Development of Pegylated Interferons for the Treatment of Chronic Hepatitis C

Abstract

The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound. A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents. Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-alpha for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-alphas, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

“…The addition of a polyethyleneglycol (peg) tail produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility, without affecting therapeutic activity. 60 Changes attributed to IFN pegylation translated into improvement for patients, mainly because of longer intervals between administrations (weekly instead of every 24-48 h). Surprisingly, although pegylation of drugs usually results in a certain decrease in side effects, because of the reduced relative peak concentration after each injection, such benefit was not found for IFN as studies comparing standard versus pegylated IFN in hepatitis and chronic myelogenous leukemia patients showed similar rates of toxicity and treatment withdrawal using one or the other form.…”

Pegylated interferon for treating severe recurrent respiratory papillomatosis in a child: case report

“…7,8 It is only natural to hypothesize that the pegylated form of interferon might be also more effective for treating respiratory papillomatosis than alpha-interferon. Alpha-interferon is an immunomodulatory cytokine with antiviral and antiproliferative properties and was the first widely used adjuvant drug for treating RRP, with diverse results ranging from better prognosis to absence of response.…”

Enhanced aqueous solubility of long wavelength voltage-sensitive dyes by covalent attachment of polyethylene glycol

“…The products showed polydispersity similar to the starting mPEG-amine reagents, but shifted by approximately the mass of the dye. 16 A marked change in the TLC migration of the products from the starting materials, with no change in spectral properties, gave further evidence of dye-PEG conjugation.…”

“…The highly water-soluble PEG derivatives were prepared from different molecular weight aminomethoxy-PEGs (mPEG-NH 2 ) using standard methods and are listed in Table 2. 16,23 The combination of the hydrophilic polymer and the hydrophobic styryl dye made purification of these PEG dyes less straight forward than the sulfonated dyes. On acidic alumina the blue chromophore irreversibly disappeared for PGH-9 derivatives of mPEG molecular weights 2000 to 5000.…”

“…Poly(ethylene glycols) (PEGs) are commonly used to improve the water-solubility of small molecule pharmaceuticals and exhibit water solubility, high mobility in solution, lack of toxicity, lack of immunogenicity, and are readily cleared from the body. 16 Covalent linkage of PEGs to voltage dyes will greatly simplify protocols for probe delivery to excitable tissue. 14 In this report, we present the synthesis and spectral characterization of a set of styryl dyes which fluoresce at near infrared wavelengths.…”