Huang Yunda, Zhang Lily, Lemos Maria P, Astronomo Rena D, Narpala Sandeep, Prabhakaran Madhu, Garcia Nina Marie G, Lu Yiwen, Mize Greg J, Glantz Hayley, Colegrove Hunter, Mann Philipp, Paez Carmen A, Andersen-Nissen Erica, Hutter Julia, Dumond Julie, McDermott Adrian B, Mascola John R, Koup Richard A, Bekker Linda-Gail, McElrath M Juliana
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J Clin Pharmacol. 2025 Jun 8. doi: 10.1002/jcph.70060.
VRC01 and VRC01LS are a pair of parental and LS-modified anti-HIV IgG1-backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose. Using nonlinear mixed-effects models, we conducted the first population pharmacokinetics analysis of VRC01/LS concentrations in serum and rectal tissue, a primary site of HIV transmission. Serum concentration was described as a one-compartment model in equilibrium with one tissue compartment, with first-order elimination in both compartments. The model was parameterized with micro-constants to estimate volumes of distribution for serum and tissue, serum-tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half-life estimates were derived from the governing differential equations. To account for rectal biopsy heterogenicity between individuals, three normalization approaches were used: tissue weight adjusted, IgG concentration adjusted, and protein concentration adjusted. All three approaches rendered consistent estimates. Based on protein-concentration-normalized data, VRC01LS (vs VRC01) exhibited ∼10-fold higher concentrations over time in blood and rectal tissues, and faster blood-to-tissue distribution (K12 = 0.61 vs 0.13/day). Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum.
VRC01和VRC01LS是一对亲本抗体及经LS修饰的、以抗HIV IgG1为骨架的单克隆抗体。在一项1期临床试验（HVTN 116）中，79名未感染HIV的参与者静脉注射一剂VRC01（30 mg/kg，n = 16）或VRC01LS（30 mg/kg，n = 10），每2个月注射四剂VRC01（10 mg/kg，n = 23或30 mg/kg，n = 23），或每3个月注射三剂VRC01LS（30 mg/kg，n = 7）。在最后一剂后，对参与者进行了6个月（VRC01组）或12个月（VRC01LS组）的随访。我们使用非线性混合效应模型，首次对血清和直肠组织（HIV传播的主要部位）中的VRC01/LS浓度进行了群体药代动力学分析。血清浓度被描述为与一个组织隔室处于平衡状态的单室模型，两个隔室均存在一级消除。该模型用微观常数进行参数化，以估计血清和组织的分布容积、血清-组织分布速率（K12、K21）和消除速率常数；分布和消除半衰期估计值由控制微分方程得出。为了考虑个体间直肠活检的异质性，使用了三种归一化方法：组织重量调整、IgG浓度调整和蛋白质浓度调整。所有三种方法得出的估计值一致。基于蛋白质浓度归一化数据，VRC01LS（与VRC01相比）在血液和直肠组织中的浓度随时间高出约10倍，且血液到组织的分布更快（K12 = 0.61对0.13/天）。血清和直肠组织中VRC01的消除半衰期估计中位数为20天，VRC01LS为63天。这些数据支持较低剂量和/或较低给药频率的LS单克隆抗体可能在直肠中提供更直接的HIV暴露防护。
