FDA approved PEGylated Products
Most are PEGylated proteins and one is a PEGylated aptamer (Macugen®) administered intravitreally. The PEG components of these biopharmaceuticals vary widely in size, branching structure and attachment type.
Table 1 Marketed PEGylated Products.
Functional Group on PEG: Succinimidyl ester; Aldehyde; Maleimide
Adagen® & Oncaspar® First 2 marketed PEG protein products through PEGylation technique are pegademase (Adagen®) and pegaspargase (Oncaspar®), which results in a stable amide linkage of multiple PEGs attached to the protein ε-lysines. Information on toxicities of these two pharmaceuticals was not available on the FDA web pages.
Krystexxa® Krystexxa® (Pegloticase) is mammalian engineered uricase (urate oxidase) used to treat gout. Humans do not naturally have the enzyme, and nonmammalian sources of the enzyme are highly immunogenic. PEGylation of the mammalian-derived enzyme may reduce some of the immunogenicity but does not eliminate it completely.
PEG-Intron® PEG-Intron®, a mono-PEGylated INF-a2b, is synthesized by using a succinimidyl carbonate PEG with12 kDa. The mPEG reagent forms a covalent carbamate and/or urethane linker with amine groups on the protein. The PEG-Intron® consists of 14 positional isomers and the distribution of positional isomers is dependent on the PEGylation reaction pH value.
Pegasys® Pegasys® (PEG INF-a2a) is mono-PEGylated with a single 40-kDa branched PEG, consisting of 4 major positional isomers, Lys31, Lys121, Lys131, and Lys134, which is approved for the treatment of patients with chronic hepatitis C or chronic hepatitis B. The branching PEG structure, as shown on the left, was achieved by using lysine to link the 2 PEG chains.
Mircera® Pegasys® (PEG INF-a2a) is mono-PEGylated with a single 40-kDa branched PEG, consisting of 4 major positional isomers, Lys31, Lys121, Lys131, and Lys134, which is approved for the treatment of patients with chronic hepatitis C or chronic hepatitis B. The branching PEG structure, as shown on the left, was achieved by using lysine to link the 2 PEG chains.
Mircera® Mircera® (mPEG-Epoetin Beta) is a mono-PEGylated extended half-life version using mPEG succinimidyl butanoate (30 kDa PEG). PEGylation occurs primarily at Lys 52 and Lys 56.
Omontys® (Recalled in 2014) Omontys® (Peginesitide), is a PEGylated peptide that has no sequence homology to erythropoietin. It consists of 2 identical 21 amino acid chains peptides, covalently bound via a linker to a 40-kDa lysine branched PEG for a 45 kDa overall size. The structure of Omontys® is unique in that a linker comprised iminodiacetic acid and b alanine is used to connect the 2 peptides creating a peptide dimer. The peptide dimer is then connected by a single coupling point to the branches, which guarantee the construction of the linker only have one positional isomer.
Macugen® Macugen® (Pegaptanib) is a PEGylated 28 nucleotide aptamer for intravitreal treatment of wet age-related macular degeneration in the eye. Aptamers generally have a short half-life in vivo as they are subject to cleavage by nucleases. PEG, in this case, is a good modifier to to make them suitable for a pharmaceutical product. The candidate which was most effective at inhibiting in vivo vascular leakage (guinea pig model) was chosen for PEGylation with a single 40-kDa lysine branched PEG attached to an amine at the 5’ end.
Neulasta® Neulasta® (Pegfilgrastim) is a PEGylated form of recombinant human granulocyte colony-stimulating factor (GCSF) and was approved for the treatment of neutropenia. Neulasta® is made with 20-kDa PEG and application of aldehyde chemistry using selective N terminal amine conjugation at low pH.
Plegridy® Plegridy® (Peginterferon Beta-1) is an INF beta-1a to which a single, linear 20 kDa mPEG-O-2-methylpropionaldehyde molecule (as shown in the left) is covalently attached to the α-NH2 group of amino acid residue via reductive amination with sodium cyanoborohydride. The non-PEGylated IFN b-1a is also marketed under the name Avonex® (IFN b-1a) for the same indication.
Cimzia® Cimzia® (Certolizumab Pegol) has an engineered thiol for PEGylation, which is the only thiol-engineered PEG conjugate currently marketed. Coupling chemistries that bind PEG to free thiol groups in the protein yield a disulfide linked conjugate. Thiol-reactive agents may provide site-selective PEGylation limiting the number of positional isomers.
Source: https://peg.bocsci.com/resources/fda-approved-pegylated-products.html