May 03, 2011 psa modification of therapeutic proteins is an attractive alternative to pegylation, given that psa is biodegradable and nonimmunogenic. Alternative therapies for the management of inhibitors. Sitespecific enzymatic polysialylation of therapeutic proteins using bacterial enzymes article pdf available in proceedings of the national academy of sciences 10818. Among the currently developed approaches, glycoengineering is one of the most. For this ready reference, the internationally renowned authority in the field, roland kontermann, has assembled a team of outstanding contributors from industry and academia to convey the worldwide knowledge on modifying therapeutic proteins in order to optimize their pharmacological potential. Polysialic acid polysia is a posttranslational modification found on only a handful of proteins in the central nervous and immune systems. Optimal and consistent protein glycosylation in mammalian. Clinical application of polysialylated deoxyribonuclease and. In vertebrates, polysialic acid psa is typically added to the neural cell. Ashishranjansharma, 1 shyamalkumarkundu, 2 jusuknam, 1 garimasharma, 1 c. Abstracta new protein derivatization method was developed with a block copolymer to reduce the immunogenicity of therapeutic proteins.
Peg molecules and pegprotein conjugates with pegs of below 20 kda are eliminated by renal filtration, while protein conjugates with larger peg molecules are cleared from the body by other pathways, such as liver uptake. Sitespecific polysialylation of an antitumor singlechain fv. Studies upon our own bioprocesses to produce fusion proteins and monoclonal antibodies have shown an intricate relationship between these variables and the resulting protein quality. Besides being a clinically relevant therapeutic protein, a1at is an ideal protein for enzymatic polysialylation because of its wellstudied glycans. The pathway takes advantage of a bacterial cytoplasmic polypeptide.
Glycosylation optimization will improve therapeutic efficacy and is an ongoing goal for researchers in academia and industry alike. Qiurong li therapeutic modulation and reestablishment. Year, volume clinical application of polysialylated. While protein therapeutics are invaluable in managing numerous diseases, many require frequent injections to maintain. Glycoproteomic measurement of sitespecific polysialylation biorxiv. Polysialylation of vertebrate cells using purified pstnm enzymatic.
There are several therapeutic proteins needing increasing of their stability, pharmacokinetic, and pharmacodynamics parameters. Chemical coupling of a variety of polymers to therapeutic proteins has been studied as a way of improving their pharmacokinetics and pharmacodynamics in vivo. This is an open access article distributed under the terms of the creative commons attributionnoncommercialsharealike 3. Sitespecific enzymatic polysialylation of therapeutic proteins using bacterial enzymes. Aggregation problems have been implicated in adverse reactions and other safety issues since the beginning. Bacterial polysts have utility in the modification of therapeutic proteins to improve serum halflife, and the potential for tissue engineering. Engineering polysialylation of scfvs and its effects on. A biosynthetic route for polysialylating proteins in. Controlling glycosylation in fusion protein manufacturing.
This puts further emphasis on the quality and the consistency of the production process to ensure the safety of therapeutic proteins. Additionally, new drugdelivery systems, such as microspheres, liposomes and nano or microparticles, are employed to optimize drug properties. Therapeutic peptides and proteins are often vulnerable to proteolysis in the circulating blood, thus necessitating their administration in increased amounts. Er, and then the golgi, lysosomes, integral membrane proteins, etc. The result is a comprehensive work covering all approaches and aspects of the topic in one handy. Extending in vivo halflife of therapeutic proteins. Structure, function and genetics,probiotics and antimicrobial proteins. To date, polysialylation of therapeutic proteins has only been achieved in vitro by chemical or chemoenzymatic strategies.
Numerous strategies have been employed toward this end, including covalent modification of the proteins. Modulation of antibody pharmacokinetics by chemical polysialylation. Forward looking statements this presentation contains forwardlooking statements, as that term is defined under the private. The oxygen transfer from hydroperoxides to the nucleophilic substrates i n solution is generally accepted as a s.
The sitespecifically polysialylated mfe23 scfv demonstrated up to 30fold improved tumor uptake while displaying favorable tumor. Polysialylation of epo resulted in retention of protein structure and. The nrc has demonstrated the ability of this system to modify three glycoproteins with varying n linked glycan compositions including the human therapeutic proteins alpha1antitrypsin a1at and factor ix, as well as bovine fetuin. Review pegylation of therapeutic proteins simona jevs.
Intrabodies against the polysialyltransferases st8siaii and st8siaiv inhibit polysialylation of ncam in rhabdomyosarcoma tumor cells. Their development benefits from known therapeutic approaches and mechanisms of action. Conjugates have been shown to possess greater stability, lower. We have shown that polysialylation of asparaginase an enzyme used in the treatment of certain forms of leukaemia preserves its activity in the presence of serum at 37 c. Immunodetection can detect protein polysialylation,10, 35, 36 and detection with and without endosialidase treatment allows inference of the presence of psamodified proteins. The natural way to improve the stability and pharmacokinetics of protein and peptide drugs. Polysialylation of a1at was achieved without adversely affecting its function as an elastase inhibitor. Engineering polysialylation of scfvs and its effects on function. Identification of a longeracting experimental therapy in mice and monkeys. Results the bacterial sialyltransferase cstii can modify a variety of nglycan types. Numerous strategies have been employed towards this end, including covalent modification, such as through pegylation the chemical. A bacterial expression platform for production of therapeutic.
The addition of polysia to therapeutic proteins improves pharmacokinetics and reduces immunogenicity. Clinical implications of molecular pegylation on therapeutic proteins. This article has not been copyedited and formatted. Modulation of antibody pharmacokinetics by chemical. This was not a problem for producing insulin and human growth hormone since these proteins do not undergo glycosylation in their natural human form. This problem is further compounded in a pharmaceutical setting as protein drugs are routinely exposed to several destabilizing. Psa modification of therapeutic proteins is an attractive alternative to pegylation, given that psa is biodegradable and nonimmunogenic. Xenetic biosciences presents case study of polyxen.
Georgepriyadoss, 3 sangsoolee, 1 andchiranjibchakraborty 1,4. Glycosylation of therapeutic proteins springerlink. Sitespecific enzymatic polysialylation of therapeutic proteins using. Therapeutic proteins are important tools for the treatment of numerous diseases. Sitespecific enzymatic polysialylation of therapeutic proteins. Biobetters typically are defined as being based on innovative biologics but with improved properties 2. Role of proteins in fitness list of high impact articles. After demonstrating the ability of this system to modify a variety of proteins, the effect of polysialylation on the activity and.
Psa has been chemically conjugated to a few clinically relevant therapeutic proteins and was shown to improve their circulating halflife without adversely affecting their function 10, 11. Pdf clinical application of polysialylated therapeutic proteins. Many of them are innovative therapeutic proteins, but a growing number represent biosimilars and biobetters figure 1 1. Sitespecific enzymatic polysialylation of therapeutic. Smirnov iv1, vorobiev ii, belogurov aa, genkin dd, deyev sm, gabibov ag. May 03, 2011 therapeutic proteins are important tools for the treatment of numerous diseases. One major drawback to the use of proteins as therapeutics is that they often exhibit short in vivo halflives, caused by instability, susceptibility to proteolysis, neutralization. Wakarchuka,b,1 adepartment of molecular and cellular biology, university of guelph, guelph, on, canada n1g 2w1. To investigate if prp directs polysts to ncam1 to facilitate its polysialylation, we made use of the n2a cell model, which was known to lack both polysts. Sitespecific enzymatic polysialylation of therapeutic proteins using bacterial enzymes theresa lindhouta, umar iqbalb, lisa m. Here, a range of novel ncam fusion proteins are presented which aim to refine the technological. Modification with polysialic acidpeg copolymer as a new method.
Based upon polysialylation technology, gre goriadis. Improving the therapeutic efficacy of peptides and proteins. In this work, we develop a biosynthetic pathway for sitespecific polysialylation of recombinant proteins in the cytoplasm of escherichia coli. During their development and administration, proteinbased drugs routinely display suboptimal therapeutic efficacies due to their poor physicochemical and pharmacological properties.
Irreversible aggregation is a major problem for longterm storage stability of therapeutic proteins and for their shipping and handling. These innate liabilities have driven the development of molecular strategies to improve the therapeutic behavior of protein drugs. Gylation of proteins, are not subjected to metabolism, and the elimination mechanism depends on their molecular mass. The pipelines of pharmaceutical companies are full of biological drugs. They demonstrate that this glycan can be produced on two examples of human therapeutic proteins.
Aug 26, 2005 therapeutic peptides and proteins are often vulnerable to proteolysis in the circulating blood, thus necessitating their administration in increased amounts. The polysialylation of a1at did not adversely affect its in vitro inhibition activity against human neutrophil elastase. Among the currently developed approaches, glycoengineering is one of the. Review article next generation delivery system for proteins and genes of therapeutic purpose. As disclosed herein, the addition of watersoluble polymers is one way to improve the properties of therapeutic proteins.
Immunogenicity of therapeutic proteins nephrology dialysis. Pegylation of therapeutic proteins creative pegworks. In vivo polysialylation to enhance the pharmacokinetic. One major drawback to the use of proteins as therapeutics is that they often exhibit short in vivo halflives, caused by instability, susceptibility to proteolysis, neutralization by antibodies, andor clearance from the bloodstream. Numerous strategies have been employed towards this end, including covalent modification, such as through pegylation the chemical addition of chains of polyethylene glycol peg to therapeutic proteins. Nov 29, 2012 for two reasons, therapeutic proteins. Sitespecific polysialylation of an antitumor singlechain. Numerous strategies have been employed towards this end, including covalent modification, such as through pegylation the chemical addition of chains of. Proteins drugs generally display low in vitro molecular stabilities during their pharmaceutical development lifecycle due to their inherently liable structural elements coupled with several innate physical and chemical instabilities. Aug 16, 2012 during their development and administration, proteinbased drugs routinely display suboptimal therapeutic efficacies due to their poor physicochemical and pharmacological properties.
Review article next generation delivery system for. Extending in vivo halflife of therapeutic proteins l11944. This study shows that polysialylation of psarfviii resulted in prolongations of rfviii circulation time and procoagulant activity, together with a favorable nonclinical safety profile of the experimental therapeutic. Chemical polysialylation of recombinant human proteins. Pdf clinical application of polysialylated therapeutic.
The chain length of the polysialic acid addition was optimized by controlling reaction conditions. Controlling glycosylation in fusion protein manufacturing to. Problems were, however, anticipated for many other recombinant proteins with therapeutic value, since most of the human extracellular proteins and even some intra. Clinical implications of molecular pegylation on therapeutic. The polysialylation of a1at resulted in a significantly improved pharmacokinetic profile when the modified proteins were injected into cd1 mice. International therapeutic proteins tasmanian antitoxins. Designing a storage formulation to provide an acceptable shelf life is one of the most challenging tasks in the process of drug development46. The posttranslational modification of therapeutic proteins is one means of improving their circulating halflife, thereby improving their efficiency. Progress has been made in the field of glycobiology since this forum took place, and those updates can be found in articles referenced herein. In certain embodiments of the present disclosure, the polypeptide is exemplified by the following therapeutic proteins. International therapeutic proteins supplies tasmaniaproduced antitoxins, snake antivenins antivenoms and other biologics to corporate and government clients worldwide. Reida,b, jianjun lib, xin liub, maria morenob, and warren w. This demonstration of a platform technology for glycosylation has the potential to improve serum halflife of therapeutic proteins made in bacteria.
Jp2014520094a therapeutic proteins with increased half. A polysialylation technology for enhancing therapeutic proteins and its clinical application pegs boston may 15, 2017 2. Improving the therapeutic efficacy of peptides and. Review article next generation delivery system for proteins. Design of drug with prolonged therapeutic action is one of the rapid developing fields of modern medical science and required implementation of different methods of protein chemistry and molecular biology. However, the future of polysialylation as a means to produce new drug entities that will improve the quality of life in patients treated with a wide range of peptide and protein drugs will depend on whether the present approach is as efficient as existing technologies. Glycoproteomic measurement of sitespecific polysialylation. Pdf sitespecific enzymatic polysialylation of therapeutic. Conjugates have been shown to possess greater stability, lower immunogenicity, and a longer blood circulation time due to the chemicophysical properties of these hydrophilic long chain molecules. Polysialylation of peptides and proteins can circumvent many of the problems encountered in their direct use as therapeutics. In vivo polysialylation to enhance the pharmacokinetic profile of therapeutic proteins and immunomodulation an important factor for the clinical and commercial success of protein based drugs lies in optimal bioavailability, which is a major challenge for pharmaceutical industry. The current physicochemical characterization methods do not allow us to fully predict the biological and clinical properties of biopharmaceuticals.
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