Research Article: Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults

Date Published: January 24, 2018

Publisher: Public Library of Science

Author(s): Martin R. Gaudinski, Emily E. Coates, Katherine V. Houser, Grace L. Chen, Galina Yamshchikov, Jamie G. Saunders, LaSonji A. Holman, Ingelise Gordon, Sarah Plummer, Cynthia S. Hendel, Michelle Conan-Cibotti, Margarita Gomez Lorenzo, Sandra Sitar, Kevin Carlton, Carolyn Laurencot, Robert T. Bailer, Sandeep Narpala, Adrian B. McDermott, Aryan M. Namboodiri, Janardan P. Pandey, Richard M. Schwartz, Zonghui Hu, Richard A. Koup, Edmund Capparelli, Barney S. Graham, John R. Mascola, Julie E. Ledgerwood, Marcus Altfeld

Abstract: BackgroundVRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.Methods and findingsThis Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21–50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7) and 326 ± 35 μg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2) and 25 ± 5 μg/mL (n = 9), respectively. Over the 5–40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions.ConclusionsThe human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection.Trial NCT02599896

Partial Text: Advances in our understanding of the humoral immune responses against HIV-1 have led to the appreciation that broadly reactive neutralizing antibodies arise during the course of infection in some individuals [1–4]. Detailed studies of such donors, including the application of technologies to recover immunoglobulin genes from antigen-specific sorted or cultured B cells, have led to the isolation and characterization of numerous broadly neutralizing monoclonal antibodies (bnMAbs) targeting HIV-1 envelope glycoprotein (Env). These bnMAbs target distinct antigenic sites on the native HIV-1 Env trimer shared by multiple viral clades, including the CD4-binding site, the variable region 1 and 2 (V1V2) apex, the glycan-V3 region, the membrane-proximal external region (MPER), and the interface region between glycoprotein (gp)120 and gp41 [1–5]. Several human bnMAbs have been developed and tested in Phase I studies, including VRC01 and 3BNC117 to the CD4-binding site and 10–1074 to the glycan-V3 region [6–9]. The potency and breadth of the current generation of bnMAbs have led to interest in their clinical use both for prophylaxis and treatment of HIV-1 infection [10–12].

An expanded armamentarium of prevention and treatment methods is required to more adequately control the HIV-1 pandemic [35]. Mounting laboratory, preclinical, and clinical experience with HIV-1 bnMAbs has provided a greater understanding of their potency, breadth of reactivity, and potential to prevent or treat HIV-1 infection [6,9,36,37]. This experience is being acquired in tandem with two related international placebo-controlled Phase IIb efficacy trials assessing the impact of passive infusion of VRC01 on the risk of acquiring HIV-1 infection ( NCT02716675, NCT02256631). In this Phase I study, we evaluated a variant of VRC01, designed to have an extended serum half-life, for safety and PK parameters. We observed that VRC01LS was safe and well tolerated and displayed a serum half-life more than four times longer than wild-type VRC01 as indicated by historical data [11,12]. The VRC01LS antibody retained its neutralizing activity in serum for the 48-week duration of this study, and no antibodies to VRC01LS were detected.



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