Tixagevimab

SARS-CoV-2, the causative agent of COVID-19, enters cells via the interaction between the trimeric spike (S) glycoprotein and host cell angiotensin-converting enzyme 2 (ACE2). Of the two subunits comprising the trimeric S glycoprotein, the S1 subunit binds ACE2 via its receptor-binding domain (RBD) while the central S2 subunit mediates fusion following S1 shedding. Large-scale screens suggest that the most potently neutralizing antibodies recovered from the B cells of those convalescing following natural infection with SARS-CoV-2 bind to the RBD of S1 and are capable of disrupting the interaction between the RBD and human ACE2.

Tixagevimab (AZD8895)is a recombinant human IgG1κ monoclonal antibody based on a neutralizing antibody (COV2-2196) isolated from patients with a natural history of SARS-CoV-2 infection and modified through specific amino acid substitutions to extend its half-life and reduce antibody effector functions. Tixagevimab binds to a non-overlapping region of the S1 RBD as cilgavimab but is only capable of binding the S protein in its "up" conformation (KD of 2.76 pM). Cell culture studies suggest little to no antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or antibody-dependent natural killer cell activation (ADNKA), suggesting the protective effect is due solely to inhibition of the RBD-ACE2 interaction. Tixagevimab inhibits RBD-ACE2 binding with an IC50 of 0.32 nM (48 ng/mL) and neutralizes SARS-CoV-2 (strain USA-WA1/2020) in a cellular assay with an EC50 value of 60.7 pM (9 ng/mL).

As with other antiviral treatments, there is a risk of resistant variants emerging during treatment. Experiments to identify escape variants during culture of recombinant vesicular stomatitis virus expressing the S protein (VSV-SARS-CoV-2) or authentic SARS-CoV-2 (strain USA-WA1/2020) identified K444E, K444R, and R346I as potential single-nucleotide escape variants for cilgavimab (conferring a >200-fold reduction in susceptibility). However, no escape variants were identified to tixagevimab or the combination of cilgavimab and tixagevimab.