Lipid-Rapamycin Nanovaccines Overcome the Antidrug Antibody Barrier in Biologic Therapies

Antidrug antibodies (ADAs) against biologics present a major challenge for sustained biotherapy, including enzyme replacement therapies and adeno-associated virus (AAV) gene therapies. These antibodies arise from undesirable immune responses, leading to altered pharmacokinetics, reduced efficacy, and adverse reactions. In this study, we introduced a rationally designed lipid-rapamycin (Rapa)-based nanovaccine to restore immune tolerance to biologics and overcome drug resistance. The nanovaccine significantly decreased ADA responses when used in a tolerogenic regimen with keyhole limpet hemocyanin (KLH), uricase, pegylated uricase, and AAV8 vector gene therapy. This approach facilitated three rechallenges with pegylated uricase after a 5 week rest from the nanovaccine, thereby enhancing its urate-lowering efficacy. Furthermore, the nanovaccine allowed for the successful intravenous readministration of AAV8 vector expressing secreted embryonic alkaline phosphatase (AAV8-SEAP), achieving sustained viral DNA and transcript levels in target tissues. The nanovaccine prompted antigen-presenting cells (APCs) in the liver to exhibit dynamic changes in CD80, CD86, MHCII, and PD-L1, which promoted the development of immunoregulatory T cells in response to biologic challenges. Notably, the nanovaccine exerted a minimal impact on CD8⁺ T cells, natural killer (NK) cells, and NK T cells, preserving the body's normal immune response to pathogens and tumors. Overall, the universal nanovaccine addressed biologic resistance by mitigating ADA-related issues, thereby enabling a prolonged therapeutic efficacy for antibodies, proteins, and gene therapies.