Complement activation by AAV-neutralizing antibody complexes
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Exploris 480
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Mireia Fernandez Ocana
PROVIDER: MSV000091454 | MassIVE | Thu Mar 09 07:43:00 GMT 2023
REPOSITORIES: MassIVE
Publications
Complement Activation by Adeno-Associated Virus-Neutralizing Antibody Complexes.
West Cara C Federspiel Joel D JD Rogers Kara K Khatri Arpana A Rao-Dayton Sheila S Ocana Mireia Fernandez MF Lim Sean S D'Antona Aaron Michael AM Casinghino Sandra S Somanathan Suryanarayan S
Human gene therapy 20230601 11-12
Treatment of monogenetic disorders using vectors based on adeno-associated virus (AAV) is an area of intense interest. AAV is non-pathogenic human virus, and preexisting capsid antibodies are prevalent in the population posing a challenge to the safety and efficacy of AAV-mediated gene therapies. In this study, we investigated the risk of AAV-mediated complement activation when sera from a cohort of human donors were exposed to AAV9 capsid. Seropositive donor sera carrying neutralizing antibodie ...[more]
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Project description:Treatment of monogenetic disorders using vectors based on adeno-associated virus (AAV) is an area of intense interest. AAV is non-pathogenic human virus, and preexisting capsid antibodies are prevalent in the population posing a challenge to the safety and efficacy of AAV-mediated gene therapies. In this study, we investigated the risk of AAV-mediated complement activation when sera from a cohort of human donors were exposed to AAV9 capsid. Seropositive donor sera carrying neutralizing antibodies from a previous environmental exposure activated complement when admixed with AAV9 capsids and complement activation was associated with donors who had higher levels of anti-AAV IgG1 antibodies. These findings were consistent with mass spectrometry analysis that identified increased binding of immunoglobulins and complement factors when AAV9 capsids were admixed with seropositive sera. Finally, complement activation was abrogated after IgG-depletion using affinity columns or serum pretreatment with an IgG degrading enzyme. Overall, these results demonstrate an important role of preexisting neutralizing antibodies in activating complement; a risk that can be mitigated by using adequate immunosuppression strategies when dosing seropositive patients with vector.
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