AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans

Y.-M. Loo,P. M. McTamney, R. H. Arends, R. A. Gasser, M. E. Abram, A. Aksyuk, S. Diallo, D. J. Flores,E. J. Kelly, K. Ren, R. Roque, K. Rosenthal, K. Streicher, K. M. Tuffy,N. J. Bond,O. Cornwell,J. Bouquet, L. I. Cheng, J. Dunyak,Y. Huang,A. I. Rosenbaum, H. Andersen,R. H. Carnahan,J. E. Crowe, A. I. Kuehne,A. S. Herbert,J. M. Dye, H. Bright, N. L. Kallewaard, M. N. Pangalos,M. T. Esser

medRxiv(2021)

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摘要
Despite the success of SARS-CoV-2 vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of 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 non-overlapping epitopes on the spike protein receptor binding domain to potently 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 abrogate effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry. Together, these two mAbs create a higher barrier to viral escape and a wider breadth of coverage, neutralizing all known SARS-CoV-2 variants of concern. In a non-human primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, while therapeutic administration accelerated virus clearance from lung. In an ongoing Phase I study in healthy participants (NCT04507256), 300 mg intramuscular AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers >10-fold above those of convalescent sera for >=3 months, which remained 3-fold above those of convalescent sera 9 months post-AZD7442 administration. Approximately 1-2% of serum AZD7442 levels were detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentrations suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.
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