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Tixagevimab is an extended half-life recombinant monoclonal IgG1κ antibody directed against the SARS-CoV-2 S protein for COVID-19 prophylaxis in individuals unable to undergo COVID-19 immunization.
Tixagevimab is an extended half-life recombinant monoclonal IgG1κ antibody directed against the SARS-CoV-2 S protein for COVID-19 prophylaxis in individuals unable to undergo COVID-19 immunization.
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 (K 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 IC of 0.32 nM (48 ng/mL) and neutralizes SARS-CoV-2 (strain USA-WA1/2020) in a cellular assay with an EC 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.
Tixagevimab has been issued an emergency use authorization (EUA) by the FDA, in combination with cilgavimab, for the pre-exposure prophylaxis of COVID-19 in adult and pediatric patients aged 12 years and older weighing at least 40 kg. Furthermore, patients must not be currently infected with SARS-CoV-2 or have had known exposure to an individual infected with SARS-CoV-2 and must either be immunocompromised due to a medical condition, medication, or treatment or be otherwise ineligible for vaccination with any eligible COVID-19 vaccine due to a history of severe adverse reactions. In the US, the combination of tixagevimab and cilgavimab is not authorized for the treatment or post-exposure prophylaxis of COVID-19 and is not a substitute for COVID-19 vaccination. Individuals receiving therapy following COVID-19 vaccination should wait at least two weeks. In Europe and Canada, cilgavimab in combination with tixagevimab is an approved pre-exposure prophylaxis therapy for COVID-19 in adults and adolescents aged 12 years and older weighing at least 40 kg.
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