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General Description:

Ansuvimab, identified by CAS number 2375952-29-5, is a notable compound with significant therapeutic applications. Infection with pathogenic filoviruses, such as _Zaire ebolavirus_ (Ebola virus, EBOV), can cause severe hemorrhagic fever in humans, resulting in frequent outbreaks with case fatality rates as high as 90%. Virtually all steps of the EBOV lifecycle have been targeted for therapeutic development. However, to date, the most successful method appears to be the development of monoclonal antibodies (mAbs) against the GP_1,2 surface glycoprotein, as evidenced by the previously approved INMAZEB™ (REGN-EB3, a cocktail of , , and ), the now approved ansuvimab, and ZMapp, which remains in clinical trials. Ansuvimab, formerly mAb114, is a fully human IgG1 mAb derived from a survivor of the 1995 Kikwit EBOV outbreak 11 years after infection, which displays strong glycan-independent binding to a conserved region of the GP_1,2 protein that is responsible for interacting with the host NPC1 protein to mediate EBOV endolysosomal escape, a key step in the EBOV lifecycle. A randomized, controlled trial of four investigational therapies for Ebola virus disease (EVD) in the Democratic Republic of Congo during a previous outbreak that began in 2018 compared ansuvimab, REGN-EB3, ZMapp, and , a nucleoside analogue designed to inhibit viral replication, showed ansuvimab and REGN-EB3 to be superior, with improved patient survival and faster viral clearance rates. Ansuvimab received FDA approval on December 21, 2020, and is currently marketed as Ebanga by Ridgeback Biotherapeutics, LP. Ansuvimab is just the second FDA-approved treatment for EVD.

Indications:

This drug is primarily indicated for: Ansuvimab is indicated for the treatment of _Zaire ebolavirus_ infection in adult and pediatric patients, including neonates born to a mother who tests positive for _Zaire ebolavirus_ by RT-PCR. Ansuvimab has not been shown to be effective against other species within the _Ebolavirus_ and _Marburgvirus_ genera; factors such as the possible emergence of resistant strains suggest local information on circulating _Zaire ebolavirus_ strains should be consulted before initiating treatment. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ansuvimab undergoes metabolic processing primarily in: Ansuvimab is expected to be degraded by various proteolytic and catabolic processes within the body, like other monoclonal antibodies. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ansuvimab are crucial for its therapeutic efficacy: The absorption of ansuvimab was evaluated in 18 healthy volunteers aged 18-60 years in an open-label phase 1 study. Ansuvimab administered at 5 mg/kg produced a C_max of 198.45 ± 45.15 μg/mL, a T_max of 3.21 ± 1.56 h, and an AUC_0-28d of 1480 ± 304 μg\*day/mL. The corresponding values for 25 mg/kg were: C_max of 829.38 ± 237.40 μg/mL, T_max of 2.99 ± 2.16 h, and AUC_0-28d of 8586 ± 900 μg\*day/mL, while the corresponding values for 50 mg/kg were: C_max of 1961.21 ± 339.83 μg/mL, T_max of 2.75 ± 1.63 h, and AUC_0-28d of 18588 ± 3627 μg\*day/mL. Overall, the pharmacokinetic profile of ansuvimab is consistent with other IgG1 monoclonal antibodies. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ansuvimab is an important consideration for its dosing schedule: The half-life of ansuvimab following a single administration of 5 mg/kg, 25 mg/kg, or 50 mg/kg was 20.1 ± 6.9, 26.7 ± 3.8, and 23.6 (no calculated standard deviation available) days, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Ansuvimab is distributed throughout the body with a volume of distribution of: The steady-state volume of distribution in healthy volunteers administered a single dose of 5 mg/kg, 25 mg/kg, or 50 mg/kg ansuvimab was 5.08 ± 0.88, 3.93 ± 0.50, and 4.16 ± 0.74 L, respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ansuvimab is a critical factor in determining its safe and effective dosage: The clearance of ansuvimab following a single administration of 5 mg/kg, 25 mg/kg, or 50 mg/kg was 199 ± 45, 108 ± 21, and 115 ± 15 mL/day, respectively. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ansuvimab exerts its therapeutic effects through: Ansuvimab is a human IgG1 monoclonal antibody directed against the _Zaire ebolavirus_ GP_1,2 surface glycoprotein that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. The exposure-response relationship of ansuvimab is not currently understood, although the recommended treatment comprises only a single dose. Despite a good overall safety profile, ansuvimab treatment carries a risk of potentially life-threatening hypersensitivity reactions, including infusion-related reactions; in the case of hypersensitivity reactions, ansuvimab should be discontinued, and supportive care initiated immediately. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ansuvimab functions by: _Zaire ebolavirus_ (Ebola virus, EBOV) is one of six species within the _Ebolavirus_ genus, which itself is one of six genera within the _Filoviridae_ family. Infection with pathogenic filoviruses such as EBOV in humans can result in hemorrhagic fever with very high fatality rates (25-90%). Following infection, a variable latency period of ~2-21 days occurs before the onset of symptoms, which are vague at first, including fatigue, fever, aches, myalgia, and gastrointestinal complaints, but that progress in severe disease to both internal and external bleeding, multiorgan failure, secondary infections, meningoencephalitis, hypotension, and shock. The pathogenesis of EBOV is poorly understood but is thought to be multifactorial: immune suppression, cytokine dysregulation, vascular dysfunction, and abnormal coagulation. EBOV is a non-segmented negative-sense RNA virus whose genome comprises seven genes, including the GP_1,2 glycoprotein involved in host cell entry and subsequent viral escape into the cytoplasm. GP_1,2 binds to one of several possible host receptors such as various lectins and TYRO3 receptor tyrosine kinases, β1 integrins, the asialoglycoprotein receptor, human folate receptor-α, and TIM1. Following internalization into endolysosomes by macropinocytosis, GP_1,2 is cleaved by host cathepsins into a fusion-competent form termed GP_CL, which subsequently binds the Niemann-Pick C1 protein (NPC1) to induce fusion of the host endolysosomal and viral membranes that releases the viral nucleocapsids into the host cytoplasm. The EBOV GP is a class I fusion protein comprising GP₁ and GP₂ subunits, transcribed as a single gene and proteolytically processed into individual subunits linked by disulphide bonds; three subunit heterodimers subsequently associate to form the mature chalice-shaped GP_1,2. Ansuvimab (formerly mAb114) is a fully human IgG1 monoclonal antibody (mAb) derived from an Ebola virus disease (EVD) survivor from the 1995 Kikwit EBOV outbreak 11 years after infection that binds to GP_1,2 over a region encompassing both the glycan cap and GP₁ core, although the glycan cap is dispensable for binding. Furthermore, structural studies reveal that ansuvimab binds to regions of the GP₁ core thought to be important for GP_CL interaction with NPC1 and blocks NPC1-GP interactions _in vitro_. Further _in vitro_ studies revealed that ansuvimab exhibits strong GP binding (EC₅₀ of 0.02 μg/mL), the ability to neutralize GP-expressing lentiviral particles (IC₅₀ of 0.09 μg/mL), and strong antibody-dependent cell-mediated cytotoxicity (ADCC) at concentrations of 0.03 μg/mL. Hence, the proposed ansuvimab mechanism of action is through direct blockage of EBOV endolysosome escape and ADCC-mediated killing of EBOV-infected cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Ansuvimab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Anti-Infective Agents, Antibodies, Antibodies, Monoclonal, Antiviral Agents, Blood Proteins, Globulins, Immunoglobulins, Immunoproteins, Proteins, Serum Globulins, Treatments for Ebola Virus Disease. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Ansuvimab include:

• Molecular Weight: 147000.0
• Molecular Formula: C6368H9924N1724O1994S44