Effect of neutralizing sera on factor x-mediated adenovirus serotype 5 gene transfer

Alan L Parker; Simon N Waddington; Suzanne M K Buckley; Jerome Custers; Menzo J E Havenga; Nico van Rooijen; Jaap Goudsmit; John H McVey; Stuart A Nicklin; Andrew H Baker

doi:10.1128/JVI.01878-08

Effect of neutralizing sera on factor x-mediated adenovirus serotype 5 gene transfer

Alan L Parker, Simon N Waddington, Suzanne M K Buckley, Jerome Custers, Menzo J E Havenga, Nico van Rooijen, Jaap Goudsmit, John H McVey, Stuart A Nicklin, Andrew H Baker

Research output: Contribution to journal › Article › peer-review

Abstract

The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based vectors in vitro. Neutralizing activity correlated well with the ability to inhibit Ad5-mediated liver transduction, suggesting that prescreening patient sera in this manner accurately predicts the efficacy of Ad5-based gene therapies. Neutralization in vitro can be partially bypassed by pseudotyping with Ad45 fiber protein, indicating that a proportion of neutralizing antibodies are directed against the Ad5 fiber.

Original language	English
Pages (from-to)	479-83
Number of pages	5
Journal	Journal of Virology
Volume	83
Issue number	1
DOIs	https://doi.org/10.1128/JVI.01878-08
Publication status	Published - Jan 2009

Keywords / Materials (for Non-textual outputs)

Adenoviridae
Cell Line, Tumor
Factor X
Genetic Therapy
Genetic Vectors
Hepatocytes
Humans
Immune Sera
Neutralization Tests
Transduction, Genetic
Virus Attachment

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10.1128/JVI.01878-08

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title = "Effect of neutralizing sera on factor x-mediated adenovirus serotype 5 gene transfer",

abstract = "The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based vectors in vitro. Neutralizing activity correlated well with the ability to inhibit Ad5-mediated liver transduction, suggesting that prescreening patient sera in this manner accurately predicts the efficacy of Ad5-based gene therapies. Neutralization in vitro can be partially bypassed by pseudotyping with Ad45 fiber protein, indicating that a proportion of neutralizing antibodies are directed against the Ad5 fiber.",

keywords = "Adenoviridae, Cell Line, Tumor, Factor X, Genetic Therapy, Genetic Vectors, Hepatocytes, Humans, Immune Sera, Neutralization Tests, Transduction, Genetic, Virus Attachment",

author = "Parker, \{Alan L\} and Waddington, \{Simon N\} and Buckley, \{Suzanne M K\} and Jerome Custers and Havenga, \{Menzo J E\} and \{van Rooijen\}, Nico and Jaap Goudsmit and McVey, \{John H\} and Nicklin, \{Stuart A\} and Baker, \{Andrew H\}",

year = "2009",

month = jan,

doi = "10.1128/JVI.01878-08",

language = "English",

volume = "83",

pages = "479--83",

journal = "Journal of Virology",

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publisher = "American Society for Microbiology",

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T1 - Effect of neutralizing sera on factor x-mediated adenovirus serotype 5 gene transfer

AU - Parker, Alan L

AU - Waddington, Simon N

AU - Buckley, Suzanne M K

AU - Custers, Jerome

AU - Havenga, Menzo J E

AU - van Rooijen, Nico

AU - Goudsmit, Jaap

AU - McVey, John H

AU - Nicklin, Stuart A

AU - Baker, Andrew H

PY - 2009/1

Y1 - 2009/1

N2 - The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based vectors in vitro. Neutralizing activity correlated well with the ability to inhibit Ad5-mediated liver transduction, suggesting that prescreening patient sera in this manner accurately predicts the efficacy of Ad5-based gene therapies. Neutralization in vitro can be partially bypassed by pseudotyping with Ad45 fiber protein, indicating that a proportion of neutralizing antibodies are directed against the Ad5 fiber.

AB - The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based vectors in vitro. Neutralizing activity correlated well with the ability to inhibit Ad5-mediated liver transduction, suggesting that prescreening patient sera in this manner accurately predicts the efficacy of Ad5-based gene therapies. Neutralization in vitro can be partially bypassed by pseudotyping with Ad45 fiber protein, indicating that a proportion of neutralizing antibodies are directed against the Ad5 fiber.

KW - Adenoviridae

KW - Cell Line, Tumor

KW - Factor X

KW - Genetic Therapy

KW - Genetic Vectors

KW - Hepatocytes

KW - Humans

KW - Immune Sera

KW - Neutralization Tests

KW - Transduction, Genetic

KW - Virus Attachment

U2 - 10.1128/JVI.01878-08

DO - 10.1128/JVI.01878-08

M3 - Article

C2 - 18945780

SN - 0022-538X

VL - 83

SP - 479

EP - 483

JO - Journal of Virology

JF - Journal of Virology

IS - 1

ER -

Effect of neutralizing sera on factor x-mediated adenovirus serotype 5 gene transfer

Abstract

Keywords / Materials (for Non-textual outputs)

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