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

Hao，Xiaohua1; Zhang，Zheng2; Ma，Ji3; Cheng，Lin2; Ji，Yun3; Liu，Yang3; Zhao，Dong1; Zhang，Wen1; Li，Chunming3; Yan，Li3; Margolis，David3; Zhu，Qing3; Zhang，Yao4; Zhang，Fujie1

2022-09-06

10.3389/fphar.2022.983505

Frontiers in Pharmacology   影响因子和分区

1663-9812

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.

extended half-life monoclonal antibody neutralizing activity pharmacokinetics safety SARS-CoV-2

SCI

英语

其他

[2020YFC0861200] ; [2021YFC0864500] ; [JSGG20200207155251653] ; [JSGG20200807171401008]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000863764700001

FRONTIERS MEDIA SA

2-s2.0-85138340031

Scopus

1.Beijing Ditan Hospital,Capital Medical University,Beijing,China
2.Institute for Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People’s Hospital,The Second Affiliated Hospital,School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,China
3.Brii Biosciences Inc,Durham,United States
4.TSB Therapeutics,Beijing,China

Hao，Xiaohua,Zhang，Zheng,Ma，Ji,et al. 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[J]. Frontiers in Pharmacology,2022,13.

Hao，Xiaohua.,Zhang，Zheng.,Ma，Ji.,Cheng，Lin.,Ji，Yun.,...&Zhang，Fujie.(2022).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.Frontiers in Pharmacology,13.

Hao，Xiaohua,et al."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".Frontiers in Pharmacology 13(2022).