Mirvetuximab soravtansine
Identification
- Summary
Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate used to treat folate receptor alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
- Brand Names
- Elahere
- Generic Name
- Mirvetuximab soravtansine
- DrugBank Accession Number
- DB12489
- Background
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).3,5 DM4 is conjugated to the antibody with a drug-to-antibody ratio of 3.5:1.2
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.1 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.1
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).5,6
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- 150000.0 Da (approximate)
- Sequences
>Heavy chain QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFY NQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG
>Light chain DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEA GVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA FormatReferences:
- WHO: International Nonproprietary Names for Pharmaceutical Substances (INN) [Link]
- Synonyms
- Anti-FOLR1-monoclonal-antibody-maytansinoid-conjugate-IMGN-853
- Mirvetuximab soravtansine
- Mirvetuximab soravtansine-gynx
- External IDs
- IMGN-853
- IMGN853
Pharmacology
- Indication
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.5
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.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Platinum resistant primary peritoneal cancer •••••••••••• ••••• •••••••• • •• • ••••• •••••••• ••••••••• •••••••• ••••••••• Treatment of Platinum-resistant epithelial ovarian cancer •••••••••••• ••••• •••••••• • •• • ••••• •••••••• ••••••••• •••••••• ••••••••• Treatment of Platinum drug resistant fallopian tube cancer •••••••••••• ••••• •••••••• • •• • ••••• •••••••• ••••••••• •••••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
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.5 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.5
- Mechanism of action
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.5 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.4 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.1,5 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.2,4
Target Actions Organism AFolate receptor alpha binderHumans - Absorption
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 Cmax of 137.3 µg/mL, 4.11 ng/mL and 6.98 ng/mL, and a corresponding AUCtau of 20.65 h⋅mg/mL, 530 h⋅ng/mL and 1848 h⋅ng/mL.5 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.5
- Volume of distribution
Mirvetuximab soravtansine-gynx has a steady-state volume of distribution of 2.63 L.5
- Protein binding
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%.5
- Metabolism
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 CYP3A4.5
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- Route of elimination
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.5
- Half-life
After the first dose, the geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx is 4.8 days.5 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.5
- Clearance
The total plasma clearance of mirvetuximab soravtansine-gynx is 18.9 mL/hour.5 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.5
- Adverse Effects
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- Toxicity
Toxicity information regarding mirvetuximab soravtansine-gynx is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as ocular toxicity, pneumonitis and peripheral neuropathy.5 Symptomatic and supportive measures are recommended.
Carcinogenicity studies with mirvetuximab soravtansine-gynx or DM4 have not been performed. An in vivo rat bone marrow micronucleus study showed that DM4 and its metabolite, S-methyl DM4, are clastogenic. DM4 and S-methyl DM4 did not show evidence of mutagenicity in the bacterial reverse mutation (Ames) assay. The effects of mirvetuximab soravtansine-gynx or DM4 on fertility studies have not been evaluated.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Mirvetuximab Soravtansine. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Mirvetuximab Soravtansine. Aducanumab The risk or severity of adverse effects can be increased when Aducanumab is combined with Mirvetuximab Soravtansine. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Mirvetuximab Soravtansine. Alirocumab The risk or severity of adverse effects can be increased when Alirocumab is combined with Mirvetuximab Soravtansine. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Elahere (ImmunoGen, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Elahere Injection, solution 100 mg/20mL Intravenous ImmunoGen, Inc. 2022-11-14 Not applicable US
Categories
- Drug Categories
- 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
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 98DE7VN88D
- CAS number
- 1453084-37-1
References
- Synthesis Reference
Payne, G. et al. (2016). Methods for formulating antibody drug conjugate compositions. World Intellectual Property Organization WO 2016/036861 A1. Available at: https://patentimages.storage.googleapis.com/81/ac/da/92f7eb5933228f/WO2016036861A1.pdf
- General References
- Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Vergote I, Ponte JF, Birrer MJ: A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018 Jan;14(2):123-136. doi: 10.2217/fon-2017-0379. Epub 2017 Nov 3. [Article]
- Nerone M, Grande MD, Sessa C, Colombo I: Advancing antibody-drug conjugates in gynecological malignancies: myth or reality? Explor Target Antitumor Ther. 2022;3(2):149-171. doi: 10.37349/etat.2022.00077. Epub 2022 Apr 19. [Article]
- Martin-Sabroso C, Lozza I, Torres-Suarez AI, Fraguas-Sanchez AI: Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives. Pharmaceutics. 2021 Oct 15;13(10). pii: pharmaceutics13101705. doi: 10.3390/pharmaceutics13101705. [Article]
- Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM: IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors. Mol Cancer Ther. 2015 Jul;14(7):1605-13. doi: 10.1158/1535-7163.MCT-14-1095. Epub 2015 Apr 22. [Article]
- FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]
- OncLive: FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer [Link]
- External Links
- PubChem Compound
- 131704323
- PubChem Substance
- 347828725
- ChemSpider
- 64873336
- 2621548
- Wikipedia
- Mirvetuximab_soravtansine
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Epithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer 1 3 Completed Treatment Epithelial Ovarian Cancer / Fallopian Tube Cancer / Ovarian Cancer / Primary Peritoneal Carcinoma 1 3 Completed Treatment Epithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer 1 3 Recruiting Treatment Epithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer 1 3 Recruiting Treatment Fallopian Tube Cancer / Ovarian Cancer / Peritoneal Cancer 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 100 mg/20mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- General Function
- Receptor activity
- Specific Function
- Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analo...
- Gene Name
- FOLR1
- Uniprot ID
- P15328
- Uniprot Name
- Folate receptor alpha
- Molecular Weight
- 29818.94 Da
References
- Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Vergote I, Ponte JF, Birrer MJ: A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018 Jan;14(2):123-136. doi: 10.2217/fon-2017-0379. Epub 2017 Nov 3. [Article]
- Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM: IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors. Mol Cancer Ther. 2015 Jul;14(7):1605-13. doi: 10.1158/1535-7163.MCT-14-1095. Epub 2015 Apr 22. [Article]
- FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- Curator comments
- DM4, the small molecule component of mirvetuximab soravtansine, is metabolized by CYP3A4. In vitro, DM4 is also a time-dependent inhibitor of CYP3A4; however, this effect has not been detected in vivo.
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Davis JA, Rock DA, Wienkers LC, Pearson JT: In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates. Drug Metab Dispos. 2012 Oct;40(10):1927-34. doi: 10.1124/dmd.112.046169. Epub 2012 Jun 29. [Article]
- FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- Curator comments
- In vitro studies have shown that DM4, the small molecule component of mirvetuximab soravtansine, is a substrate of P-glycoprotein. However, this effect has not been detected in vivo.
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]
Drug created at October 20, 2016 22:35 / Updated at December 06, 2022 13:40