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General Description:

Tixagevimab, identified by CAS number 2420564-02-7, is a notable compound with significant therapeutic applications. 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. Tixagevimab (formerly AZD8895) 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. As the RBD binding site of tixagevimab does not overlap with that of , the two can be administered to synergistically impair SARS-CoV-2 infection in individuals who may be exposed to the virus. Tixagevimab is not approved for any indication by the FDA. Tixagevimab, in combination with , 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). EVUSHELD was granted marketing authorization by the EMA on March 28, 2022, and was approved in Canada soon after, on April 14, 2022. In October 2022, the FDA and Health Canada released safety alerts regarding the risk of developing COVID-19 when exposed to SARS-CoV-2 variants not neutralized by EVUSHELD. Certain SARS-CoV-2 Omicron subvariants may be associated with resistance to monoclonal antibodies, such as EVUSHELD. The FDA and Health Canada advise healthcare providers to inform patients of this risk.

Indications:

This drug is primarily indicated for: Tixagevimab has been issued an emergency use authorization (EUA) by the FDA, in combination with , 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 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 is an approved pre-exposure prophylaxis therapy for COVID-19 in adults and adolescents aged 12 years and older weighing at least 40 kg. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tixagevimab undergoes metabolic processing primarily in: As a monoclonal antibody, tixagevimab is expected to undergo proteolytic degradation. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tixagevimab are crucial for its therapeutic efficacy: A single 150 mg intramuscular dose of tixagevimab, given concurrently with 150 mg of , resulted in a C_max geometric mean (%CV) of 16.5 (35.6) μg/mL in a median T_max of 14.0 (range 3.1-30) days. The observed geometric mean (%CV) one, 150, or 210 days following dosing was 4.4 (92.2), 6.6 (25.6), and 4.0 (31.6) μg/mL. This single dose resulted in an AUC_0-∞ of 2529 (30.2) μg\*day/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tixagevimab is an important consideration for its dosing schedule: Tixagevimab has a half-life of 87.9 ± 13.9 days. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Tixagevimab from the body primarily occurs through: Tixagevimab is unlikely to undergo renal excretion. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tixagevimab is distributed throughout the body with a volume of distribution of: Tixagevimab has an apparent volume of distribution of 7.7 ± 1.97 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tixagevimab is a critical factor in determining its safe and effective dosage: Tixagevimab has an apparent clearance of 0.062 ± 0.019 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tixagevimab exerts its therapeutic effects through: Tixagevimab is an extended half-life recombinant human IgG1κ monoclonal antibody directed against the SARS-CoV-2 spike (S) protein. Administered concurrently with , 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tixagevimab functions by: 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 but is only capable of binding the S protein in its "up" conformation (K_D 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 (conferring a >200-fold reduction in susceptibility). However, no escape variants were identified to tixagevimab or the combination of and tixagevimab. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tixagevimab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Tixagevimab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antiinfectives for Systemic Use, Antiviral Agents, Antiviral monoclonal antibodies, Antivirals for Systemic Use, Blood Proteins, Experimental Unapproved Treatments for COVID-19, Globulins, Immune Sera and Immunoglobulins, Immunoglobulins, Immunoproteins, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tixagevimab include:

• Molecular Weight: 149000.0
• Molecular Formula: C6488H10034N1746O2038S50