{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:06:25Z","timestamp":1793286385638,"version":"4.5.0"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Nb\n                      <jats:sub>457<\/jats:sub>\n                      is a novel anti-CD4 nanobody derived from a CD4-immunized alpaca, exhibiting high potency and broad-spectrum activity against HIV-1. This study aims to use pharmacokinetic-pharmacodynamic (PK-PD) modeling that characterizes the time-course of Nb\n                      <jats:sub>457<\/jats:sub>\n                      trimeric nanobody Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      and viral load in mice. The serum concentrations of Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      and HIV-1 load were modeled using a target-mediated drug disposition (TMDD) PK-PD model following intraperitoneal and subcutaneous administration of 400 \u00b5g in mice. All model parameters were estimated with high precision, with relative standard errors below 50%. The TMDD PK-PD model successfully captured the observed PK\/PD profiles, demonstrating the strong therapeutic potential of Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      for HIV-1 treatment. Furthermore, the model was extrapolated to assess the feasibility of Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      for HIV-1 treatment in humans. The simulated viral growth trajectories at a dose of 20 mg\/kg once every 2 days resulted in a downward trend in the slope of the viral trajectory, suggesting a failure to maintain replication and ultimately leading to viral suppression. Additionally, increasing the dosage or frequency of administration could further enhance the inhibition of viral replication. The simulated human PK-PD supports Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      as a promising anti-HIV-1 agent. This mechanistic TMDD PK-PD model provides a valuable tool to support the clinical development of Nb\n                      <jats:sub>457<\/jats:sub>\n                      -Nb\n                      <jats:sub>HSA<\/jats:sub>\n                      -Nb\n                      <jats:sub>457<\/jats:sub>\n                      by enabling simulations of various dosing strategies to evaluate its efficacy and safety.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>HIV-1 continues to pose a global health crisis, with millions of individuals depending on lifelong antiretroviral therapy, which faces significant challenges such as drug resistance and adherence issues. Nanobodies, which are small antibody fragments, present a promising alternative due to their high specificity, stability, and ease of production. Our study introduces Nb457-NbHSA-Nb457, a novel trimeric nanobody engineered to block HIV-1 entry by binding to CD4, the primary receptor for the virus. Using advanced pharmacokinetic-pharmacodynamic modeling, we predict the behavior of this therapy in humans, effectively bridging preclinical findings to clinical application. This research not only advances a new class of HIV therapeutics but also establishes a framework to expedite the development of nanobody-based drugs for infectious diseases, offering hope for simpler and more effective treatments to combat the pandemic.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00805-25","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T13:01:36Z","timestamp":1758286896000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacokinetic-pharmacodynamic modeling of a highly potent and broadly neutralizing anti-CD4 trimeric nanobody to inhibit HIV-1 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