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Curia signs license agreement with MilliporeSigma to support production of proteins and antibodiesALBANY, N.Y., June 20, 2023 (GLOBE NEWSWIRE) -- Curia, a leading contract research, development and manufacturing organization, today announced it has signed a licensing agreement with MilliporeSigma, the North American Life Sciences Business of Merck KGaA, Darmstadt, Germany, that enables Curia and its clients to use the CHOZN® GS-/- cell line for production of therapeutic proteins and antibodies. Following the agreement, the CHOZN GS-/- cell line has been integrated into Curia’s cell line development workflow and is immediately available to Curia customers. CHOZN® platform is a Chinese Hamster Ovary (CHO) mammalian cell expression system that allows for faster, simpler selection and scale-up of high-producing clones for production of biologics and therapeutic recombinant proteins. It includes high-performing CHO cell lines, paired media and feeds, optimized expression vectors and robust protocols. The glutamine synthetase GS knockout (GS-/-) cell line of the CHOZN platform is specially designed to help streamline selection, identification and scale-up of high-producing clones ideal for GMP manufacturing of recombinant protein drugs. “We continue to strengthen our biologics development offerings from discovery through clinical manufacturing,” said Christopher Conway, President R&D, Curia. “The CHOZN GS-/- cell line platform adds a widely accepted and commercially viable cell line to our capabilities. Our integrated offering accelerates therapeutic protein and antibody production and offers seamless tech transfer for optimal flexibility.” Curia’s protein and antibody development experts offer a track record of accelerating progress, with a timeline in as little as 12 months from cell line development to phase I drug substance, depending on the manufacturability of the candidates. The addition of the CHOZN platform strengthens Curia’s offerings as a complement to its existing proprietary CHO cell line, providing customers with a highly versatile and broadly applicable solution. About CuriaCuria is a leading contract research, development, and manufacturing organization providing products and services from R&D through commercial manufacturing to pharmaceutical and biopharmaceutical customers. Curia’s nearly 4,000 employees at 29 locations across the U.S., Europe, and Asia help its customers advance from curiosity to cure. Learn more at CuriaGlobal.com. Curia Contact Information:Viana Bhagan+1 518 512 2111corporatecommunications@CuriaGlobal.com

Researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Johns Hopkins Medicine researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Scientists have dubbed this type of targeted approach a "prodrug" -- a medicine designed to release its payload in a particular area of the body and in no other areas. The Johns Hopkins-discovered prodrug, called DRP-104 (sirpiglenastat), is in early-stage clinical trials in people with advanced solid tumors. The newly published studies in mice show that the augmented drug preferentially eliminates cancer cells but does not harm healthy cells. A report of their experiments is published November 16 in Science Advances. "Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach. What is unique about our approach is that we utilized a novel chemistry design to create a prodrug that was simultaneously bio-activated in cancer cells but bio-inactivated in healthy tissues such as the gut. This preferential targeting of the payload to cancer cells is now enabling this efficacious class of drugs to be reevaluated safely in people," says study author Barbara Slusher, Ph.D., M.A.S., director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience, medicine and oncology at the Johns Hopkins University School of Medicine. The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine. Co-author Rana Rais, Ph.D., an associate professor of neurology and pharmacology, says, "DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut." Development of this promising class of drugs did not resume until Slusher, Rais and team decided to make chemical modifications to DON. "We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut," says Slusher, who is a member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. "This specific prodrug design made DON targeted to its intended destination (tumor) and have less of an impact on healthy cells elsewhere." For the new study, researchers gave the original DON drug and the souped-up DRP-104 drug to mice implanted with tumors. In mice that received DRP-104, the researchers found 11 times more active drug in the tumor compared with the gastrointestinal tract (gut). Both drugs completely wiped out the tumor, but DON caused more gut toxicity in the mice than DRP-104. Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals Inc, which licensed this new prodrug for clinical development. DRP-104 is in phase I/II clinical trials at sites across the U.S., including the Johns Hopkins Kimmel Cancer Center, for people with advanced-stage solid tumors. Slusher says her Johns Hopkins Drug Discovery lab is also actively looking for other drugs that have failed clinical trials because of toxicity problems. They hope to apply this same prodrug design to medicines for other conditions. This research was funded by the National Institutes of Health's National Cancer Institute and National Institute of Neurological Disorders and Stroke R01CA193895, R01CA229451, R01NS103927, R01CA226765, Bloomberg Kimmel for Cancer Immunotherapy at Johns Hopkins and CureSearch for Children's Cancer. Additional Johns Hopkins authors of the study includeKathryn Lemberg, Lukáš Tenora, Matthew Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie Aguilar, Liang Zhao, Diane Peters, Carolyn Tallon, Rajeev Pandey, Ajit Thomas, Ranjeet Dash, Tanguy Seiwert, Robert Leone and Jonathan Powell. Pavel Majer is from the Academy of Sciences of the Czech Republic. Slusher, Rais, Tenora, Majer, Alt and Powell are inventors on Johns Hopkins University patents covering novel glutamine antagonist prodrugs described in this research. These patents have been licensed to Dracen Pharmaceuticals Inc. Slusher, Rais, Majer and Powell are founders and hold equity in Dracen Pharmaceuticals Inc. Slusher also serves as a scientific consultant to Dracen. Under a license agreement between Dracen Pharmaceuticals, Inc. and the Johns Hopkins University, the University is entitled to royalty distributions related to technology cited in the study and referenced in this story. This arrangement has been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

A new study reveals the oligomeric molecular structure of the MOR-Gal1R complex, a component present in the brain which is involved in the analgesic and addictive effects of certain opioids. A study published in the journal Pharmacological Research reveals the oligomeric molecular structure of the MOR-Gal1R complex, a component present in the brain which is involved in the analgesic and addictive effects of certain opioids. The study includes the participation of the experts Vicent Casadó, Estefanía Moreno and Verònica Casadó-Anguera, from the Molecular Neuropharmacology Research Group of the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB). The study is coordinated by the experts Vicent Casadó (UB-IBUB), Leonardo Pardo (UAB), Leigh Daniel Plant (Boston Northeastern University, United States) and Sergi Ferré (National Institute on Drug Abuse, NIH, United States).This preclinical study, based on the use of cellular models and leading biophysical, biochemical and pharmacological techniques (total internal reflection fluorescence microscopy, TIRF), has been distinguished for its scientific interest in the website of the NIH's National Institute on Drug Abuse. Receptors, macrostructures and pharmacological activity Gal1R and MOR receptors belong to the family of G protein-coupled receptors (GPCRs) that take part in the transduction of different cellular signals and the control of essential cell functions. These structures can form dimers -- homodimers or heterodimers -- that determine functional and pharmacological properties that are different from those of the individual components. The study shows different in vitro evidences that reveal the preference of Gal1R and MOR receptors to form homodimeric complexes (MOR-MOR or Gal1R-Gal1R) in cell cultures when they are expressed separately. When expressed together, tetrameric complexes (heterotetramers) are formed by homodimers of both receptors (MOR-MOR-Gal1R-Gal1R-Gal1R). "This heterotetrameric structure is even more complex because when the homodimers of both receptors join to form the MOR-MOR macrocomplex, the interaction and corresponding signalling is maintained by means of their characteristic G protein (the G protein inhibitory to adenylate cyclase or Gi)," says Vicent Casadó, member of the Department of Biochemistry and Molecular Biomedicine and the IBUB. "However, Gal1R-Gal1R exchanges its characteristic inhibitory G-protein for the adenylyl cyclase-stimulating G-protein (Gs). This higherorder oligomeric complex contains more than 10 protein subunits considering the four receptors, the two heterotrimeric G-proteins and the adenylyl cyclase enzyme on which both G-proteins act to up- or down-regulate the intracellular levels of the cyclic AMP messenger," adds the expert. Determining the molecular characteristics of this macrostructure would explain the molecular mechanism by which the neuropeptide galanin -- which has neurotrophic and neuroprotective properties -- causes a decrease in the release of dopamine into the nucleus accumbens induced by opioids, as described by the same team (Journal of Neuroscience, 2016). "This would be possible because when the Gal1R ligand binds to the heteromer, it activates the Gs protein, which interacts with the same adenylyl cyclase that was inhibited by the MOR-activated Gi protein, so it counteracts the secondary effects that opioid ligands have in activating the MOR receptors in the ventral tegmental area," says researcher Estefanía Moreno, member of the Department of Biochemistry and Molecular Biomedicine and IBUB. Searching for new non-addictive drugs In previous studies, the team from the Faculty of Biology and the IBUB had already showed that the greater proportion of analgesic -- and not euphoric -- effects of methadone administration make this compound the most indicated non-addictive option for the treatment of chronic pain (Journal of Clinical Investigation, 2019). This could be explained by the fact that methadone acts preferentially on MOR receptors when they do not form heteromers with Gal1R receptors, and therefore, its effect is mainly peripheral. "Now, knowing this tetrameric macrostructure of the receptor complex -- in addition to the differential capacities of opioid ligands to activate MOR depending on the formation of oligomeric complexes with other receptors -- will facilitate the future design of opioid drugs that can bind with a greater affinity or can bind more effectively the signal pathways with mu-opioid receptor homodimers than with the MOR-Gal1R heterotetramers," notes researcher Verònica Casadó-Anguera. Specifically, it would be about μ-opioid receptor drugs capable of discriminating between homodimers of these compounds and their heterotetramers with galanin receptors. "It is also possible to design a strategy that combines opioid ligands with Gal1R ligands that bind to the heterotetramer and inhibit the activation of the dopamine system and, therefore, addiction. Thus, these therapies are expected to have a greater analgesic effect and less addictive activity," concluded the research team.