Assessment of Immune Responses Against AAV Encoded Transgene Products.

The number of clinical investigations and approved applications of adeno-associated virus (AAV) based transgene product (TP) delivery has grown steadily. There also has been a growing interest in understanding how anti-AAV and anti-TP immune responses affect the safety and efficacy of these gene therapy treatments. While considerations related to anti-AAV immunity have been discussed in other works, this manuscript focuses on the assessment of anti-TP immune responses, including both humoral and cellular responses. The development of anti-TP antibodies or a cytotoxic cellular response may lead to increased clearance of the TP, elimination of AAV-transduced cells, and consequently, affect the overall durability and efficacy of the treatment. Additionally, the binding and neutralization of residual endogenous protein by anti-TP antibodies might further worsen the clinical condition under treatment. Several topics are explored in this manuscript, including immunogenicity risk factors that can be considered when evaluating the overall risk and impact of anti-TP immunogenicity, potential implications of anti-TP immunogenicity, the importance of assessing anti-TP immunogenicity, and the commonly used analytical methodologies. The manuscript proposes an approach to determining the scope of anti-TP immunogenicity assessment for clinical and non-clinical studies, based on the TP nature, other intrinsic and extrinsic risk factors. Authored by a group of scientists involved in AAV-based therapeutic development from various industry organizations, the manuscript aims to provide recommendations and guidance to industry sponsors, academic laboratories, and regulatory agencies working on AAV-based modalities, with the goal of achieving a more consistent approach to the assessment of anti-TP immune response.