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| Primary information |
|---|
| ID | 15814 |
| Therapeutic ID | Th1631 |
| Protein Name | Dostarlimab |
| Sequence | >Th1631_Dostarlimab
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
|
| Molecular Weight | 144000 |
| Chemical Formula | C6420H9832N1680O2014S44 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The mean terminal elimination half-life of dostarlimab is 25.4 days.[L33320] |
| Description | Dostarlimab is an IgG4 humanized monoclonal antibody targeted against the human programmed death receptor-1 (PD-1).[L33320] PD-1 receptors are found on T-cells and, when activated, serve to inhibit immune responses - some cancers leverage this system by overexpressing PD-1 ligands, thereby effectively inhibiting the anti-tumor immune response that would typically attempt to destroy the cancerous cells.[A234379] Agents acting on the PD-1 pathway, such as [nivolumab] and [pembrolizumab], facilitate endogenous immune-mediated anti-tumor activity and may therefore be used to treat a wide variety of cancers, including those of the skin, lung, kidneys, and liver. In April 2021, dostarlimab was granted an accelerated approval by the FDA - as GlaxoSmithKline's dostarlimab-gxly (Jemperli) - for the treatment of adult patients with recurrent or advanced mismatch repair deficient (dMMR) endometrial cancer experiencing disease progression despite treatment with platinum-containing chemotherapy regimens.[L33340] As this accelerated approval was granted only for the treatment of dMMR endometrial cancers, it was approved alongside a companion diagnostic device - the VENTANA MMR RxDx Panel - for use in selecting appropriate patients for treatment.[L33340] |
| Indication/Disease | Dostarlimab-gxly is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed despite ongoing or prior treatment with a platinum-containing chemotherapy regimen.[L33320] |
| Pharmacodynamics | Dostarlimab is an immunotherapy that facilitates the body's endogenous anti-tumor immune response in the treatment cancer.[L33320] It is administered over a span of 30 minutes via intravenous infusion every three to six weeks depending on the cycle.[L33320] Agents that interfere with the PD-1/PD-L1 pathway, including dostarlimab, remove an important immune system inhibitory response and may therefore induce immune-mediated adverse reactions which can be severe or fatal. These reactions can occur in any organ system and can occur at any time after starting therapy, and while they most often manifest during therapy they may also appear after discontinuing the causative agent. Patients receiving therapy with dostarlimab should be monitored closely for evidence of an underlying immune-mediated reaction and evaluated and treated promptly if an immune-mediated reaction is suspected.[L33320] |
| Mechanism of Action | Approximately 13-30% of recurrent endometrial cancers involve microsatellite instability (MSI) or mismatch repair deficiency (dMMR).[A234379,A234389] The mutations resulting in dMMR endometrial cancers are primarily somatic in nature (~90%), although 5-10% of cases involve germline mutations.[A234389] Cancers that have mutations resulting in dMMR can upregulate the expression of programmed death receptor-1 (PD-1) ligands 1 and 2 (PD-L1 and -L2) - PD-1 is found on T-cells and, when activated, inhibits their proliferation and the production of cytokines.[L33320] The binding of these ligands to PD-1 thereby functions as an immune checkpoint that downregulates the anti-tumor immune response.[A234379] Dostarlimab is a monoclonal antibody targeted against PD-1 - it binds to the receptor and prevents interactions with PD-L1 and PD-L2, thus allowing the anti-tumor immune response to proceed unimpeded.[L33320] |
| Toxicity | There are no data regarding overdose with dostarlimab. Symptoms of overdosage are likely to be consistent with the adverse effect profile of dostarlimab and may therefore involve significant immune-mediated reactions.[L33320] |
| Metabolism | The metabolism of dostarlimab has not been characterized, but it is expected to be degraded via catabolic pathways into smaller peptides and amino acids.[L33320,A216712] |
| Absorption | During the first cycle, and administered at 500mg intravenously every 3 weeks, the mean Cmax and AUC0-tau of dostarlimab-gxly are 171 mcg/mL and 35,730 mcg.h/mL, respectively. When administered at 1000mg every 6 weeks, the mean Cmax and AUC0-tau are 309 mcg/mL and 95,820 mcg.h/mL, respectively.[L33320] |
| At steady-state, the mean volume of distribution of dostarlimab is 5.3L.[L33320] |
| Clearance | At steady-state, the mean clearance of dostarlimab is 0.007 L/h.[L33320] |
| Categories | Immunoglobulins |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Programmed cell death protein 1 |
| 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 |