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General Description:

Isatuximab, identified by CAS number 1461640-62-9, is a notable compound with significant therapeutic applications. 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.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Isatuximab undergoes metabolic processing primarily in: Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Isatuximab are crucial for its therapeutic efficacy: When administered at the recommended dose and schedule, the steady-state C_max and AUC were found to be 351 µg/mL and 72,600 μg∙h/mL, respectively. 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. T_max ranges from approximately 2 to 5 hours, increasing with dose and with repeated dosing. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Volume of Distribution:

Isatuximab is distributed throughout the body with a volume of distribution of: The predicted volume of distribution of isatuximab is 8.13 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Isatuximab is a critical factor in determining its safe and effective dosage: Total clearance decreases with increasing dose and with multiple dosing. At steady-state, it takes approximately 2 months to eliminate ≥99% of isatuximab from plasma following the last dose. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Isatuximab exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Isatuximab functions by: 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Isatuximab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Isatuximab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Blood Proteins, Cancer immunotherapy, CD38 (Clusters of Differentiation 38) inhibitors, CD38-directed Antibody Interactions, CD38-directed Cytolytic Antibody, Globulins, Immunoglobulins, Immunoproteins, Immunotherapy, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Multiple Myeloma, drug therapy, Narrow Therapeutic Index Drugs, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Isatuximab include:

• Molecular Weight: 148000.0