Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies.
10-1074
3BNC117
AAV
ADA
HIV-1
NIH45-46
PGT121
anti-drug antibodies
bNAbs
broadly neutralizing antibodies
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
06 03 2019
06 03 2019
Historique:
received:
19
08
2018
revised:
04
01
2019
accepted:
08
01
2019
pmc-release:
06
03
2020
pubmed:
2
2
2019
medline:
18
12
2019
entrez:
2
2
2019
Statut:
ppublish
Résumé
Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs.
Identifiants
pubmed: 30704961
pii: S1525-0016(19)30007-3
doi: 10.1016/j.ymthe.2019.01.004
pmc: PMC6403482
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Immunoglobulin G
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
650-660Subventions
Organisme : NHLBI NIH HHS
ID : UG3 HL147367
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI080324
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI100263
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129868
Pays : United States
Organisme : CCR NIH HHS
ID : HHSN261200800001C
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI098446
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NIAID NIH HHS
ID : F32 AI122980
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI091476
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI126623
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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