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| Primary information |
|---|
| ID | 16055 |
| Therapeutic ID | Th1669 |
| Protein Name | Cilgavimab |
| Sequence | >Th1669_Cilgavimab
EVQLVESGGGLVKPGGSLRLSCAASGFTFRDVWMSWVRQAPGKGLEWVGRIKSKIDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTAGSYYYDTVGPGLPEGKFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
|
| Molecular Weight | 152000 |
| Chemical Formula | C6626H10218N1750O2078S44 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Cilgavimab has a half-life of 82.9 ± 12.3 days.[L39411] |
| Description | 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). Blocking the interaction between the receptor-binding domain (RBD) of the S1 subunit and ACE2 inhibits viral host cell entry; animal studies indicate that antibodies capable of blocking this interaction reduce viral load and improve clinical symptoms of infection.[A243356, A243361] Cilgavimab (formerly AZD1061) is a recombinant monoclonal antibody produced in Chinese hamster ovary (CHO) cells derived from a neutralizing antibody isolated from a patient with a natural history of SARS-CoV-2 infection and modified through targeted amino acid substitutions to exhibit an extended (~85-day) half-life.[A243351, A243356, L39411] As the RBD binding site of cilgavimab does not overlap with that of [tixagevimab], the two can be administered to synergistically impair SARS-CoV-2 infection in individuals who may be exposed to the virus.[A243351, A243361, L39411] Cilgavimab is not approved for any indication by the FDA. Cilgavimab, in combination with [tixagevimab], was issued an FDA emergency use authorization (EUA) on December 9, 2021, for the pre-exposure prophylaxis of COVID-19 in individuals at increased risk for whom vaccination is not recommended. The combination is co-packaged and available under the name EVUSHELD (formerly AZD7442).[L39411] |
| Indication/Disease | 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.[L39411] 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.[L39411] |
| Pharmacodynamics | Cilgavimab is an extended half-life recombinant human IgG1 monoclonal antibody directed against the SARS-CoV-2 spike (S) protein. Administered concurrently with [tixagevimab], the combination carries a risk of hypersensitivity reactions and requires caution when administering to patients with thrombocytopenia or a coagulation disorder. Based on limited clinical experience, caution should also be exercised in patients with cardiac risk factors or a history of cardiovascular disease. As there is limited experience with this combination, unexpected serious adverse events may occur.[L39411] |
| Mechanism of Action | 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.[A243351, A243356] 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.[A243356] Cilgavimab (AZD1061) is a recombinant human IgG1 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.[L39411] 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 KD of 13.0 pM.[A243356, A243361, L39411] 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 IC50 of 0.53 nM (80 ng/mL) and neutralizes SARS-CoV-2 (strain USA-WA1/2020) in a cellular assay with an EC50 value of 211.5 pM (32 ng/mL).[L39411] 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].[A243361, L39411] |
| Toxicity | Toxicity information regarding cilgavimab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects. Symptomatic and supportive measures are recommended.[L39411] |
| Metabolism | As a monoclonal antibody, cilgavimab is expected to undergo proteolytic degradation.[L39411] |
| Absorption | A single 150 mg intramuscular dose of cilgavimab, given concurrently with 150 mg of [tixagevimab], resulted in a Cmax geometric mean (%CV) of 15.3 (38.5) µg/mL in a median Tmax of 14.0 (range 3.1-60) days. The observed geometric mean (%CV) one, 150, or 210 days following dosing was 3.9 (94.4), 5.5 (35.2), and 3.9 (37.1) µg/mL. This single dose resulted in an AUC0-8 of 2133 (31.7) µg |
| Cilgavimab has an apparent volume of distribution of 8.7 ± 2.73 L.[L39411] |
| Clearance | Cilgavimab has an apparent clearance of 0.074 ± 0.028 L/day.[L39411] |
| Categories | Antiviral Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Spike glycoprotein |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |