The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans
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Abstract
Despite the success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19 and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct, nonoverlapping epitopes on the spike protein receptor binding domain to neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and reduce effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry, and neutralize all tested SARS-CoV-2 variants of concern. In a nonhuman primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, whereas therapeutic administration accelerated virus clearance from the lung. In an ongoing phase 1 study in healthy participants (NCT04507256), a 300-mg intramuscular injection of AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers greater than 10-fold above those of convalescent serum for at least 3 months, which remained threefold above those of convalescent serum at 9 months after AZD7442 administration. About 1 to 2% of serum AZD7442 was detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentration suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.
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SciScore for 10.1101/2021.08.30.21262666: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Euthanasia Agents: At study termination, animals were euthanized by IV injection of a commercially available veterinary euthanasia solution, followed by exsanguination.
IACUC: SARS-CoV-2 Challenge Studies in NHPs: Group designation and study design: Animal studies (IACUC protocol no. 20-035 and 21-018P) were approved by the Institutional Animal Care and Use Committee and conduced at BIOQUAL, Inc. (Rockville, MD, USA) in adherence of the following standards of the Association for Assessment and Accreditation of Laboratory Animal Care: the 8th edition of the Guide for the Care and Use of Laboratory Animals; the Animal Welfare Act; and the 2015 reprint of the Public Health Service Policy on …SciScore for 10.1101/2021.08.30.21262666: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Euthanasia Agents: At study termination, animals were euthanized by IV injection of a commercially available veterinary euthanasia solution, followed by exsanguination.
IACUC: SARS-CoV-2 Challenge Studies in NHPs: Group designation and study design: Animal studies (IACUC protocol no. 20-035 and 21-018P) were approved by the Institutional Animal Care and Use Committee and conduced at BIOQUAL, Inc. (Rockville, MD, USA) in adherence of the following standards of the Association for Assessment and Accreditation of Laboratory Animal Care: the 8th edition of the Guide for the Care and Use of Laboratory Animals; the Animal Welfare Act; and the 2015 reprint of the Public Health Service Policy on Human Care and Use of Laboratory Animals.
Consent: All participants provided written informed consent before entering the study.
IRB: The study protocol and informed consent documentation were reviewed and approved by the study site institutional review board.Sex as a biological variable Cynomolgus monkeys were received from Orient BioResource (Alice, Tx, USA) and were between 2.2 and 5.1 years-old; males weighing between 1.9 and 2.6 kg and females weighing between 2.2 and 2.5 kg at the time of dosing. Randomization Animals were randomized and assigned to groups using a computer-based procedure prior to transfer to study; males and females were randomized separately. Blinding Participants, investigators, clinical staff, and the study monitor were all blinded from the assigned intervention. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources After incubation, cells were formalin-fixed followed by incubation with a monoclonal antibody targeting the viral nucleocapsid protein, followed by a secondary anti-human IgG peroxidase conjugate and KPL TrueBlue™ substrate. anti-human IgGsuggested: NoneExperimental Models: Cell Lines Sentences Resources Cynomolgus macaques were challenged with a stock, obtained from BEI Resources, cat. no. NR-53872, lot 70040665, 6.9 × 104 TCID50 per mL in Vero E6 cells. Vero E6suggested: RRID:CVCL_XD71)Recombinant DNA Sentences Resources To generate a standard curve for the SARS-CoV-2 E gene sgmRNA assay, the SARS-CoV-2 E gene sgmRNA was cloned into a pcDNA3.1 expression plasmid. pcDNA3.1suggested: RRID:Addgene_79663)Software and Algorithms Sentences Resources Background-subtracted absorbance values for each standard was fit to a non-linear, sigmoidal (4PL) curve using GraphPad Prism, and the ensuing curve used to calculate concentrations of human IgG in each serum sample. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04507256 Active, not recruiting AZD7442 - a Potential Combination Therapy for the Prevention… NCT04625725 Active, not recruiting Phase III Double-blind, Placebo-controlled Study of AZD7442 … NCT04723394 Active, not recruiting Phase III Study of AZD7442 for Treatment of COVID-19 in Outp… NCT04518410 Recruiting ACTIV-2: A Study for Outpatients With COVID-19 NCT04501978 Recruiting ACTIV-3: Therapeutics for Inpatients With COVID-19 NCT04315948 Recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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