Dynamic PET imaging predicts broadly neutralizing antibody distribution and HIV prevention efficacy

Area of Science:

• Immunology
• Pharmacology
• Medical Imaging

Background:

• HIV remains a global health challenge despite advances in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP).
• Broadly neutralizing antibodies (bNAbs) show promise as long-acting ART, PrEP, and part of curative HIV regimens, but clinical dose optimization is difficult.
• Current methods for assessing bNAb tissue levels are invasive and impractical.

Purpose of the Study:

• To demonstrate the utility of serial whole-body positron emission tomography (PET) imaging and physiological-based pharmacokinetic (PBPK) modeling for predicting bNAb tissue exposure and prevention efficacy.
• To establish a noninvasive method for determining bNAb penetration relevant to preventing HIV acquisition.

Main Methods:

• Microdosing of the bNAb VRC01 in HIV-negative individuals.
• Serial whole-body PET imaging to track bNAb distribution.
• Physiological-based pharmacokinetic (PBPK) modeling to predict plasma and tissue exposure.
• Analysis of two VRC01 prevention trials.

Main Results:

• PET-PBPK modeling accurately predicted therapeutic plasma and tissue exposure of VRC01.
• A >51-fold anorectal tissue VRC01 level to inhibitory concentration (IC80) target was predicted to achieve 90% prevention efficacy.
• This contrasts with a >200-fold target based on plasma levels from the primary trial analysis.

Conclusions:

• PET-PET imaging coupled with PBPK modeling offers a promising noninvasive approach to assess bNAb tissue penetration.
• This method can provide concentrations more closely linked to preventing HIV acquisition than plasma levels alone.
• These PET-PBPK approaches can facilitate more efficient development and clinical translation of bNAb therapeutics for HIV prevention and treatment.