rapid rate protocol that reduces infusion time from 195 min to 90 min after completion of two doses. This retrospective, observational cohort study examined 73 patients who received daratumumab in the outpatient setting between December 2015 and April 2020. Patients were included if they were 18 years or older, had an International Classification of Disease (ICD)-10 diagnosis code for multiple myeloma, and received daratumumab intravenously. The primary outcome was a comparison of IRRs between those who did and did not receive montelukast. Secondary outcomes included IRR symptoms, rescue medications utilized for IRRs, and rapid rate administration outcomes. Montelukast use was associated with a lower rate of IRRs (44.4% vs. 65.2%, p = 0.044). Pulmonary IRR symptoms were more common in those who did not receive montelukast. Rapid rate administration of daratumumab did not lead to any IRRs. Adding montelukast as a pre-medication for daratumumab infusions led to a reduction in IRRs, and rapid rate administration was found to be safe after completion of two full doses of daratumumab.

Lipoxygenase (LOX) Pathway: A Promising Target to Combat Cancer

: Leukotrienes are one of the major eicosanoid lipid mediators being produced as a result of oxidative transformation of arachidonic acid. Subsequently, they get converted into various cellular signaling hormones by a series of enzymes of myeloid origin to mediateor debilitate inflammation. Interestingly, the available literature demonstrates the pivotal role of eicosanoids in neurodegenerative, obesity, diabetes, cardiovascular diseases and cancers as well. The aberrant metabolism of arachidonic acid by LOX pathway is a common feature of epithelial derived malignancies and suggests the contributory role of dietary fats in carcinogenesis. The enzymes and receptors of the LOX pathway play a significant role in cell proliferation, differentiation and regulation of apoptosis through multiple signaling pathways and have been reported to be involved in various cancers including prostate, colon, lung and pancreatic cancers. So far, leukotriene receptor antagonists and 5-LOX inhibitors have reached up to the clinical trials for treating various diseases. Keeping its various roles in cancer, the review highlights the components of the leukotriene synthesizing machinery, emerging opportunities for pharmacological intervention, and the probability of considering lipoxygenases and leukotriene receptors as good candidates for clinical chemoprevention studies.

Small-wedge synchrotron and serial XFEL datasets for Cysteinyl leukotriene GPCRs

Structural studies of challenging targets such as G protein-coupled receptors (GPCRs) have accelerated during the last several years due to the development of new approaches, including small-wedge and serial crystallography. Here, we describe the deposition of seven datasets consisting of X-ray diffraction images acquired from lipidic cubic phase (LCP) grown microcrystals of two human GPCRs, Cysteinyl leukotriene receptors 1 and 2 (CysLT1R and CysLT2R), in complex with various antagonists. Five datasets were collected using small-wedge synchrotron crystallography (SWSX) at the European Synchrotron Radiation Facility with multiple crystals under cryo-conditions. Two datasets were collected using X-ray free electron laser (XFEL) serial femtosecond crystallography (SFX) at the Linac Coherent Light Source, with microcrystals delivered at room temperature into the beam within LCP matrix by a viscous media microextrusion injector. All seven datasets have been deposited in the open-access databases Zenodo and CXIDB. Here, we describe sample preparation and annotate crystallization conditions for each partial and full datasets. We also document full processing pipelines and provide wrapper scripts for SWSX and SFX data processing.A Correction to this paper has been published: https://doi.org/10.1038/s41597-020-00759-w

Leukotriene receptors (version 2020.3) in the IUPHAR/BPS Guide to Pharmacology Database

The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [34, 37]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [196] and the vanilloid TRPV1 ligand-gated nonselective cation channel [217]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [37]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [96, 243, 272], GPR17 [57] and GPR99 [168].

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT1R has been used for treating asthma and associated diseases for over two decades, CysLT2R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.