Randomized, placebo-controlled, single-blind phase 1 studies of the safety, tolerability, and pharmacokinetics of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies with an extended half-life in healthy adults

Xiaohua Hao, Zheng Zhang, Ji Ma, Lin Cheng, Yun Ji, Yang Liu, Dong Zhao, Wen Zhang, Chunming Li, Li Yan, David Margolis, Qing Zhu, Yao Zhang, Fujie Zhang, Xiaohua Hao, Zheng Zhang, Ji Ma, Lin Cheng, Yun Ji, Yang Liu, Dong Zhao, Wen Zhang, Chunming Li, Li Yan, David Margolis, Qing Zhu, Yao Zhang, Fujie Zhang

Abstract

Background: BRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies as a cocktail therapy for treating COVID-19 with a modified Fc region that extends half-life. Methods: Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in first-in-human, placebo-controlled, single ascending dose phase 1 studies in healthy adults. 44 participants received a single intravenous infusion of single BRII-196 or BRII-198 up to 3,000 mg, or BRII-196 and BRII-198 combination up to 1500/1500 mg, or placebo and were followed up for 180 days. Primary endpoints were incidence of adverse events (AEs) and changes from pre-dose baseline in clinical assessments. Secondary endpoints included pharmacokinetics profiles of BRII-196/BRII-198 and detection of anti-drug antibodies (ADAs). Plasma neutralization activities against SARS-CoV-2 Delta live virus in comparison to post-vaccination plasma were evaluated as exploratory endpoints. Results: All infusions were well-tolerated without systemic or local infusion reactions, dose-limiting AEs, serious AEs, or deaths. Most treatment-emergent AEs were isolated asymptomatic laboratory abnormalities of grade 1-2 in severity. BRII-196 and BRII-198 displayed pharmacokinetics characteristic of Fc-engineered human IgG1 with mean terminal half-lives of 44.6-48.6 days and 72.2-83.0 days, respectively, with no evidence of interaction or significant anti-drug antibody development. Neutralizing activities against the live virus of the SARS-CoV-2 Delta variant were maintained in plasma samples taken on day 180 post-infusion. Conclusion: BRII-196 and BRII-198 are safe, well-tolerated, and suitable therapeutic or prophylactic options for SARS-CoV-2 infection. Clinical Trial Registration: ClinicalTrials.gov under identifiers NCT04479631, NCT04479644, and NCT04691180.

Keywords: SARS-CoV-2; extended half-life; monoclonal antibody; neutralizing activity; pharmacokinetics; safety.

Conflict of interest statement

Author YZ is employed by TSB Therapeutics (Beijing) Co. Ltd. and authors JM, YJ, CL, YL, LY, DM, and QZ are employed by Brii Biosciences INC., Durham, NC, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from TSB Therapeutics (Beijing) Co. Ltd. and Brii Biosciences INC., Durham, NC, United States. The funder had the following involvement with the study: study design, data collection and analysis, decision to publish, and preparation of the manuscript.

Copyright © 2022 Hao, Zhang, Ma, Cheng, Ji, Liu, Zhao, Zhang, Li, Yan, Margolis, Zhu, Zhang and Zhang.

Figures

FIGURE 1
FIGURE 1
Observed mean (±Standard deviation) serum concentration - time profiles of BRII-196 and BRII-198 following a single intravenous infusion administration to the healthy adult participants.
FIGURE 2
FIGURE 2
Neutralization activities Against the SARS-CoV-2 delta variant. The dotted line indicates the limit of detection of 20-fold dilution. The results below this limit were set to 10 for visualization.

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