PEGylation of Proteins: A Structural Approach - Structural properties of PEGylated proteins could play an increasingly important role in developing optimal therapeutic protein drugs. - BioPharm


PEGylation of Proteins: A Structural Approach
Structural properties of PEGylated proteins could play an increasingly important role in developing optimal therapeutic protein drugs.

BioPharm International
Volume 19, Issue 4


Table 1. Examples of PEGylated protein drugs*
Despite the manufacturing complexity, PEGylated drug conjugates are an attractive delivery system for therapeutic proteins.47 A series of therapeutic PEGylated proteins, ranging from marketed products to pre-clinical studies, is summarized in Table 1. Among the most recent clinically approved PEGylated drugs in the US are PEG-aspargase 48 and PEG-visomant.49 The field is still expanding, with more and more proteins being conjugated with PEG to improve the molecule's properties (Table 2). PEGylated drugs encompass a large range of medical treatments, from enzyme replacement50 to blood substitute, 51 protein and peptide anticancer drugs52,53 , antibody fragments54-56 , cytokines57 , and adenovirus and adenovirus.58

Table 2. Various attempts to PEGylate proteins
Cancer drugs are a main target for therapeutics today.24,59 Various anti-cancer agents have a suboptimal pharmacokinetics profile that necessitates prolonged or repetitive administration. PEGylation of these agents may help overcome these shortcomings without compromising the agents' efficacy. Several such PEGylated agents have been developed and evaluated in patients with oncology-related disorders. Attempts have been made to use PEGylated antibodies54 or enzymes60,61 to treat various types of cancer. Special attention is given to targeting the drug directly to the tumor, with the aim of avoiding the undesirable side effects associated with large amounts of chemotherapeutics, implantable devices, or inter veinous lines directed to the affected area.52,53 Initial studies performed with a PEGylated antibody showed enhanced tumor localization of the drug.54,61

Interferons, the standard treatment for hepatitis C, are an example of the clinical challenges involved in protein therapy.62 Serum concentrations of interferons decay quickly during the initial 24 hours, requiring multiple (three times a week) doses that can contribute to severe side effects. PEGASYS is a PEGylated form of interferon -α2a in which a 40-kDa branched PEG is attached to the protein.9 The result is a structure that lasts in vivo for more than 168 hours (elimination half-life of 77 hours versus 9 hours for the native interferon), and allows a once-a-week subcutaneous injection regimen at a lower effective dose. A Phase 3 study with 271 cirrhotic patients showed 43% of the patients receiving PEGASYS had viral clearance at the end of the 48 week treatment. For inpatients with chronic hepatitis C and cirrhosis, 180 μg PEG-interferon α-2a administered once weekly was shown to be more effective than three million units of standard interferon α-2a administered three times weekly.9 PEGASYS has received regulatory approval for treatment of hepatitis C, illustrating the value of pursuing PEGylation as a methodology for drug delivery.


The fact that several PEGylated proteins are approved for use and more PEGylated protein drugs are currently in clinical trials is proof of the advantages provided by this drug delivery route. As new proteins are designated as potential therapeutics, PEGylation will continue to grow as a viable and important option.

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