Name
Anti-drug antibody responses to AAV-mediated monoclonal antibody expression in a sheep model
Presenter
Erin Howard, University of Guelph
Co-Author(s)
Erin L. Howard 1, Victor Sun 1, Justin Ali 1,Yanlong Pei 1, Leonardo Susta 1, Ami Patel 2, Sarah K. Wootton *1 1 Department of Pathobiology, University of Guelph, Guelph, N1G 2W1, Canada 2 Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom
Abstract Category
Fighting & Responding
Abstract
Vectored immunoprophylaxis (VIP) is an emerging strategy for infectious disease prevention in which viral vectors deliver genes encoding monoclonal antibodies (mAbs), enabling sustained in vivo antibody expression. Adeno-associated virus (AAV) vectors are commonly used for VIP due to their favourable safety profile and ability to mediate long-term transgene expression. However, AAV-VIP studies in non-human primates and humans frequently report loss of mAb expression due to the development of anti-drug antibodies (ADAs) and anti-capsid immune responses. In contrast, prolonged expression of a human anti-Marburg virus mAb (MR191) with minimal ADA formation has been reported in a sheep model, suggesting that host factors, vector properties, and antibody sequence characteristics may influence immunogenicity. To investigate determinants of ADA formation in AAV-VIP, we engineered AAV vectors encoding either MR191 or the highly somatically mutated HIV broadly neutralizing antibody VRC07 and packaged them into AAV6.2FF or AAV8 capsids. Preliminary mouse studies demonstrated higher serum mAb expression for MR191 (AAV6.2FF: 817 ug/mL, AAV8: 476 ug/mL) compared to VRC07 (AAV6.2FF: 25 ug/mL, AAV8: 116 ug/mL). MR191 expression was highest with AAV6.2FF, whereas VRC07 expression was greater with AAV8, suggesting that capsid tropism and tissue targeting may modulate immune responses to highly mutated mAbs. Ongoing studies in sheep will evaluate the impact of antibody sequence divergence, AAV serotype, and host age on mAb expression durability, ADA formation, and vector biodistribution. These findings aim to inform vector and transgene design strategies to improve the longevity and translational potential of AAV-based VIP.