September
14,
2017
Allan S. Hoffman, ScD
Professor Emeritus
Department of Bioengineering
University of Washington
The idea to conjugate PEG [poly(ethylene glycol)] to a protein, i.e., to “PEGylate” the protein, was first proposed by Prof. Frank Davis (Rutgers Univ.) in the late 1960s-early 1970s. (1) He wanted to make the new recombinant proteins less immunogenic in our bodies, in order to enhance their circulation and activity lifetimes. He thought that if he could conjugate a hydrophilic polymer to the “new” protein, it might shield the drug and prevent its recognition by the immune system as a foreign molecule. Davis “discovered” mPEG (methoxy-PEG or CH3-O-PEG-OH) in a “company catalog”, and he proposed to conjugate the one, reactive –PEG-OH end group to the protein. Davis’ PhD student, Abraham Abuchowski, carried out his PhD research on the topic of PEGylated proteins. They published their results in J Biol Chem in 1977 (2). A few years later (in 1981) Abuchowski founded the first “PEGylation” company, which he and his colleagues named Enzon®. Two PEGylated drugs that began at Enzon® have become “blockbuster” drugs, with huge sales. These are 1) PEGASYS® a PEGylated Interferon for treatment of chronic hepatitis C (Roche Pharmaceuticals), and 2) Neulasta®, a PEGylated G-CSF for treatment of neutropenia, a condition exhibiting an abnormally low count of neutrophils in the blood (Amgen Pharmaceuticals). The mechanism of protection of biological drug molecules by PEG is related to the entrapment of secondary waters of hydration by the ether oxygen when the PEG molecule is able to form a random coil. Hoffman (3), and Tanaka (4) have studied this phenomenon. It is sensitive to PEG MW, and occurs above a minimum PEG molecular weight of ca. 1500-2000 when the PEG chain is able to form a coil. (3) Recently encountered problems with some PEGylated drug compositions include their enhanced clearance rates from circulation upon a second dose. Antibodies to PEG have been discovered and they may be responsible for such enhanced clearance rates. (5) This lecture will conclude with a brief discussion of the use of other proposed “protective” agents, such as zwitterions (6,7), albumin, hyaluronic acid polymers, and trehalose polymers. (8) Such agents might some day be alternate choices to PEGylation, as a way to extend active drug circulation lifetimes, especially during chronic dosing regimes.
References:
(1) FF Davis, ADDR, 54 (2002) 457-458
(2) A Abuchowski, et al, J Biol Chem, 252 (1977) 3578-3581
(3) AS Hoffman, Acta Biomaterialia, (2016), 40, 1–5
(4) H Kitano, M Tanaka, et al., Langmuir, 2005; 21: 11932–11940
(5) BM Chen, SR Roffler, et al, Anal Chem, 2016, 88, 10661−10666
(6) K Ishihara, K Fukazawa, (2014), RSC Pol. Chem Ser.11, RSC Publ, NY
(7) P Zhang, S Jiang, et al. PNAS, 112 (2015) 12046-12051
(8) N Teremoto, et al, Molecules, 2008, 13, 1773-1816
