Ximu Li, Mengyao Ma, Ni An, Xiaoxuan Yao, Guzailinuer Yasen, Mingyuan Zhong, Zheng Jin, Zhonggui He, Yongjun Wang, Hongzhuo Liu
{"title":"脂质-雷帕霉素纳米疫苗在生物治疗中克服了抗药物抗体屏障","authors":"Ximu Li, Mengyao Ma, Ni An, Xiaoxuan Yao, Guzailinuer Yasen, Mingyuan Zhong, Zheng Jin, Zhonggui He, Yongjun Wang, Hongzhuo Liu","doi":"10.1021/acsnano.4c11928","DOIUrl":null,"url":null,"abstract":"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<sup>+</sup> 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.","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"18 1","pages":""},"PeriodicalIF":16.0000,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lipid-Rapamycin Nanovaccines Overcome the Antidrug Antibody Barrier in Biologic Therapies\",\"authors\":\"Ximu Li, Mengyao Ma, Ni An, Xiaoxuan Yao, Guzailinuer Yasen, Mingyuan Zhong, Zheng Jin, Zhonggui He, Yongjun Wang, Hongzhuo Liu\",\"doi\":\"10.1021/acsnano.4c11928\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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<sup>+</sup> T cells, natural killer (NK) cells, and NK T cells, preserving the body’s normal immune response to pathogens and tumors. 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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.
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.