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Effect of pegylation on pharmaceuticals

Nature Reviews Drug Discovery volume 2, pages 214–221 (2003)Cite this article

Key Points

  • Polypeptides that are being discovered by the biotechnology industry hold great promise as new drug candidates to target specific disease symptoms.

  • However, polypeptide drugs are rapidly degraded by proteolytic enzymes and neutralized by antibodies, among other shortcomings. This reduces their half-life and circulation time, thereby limiting their therapeutic effectiveness.

  • Pegylation of polypeptide drugs protects them and improves their pharmacodynamic and pharmacokinetic profiles.

  • The pegylation process attaches repeating units of polyethylene glycol (PEG) to a polypeptide drug. For the past 30 years, scientists have improved various chemistries to build PEG polymers and attach them to a polypeptide drug of choice.

  • Among the first pegylated drugs approved by the FDA in the early 1990s were pegaspargase for leukemia and pegademase for severe combined immunodeficiency disorder. More recently, pegylated drugs for the treatment of hepatitis C, acromegaly, rheumatoid arthritis, neutropenia, various cancers, wound healing, and other disorders either have been approved or are undergoing clinical trials.

  • Researchers will continue to perfect the chemistries employed in pegylation to develop more polypeptide therapeutic products.

Abstract

Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, pegylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance.

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Figure 1: Structural formulae of polyethylene glycol (PEG) molecules.
Figure 2: Method for the activation of PEG molecules.
Figure 3: Reductive amination using PEG–propionaldehyde.
Figure 4: Pharmacokinetic profiles for interferon (IFN)-α2a and 40 kDa polyethylene glycol (PEG)–IFN-α2a.

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Authors and Affiliations

  1. Nektar Therapeutics, 490 Discovery Drive, Huntsville, 35806, Alabama, USA

    J. Milton Harris

  2. Nektar Therapeutics, 150 Industrial Road, San Carlos, 94070, California, USA

    Robert B. Chess

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DATABASES

CancerGov

Acute lymphoblastic leukemia

chronic lymphocytic leukemia

chronic mylogenous leukemia

Online Mendelian Inheritance in Man

Crohn's disease

rheumatoid arthritis

FURTHER INFORMATION

Blood–brain barrier

Glossary

HALF-LIFE

The amount of time it takes for one-half of a drug dose to be lost through biological processes.

SHELF LIFE

The amount of time a stored drug retains its activity.

LIPOSOME

Phospholipid capsules that protect enclosed drugs from degradation.

RETICULOENDOTHELIAL SYSTEM

A community of phagocytic cells of the body, located primarily in the spleen, liver and lymph nodes, that protect against infection.

COMPLEMENT

A complex series of blood proteins whose actions augment the work of antibodies to destroy bacteria, produce inflammation and regulate immune reactions.

PHARMACOKINETICS

The movement of drugs throughout the body, including their absorption, distribution, metabolism and excretion, and the mathematical models that describe these actions.

PHARMACODYNAMICS

Changes in measurable clinical parameters related to a drug, such as increase in antitumour activity, decrease in nausea, or decrease in viral load.

DIOL

PEG with two terminal hydroxyl groups that lead to crosslinking and loss of activity.

THIOL

An–SH group.

HETEROBIFUNCTIONAL

PEGs with two different terminal groups, making them capable of performing different functions.

ACROMEGALY

A disease characterized by abnormal enlargement of the skull, jaw, hands and feet, which is caused by excessive secretion of growth hormone by the pituary gland.

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Harris, J., Chess, R. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2, 214–221 (2003). https://doi.org/10.1038/nrd1033

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