"Releasable PEGylation opens new opportunities to capture the inherent benefit of PEG technology, particularly with compounds that are not suitable for permanent PEGylation," said Dr.
PEGylation, or bioconjugation of a therapeutic molecule with poly (ethylene glycol) polymers, is designed to improve the pharmaceutical properties of a drug molecule. Permanent bioconjugation, however, can diminish the pharmacological properties of the modified molecule, owing to an altered structure or function of the bioconjugate when compared to the native molecule. To address this, Enzon has developed the releasable PEGylation technology, wherein PEG polymers are shed via a controlled release mechanism to release the intact parent drug. Releasable PEGs may offer the greatest benefits to smaller molecules, peptides, antibody fragments and analogues of binding scaffold, which are inactivated by the bulky PEG partner, and may also benefit protein therapeutics such as toxins and signal transduction domains.
In the presented data, Enzon explored the modification of IFN-β-1b, a first-line therapy for relapsing-remitting multiple sclerosis, with both permanent and releasable PEGylation. IFN-β-1b clears rapidly following subcutaneous administration and has demonstrated substantial immunogenicity, including generation of neutralizing antibodies. Pharmacokinetic analysis of both permanent and releasable PEG-IFN-β-1b compounds in mice showed a 50-fold to 330-fold increase in area under the curve as compared to native IFN-β-1b, a result which addresses the exposure limitations of the native protein. The data support investigation of the efficacy and other pharmacodynamic properties of the releasable PEGylated conjugates of IFN-β-1b.
Enzon used an anti-TNF-α Fab as a model compound for assessing the benefits of releasable PEG. Anti-TNF-α therapies have utility in rheumatoid arthritis and other autoimmune diseases. In the in vitro binding and efficacy studies of releasable PEG-Fab conjugates, the released Fab had comparable binding affinity to TNF-α as analyzed by
In order to apply permanent PEGylation to sensitive protein molecules, reengineering the parent protein to provide tags for PEG attachment away from functional domains is sometimes performed. In distinction, releasable PEG linkers can react with the primary amine of lysine residues without the need to modify the protein. The releasable PEG drug conjugate will have prolonged half-life compared to the parent drug, and its full biological activity can be realized after the intact drug molecule is released inside the body. Releasable PEG linkers can provide a practical option to improve the pharmaceutical properties of lead protein molecules without the need for reengineering.
About Enzon's Customized PEGylation Linker Technology
PEGylation has successfully been used on various pharmaceutical compounds, including enzymes, peptides and antibodies, to improve their pharmaceutical properties through the chemical attachment of polyethylene glycol (PEG) using our Customized Linker Technology. PEGylation technology employs proprietary chemical linkers designed to either release the native molecule at a controlled rate or provide permanent linkage that will maximize inherent activity of the parent molecule. In some cases, PEGylation can render a compound therapeutically effective, whereas the unmodified form had only limited clinical utility.
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Andrea Rabney Argot Partners212.600.1902 Email Contact Media Contact: Eliza Schleifstein Argot Partners212.600.1902 Email Contact
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