| Candidate ID: | R1544 |
| Source ID: | DB14811 |
| Source Type: | approved; investigational |
| Compound Type: |
biotech
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| Compound Name: |
Isatuximab
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| Synonyms: |
Isatuximab; isatuximab-irfc
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| Molecular Formula: |
--
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| SMILES: |
--
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| DrugBank Description: |
Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary (CHO) cell line. Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains. 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. Along with , 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, isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma. It is manufactured by Sanofi-Aventis U.S. under the brand name Sarclisa.
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| CAS Number: |
1461640-62-9
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| Molecular Weight: |
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| DrugBank Indication: |
Isatuximab is indicated in combination with and for the treatment of multiple myeloma in adults who have received at least two prior therapies including and a proteasome inhibitor. It is also indicated in combination and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
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| DrugBank Pharmacology: |
Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation. 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. Isatuximab is given in combination with 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. Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.
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. 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. 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.
Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.
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| DrugBank MoA: |
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.
Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins. 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. 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.
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| Targets: |
ADP-ribosyl cyclase 1 binder&antibody
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| Inclusion Criteria: |
Therapeutic strategy associated
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