# Pharmacokinetic-pharmacodynamic modeling of a highly potent and broadly neutralizing anti-CD4 trimeric nanobody to inhibit HIV-1 infection

## TL;DR

A new nanobody called Nb457-NbHSA-Nb457 shows strong potential to inhibit HIV-1 infection, with modeling suggesting it could effectively suppress the virus in humans.

## Contribution

The study introduces a novel trimeric nanobody and demonstrates its therapeutic potential through pharmacokinetic-pharmacodynamic modeling for HIV treatment.

## Key findings

- The TMDD PK-PD model accurately predicted the behavior of Nb457-NbHSA-Nb457 in mice and extrapolated to humans.
- Simulated dosing strategies suggest viral suppression with a 20 mg/kg dose every 2 days.
- Higher dosages or more frequent administration could further inhibit HIV-1 replication.

## Abstract

Nb457 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 Nb457 trimeric nanobody Nb457-NbHSA-Nb457 and viral load in mice. The serum concentrations of Nb457-NbHSA-Nb457 and HIV-1 load were modeled using a target-mediated drug disposition (TMDD) PK-PD model following intraperitoneal and subcutaneous administration of 400 µg 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 Nb457-NbHSA-Nb457 for HIV-1 treatment. Furthermore, the model was extrapolated to assess the feasibility of Nb457-NbHSA-Nb457 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 Nb457-NbHSA-Nb457 as a promising anti-HIV-1 agent. This mechanistic TMDD PK-PD model provides a valuable tool to support the clinical development of Nb457-NbHSA-Nb457 by enabling simulations of various dosing strategies to evaluate its efficacy and safety.

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.