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| Primary information |
|---|
| ID | 16172 |
| Therapeutic ID | Th1686 |
| Protein Name | Tisotumab vedotin |
| Sequence | NA
|
| Molecular Weight | 153000 |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively.[L38424] |
| Description | Tisotumab vedotin is a tissue factor-directed antibody-drug conjugate (ADC) comprised of an anti-tissue factor (TF) human IgG1-kappa antibody conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, via a protease-cleavable valine-citrulline linker. Each monoclonal antibody molecule carries an average of four MMAE molecules. Tisotumab vedotin is the first TF-directed ADC [A238914] that works by binding to TFs expressed on solid tumours. TF is a primary initiator of the extrinsic blood coagulation cascade [L38424] and plays a key role in tumor-associated angiogenesis, progression, and metastasis for tumor survival. TF is a novel target for cancers, as it is often overexpressed on solid tumours, including cervical cancer, and it is associated with poor clinical outcomes. Tisotumab vedotin targets TF-expressing cells to deliver MMAE to induce direct cytotoxicity and bystander killing of neighboring cells.[A238914] On September 20, 2021, the FDA granted accelerated approval to tisotumab vedotin-tftv for the treatment of recurrent or metastatic cervical cancer in adults in whom the disease progressed during or after chemotherapy. This is the first and only approved antibody-drug conjugate for this therapeutic indication. The approval was based on tumour response and the durability of the response as demonstrated in InnovaTV 204 (NCT03438396): in this trial, the objective response rate was 24% and the median response duration was 8.3 months.[L38429] Tisotumab vedotin-tftv is marketed under the trade name Tivdak as an intravenous injection. Tisotumab vedotin is currently under investigation as a treatment for other solid tumors, including ovarian, lung, colorectal, pancreatic, and head and neck cancers. It is also being investigated for the combination use with other chemotherapeutic agents for recurrent or metastatic cervical cancer.[A238924] |
| Indication/Disease | Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.[L38424] |
| Pharmacodynamics | Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells [A238914] and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.[L38424] |
| Mechanism of Action | Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death.[L38424] Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to _in vitro_ studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fc receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant activity.[A238914] |
| Toxicity | There is no information on the LD50 values and overdose profile of tisotumab vedotin. Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types.[L38424] |
| Metabolism | Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 _in vitro_.[L38424] |
| Absorption | Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) Cmax of tisotumab vedotin-tftv was 40.8 (8.12) µg/mL and the mean (± SD) AUC was 57.5 (13.4) day x µg/mL. The mean (± SD) Cmax of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The Cmax of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle.[L38424] |
| The tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L.[L38424] |
| Clearance | The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv.[L38424] |
| Categories | Cytochrome P-450 Substrates |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Tissue factor |
| 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 |