139: Imaging-based Anti-HIV Antibody Exposure in Anorectal Tissue Is More Closely Linked to Protective Efficacy During Clinical Prevention Trials

Statement of Purpose, Innovation or Hypothesis: HIV remains a global public health burden with 1.3 million new cases in 2022 alone[1]. Broadly neutralizing antibodies (bNAbs) are a novel class of monoclonal antibodies that bind conserved protein domains on HIV and are of great interest for use as long-acting pre-exposure prophylaxis (PrEP), treatment and cure[2]. Recent PrEP clinical trials of the bnAb VRC01 (i.e., the AMP Trials[3, 4]) established a relationship between plasma exposure, viral susceptibility, and clinical prevention efficacy (PE) indicating that plasma VRC01 levels need to exceed IC80 by 200-fold to confer 90% clinical protection[5]; This discrepancy indicates a disconnect between plasma levels observed to prevent clinical HIV infection and expected inhibitory concentrations. Our group’s positron emission topography (PET) study of VRC01 distribution provides a platform for predicting tissue exposure and corresponding PE. We hypothesize that VRC01 exposure in anorectal tissues, which is the common site of infection in men who have sex with men (MSM), will be more closely linked to PE compared to plasma[6].

Description of Methods & Materials: We have used data from our PET imaging study with ⁸⁹Zr-VRC01 (NCT03729752) to predict expected anorectal tissue exposure during the AMP trials[3, 4]. Ratios of average VRC01 radiotracer uptake in blood and tissue were calculated from PET-based standardized uptake values (SUV) across 5 people without HIV. These tissue to blood ratios were then used to predict PE in an established logistic regression model from the AMP trials and compared to existing plasma-based PE[5, 7]. All analyses were performed in R (version 4.3.1).

Data & Results: Anorectal tissue:blood VRC01 exposure ratios were 0.03 (range: 0.01 to 0.04) across participants as determined from tracer uptake (SUV). As shown in Figure 1, to achieve 90% PE, a VRC01 concentration in anorectal tissue to IC80 ratio of 7.18 (range across participants, n=5: 2.75 to 8.89) is required (Figure 1). This is 28.6-fold lower than the ratio needed in plasma, as predicted by the original clinical AMP trial PKPD models (205.85 VRC01 concentration/IC80).

Interpretation, Conclusion or Significance: Based on these studies, target site VRC01 levels in anorectal tissue are likely more closely linked to clinical PE than plasma concentrations observed during the AMP trials. These findings should be validated using rectal tissue biopsies following VRC01 administration. To our knowledge this is the first PET based PKPD analysis for bnAbs. This approach can be leveraged in future studies to predict PE of bnAbs in development, and is the first step towards a whole body physiologically-based pharmacokinetic (PBPK) analysis of PET data to inform dosing of bnAbs for prevention, treatment and cure.

Disclosures: Timothy J Henrich consults for Roche.

Citations/References: [1] World Health Organization, “Global HIV Programme - HIV data and statistics.” Accessed: Apr. 07, 2024. [Online]. Available: https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/strategic-information/hiv-data-and-statistics. [2] C. G. Rivera et al., “HIV Pre-Exposure Prophylaxis: New and Upcoming Drugs to Address the HIV Epidemic,” Drugs, vol. 83, no. 18, pp. 1677–1698, Dec. 2023, doi: 10.1007/s40265-023-01963-9. [3] P. B. Gilbert et al., “Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition,” Nat Med, vol. 28, no. 9, pp. 1924–1932, Sep. 2022, doi: 10.1038/s41591-022-01953-6. [4] M. J. McElrath et al., “Comprehensive Assessment of HIV Target Cells in the Distal Human Gut Suggests Increasing HIV Susceptibility Toward the Anus,” JAIDS Journal of Acquired Immune Deficiency Syndromes, vol. 63, no. 3, pp. 263–271, Jul. 2013, doi: 10.1097/QAI.0b013e3182898392. [5] L. Corey et al., “Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition,” New England Journal of Medicine, vol. 384, no. 11, pp. 1003–1014, Mar. 2021, doi: 10.1056/NEJMoa2031738. [6] D. R. Beckford-Vera et al., “First-in-human immunoPET imaging of HIV-1 infection using 89Zr-labeled VRC01 broadly neutralizing antibody,” Nat Commun, vol. 13, no. 1, p. 1219, Mar. 2022, doi: 10.1038/s41467-022-28727-5. [7]A. Pegu et al., “A Meta-analysis of Passive Immunization Studies Shows that Serum-Neutralizing Antibody Titer Associates with Protection against SHIV Challenge,” Cell Host Microbe, vol. 26, no. 3, pp. 336-346.e3, Sep. 2019, doi: 10.1016/j.chom.2019.08.014.

Additional Information/Authors: We would like to thank the study participants and the funders of this work: This work was funded by R01AI152932 (Timothy J Henrich, Henry VanBrocklin) and the UCSF Center for AIDS Research (P30AI027763). AD is funded by K23AI162249.’