Unknown Manufacturer • Cilgavimab has been issued an emergency use authorization (EUA) by the FDA, in combination with tixagevimab, 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 cilgavimab and tixagevimab 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.
Cilgavimab 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. Cilgavimab (AZD1061) is a recombinant human IgG1κ monoclonal antibody based on a neutralizing antibody (COV2-2130) 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. Cilgavimab binds to a non-overlapping region of the S1 RBD as tixagevimab and is capable of binding the S protein in both "up" and "down" conformations with a K of 13.0 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. Cilgavmiab inhibits RBD-ACE2 binding with an IC of 0.53 nM (80 ng/mL) and neutralizes SARS-CoV-2 (strain USA-WA1/2020) in a cellular assay with an EC value of 211.5 pM (32 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.
