1,721,195 research outputs found
Pegylation of Biological Molecules and Potential Benefits: Pharmacological Properties of Certolizumab Pegol
No full textPEGylation of biological proteins, defined as the covalent conjugation of proteins with polyethylene glycol (PEG), leads to a number of biopharmaceutical improvements, including increased half-life, increased solubility and reduced aggregation, and reduced immunogenicity. Since their introduction in 1990, PEGylated proteins have significantly improved the management of various chronic diseases, including rheumatoid arthritis (RA) and Crohn's disease. Certolizumab pegol is the only PEGylated anti-tumour necrosis factor (TNF)-α agent. It is a PEGylated, humanised, antigen-binding fragment of an anti-TNF monoclonal antibody. Unlike other anti-TNF agents, it has no crystallisable fragment (Fc) domain. Because of its novel structure, certolizumab pegol may have a different mechanism of action to the other anti-TNF agents, and also has different pharmacodynamic properties, which could possibly translate to a different safety profile. Pharmacodynamic studies have shown that certolizumab pegol binds to TNF with a higher affinity than adalimumab and infliximab. Certolizumab pegol is also more potent at neutralising soluble TNF-mediated signalling than adalimumab and infliximab, and has similar or lesser potency to etanercept. Certolizumab pegol does not cause detrimental in vitro effects such as degranulation, loss of cell integrity, apoptosis, complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Certolizumab pegol may also penetrate more effectively into inflamed arthritic tissue than other anti-TNF agents, and is not actively transported across the placenta during pregnancy. Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics. The pharmacokinetics of certolizumab pegol in patients with RA and Crohn's disease were consistent with pharmacokinetics in healthy volunteers
Polymers for Protein Conjugation
Full text linkPolyethylene glycol (PEG) at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice. Other polymers that are safe, biodegradable and custom-designed have, nevertheless, also been investigated as potential candidates for protein conjugation. This review will focus on natural polymers and synthetic linear polymers that have been used for protein delivery and the results associated with their use. Genetic fusion approaches for the preparation of protein-polypeptide conjugates will be also reviewed and compared with the best known chemical conjugation ones
Polymer-drug conjugation, recent achievementsand general strategies
No full textThe field of drug delivery is fast expanding and its potentials have already been proved by the many products on the market. Among all approaches, polymer conjugation is a well known and widely exploited technique useful to improve therapeutic properties of peptides, proteins, small molecules or oligonucleotides. Polymer conjugated drugs generally exhibit prolonged half-life, higher stability, water solubility, lower immunogenicity and antigenicity and often also specific targeting to tissues or cells. This technology, exploited for the first time in the fifties and sixties, received a great development both for the introduction and study of new and different polymers and for the progresses in the chemical strategies of coupling. Polymer-drug conjugates are already on the market for the treatment of different diseases, demonstrating the potentials of the technology. Furthermore, new polymers, in addition to the most known N-(2-hydroxypropyl)methacrylamide copolymer (HPMA), polyglutamic acid (PGA) and poly(ethylene glycol) (PEG), are continuously investigated and proposed. The review will discuss the most recent achievements in polymer conjugation with special emphasis on PEG application strategies and approved products
PEG conjugates in clinical development or use as anticancer agents: an overview
No full textDuring the almost forty years of PEGylation, several antitumour agents, either proteins, peptides or low molecular weight drugs, have been considered for polymer conjugation but only few entered clinical phase studies. The results from the first clinical trials have shared and improved the knowledge on biodistribution, clearance, mechanism of action and stability of a polymer conjugate in vivo. This has helped to design conjugates with improved features. So far, most of the PEG conjugates comprise of a protein, which in the native form has serious shortcomings that limit the full exploitation of its therapeutic action. The main issues can be short in vivo half-life, instability towards degrading enzymes or immunogenicity. PEGylation proved to be effective in shielding sensitive sites at the protein surface, such as antigenic epitopes and enzymatic degradable sequences, as well as in prolonging the drug half-life by decreasing the kidney clearance. In this review PEG conjugates of proteins or low molecular weight drugs, in clinical development or use as anticancer agents, will be taken into consideration. In the case of PEG-protein derivatives the most represented are depleting enzymes, which act by degrading amino acids essential for cancer cells. Interestingly, PEGylated conjugates have been also considered as adjuvant therapy in many standard anticancer protocols, in this regard the case of PEG-G-CSF and PEG-interferons will be presented
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