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General Description:

Mirvetuximab soravtansine, identified by CAS number 1453084-37-1, is a notable compound with significant therapeutic applications. Mirvetuximab soravtansine-gynx (IMGN853) is an antibody-drug conjugate (ADC) formed by a monoclonal antibody (M9346A) that targets folate receptor alpha (FRα), covalently joined by a cleavable disulfide linker to the genotoxic compound DM4 (also known as soravtansine or ravtansine). DM4 is conjugated to the antibody with a drug-to-antibody ratio of 3.5:1. The antibody component of mirvetuximab soravtansine-gynx binds to FRα, a receptor overexpressed on the surface of epithelial tumor cells, characteristic of ovarian, endometrial, triple-negative breast and non-small-cell lung cancers. After an ADC/receptor complex is formed, mirvetuximab soravtansine-gynx is internalized, and DM4 is released inside the cell. DM4 leads to cell-cycle arrest and apoptosis and is also able to diffuse into neighboring cells and induce further cell death. On November 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for the treatment of adult patients with FRα–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. This decision was supported by findings from the phase 3 SORAYA trial (NCT04296890).

Indications:

This drug is primarily indicated for: Mirvetuximab soravtansine is indicated for the treatment of adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Patients are selected for therapy based on an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Mirvetuximab soravtansine undergoes metabolic processing primarily in: After mirvetuximab soravtansine-gynx binds the folate receptor alpha (FRα) and is internalized via antigen-mediated endocytosis, the DM4 agent is released via proteolytic cleavage. The monoclonal antibody portion of this drug is expected to be metabolized by catabolic pathways into small peptides. Unconjugated DM4 is reduced and S-methylated to form S-methyl-DM4. DM4 and S-methyl-DM4 are the main circulating metabolites of mirvetuximab soravtansine-gynx and correspond to approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUCs. Both DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Mirvetuximab soravtansine are crucial for its therapeutic efficacy: The pharmacokinetic parameters of mirvetuximab soravtansine-gynx were evaluated in patients given a 6 mg/kg adjusted ideal body weight (AIBW) dose administered during the first treatment cycle (3 weeks). Mirvetuximab Soravtansine-gynx, the unconjugated DM4, and S-methyl-DM4 had a corresponding C_max of 137.3 µg/mL, 4.11 ng/mL and 6.98 ng/mL, and a corresponding AUC_tau of 20.65 h⋅mg/mL, 530 h⋅ng/mL and 1848 h⋅ng/mL. The peak concentration of mirvetuximab soravtansine-gynx was observed near the end of intravenous infusion, while DM4 and S-methyl-DM4 concentrations peaked 2 and 3 days after mirvetuximab soravtansine-gynx administration. After one treatment cycle, mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 reached steady-state concentrations. Following the repeated administration of mirvetuximab soravtansine-gynx, the accumulation of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were minimal. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Mirvetuximab soravtansine is an important consideration for its dosing schedule: After the first dose, the geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx is 4.8 days. The geometric mean terminal phase half-lives of the unconjugated DM4 and its metabolite, S-methyl-DM4, are 2.8 and 5.0 days, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Mirvetuximab soravtansine exhibits a strong affinity for binding with plasma proteins: Based on _in vitro_ studies, the plasma protein binding of the mirvetuximab soravtansine-gynx component DM4 and its metabolite S-methyl DM4 is higher than 99%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Mirvetuximab soravtansine from the body primarily occurs through: Mirvetuximab soravtansine-gynx metabolites S-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Mirvetuximab soravtansine is distributed throughout the body with a volume of distribution of: Mirvetuximab soravtansine-gynx has a steady-state volume of distribution of 2.63 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Mirvetuximab soravtansine is a critical factor in determining its safe and effective dosage: The total plasma clearance of mirvetuximab soravtansine-gynx is 18.9 mL/hour. The unconjugated DM4 has a total plasma clearance of 13.8 L/hour, while its metabolite, S-methyl-DM4, has a total plasma clearance of 4.3 L/hour. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Mirvetuximab soravtansine exerts its therapeutic effects through: There is an exposure-response relationship for mirvetuximab soravtansine-gynx. The increased exposure of mirvetuximab soravtansine-gynx was associated with a higher incidence of ocular adverse reactions and peripheral neuropathy grade 2 or higher. Mirvetuximab soravtansine-gynx did not cause large QTc increases (>10 msec) at the approved recommended dose. The use of mirvetuximab soravtansine-gynx has been associated with severe ocular adverse reactions, such as visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, as well as peripheral neuropathy, may also occur in patients treated with mirvetuximab soravtansine-gynx. Since mirvetuximab soravtansine-gynx contains DM4, a genotoxic compound, the use of this drug may cause embryo-fetal harm in pregnant women. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Mirvetuximab soravtansine functions by: Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC) formed by three components: a chimeric IgG1 antibody against folate receptor alpha (FRα), the small molecule anti-tubulin agent DM4 (a maytansine derivative) and a sulfo-SPDB linker that joins DM4 to the mirvetuximab antibody. FRα is expressed on the cell surface and has a restricted distribution in normal tissues. However, abnormally high levels of FRα have been detected in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, and non–small cell lung cancer of the adenocarcinoma subtype. In ovarian cancer patients, its expression is maintained in metastatic foci and recurrent carcinomas. Mirvetuximab soravtansine-gynx binds with high affinity to FRα and is then internalized through antigen-mediated endocytosis. Inside FRα-expressing tumor cells, DM4 is released via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, leading to cell cycle arrest and apoptosis. Since DM4 is electrically neutral and lipophilic, it is able to diffuse across cell membranes and lead to the death of neighboring antigen-negative cells. This "bystander effect" is an important component of mirvetuximab soravtansine-gynx, allowing it to exert a cytotoxic effect even in cells that do not express FRα on their surface. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Mirvetuximab soravtansine 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:

Mirvetuximab soravtansine is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibody-drug Conjugates, Antineoplastic Agents, Blood Proteins, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Globulins, Immunoconjugates, Immunoglobulins, Immunologic Factors, Immunoproteins, Lactams, Macrocyclic, Lactones, Microtubule Inhibition, P-glycoprotein substrates, 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 Mirvetuximab soravtansine include:

• Molecular Weight: 150000.0