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Is it time to change PEGylation of biologic drugs?

Allan S. Hoffman, Professor Hoffman studied at M.I.T., where he received B.S., M.S., and Sc.D. degrees in Chemical Engineering between 1953 and 1957. He taught on the faculty of the Chemical Engineering Department at M.I.T. for a total of ten years. For the past 47 years he has been Professor of Bioengineering and Chemical Engineering at the University of Washington in Seattle, Washington, USA. He is currently Emeritus Professor of Bioengineering at the University of Washington. He recently held a four-year appointment as WCU Distinguished Professor at the Kyungpook National University Medical School in Daegu, South Korea. He is currently an Honorary Professor at: Sichuan University, Chengdu, China; and Aarhus University, Aarhus, Denmark. Prof. Hoffman’s major research interests and activities have been in drug delivery, bioseparations and diagnostic assays, “smart” polymers, biomaterial surfaces and hydrogels. He has published over 400 peer-reviewed articles and is co-inventor on over 30 issued patents. He is co-Editor (along with BD Ratner, FJ Schoen and JE Lemons) of the “Textbook of Biomaterials Science”, Elsevier Publishers, now in its 3rd Edition. Prof. Hoffman was elected President of the US Society for Biomaterials in 1983. In 1990 he was honored by the Society for Biomaterials, Japan with the “Biomaterials Science Prize”, the first time it had ever been given to a foreigner. In 2000 he received the Founder’s Award of the Society for Biomaterials (USA). In 2003 he received the Chandra Sharma Award of the Society for Biomaterials and Artificial Organs of India. He was elected to the US National Academy of Engineering in 2005. In 2006 he was awarded the “International Award” from the Society of Polymer Science, Japan. In 2007 he received the Founder’s Award of the Controlled Release Society (USA). Special symposia have been organized to celebrate his 60th, 70th and 80th birthdays. Four other symposia have been organized by his former Asian students. These have been called “Hoffman Family Symposia” (HFS) and two have been held in Japan, one in Korea, one in Taiwan. A fifth, HFS5, is scheduled to be held in Shanghai, China this October, 2017.

Is it time to change PEGylation of biologic drugs?

Allan S. Hoffman

University of Washington


PEGylation: 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. (1) During the 1970s, Davis’ PhD student, Abraham Abuchowski, carried out his PhD research on the topic of PEGylated proteins. He published his results in J Biol Chem in 1977 (2). A few years later (in 1981) Abuchowski founded the first “PEGylation” company, which he 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 (licensed to 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 (licensed to Amgen Pharmaceuticals). Hoffman (3), and Tanaka (4) have proposed that the mechanism of protection of biological drug molecules by PEG is related to the entrapment of secondary water of hydration by the PEG molecule after it reaches a MW around 2 kD, where it is able to form a random coil. Optimum PEGylation of drugs is also sensitive to the PEG MW range, and works best for PEG molecular weights in the range of ca. 2-20 kD. (5) Antibodies to PEG: 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. (6) Other “protective” molecules: Highly hydrophilic polymers with pendant zwitterion groups have also been shown to provide protection to “fragile” biomolecular drugs. (7) K Ishihara was one of the first to identify the protective properties of zwitterion groups with his early studies of poly(2- methacryloyloxyethylphosphoryl-choline) (“polyMPC”) polymers. (8) I will finish this lecture with a brief review of such other “protective” agents, including albumin, zwitterion polymers, hyaluronic acid polymers and trehalose polymers (9), as alternative choices to PEGylation for extending active drug circulation lifetimes, especially during chronic dosing regimes.


(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) KP Antonsen & AS Hoffman, Chap. 2 in “PEG Chemistry”, Ed, JM Harris, Plenum Press (1992) NYC,
(6) BM Chen, SR Roffler, et al, Anal Chem, 2016, 88, 10661-10666
(7) P Zhang, S Jiang, et al. PNAS, 112 (2015) 12046-12051
(8) K Ishihara, K Fukazawa, (2014), RSC Pol. Chem Ser.11, RSC Publ, NY
(9) N Teremoto, et al, Molecules, 2008, 13, 1773-1816