AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults.

Autor: Cai Y; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Diallo S; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Rosenthal K; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Ren K; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Flores DJ; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Dippel A; Biologics Engineering, Oncology R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Oganesyan V; Biologics Engineering, Oncology R&D, AstraZeneca, Gaithersburg, MD 20878, USA., van Dyk N; Biologics Engineering, Oncology R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Chen X; Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Cantu E; Imaging and Data Analytics, AstraZeneca, Gaithersburg, MD 20878, USA., Choudhary R; Imaging and Data Analytics, AstraZeneca, Gaithersburg, MD 20878, USA., Sulikowski M; Imaging and Data Analytics, AstraZeneca, Cambridge CB2 0AA, UK., Adissu H; Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Chawla B; BIOQUAL Inc., Rockville, MD 20850, USA., Kar S; BIOQUAL Inc., Rockville, MD 20850, USA., Liu C; Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford OX3 7BN, UK.; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK., Dijokaite-Guraliuc A; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK., Mongkolsapaya J; Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford OX3 7BN, UK.; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand, Department of Medicine, University of Oxford, Oxford OX3 7BN, UK., Rajan S; Biologics Engineering, Oncology R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Loo YM; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Beavon R; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Webber C; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Chang LJ; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Thomas S; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Clegg L; Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Zhang H; Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Screaton GR; Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford OX3 7BN, UK.; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK., Philbin N; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Harre M; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Selim A; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Martinez-Alier N; Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 8PA, UK., Uriel A; Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital (Manchester University NHS Foundation Trust), Manchester M8 5RB, UK., Cohen TS; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Perez JL; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Esser MT; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Blair W; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA., Francica JR; Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Jun 26; Vol. 16 (753), pp. eado2817. Date of Electronic Publication: 2024 Jun 26.
DOI: 10.1126/scitranslmed.ado2817
Abstrakt: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.
Databáze: MEDLINE