An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration

Linda J Chan; Orlagh M. Feeney; Nathania J. Leong; Victoria M. McLeod; Christopher J H Porter; Charlotte C Williams; Lisa M Kaminskas

doi:10.1021/acs.biomac.7b00794

An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration

Linda J Chan, Orlagh M. Feeney, Nathania J. Leong, Victoria M. McLeod, Christopher J H Porter, Charlotte C Williams, Lisa M Kaminskas

Drug Delivery Disposition & Dynamics

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Abstract

Interferon α2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon α2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct.

Original language	English
Pages (from-to)	2866-2875
Number of pages	10
Journal	Biomacromolecules
Volume	18
Issue number	9
DOIs	https://doi.org/10.1021/acs.biomac.7b00794
Publication status	Published - 11 Sept 2017

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10.1021/acs.biomac.7b00794

117393911-oaAccepted author manuscript, 1.2 MBLicence: Unspecified

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abstract = "Interferon α2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon α2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct.",

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AU - McLeod, Victoria M.

AU - Porter, Christopher J H

AU - Williams, Charlotte C

AU - Kaminskas, Lisa M

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AB - Interferon α2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon α2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct.

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An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration

Abstract

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ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

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An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration

Abstract

UN SDGs

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ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

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