Safety and Pharmacokinetics of Monoclonal Antibodies VRC07-523LS and PGT121 Administered Subcutaneously for Human Immunodeficiency Virus Prevention

Sharana Mahomed, Nigel Garrett, Edmund V Capparelli, Farzana Osman, Ishana Harkoo, Nonhlanhla Yende-Zuma, Tanuja N Gengiah, Derseree Archary, Natasha Samsunder, Cheryl Baxter, Nonhlanhla N Mkhize, Tandile Modise, Kevin Carlton, Adrian McDermott, Penny L Moore, Quarraisha Abdool Karim, Dan H Barouch, Patricia E Fast, John R Mascola, Julie E Ledgerwood, Lynn Morris, Salim S Abdool Karim, Sharana Mahomed, Nigel Garrett, Edmund V Capparelli, Farzana Osman, Ishana Harkoo, Nonhlanhla Yende-Zuma, Tanuja N Gengiah, Derseree Archary, Natasha Samsunder, Cheryl Baxter, Nonhlanhla N Mkhize, Tandile Modise, Kevin Carlton, Adrian McDermott, Penny L Moore, Quarraisha Abdool Karim, Dan H Barouch, Patricia E Fast, John R Mascola, Julie E Ledgerwood, Lynn Morris, Salim S Abdool Karim

Abstract

Background: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa.

Methods: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals.

Results: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 μg/mL and 3.86 μg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 μg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 μg/mL and 0.22 μg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected.

Conclusions: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

Keywords: HIV; PGT121; VRC07-523LS; antibodies; monoclonal.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Screening and enrollment in the CAPRISA 012A trial. 1After administration of the first dose to the first participant in Group 1, the study team waited 3 days before administering study product to the second participant in Group 1. After administration of the first dose to the second participant, the study team waited a further 3 days before enrolling the remaining participants into Group 1. 2The next 25 participants were thereafter randomly allocated to Groups 2–6 and were randomized to receive study product or placebo at a 4:1 ratio. 3Enrollment into Group 7 occurred once 12-week safety data were reviewed for the first 8 participants enrolled. 4Dose escalation of PGT121 was assessed in group 8. After administration of study product to the first participant in Group 8, there was a safety pause of 3 days, under PSRT oversight, before administering study product to the second participant in the dose group. Once safety was established, the remaining participants were enrolled. 5Dose escalation of VRC07-523LS was assessed in Group 9. After administration of study product to the first participant in Group 9, there was a safety pause of 3 days, under PSRT oversight, before administering study product to the second participant in the dose group. Once safety was established, the remaining participants were enrolled.
Figure 2.
Figure 2.
(A) Observed VRC07-523LS median concentrations after 5, 10, and 20 mg/kg subcutaneous (SC) administrations in the CAPRISA 012A trial and concentrations after 5 mg/kg subcutaneous administration in the VRC605 trial. (B) Observed VRC07-523LS concentrations after 20 mg/kg dosing in Group 9, each colored line represents concentrations for each participant, and the black line represents the median concentration. (C) VRC07-523LS pharmacokinetic simulations at 20 mg/kg showing median antibody concentrations at different dose intervals based on the PopPK model. Table insert shows pharmacokinetic parameters after subcutaneous administrations of VRC07-523LS at 5, 10, and 20 mg/kg. AUC, area under the curve; bnAbs, broadly neutralizing antibodies; CL/F, clearance; Cmax, maximum concentration; SD, standard deviation; Tmax, time taken to reach Cmax.
Figure 3.
Figure 3.
(A) Observed PGT121 median concentrations after 3 and 10 mg/kg subcutaneous (SC) administrations in the CAPRISA 012A trial. (B) Observed PGT121 concentrations after 10 mg/kg dosing in Group 8, each colored line represents concentrations for each participant, and the black line represents the median concentration. (C) PGT121 pharmacokinetic simulations at 20 mg/kg showing median antibody concentrations at different dose intervals based on the PopPK model. Table insert shows pharmacokinetic parameters after 3 and 10 mg/kg subcutaneous administrations of PGT121. AUC, area under the curve; bnAbs, broadly neutralizing antibodies; CL/F, clearance; Cmax, maximum concentration; SD, standard deviation; Tmax, time taken to reach Cmax.

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