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| Primary information |
|---|
| ID | 15652 |
| Therapeutic ID | Th1616 |
| Protein Name | Isatuximab |
| Sequence | >Th1616_Isatuximab
QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
|
| Molecular Weight | 148000 |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | NA |
| Description | Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary (CHO) cell line.[L12099,A191799] Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.[L12099] It is a cytolytic antibody targeted against CD38, a glycoprotein found on the surface of some immune cells that is highly expressed by malignant plasma cells in multiple myeloma.[L12099] Along with [daratumumab], another anti-CD38 mAb, isatuximab constitutes a novel treatment modality for patients with difficult-to-treat multiple myeloma. Following three consecutive years on the yearly "Antibodies to watch" list published in "mAb", a peer-reviewed scientific journal dedicated to antibody research,[A38676,A191826,A191829] isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma.[L12099,L12102] It is manufactured by Sanofi-Aventis U.S. under the brand name Sarclisa.[L12102] |
| Indication/Disease | Isatuximab is indicated in combination with [pomalidomide] and [dexamethasone] for the treatment of multiple myeloma in adults who have received at least two prior therapies including [lenalidomide] and a proteasome inhibitor.[L12099] It is also indicated in combination [carfilzomib] and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.[L12099] |
| Pharmacodynamics | Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation.[L12099] It has a relatively long residence time in the body, taking approximately 2 months to clear following the final dose, and may therefore be infused on a weekly or bimonthly schedule.[L12099] Isatuximab is given in combination with [pomalidomide] due to a synergy that exists between the two - isatuximab can induce a depletion in host NK lymphocytes, yet the ADCC effect of anti-CD38 mAbs has been shown to be superior in patient samples with a high ratio of NK to myleoma cells.[A191808] Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity[A191796,A191808] and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.[A191799] Isatuximab is formulated as an intravenous infusion and its administration may result in infusion-related reactions characterized most commonly by dyspnea, cough, chills, and nausea.[L12099] All noted reactions started during the first infusion and 98% resolved on the same day. Reactions may be mitigated by pre-medication with acetaminophen, H2 antagonists, diphenyhdramine, and/or dexamethasone.[L12099] Patients with grade 1 or 2 reactions may restart the infusion at a slower rate following resolution of symptoms, but patients experiencing a grade 3 or higher reaction (e.g. hypertension, bronchospasm) should discontinue therapy indefinitely.[L12099] Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.[L12099] |
| Mechanism of Action | Multiple myeloma is a blood cancer characterized by an overproduction of malignant plasma cells in the bone marrow. A unique characteristic of myeloma cells is their dense and uniform expression of CD38 surface glycoproteins - these proteins, also expressed in relatively minor quantities on other lymphoid and myeloid cells, have been identified as performing several critical cellular functions, and this, along with their relative abundance on myeloma cells, has made them an attractive target for multiple myeloma treatment. CD38 was first identified as an activation marker, but has subsequently demonstrated roles in adhesion to endothelial CD31 proteins, as an accessory component of the synapse complex, and as an ectoenzyme involved in the metabolism of extracellular NAD+ and cytoplasmic NADP. The products of CD38’s ectoenzymatic activity include the calcium-mobilizing compound adenosine diphosphate ribose (ADPR), which can be further metabolized by CD203a/PC-1 and CD73 to adenosine, an immunosuppressive molecule that may play a role in tumour cell evasion of the immune system.[A191799] Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins.[L12099] Its activity against CD38 results in a number of downstream effects, including direct apoptosis of the affected cell and activation of immune mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC), all of which result in potent anti-tumour activity.[L12099,A191799] Via allosteric antagonism, isatuximab also inhibits CD38 ectoenzymatic activity, preventing the immunosuppressive effects of its downstream products. Isatuximab may also exert its effects via downstream promotion of lysosome-dependent cell death, upregulation of reactive oxygen species, and restoration of antitumor immune effector cell functions.[A191799] |
| Toxicity | There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose.[L12099] Symptoms of overdosage are likely to be consistent with isatuximab's adverse effect profile and may therefore include significant infusion-site reactions, gastrointestinal disturbances, and may increase the risk of infection. Treatment of overdose should involve careful monitoring of the patient and symptomatic and supportive measures as clinically indicated.[L12099] |
| Metabolism | Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides.[L12099] |
| Absorption | When administered at the recommended dose and schedule, the steady-state Cmax and AUC were found to be 351 µg/mL and 72,600 µg·h/mL, respectively.[L12099] It takes approximately 8 weeks for isatuximab to reach steady-state. Over a dosage range of 1 mg/kg to 20 mg/kg given every 2 weeks AUC increases in a greater than dose-proportional manner, whereas over a dosage range of 5 mg/kg to 20 mg/kg every 4 weeks (followed by every 2 weeks) AUC was found to increase proportionately with dose. Steady-state AUC is lower in patients with increased body weight, but not to the extent that dose adjustments are required.[L12099] Tmax ranges from approximately 2 to 5 hours, increasing with dose and with repeated dosing.[A191802] |
| The predicted volume of distribution of isatuximab is 8.13 L.[L12099] |
| Clearance | Total clearance decreases with increasing dose and with multiple dosing.[L12099] At steady-state, it takes approximately 2 months to eliminate =99% of isatuximab from plasma following the last dose.[L12099] |
| Categories | Antineoplastic Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | ADP-ribosyl cyclase 1 |
| Brand Name | Sarclisa |
| Company | Sanofi Aventis |
| Brand Description | Sanofi Aventis |
| Prescribed For | Intravenous |
| Chemical Name | 100 mg / 5 mL |
| Formulation | SARCLISA is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients [see WARNINGS AND PRECAUTIONS]. |
| Physical Appearance | low white blood cell count (neutropenia), infusion-related reactions (shortness of breath, high blood pressure, and bronchospasm), pneumonia, upper respiratory tract infection, diarrhea, anemia, low lymphocytes (lymphopenia), and low platelets (thrombocytopenia) |
| Route of Administration | Sarclisa is a prescription medicine used in combination with: the medicines pomalidomide and dexamethasone, to treat adults who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor to treat multiple myeloma. the medicines carfilzomib and dexamethasone, to treat adults... |
| Recommended Dosage | SARCLISA is indicated: |
| Contraindication | NA |
| Side Effects | SARCLISA (isatuximab-irfc) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution, essentially free of visible particles in a single-dose vial for intravenous use. Each vial contains either 100 mg/5 mL or 500 mg/25 mL of isatuximab-irfc at a concentration of 20 mg/mL with a pH of 6.0. Each mL of solution contains 20 mg isatuximabirfc, histidine (1.46 mg), histidine hydrochloride monohydrate (2.22 mg), polysorbate 80 (0.2 mg), sucrose (100 mg), and water for injection. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |