Daratumumab

Identification

Name
Daratumumab
Accession Number
DB09331
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Daratumumab is an anti-cancer drug indicated for multiple myeloma in patients who have received at least 3 prior treatments. It was granted accelerated approval by the FDA in November 2016. Marketed under the brand name Darzalex by Janssen Biotech, daratumumab is the first monoclonal antibody injection approved for this indication and provides another options for patients with multiple myeloma resistant to other therapies. Daratumumab induces apoptosis of cancer cells by targeting the CD38 epitope, which is highly expressed on haematological malignancies.

Protein structure
Db09331
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • HuMax-CD38
External IDs
JNJ-54767414
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DarzalexSolution400 mgIntravenousJanssen Pharmaceuticals2016-07-12Not applicableCanada
DarzalexInjection, solution, concentrate20 mg/mlIntravenousJanssen Cilag International Nv2016-05-20Not applicableEu
DarzalexSolution100 mgIntravenousJanssen Pharmaceuticals2016-07-12Not applicableCanada
DarzalexInjection, solution, concentrate100 mg/5mLIntravenousJanssen Biotech, Inc.2015-11-16Not applicableUs
DarzalexInjection, solution, concentrate20 mg/mlIntravenousJanssen Cilag International Nv2016-05-20Not applicableEu
Categories
UNII
4Z63YK6E0E
CAS number
945721-28-8

Pharmacology

Indication

For the treatment of patients with multiple myeloma who have received at least three prior lines of therapy (a proteasome inhibitor (PI) and an immunomodulatory agent) or who are double-refractory to a PI and an immunomodulatory agent. This indication was approved by accelerated approval based on response rate.

Associated Conditions
Pharmacodynamics

In preclinical trials, daratumumab showed synergistic activity with other multiple myeloma therapies, notably lenalidomide. Daratumumab also causes lysis in other cells that express CD38: myeloid-derived suppressor cells, a subset of regulatory T-cells, and NK cells. Decreases in absolute count and percentage of NK cells were observed during treatment. CD4+ and CD8+ T cell absolute counts as well the percentage of total lymphocytes increased in peripheral blood and bone marrow during daratumumab treatment.

Mechanism of action

Daratumumab is an immunoglobulin G1 kappa monoclonal antibody against CD38 antigen. CD38 is a transmembrane glycoprotein of many functions, including receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. CD38 is expressed on many cell types and tissues, and highly expressed in haematological malignancies including multiple myeloma tumor cells. By binding CD38, daratumumab causes inhibition of tumor cell growth and induces broad-spectrum apoptosis in multiple ways: by Fc-mediated cross linking, by immune-mediate tumor cell lysis through complement dependent cytotoxicity, antibody dependent cell cytotoxicity, and antibody dependent cellular phagocytosis.

TargetActionsOrganism
UADP-ribosyl cyclase 1
antibody
Human
Absorption

Following the recommended schedule and dose of 16 mg/kg, the mean serum Cmax value was 915 μg/mL at the end of weekly dosing, approximately 2.9-fold higher than following the first infusion. The mean predose serum concentration at the end of weekly dosing was 573 μg/mL.

Volume of distribution

4.7 L

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Approximately 18 days.

Clearance

171.4 mL/day. Clearance decreased with increasing dose and repeated dosing, indicating target-mediated pharmacokinetics.

Toxicity

Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Due to its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. The FDA label recommends to defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. Women of reproductive potential should also should use effective contraception methods during treatment and 3 months post-treatment to avoid pregnancy and exposure to the fetus while on daratumumab.

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

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Daratumumab.
AbituzumabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Abituzumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Daratumumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Daratumumab.
AducanumabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Aducanumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Daratumumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Daratumumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Daratumumab.
AmatuximabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Amatuximab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Daratumumab.
Food Interactions
No interactions found.

References

General References
  1. McKeage K: Daratumumab: First Global Approval. Drugs. 2016 Feb;76(2):275-81. doi: 10.1007/s40265-015-0536-1. [PubMed:26729183]
  2. Phipps C, Chen Y, Gopalakrishnan S, Tan D: Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 2015 Jun;6(3):120-7. doi: 10.1177/2040620715572295. [PubMed:26137203]
  3. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW: Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011 Feb 1;186(3):1840-8. doi: 10.4049/jimmunol.1003032. Epub 2010 Dec 27. [PubMed:21187443]
External Links
PubChem Substance
347910441
ChEMBL
CHEMBL1743007
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Daratumumab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (417 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentMalignant Neoplasms of Urinary Tract1
1Active Not RecruitingTreatmentMultiple Myeloma (MM)3
1CompletedTreatmentMultiple Myeloma (MM)2
1Not Yet RecruitingTreatmentBreast Adenocarcinoma / Recurrent Breast Carcinoma / Recurrent Hodgkin Lymphoma / Recurrent Mycosis Fungoides / Recurrent Non-Hodgkin Lymphoma / Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma / Refractory Hodgkin Lymphoma / Refractory Nodal Marginal Zone Lymphoma / Refractory Non-Hodgkin's lymphoma / Refractory, advanced Mycosis fungoides / Refractory, primary Cutaneous T-Cell Non-Hodgkin Lymphoma / Stage IV Breast Cancer AJCC v6 and v71
1Not Yet RecruitingTreatmentLeukemia, Plasma Cell1
1RecruitingDiagnosticPlasma Cell Myeloma / Recurrent Plasma Cell Myeloma / Secondary amyloidosis1
1RecruitingOtherHealthy Volunteers1
1RecruitingTreatmentAdenocarcinoma of the Prostate / Malignant Neoplasms of Male Genital Organs / Prostate Cancer1
1RecruitingTreatmentAmyloid Light Chain (AL) Amyloidosis / Hematopoietic/Lymphoid Cancer1
1RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
1RecruitingTreatmentMultiple Myeloma (MM)4
1, 2Active Not RecruitingTreatmentAL Amyloidosis1
1, 2Active Not RecruitingTreatmentCancer, Advanced1
1, 2Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2Not Yet RecruitingTreatmentMinimal Residual Disease / Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes / Recurrent Adult Acute Myeloid Leukemia / Recurrent Childhood Acute Myeloid Leukemia1
1, 2Not Yet RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma1
1, 2RecruitingTreatmentLymphoma, Hodgkins / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
1, 2RecruitingTreatmentMultiple Myeloma (MM)2
1, 2RecruitingTreatmentVarious Advanced Cancer1
2Active Not RecruitingTreatmentAmyloidosis1
2Active Not RecruitingTreatmentMicrosatellite Stable Colorectal Cancer / Microsatellite Unstable Colorectal Cancer / Mismatch Repair Deficient Colorectal Cancer / Mismatch Repair Proficient Colorectal Cancer / MSI Negative Colorectal Cancer / MSI Positive Colorectal Cancer1
2Active Not RecruitingTreatmentMultiple Myeloma (MM)6
2Active Not RecruitingTreatmentMultiple Myeloma (MM) / Smoldering Multiple Myeloma (SMM)1
2Active Not RecruitingTreatmentMyelodysplastic Syndromes1
2CompletedTreatmentMultiple Myeloma (MM)3
2Not Yet RecruitingPreventionMultiple Myeloma (MM)1
2Not Yet RecruitingTreatmentMultiple Myeloma (MM)3
2Not Yet RecruitingTreatmentMultiple Myeloma (MM) / Plasma Cell Myeloma2
2Not Yet RecruitingTreatmentMultiple Myeloma in Relapse1
2Not Yet RecruitingTreatmentPlasma Cell Myeloma / Secondary amyloidosis1
2Not Yet RecruitingTreatmentRecurrent Plasma Cell Myeloma1
2Not Yet RecruitingTreatmentWaldenstrom's Disease / Waldenstrom's Macroglobulinaemia, Without Mention of Remission / Waldenstrom's Macroglobulinemia of Lymph Nodes / Waldenstrom's Macroglobulinemia Recurrent / Waldenstrom's Macroglobulinemia Refractory / Waldenström's Macroglobulinemia (WM) / Waldenström; Hypergammaglobulinemia1
2RecruitingTreatmentAcute Myelogenous Leukaemia (AML) / Hematopoietic/Lymphoid Cancer / High-risk Myelodysplastic Syndrome1
2RecruitingTreatmentCancer - Multiple Myeloma / Multiple Myeloma (MM)1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome1
2RecruitingTreatmentMalignant Lymphomas1
2RecruitingTreatmentMembranoproliferative Glomerulonephritis1
2RecruitingTreatmentMinimal Residual Disease / Plasma Cell Myeloma1
2RecruitingTreatmentMonoclonal Gammopathy / Smoldering Multiple Myeloma (SMM)1
2RecruitingTreatmentMultiple Myeloma (MM)10
2RecruitingTreatmentPlasma Cell Myeloma2
2RecruitingTreatmentPrecursor Cell Lymphoblastic Leukemia-Lymphoma1
2RecruitingTreatmentRefractory Multiple Myeloma1
2RecruitingTreatmentRelapse and / or Refractory Myeloma1
2RecruitingTreatmentRelapsed/Refractory Multiple Myeloma1
2RecruitingTreatmentSmoldering Multiple Myeloma (SMM)1
2RecruitingTreatmentWaldenström's Macroglobulinemia (WM)1
2TerminatedTreatmentFollicular Lymphoma (FL) / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Mantle Cell Lymphoma (MCL)1
2WithdrawnTreatmentMalignant Neoplasms Stated as Primary Lymphoid Haematopoietic1
2WithdrawnTreatmentMalignant Neoplasms of Male Genital Organs / Prostate Cancer1
2, 3Active Not RecruitingTreatmentMultiple Myeloma (MM)1
2, 3CompletedTreatmentMultiple Myeloma (MM)1
3Active Not RecruitingTreatmentMultiple Myeloma (MM)5
3Active Not RecruitingTreatmentRelapsed Or Refractory Multiple Myeloma1
3Not Yet RecruitingTreatmentMultiple Myeloma (MM)3
3RecruitingTreatmentAmyloidosis1
3RecruitingTreatmentMultiple Myeloma (MM)4
3RecruitingTreatmentSmoldering Multiple Myeloma (SMM)1
Not AvailableAvailableNot AvailableMultiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solution, concentrateIntravenous100 mg/5mL
Injection, solution, concentrateIntravenous20 mg/ml
SolutionIntravenous100 mg
SolutionIntravenous400 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antibody
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. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW: Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011 Feb 1;186(3):1840-8. doi: 10.4049/jimmunol.1003032. Epub 2010 Dec 27. [PubMed:21187443]

Drug created on November 18, 2015 10:34 / Updated on November 18, 2018 13:31