IgM-and IgG-cleaving enzyme facilitates AAV gene transfer in AAV-seropositive macaques
- 1Department of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University
- 2Department of Surgery and Department of Molecular Genetics & Microbiology, Duke University School of Medicine
- 3Department of Pathology, University of Miami Miller School of Medicine
Abstract
AAV gene therapy is a promising approach for long-term delivery of antiviral proteins that can control HIV replication, but pre-existing circulating AAV-specific antibodies can preclude successful AAV transduction and pose a challenge for AAV vector re-administration in cases where transgene protein expression falls below effective levels. IceMG is a novel, engineered, dual-function immunoglobulin (Ig)-cleaving enzyme that cleaves human and non-human primate IgM and IgG. Here, we sought to evaluate the ability of IceMG to transiently reduce AAV-specific humoral immunity and facilitate successful AAV transduction and gene transfer in AAV-seropositive, SHIV-infected rhesus and cynomolgus macaques. Intravenous administration of IceMG to macaques resulted in cleavage and transient depletion of circulating IgG and IgM, in contrast to dosing with IdeS, an IgG-specific immunoglobulin-cleaving enzyme, which resulted in cleavage and transient depletion of IgG but not IgM. Dosing of either IceMG or IdeS temporarily decreased SHIV Env-binding IgG plasma concentrations, which were associated with concomitant increases in SHIV plasma viral loads, underscoring the role of Env-specific humoral immunity in SHIV control. Critically, IceMG or IdeS dosing also transiently decreased AAV9-specific neutralizing antibody titers in AAV-seropositive macaques that had previously received AAV9 vectors. Re-dosing macaques with IceMG or IdeS months later reduced circulating intact IgG, SHIV Env-binding IgG titers, and AAV-specific neutralizing antibody titers with similar efficacy as the initial dose. Finally, IceMG administration to macaques prior to AAV9 vector boosting enabled a second round of successful AAV transduction and transgene expression, in contrast to macaques that did not receive IceMG where AAV vector boosting failed to produce detectable transgene. However, AAV vector boosting also led to rebound of AAV-specific neutralizing antibody titers in all macaques, and in some cases, increases in anti-drug antibodies (ADA) targeting the AAV vector transgene protein and subsequent loss of transgene protein from circulation. Overall, these results substantiate the use of Ig-cleaving enzymes as tools to overcome pre-existing AAV humoral immunity, but highlight other challenges that follow AAV vector re-administration, such as resurgence of AAV humoral immunity and AAV transgene-directed ADA.
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BibTeX
@article{wu2026igmand,
title = {{IgM-and IgG-cleaving enzyme facilitates AAV gene transfer in AAV-seropositive macaques}},
author = {Helen L. Wu and Zachary C. Elmore and Mark A. Ochoa and Allyson J. McCullen and Mischa K. Brown and Hannah K. Fisher and Sofia K. Potter and Mary Grace E. Mott and Joshua A. Hull and Sebastian P. Fuchs and Ava Dickinson and Lauren Bailey and Kimberly Armantrout and Christine Shriver-Munsch and Aaron Barber-Axthelm and Scott Hansen and Ronald C. Desrosiers and Aravind Asokan and Jonah B. Sacha},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1966044},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966044/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IgM-and IgG-cleaving enzyme facilitates AAV gene transfer in AAV-seropositive macaques
AU - Helen L. Wu
AU - Zachary C. Elmore
AU - Mark A. Ochoa
AU - Allyson J. McCullen
AU - Mischa K. Brown
AU - Hannah K. Fisher
AU - Sofia K. Potter
AU - Mary Grace E. Mott
AU - Joshua A. Hull
AU - Sebastian P. Fuchs
AU - Ava Dickinson
AU - Lauren Bailey
AU - Kimberly Armantrout
AU - Christine Shriver-Munsch
AU - Aaron Barber-Axthelm
AU - Scott Hansen
AU - Ronald C. Desrosiers
AU - Aravind Asokan
AU - Jonah B. Sacha
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1966044
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1966044/full
AB - AAV gene therapy is a promising approach for long-term delivery of antiviral proteins that can control HIV replication, but pre-existing circulating AAV-specific antibodies can preclude successful AAV transduction and pose a challenge for AAV vector re-administration in cases where transgene protein expression falls below effective levels. IceMG is a novel, engineered, dual-function immunoglobulin (Ig)-cleaving enzyme that cleaves human and non-human primate IgM and IgG. Here, we sought to evaluate the ability of IceMG to transiently reduce AAV-specific humoral immunity and facilitate successful AAV transduction and gene transfer in AAV-seropositive, SHIV-infected rhesus and cynomolgus macaques. Intravenous administration of IceMG to macaques resulted in cleavage and transient depletion of circulating IgG and IgM, in contrast to dosing with IdeS, an IgG-specific immunoglobulin-cleaving enzyme, which resulted in cleavage and transient depletion of IgG but not IgM. Dosing of either IceMG or IdeS temporarily decreased SHIV Env-binding IgG plasma concentrations, which were associated with concomitant increases in SHIV plasma viral loads, underscoring the role of Env-specific humoral immunity in SHIV control. Critically, IceMG or IdeS dosing also transiently decreased AAV9-specific neutralizing antibody titers in AAV-seropositive macaques that had previously received AAV9 vectors. Re-dosing macaques with IceMG or IdeS months later reduced circulating intact IgG, SHIV Env-binding IgG titers, and AAV-specific neutralizing antibody titers with similar efficacy as the initial dose. Finally, IceMG administration to macaques prior to AAV9 vector boosting enabled a second round of successful AAV transduction and transgene expression, in contrast to macaques that did not receive IceMG where AAV vector boosting failed to produce detectable transgene. However, AAV vector boosting also led to rebound of AAV-specific neutralizing antibody titers in all macaques, and in some cases, increases in anti-drug antibodies (ADA) targeting the AAV vector transgene protein and subsequent loss of transgene protein from circulation. Overall, these results substantiate the use of Ig-cleaving enzymes as tools to overcome pre-existing AAV humoral immunity, but highlight other challenges that follow AAV vector re-administration, such as resurgence of AAV humoral immunity and AAV transgene-directed ADA.
SN - 1664-3224
ER -