FDA approved PEGylated Products

PEGylation has been the most clinically proven half-life extension technology since the early 1990s, and its safety has been demonstrated in humans for more than 30 years. PEGylated drugs are approved in most countries for intravenous, oral, and dermal use in humans. Currently, PEGylation modification can be used to modify proteins and peptides, oligonucleotides, antibody fragments, organic small molecules, and nanoparticles.

Fig. 1. Groups of PEGylated agents based on sizes of PEG and parent drugs (Bioeng Transl Med. 2023, 9(1): e10600).

Because most protein drugs, peptide drugs, and chemical drugs are accompanied by some insurmountable problems when exerting their effects, such as short action cycles, large immunogenicity, and toxic and side effects. Polyethylene glycol is neutral, non-toxic, has unique physical and chemical properties and good biocompatibility, and is one of the few chemical substances approved by the FDA for in vivo injection. Therefore, chemically linking activated polyethylene glycol to proteins, peptides, small molecule drugs and liposomes, that is, PEGylation of drug molecules, can effectively increase the biological half-life of drug molecules and reduce their toxic side effects.

Representative PEGylated Drugs

Since 1990, PEGylated biopharmaceuticals have been introduced into the marketplace as drugs for human use. 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; Biotin; Amine; Azide; Boc/Fmoc; Carboxylic Acid; Cholesterol; DBCO, etc.

What are the Examples of PEGylated Drugs?

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®

PEG-Intron®

Pegasys®

Mircera®

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 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®

Cimzia®

PEG Modification Process

Step1: Before performing PEG modification, you need to find high-purity PEG raw materials and then modify them.

Step2: Activate PEG. PEG modification of proteins is mainly achieved through the reaction of PEG terminal hydroxyl groups with protein amino acid residues. However, PEG terminal hydroxyl groups have very poor activity, so they must be activated with an activator to covalently modify proteins under mild conditions in the body.

Step3: Select appropriate protein amino acid residue sites or small molecule drug sites for site-directed modification. Use activated PEG to carry out site-specific modification of appropriate protein amino acid residues to improve the efficacy of natural proteins.

Step 4: After obtaining the PEG-drug complex, in order to avoid other impurities contained in the complex from adversely affecting the drug efficacy, it is separated and purified to obtain a single complex.

PEG Derivatives by Functional Groups

BOC Sciences offers a variety of PEG products modified with different functional groups to meet specific research needs. Some common functional groups that can be incorporated into PEG molecules include carboxylic acid (-COOH), amine (-NH2), thiol (-SH), and hydroxyl (-OH). For example, BOC Sciences offers PEG products modified with carboxylic acid groups that can be used to conjugate to molecules containing amine groups through the formation of amide bonds. These PEG products can be used in drug delivery systems, protein conjugation, and surface modification of nanoparticles. Similarly, PEG products modified with amine groups can be used to conjugate molecules containing carboxylic acid groups through the formation of amide bonds. These PEG products are commonly used in protein labeling, drug delivery, and bioconjugation applications.

References

1. Gao, Y. et al. PEGylated therapeutics in the clinic. Bioeng Transl Med. 2023, 9(1): e10600.
2. Hamidi, M. et al. Pharmacokinetic consequences of pegylation. Drug delivery. 2006, 13(6): 399-409.
3. Turecek, P.L. et al. PEGylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs. Journal of pharmaceutical sciences. 2016, 105 (2): 460-475.
4. Dozier, J.K. et al. Site-specific PEGylation of therapeutic proteins. International journal of molecular sciences. 2015, 16(10): 25831-25864.