Isatuximab

Uses

Isatuximab is a chimeric monoclonal antibody targeted against surface CD38 glycoproteins for the treatment of multiple myeloma in patients who have failed previous therapies.

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.

Isatuximab is also used to associated treatment for these conditions: Multiple Myeloma (MM)

How Isatuximab works

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.

Toxicity

There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose. 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.

Food Interaction

Isatuximab Disease Interaction

Moderate: hepatic impairment

Volume of Distribution

The predicted volume of distribution of isatuximab is 8.13 L.

Elimination Route

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.

Clearance

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.

Innovators Monograph

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