Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7, 21-39

Department of Emergency Medicine, Brown Medical School, 593 Eddy Street, Providence, Rhode Island 02093, USA.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 02/2008; 7(1):21-39. DOI: 10.1038/nrd2399
Source: PubMed

ABSTRACT Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

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    • "Considering their effects on translation, SINEUPs may definitely find applications in protein manufacturing. More than 130 therapeutic proteins are currently in use and many more are under development, including antibodies (Leader et al., 2008; Matasci et al., 2008). Most production strategies have concentrated efforts in optimizing culture conditions and transcription of recombinant genes leaving room for improvement at post-transcriptional level (Lai et al., 2013). "
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    ABSTRACT: Whenever the function of a recombinant protein depends on post-translational processing, mammalian cells become an indispensable tool for their production. This is particularly true for biologics and therapeutic monoclonal antibodies (MAbs). Despite some drawbacks, Chinese Hamster Ovary (CHO) cells are the workhorse for MAbs production in academia and industry. Several methodologies have been adopted to improve expression and stability, including methods based on selective pressure or cell engineering. We have previously identified SINEUPs as a new functional class of natural and synthetic long non-coding RNAs that through the activity of an inverted SINEB2 element are able to promote translation of partially overlapping sense coding mRNAs. Here we show that by taking advantage of their modular structure, synthetic SINEUPs can be designed to increase production of secreted proteins. Furthermore, by experimentally validating antisense to elastin (AS-eln) RNA as a natural SINEUP, we show that SINEUP-mediated control may target extracellular proteins. These results lead us to propose synthetic SINEUPs as new versatile tools to optimize production of secreted proteins in manufacturing pipelines and natural SINEUPs as new regulatory RNAs in the secretory pathways. Copyright © 2015. Published by Elsevier B.V.
    Gene 06/2015; DOI:10.1016/j.gene.2015.05.070 · 2.08 Impact Factor
    • "The interaction between proteins and polyelectrolytes has been receiving increasing attention in pharmaceutical sciences because of the growing importance of protein drugs [1]. The latter is mainly related to their specificity and the lack of toxic metabolites, resulting in considerably less interference with untargeted biological processes and, hence, less adverse effects and increased clinical efficiency [2]. Successfully developing protein drugs, however, requires the availability of highly pure protein batches as well as suitable formulations that guarantee the physical and chemical stability of the protein [3] [4] [5] until its delivery at the target site. "
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    ABSTRACT: The purpose of this study was to investigate the formation and growth kinetics of complexes between proteins and oppositely charged polyelectrolytes. Equal volumes of IgG and dextran sulfate (DS) solutions, 0.01 mg/ml each in 10 mM phosphate, pH 6.2, were mixed. At different time points, samples were taken and analyzed by nanoparticle tracking analysis (NTA), Micro-Flow Imaging (MFI) and size-exclusion chromatography (SEC). SEC showed a huge drop in monomer content (approximately 85%) already 2 minutes after mixing, while a very high nanoparticle (size up to 500 nm) concentration (ca. 9x10(8)/mL) was detected by NTA. The nanoparticle concentration gradually decreased over time, while the average particle size increased. After a lag time of about 1.5 h, a steady increase in microparticles was measured by MFI. The microparticle concentration kept increasing up to about 1.5x10(6)/mL until it started to slightly decrease after 10 h. The average size of the microparticles remained in the low-μm range (1-2 μm) with a slight increase and broadening of the size distribution in time. The experimental data could be fitted with Smoluchowski's perikinetic coagulation model, which was validated by studying particle growth kinetics in IgG:DS mixtures of different concentrations. In conclusion, the combination of NTA and MFI provided novel insight into the kinetics and mechanism of protein-polyelectrolyte complex formation. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 04/2015; 93. DOI:10.1016/j.ejpb.2015.04.021 · 4.25 Impact Factor
    • "Since their first production in 1975 [1], monoclonal antibodies (mAbs) have become powerful tools in basic research and increasingly have gained prominence in diagnosis and therapy [2] [3]. For the latter purposes, large amounts of pure mAbs need to be purified to high stringency. "
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    ABSTRACT: The application of several pyridine-based compounds as immobilised ligands has been investigated for the purification of monoclonal antibodies via mixed mode chromatography. The ligands employed were 4′-terpyridinysulfanylethylamine (4′-TerPSEA), 5-bromo-2-pyridinylsulfanylethylamine (5-Br-2-PSEA), 2-quinolinylsulfanylethylamine (2-QSEA) and 4-pyridinylsulfanylethylamine (4-PSEA). The performance attributes of adsorbents, derived from the immobilisation of these different ligands onto Sepharose 6 Fast Flow™, was evaluated from batch adsorption studies and from chromatographic experiments with humanised IgG1, IgG2 and IgG4 monoclonal antibodies produced by stable CHO cell lines cultured in chemical defined media. These results demonstrated that monoclonal antibodies of different subclasses can be efficiently purified from crude CHO cell culture supernatants using these new chemical affinity chromatographic systems. Moreover, the majority of the CHO host proteins could be eliminated during the chromatographic purification step with these resins, as monitored by a specific ELISA assay.
    Separation and Purification Technology 03/2015; 142:332-339. DOI:10.1016/j.seppur.2015.01.006 · 3.07 Impact Factor
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