Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood

• DOI: 10.3389/fimmu.2022.999021
• Publication Date: 2022-09-16T10:28:31Z
• Authors: Corinne J. Smith; Nikki Ross; Ali Kamal; Kevin Y. Kim; Elizabeth Kropf; Pascal Deschatelets; Cedric Francois; William J. Quinn; Inderpal Singh; Anna Majowicz; Federico Mingozzi; Klaudia Kuranda
• Keywords: Adeno-associated virus

AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses significant challenge durability and safety of AAV-mediated therapy. Here, we characterize innate in human whole blood. We identified neutrophils, monocyte-related dendritic cells, monocytes as most prevalent cell subsets able internalize particles, while conventional cells were activated terms CD86 co-stimulatory molecule upregulation. Although low titers (≤1:10) neutralizing antibodies (NAb) blood did not have profound effects on AAV, higher NAb (≥1:100) significantly increased pro-inflammatory cytokine/chemokine secretion, uptake by antigen presenting (APCs) complement activation. Interestingly, both full empty viral particles equally potent inducing activation cytokine secretion. By using compstatin-based C3 C3b inhibitor, APL-9, demonstrated that pathway inhibition lowered levels APCs, uptake, secretion AAV. Together these results suggest pre-existing humoral immunity may contribute trigger adverse responses observed AAV-based therapy, blockade warrant further investigation potential strategy decreasing immunogenicity therapeutics.