The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans

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 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 3-fold above those of convalescent serum at 9 months post-AZD7442 administration. Approximately 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.

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

“…2k ). This relationship is consistent with its likely mechanism of action, virus neutralization and inhibition of entry 17,18 . The AZD7442-TM version we used, like the clinical drug Evusheld, encodes for modifications in the constant region of the mAb heavy chains that profoundly decrease binding to Fc-gamma receptors (FcγRs) and complement components ( 19 and Fig 3a ).…”

“…We also assessed whether the reductions in mAb neutralization potency against Omicron variant strains correlated with the observed changes in viral burden. For AZD7442-TM, which contains L234F/L235E/P331S modifications that abolish Fc receptor engagement 13 and were introduced to decrease the potential risk of antibody-dependent enhancement of disease 18 , antibody-mediated reductions in viral titer corresponded directly with neutralization activity against Omicron variant strains; thus, neutralization is likely a key protective mechanism for these RBM-specific mAbs. For S309-LS, which only contains half-life extending M428L/N434S modifications in the human IgG1 Fc domain, and exhibits Fc effector functions including ADCC and ADCP 11 , changes in neutralization potency did not linearly relate to changes in lung viral titer.…”

“…The mAbs studied in this paper, S309, AZD8895, AZD1061, and the AZD7442 cocktail have been described previously 4,11,18 .…”

Sensitive detection of SARS-CoV-2 spike protein using vertically-oriented silicon nanowire array-based biosensor

“…Therefore, we have successfully demonstrated a proof-of-principle for a vSiNW based biosensor platform for sensitive and selective detection of SARS-CoV-2. Future efforts will involve utilizing antibodies instead of ACE2 as the receptor for the spike protein given antibodies have many fold higher binding affinity to the protein than ACE2 [ 47 ], which would result in significantly improved sensitivity and LOD of our biosensor platform.…”

Seroneutralization of Omicron BA.1 and BA.2 in patients receiving anti-SARS-CoV-2 monoclonal antibodies

“…Postexposure administration of Ronapreve prevented 84% of infections in a randomized clinical trial, performed before Omicron circulation (O'Brien et al, 2021). In a preclinical model, Evusheld protected macaques from infection with an ancestral SARS-CoV-2 (Loo et al, 2022).…”