Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of VRC01 and VRC01LS in People Without HIV in a Phase 1 Clinical Trial (HVTN 116)
Authors: Zhang Lily , Lemos Maria , Astronomo Rena , Narpala Sandeep , Prabhakaran Madhu , Lu Yiwen , Dumond Julie , Mize Greg , Glantz Hayley , Colegrove Hunter , Mann Philipp , Paez Carmen , Hutter Julia , McDermott Andrian , Mascola John , Bekker Linda-Gail , McElrath M. 
Published: February 2025

Objectives: VRC01 [1-3] and VRC01LS [4] are a pair of parental/LS-modified anti-HIV broadly neutralizing IgG1-backboned monoclonal antibodies (mAbs). In HVTN 116, 36 male- and 43 female-sex-at-birth participants received intravenously 1 dose of VRC01 (n=16) or VRC01LS (n=10) at 30 mg/kg, 4 doses of VRC01 at 10 mg/kg (n=23), 30 mg/kg (n=23) every 2 months, or 3 doses of VRC01LS at 30 mg/kg (n=7) every 3 months and were followed for 6 (VRC01) or 12 months (VRC01LS) after the last dose. To gain critical comparative understanding of the impact of the LS-modification on the mAb disposition process, and to aid the planning of future anti-HIV LS-mAb trials, we conducted the first population PK analysis of VRC01/LS concentrations in both serum and rectal tissue, a primary site of HIV transmission.Methods: VRC01/LS concentrations in serum and homogenized rectal biopsies were measured via a Singulex assay, using the anti-idiotypic 5C9 antibody. Total IgG and protein concentrations of the samples were measured with ELISA and Quant-iT Protein assays, respectively. Serum and rectal tissue concentration data were collected at 5-12 timepoints per participant. Serum concentration was described as a 1-compartment model in equilibrium with 1 tissue compartment, where both serum and tissue compartments displayed first-order elimination. The model was parameterized with microconstants to estimate serum volume of distribution, tissue volume of distribution, serum-tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half-life estimates were derived via solving the governing differential equations. Nonlinear mixed effect models with exponential random effects and proportional residual error were used. To account for heterogenicity in the size and mAb amount in rectal tissues, 3 adjustment approaches were considered based on tissue weight, IgG concentration, and protein concentration. Results: The PK model fitted the data well with high concordance between observed and predicted concentrations, and all 3 adjustments rendered consistent estimates of the rate constants for both mAbs. Based on protein-concentration-adjusted data, VRC01LS (vs. VRC01) exhibited ~10-fold higher concentrations over time in both blood and rectal tissues, faster distribution from blood to rectal tissues (K12=0.61 vs 0.13/day), but a similar rate from rectal tissue back to blood (K21 = 0.08 vs. 0.06/day). Median distribution and elimination half-life estimates were, respectively, 3 and 20 days for VRC01, and 1 and 63 days for VRC01LS, in both serum and rectal tissues. No significant differences were observed between sexes in these estimates.Conclusions: Compared to VRC01, VRC01LS had higher concentrations in both blood and rectal tissues, distributed faster from blood to rectal tissue and slower elimination in both compartments. These data support lower dosage and/or less frequent dosing of LS mAb variants in HIV prevention trials.Citations: [1] Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O'Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010 Aug 13;329(5993):856-61. doi: 10.1126/science.1187659.[2] Corey, L.; Gilbert, P.B.; Juraska, M.; Montefiori, D.C.; Morris, L.; Karuna, S.T.; Edupuganti, S.; Mgodi, N.M.; Decamp, A.C.; Rudnicki, E.; et al. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N. Engl. J. Med. 2021, 384, 1003–1014.[3] Seaton, K.E.; Huang, Y.; Karuna, S.; Heptinstall, J.R.; Brackett, C.; Chiong, K.; Zhang, L.; Yates, N.L.; Sampson, M.; Rudnicki, E.; et al. Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. EBioMedicine 2023, 93, 104590.[4] Gaudinski, M.R.; Coates, E.E.; Houser, K.V.; Chen, G.L.; Yamshchikov, G.; Saunders, J.G.; Holman, L.A.; Gordon, I.; Plummer, S.; Hendel, C.S.; et al. Safety and Pharmacokinetics of the Fc-Modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018, 15, e1002493.