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- Title
The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans.
- Authors
Loo, Yueh-Ming; McTamney, Patrick M.; Arends, Rosalinda H.; Abram, Michael E.; Aksyuk, Anastasia A.; Diallo, Seme; Flores, Daniel J.; Kelly, Elizabeth J.; Ren, Kuishu; Roque, Richard; Rosenthal, Kim; Streicher, Katie; Tuffy, Kevin M.; Bond, Nicholas J.; Cornwell, Owen; Bouquet, Jerome; Cheng, Lily I.; Dunyak, James; Huang, Yue; Rosenbaum, Anton I.
- 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. Long-lasting antibodies: Although monoclonal antibody therapeutics have considerably improved outcomes for individuals with COVID-19, their utility as a prophylactic intervention is restricted by the emergence of variants of concern (VOCs) and by short half-lives. To address this, Loo et al. evaluated a pair of antibodies, collectively termed AZD7442, which bind to two distinct epitopes on the receptor binding domain of the SARS-CoV-2 spike protein and have been modified to have an extended half-life. The antibody combination protected nonhuman primates from infection with SARS-CoV-2 when administered prophylactically or therapeutically. The antibodies were also resistant to all tested VOC, including the delta variant. Last, the authors showed that AZD7442 administration to healthy adults resulted in neutralizing antibody titers that were projected to confer long-term protection.
- Subjects
COVID-19; MONOCLONAL antibodies; IMMUNOGLOBULINS; SARS-CoV-2; SARS-CoV-2 Delta variant; CONVALESCENT plasma
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 635, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abl8124