1,721,099 research outputs found
Atacicept, a homodimeric fusion protein for the potential treatment of diseases triggered by plasma cells
No full textAtacicept (TACI:Fc5) is a homodimeric fusion protein obtained through recombinant DNA technology being developed by Merck Serono SA, under license from ZymoGenetics Inc, for the potential treatment of B-cell diseases. Atacicept is undergoing phase II/III clinical trials for systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, multiple sclerosis, as well as for several B-cell malignancies
Biologics targeted at TNF: design, production and challenges
Full text linkSeveral biotech-derived drugs aimed at Tumor Necrosis Factor (TNF) have been licensed in the last years, profoundly changing the therapy of several autoimmune diseases based on inflammation, affecting the life of patients and bringing to the market attention the growth potentials of biologics directed at cytokines. The proof of principles that led to the design of these compounds dates back from the nineties, when the involvement of TNF in rheumatoid arthritis was proved by the ability of specific anti-TNF proteins to modulate the inflammatory response in animal models. Monoclonal antibodies aimed at neutralizing the excess TNF were developed with therapeutic purposes, and a chimeric and a full human antibody are now approved for several clinical indications. The design of soluble receptors able to bind and neutralize human TNF paralleled the development of antibodies as therapeutics, and the clinical success of these drugs was achieved by the clever design of a novel recombinant dimeric protein, consisting of the extracellular portion of human TNF receptor linked to the constant portion of a human immunoglobulin. All approved biologics designed to bind and neutralize TNF were obtained through the power of biotechnological methods: the development of these important biopharmaceutical products, their means of production and the challenges they face will be analyzed here in details
Monoclonal antibodies in cancer therapy
No full textThe recent approval of cetuximab and bevacizumab by FDA for the treatment of
metastatic colorectal cancer witnesses the investments of biotech companies in
the development of monoclonal antibodies (Mabs) as cancer therapeutics. Several
analyses point to the growth of the market for these drugs, and forecast an even
higher expansion of sales following completion of several clinical trials, both
of approved Mabs tested for other cancers, and of new Mabs aimed at different
tumor antigens. Not unsurprisingly, the latest additions to the number of
therapeutic Mabs belong to the classes of chimeric and humanized antibodies. A
great effort has been made in the last years to overcome the intrinsic
limitations of the technology used to produce monoclonal antibodies. The
knowledge accumulated in the search of newer ways of production of recombinant
therapeutic proteins is reflected by the number of fully human Mabs in the
pipeline. Moreover, a thorough understanding of the cellular and molecular events
underlying the activity of cancer-aimed antibodies allows the optimisation of
these drugs for the treatment of high incidence solid tumors
Emerging trends and targets in antiviral drug discovery
No full textThe modern paradigm in antiviral drug discovery is exemplified by the therapy of AIDS: the success of HAART in the treatment of patients infected with HIV was made possible by the development of a considerable number of compounds targeted to specific steps of virus replication. The currently combined-therapy regimen exploits drugs aimed at HIV reverse transcriptase (NRTI and NNRTI) and protease (PI), but intensive research in genome sequencing, structural biology and structure-based drug design led to the discovery of newer molecules targeted to other and distinct steps in HIV replication. The “deceptive simplicity” (1) of HIV is in patent contrast with its ability to persistently infect humans: indeed current research regards also cellular targets exploited by the virus, such as the chemokine receptors CCR5 and CXCR4.
Since toxicity and emergence of resistance can lead to failure of therapies, and the development of effective vaccines remains unachieved, AIDS treatment relies still on the search of newer viral targets for newer classes of drugs. Nef is an attractive target, exploited in high-throughput screening, as well as the RNase H activity of reverse transcriptase. Other emerging steps and targets in viral life cycle are the strand transfer events catalyzed by the viral nucleocapsid protein (NC) of HIV, a small basic protein that binds nucleic acids. RNA as a target for novel HIV-1 inhibitors largely proceeded through exploitation of the ligand-induced refolding of the transactivation response element TAR, or by the search of leads for the stem-loop element of Rev-responsible-element (RRE) in HIV.
RNA elements are key players in the replication of other viruses, such as the IRES of hepatitis C (HCV): about 3% of worldwide population is affected by HCV, a chronic infection in the liver that eventually causes cirrhosis and hepatocellular carcinoma. HCV causes now more deaths per year than HIV-1 (2). The concern for this “silent pandemic” led to an intensive research on HCV in the last 10 years, culminating in the recent approval of HCV protease inhibitors. The conspicuous science advancements in HIV field have helped to shape HCV research: despite being different viruses, parallels in HIV and HCV life cycles were drawn (3). It is hoped that the “lessons learned” from HIV drug development could lead to rapid achievements in HCV drug discovery
Dall’evoluzione in vitro alle nanotecnologie: gli aptameri come biosensori
No full textUna nuova frontiera per la ricerca nel campo dei biosensori è stata aperta in anni recenti dall’uso degli aptameri come elementi di riconoscimento molecolare. Gli aptameri sono piccole molecole di DNA o RNA selezionate per legare con elevata affinità un determinato bersaglio, sia esso una molecola semplice oppure una struttura complessa come una proteina o una superficie cellulare. La Selex, acronimo di Systematic Evolution of Ligands by EXponential enrichment, è la metodologia di evoluzione in vitro che permette di ottenere l’aptamero con l’attività specifica desiderata a partire da una libreria di acidi nucleici, sfruttando i principi di variazione, selezione e replicazione.
La Selex è stata resa possibile dagli sviluppi della tecnologia del DNA ricombinante e dal progresso tecnologico che per mezzo della sintesi chimica automatizzata ha permesso di ottenere a costi contenuti librerie combinatoriali di acidi nucleici. Il processo di selezione di individui presenti nella libreria e della loro successiva amplificazione permette di isolare tra molteplici e differenti conformazioni quella con il fenotipo adatto (aptus), coniugando in questo modo chimica e biologia. Gli aptameri selezionati possono poi essere facilmente modificati e funzionalizzati in modo da impiegarli nelle più svariate tecniche di rilevazione e offrire così nuove possibilità di ingegnerizzazione e nanofabbricazione rispetto a quelle fin qui usate nei biosensori convenzionali
Drugs acting on the beta isoform of human topoisomerase II (p180)
No full textTopoisomerase II is the target of several anticancer agents. The discovery of a second enzyme, called topoisomerase II beta, genetically distinct from alpha, prompted the investigation on the different functional roles of the two isoforms. Whereas the first recognized isozyme is essential for life due to its role in chromosome condensation and segregation, beta functions remained elusive, although its importance in neural development is appearing clearer. Topoisomerase II beta is regulated differently than alpha, and its level of expression does not change significantly during cell cycle. The presence of this isoform in non-proliferating cells suggests that drug preferentially aimed at beta may be active in slow growing tumors. Topoisomerase II poisons were hence evaluated in light of their selectivity toward one or the other isozyme, indicating how the beta isoform may represent an important target for selected classes of drugs. Newer compounds were also synthesized and tested for their potential antitumor activity and their topoisomerase II beta poisoning. The literature dealing with "old" and "new" drugs targeted at topoisomerase II is reviewed trying to link, whenever possible, selective poisoning and cytotoxic effects to chemical structures, in the hope to indicate new lead compounds that will contribute to unveil molecular determinants of selectivity
From Proteins to Nucleic Acid-Based Drugs: The Role of Biotech in Anti-VEGF Therapy
No full textCancer cells, by releasing pro-angiogenic factors, stimulate the growth of the thick capillary net necessary for the nourishment of the tumor mass. The battle to defeat cancer uses today different approaches based on the inhibition of pathological angiogenesis: several compounds, either synthetic or biotech, aimed at this complex process, are under development. Vascular endothelial growth factor (VEGF) is considered the main target for an anti-cancer therapy based on angiogenesis inhibition; the goal is to block the interaction between this cytokine and its receptors in order to stop the intracellular signaling pathways leading to endothelium remodeling. FDA recently approved two drugs specifically aimed at VEGF, bevacizumab, a humanized monoclonal antibody, and pegaptinib, a pegylated aptamer with application in ophthalmic pathologies. These two approvals validate anti-VEGF therapy for clinical use, and show how biotech companies are investing on angiogenesis using different approaches, i.e. exploiting protein drugs and oligonucleotide-based therapeutics. Monoclonal antibodies, as well as other high molecular weight products like cytokine-traps, aptamers and short interfering RNA (siRNA), are designed to target VEGF and its receptors. Their design, production and clinical advancement in cancer and other pathological conditions linked to angiogenesis will be specifically addressed in this review
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