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Adenovirus-Antibody Complexes Contributed to Lethal Systemic Inflammation in a Gene Therapy Trial.

Authors
  • Somanathan, Suryanarayan1
  • Calcedo, Roberto1
  • Wilson, James M2
  • 1 Gene Therapy Program, Departments of Medicine and Pediatrics, University of Pennsylvania, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • 2 Gene Therapy Program, Departments of Medicine and Pediatrics, University of Pennsylvania, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA. Electronic address: [email protected]
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Mar 04, 2020
Volume
28
Issue
3
Pages
784–793
Identifiers
DOI: 10.1016/j.ymthe.2020.01.006
PMID: 32035027
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Intra-arterial administration of an adenovirus serotype 5 (Ad5) vector in a gene therapy trial caused lethal, systemic inflammation in subject 019 with ornithine transcarbamylase deficiency. This unanticipated inflammatory response was absent in another subject receiving the same vector dose and in 16 subjects receiving lower vector doses. We hypothesized that an immune memory to a previous natural adenovirus infection enhanced the immune response to high-dose systemic Ad5 vector, causing the exaggerated immune response in subject 019. To investigate this, we found that rabbit polyclonal sera to Ad5 and pooled human immunoglobulin (Ig) inhibited Ad5 vector transduction of non-immune cells in vitro, but enhanced transduction and activation of human dendritic cells (DCs). Sera from approximately 7% of normal human subjects and 50% of patients treated topically with Ad5 vectors enhanced Ad5 transduction and activation of DCs, apparently from formation of Ig-Ad5 immune complexes and binding to DCs through FcγR. Subject 019's blood substantially increased Ad5-vector activation of human DC primary cultures at levels exceeding those from normal subjects. Although this study is based on one event in a single subject, the results implicate a pre-existing humoral immune response to Ad5 in the lethal systemic inflammatory response that occurred in subject 019. Copyright © 2020. Published by Elsevier Inc.

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