Isatuximab

Identification

Name
Isatuximab
Accession Number
DB14811
Description

Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary (CHO) cell line.9,2 Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.9 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.9 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,6,7,8 isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma.9,10 It is manufactured by Sanofi-Aventis U.S. under the brand name Sarclisa.10

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da
Sequences
Not Available
Synonyms
  • Isatuximab
  • isatuximab-irfc
External IDs
  • Hu 38SB19
  • SAR 650984
  • SAR-650984
  • SAR650984

Pharmacology

Indication

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.9

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation.9 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.9 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.5 Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity1,5 and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.2

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.9 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.9 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.9

Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.9

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.2

Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins.9 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.9,2 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.2

TargetActionsOrganism
UADP-ribosyl cyclase 1
inhibitor
Humans
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.9 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.9 Tmax ranges from approximately 2 to 5 hours, increasing with dose and with repeated dosing.3

Volume of distribution

The predicted volume of distribution of isatuximab is 8.13 L.9

Protein binding
Not Available
Metabolism

Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides.9

Route of elimination
Not Available
Half-life
Not Available
Clearance

Total clearance decreases with increasing dose and with multiple dosing.9 At steady-state, it takes approximately 2 months to eliminate ≥99% of isatuximab from plasma following the last dose.9

Adverse Effects
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Toxicity

There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose.9 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.9

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Isatuximab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Isatuximab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Isatuximab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Isatuximab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Isatuximab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Isatuximab.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Isatuximab.
Asfotase alfaThe risk or severity of adverse effects can be increased when Asfotase alfa is combined with Isatuximab.
AtezolizumabThe risk or severity of adverse effects can be increased when Atezolizumab is combined with Isatuximab.
AvelumabThe risk or severity of adverse effects can be increased when Avelumab is combined with Isatuximab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SarclisaInjection, solution, concentrate500 mg/25mLIntravenoussanof-aventis U.S. LLC2020-03-02Not applicableUS flag
SarclisaSolution500 mgIntravenousSanofi Aventis2020-07-03Not applicableCanada flag
SarclisaInjection, solution, concentrate100 mg/5mLIntravenoussanof-aventis U.S. LLC2020-03-02Not applicableUS flag
SarclisaSolution100 mgIntravenousSanofi Aventis2020-07-03Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
R30772KCU0
CAS number
1461640-62-9

References

General References
  1. Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, Blanco L, Lasa M, Maiso P, Rodriguez I, Garate S, Jelinek T, Segura V, Moreno C, Merino J, Rodriguez-Otero P, Panizo C, Prosper F, San-Miguel JF, Paiva B: The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma. Clin Cancer Res. 2019 May 15;25(10):3176-3187. doi: 10.1158/1078-0432.CCR-18-1597. Epub 2019 Jan 28. [PubMed:30692097]
  2. Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F: CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Front Immunol. 2018 Nov 28;9:2722. doi: 10.3389/fimmu.2018.02722. eCollection 2018. [PubMed:30546360]
  3. Mikhael J, Richardson P, Usmani SZ, Raje N, Bensinger W, Karanes C, Campana F, Kanagavel D, Dubin F, Liu Q, Semiond D, Anderson K: A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Blood. 2019 Jul 11;134(2):123-133. doi: 10.1182/blood-2019-02-895193. Epub 2019 Mar 12. [PubMed:30862646]
  4. Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, Solanki M, Meng R, Lee H, Wiederschain D, Zhu C, Rak A, Anderson KC: Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab. Cells. 2019 Nov 26;8(12). pii: cells8121522. doi: 10.3390/cells8121522. [PubMed:31779273]
  5. van de Donk NWCJ, Usmani SZ: CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance. Front Immunol. 2018 Sep 20;9:2134. doi: 10.3389/fimmu.2018.02134. eCollection 2018. [PubMed:30294326]
  6. Kaplon H, Reichert JM: Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203. doi: 10.1080/19420862.2018.1415671. Epub 2018 Jan 16. [PubMed:29300693]
  7. Kaplon H, Reichert JM: Antibodies to watch in 2019. MAbs. 2019 Feb/Mar;11(2):219-238. doi: 10.1080/19420862.2018.1556465. Epub 2018 Dec 22. [PubMed:30516432]
  8. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [PubMed:31847708]
  9. FDA Approved Drug Products: Sarclisa (isatuximab-irfc) for intravenous injection [Link]
  10. FDA News Release: Isatuximab Approval [Link]
RxNav
2282018
Wikipedia
Isatuximab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (477 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMultiple Myeloma (MM)1
3Active Not RecruitingTreatmentPlasma Cell Myeloma3
3Not Yet RecruitingTreatmentMultiple Myeloma (MM)1
3RecruitingTreatmentPlasma Cell Myeloma1
2Active Not RecruitingTreatmentAmorphous, Eosinophilic, and Acellular Deposit / Constipation / Diarrhea / Early satiety / Gastrointestinal Hemorrhage / Hepatomegaly / Lymphadenopathy / Macroglossia / Nausea / Primary Systemic Amyloidosis / Purpura / Recurrent Primary Amyloidosis / Refractory Primary Amyloidosis1
2Active Not RecruitingTreatmentSmoldering Plasma Cell Myeloma1
2Not Yet RecruitingTreatmentMultiple Myeloma (MM)2
2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Myeloid Leukemia (AML)1
2RecruitingTreatmentMultiple Myeloma (MM)2
2RecruitingTreatmentMultiple Myeloma in Relapse / Refractory Multiple Myeloma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous100 mg/5mL
Injection, solution, concentrateIntravenous500 mg/25mL
SolutionIntravenous100 mg
SolutionIntravenous500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transferase activity
Specific Function
Synthesizes the second messagers cyclic ADP-ribose and nicotinate-adenine dinucleotide phosphate, the former a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activ...
Gene Name
CD38
Uniprot ID
P28907
Uniprot Name
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Molecular Weight
34328.145 Da
References
  1. FDA Approved Drug Products: Sarclisa (isatuximab-irfc) for intravenous injection [Link]

Drug created on May 20, 2019 08:28 / Updated on October 26, 2020 22:41

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