Ofatumumab

Identification

Name
Ofatumumab
Accession Number
DB06650
Description

Ofatumumab is a novel anti-CD20 monoclonal antibody that targets B-cells. It is an IgG1κ human monoclonal antibody produced from a recombinant murine cell line (NS0) via transgenic mouse and hybridoma technology.6 Ofatumumab works by recognizing antigens that are expressed on the tumour cells in certain cancers; however, the antigen is not tumour-specific and can also be found in normal B-cells.1 Ofatumumab was first approved by the FDA in 2009.8 It is used in the treatment of recurrent, progressive, or recurrent chronic lymphocytic leukemia (CLL) or CLL in treatment-naive patients in whom fludarabine-based therapy is considered inappropriate. Ofatumumab is used as monotherapy or in combination with other medications, depending on the patient profile and previous treatment history.6 Although it has a similar molecular mechanism of action as rituximab, another CD-20 monoclonal antibody used in the treatment of rheumatoid arthritis and B-cell non-Hodgkin's lymphoma, ofatumumab has a higher affinity towards CD20.1

Ofatumumab is available for intravenous administration and is marketed as Arzerra. In Phase III clinical trials consisting of subjects with relapsing forms of multiple sclerosis (RMS), subcutaneous administration of ofatumumab reduced the number of relapses and delayed disease progression. In February 2020, FDA and EMA approved Supplemental Biologics License Application (sBLA) and Marketing Authorization Application (MAA), respectively, for ofatumumab for the treatment of RMS in adults.7 The FDA subsequently approved ofatumumab for the treatment of RMS on August 20, 2020.9 The potential therapeutic use of ofatumumab in various lymphomas and rheumatoid arthritis has also been investigated.4

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db06650
Protein Chemical Formula
C6480H10022N1742O2020S44
Protein Average Weight
146100.0 Da
Sequences
>Ofatumumab Heavy Chain
EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSIGY
ADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTV
SSASTKGPSVFPLAPGSSKSTSGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP
>Ofatumumab Light Chain
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNR
Download FASTA Format
Synonyms
  • HuMax-CD20
  • HuMax-CD20, 2F2
  • Ofatumumab
  • Ofatumumabum
External IDs
  • GSK 1841157
  • GSK-1841157
  • GSK1841157
  • GSKI841157
  • HSDB 8170
  • OMB 157
  • OMB-157
  • OMB157

Pharmacology

Indication

Ofatumumab is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate.6

In patients with recurrent or progressive CLL, ofatumumab is indicated for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.6

Ofatumumab is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.6

Ofatumumab is also indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including active secondary progressive disease, clinically isolated syndrome, and relapsing-remitting disease.9

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ofatumumab works by binding to and blocking the action of CD-20, a molecule expressed on the surface of both healthy and leukemic B lymphocytes. In patients with previously untreated chronic lymphocytic leukemia (CLL), ofatumumab caused B-cell depletion in the peripheral blood after six months following the last dose. However, observable depletion of B cells in the peripheral blood does not directly correlate with the depletion of B-cells in solid organs or malignant tumours.6 In vitro, ofatumumab induces complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).1

Mechanism of action

CD20 is expressed on normal pre-B lymphocytes and mature B lymphocytes, as well as malignant B lymphocytes. Numerous studies demonstrate that the depletion of B-cells can significantly alleviate symptoms of many forms of leukemia and lymphoma, which are malignancies associated with B-cell dysfunctions and high expression of CD20.4

Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab binds to CD20, and this drug-target interaction does not result in immediate shedding and internalization of CD20 from the plasma membrane of B lymphocytes.2,6 This allows ofatumumab to persist on the B lymphocyte cell surface for an extended period and recruit immunological molecules or FcR-expressing innate effectors, such as macrophages, that mediate immune effector functions with strong cytotoxic effects.2,4 These immune effector functions include complement-dependent cytotoxicity (CCD) and antibody-dependent cellular cytotoxicity (ADCC), which promote the lysis of malignant B-cells.2,4,6 Complement-dependent cytotoxicity (CDC) involves translocation of the CD20 molecule into lipid rafts, which are involved in cell signalling and receptor trafficking.1

The mechanism by which ofatumumab exerts a therapeutic effect in multiple sclerosis patients is unknown but is presumed to still occur as a consequence of its ability to bind CD20.9

TargetActionsOrganism
AB-lymphocyte antigen CD20
antibody
Humans
Absorption

In one study consisting of patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma, the Cmax was 94 μg/mL and the Tmax was 7.3 hours following the first infusion of 300 mg ofatumumab.5

Following subcutaneous injection, ofatumumab is thought to be absorbed primarily into the lymphatic system. Subcutaneous dosing of 20 mg every four weeks resulted in a mean AUCtau of 483 μg*h/mL and a mean steady-state Cmax of 1.43 μg/mL.9

Volume of distribution

In patients with CLL, the mean volume of distribution at steady-state was 5.8 L.6

Repeated subcutaneous dosing with 20 mg of ofatumumab resulted in a steady-state volume of distribution of 5.42 L.9

Protein binding

There is limited information on the serum protein binding profile of ofatumumab.

Metabolism

Like other monoclonal antibodies, ofatumumab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway.3

Route of elimination

Ofatumumab undergoes elimination by a target-independent route and a target (B cell)-mediated route, with a dose-dependent clearance in the dose range of 100 to 2000 mg. As ofatumumab causes B-cell depletion, the clearance of ofatumumab mediated by B-cells is decreased substantially after subsequent drug infusions.6

Half-life

In patients with CLL, the mean half-life at steady state was 17.1 days.6 Similarly, in patients given ofatumumab subcutaneously, the steady-state elimination half-life was estimated at 16 days.9

Clearance

In patients with CLL, the mean clearance at steady-state was 11.6 mL/hour.6

In patients administered ofatumumab subcutaneously in repeated 20 mg injections, the steady-state clearance following B-cell depletion was estimated to be 0.34 L/day.9

Adverse Effects
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Toxicity

There is limited information on overdose of ofatumumab. Ofatumumab may cause B-cell depletion in the fetus when administered in pregnant women.6

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 Ofatumumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ofatumumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ofatumumab.
AlirocumabThe risk or severity of adverse effects can be increased when Ofatumumab is combined with Alirocumab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Ofatumumab is combined with Anthrax immune globulin human.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Ofatumumab is combined with Antilymphocyte immunoglobulin (horse).
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Ofatumumab.
Asfotase alfaThe risk or severity of adverse effects can be increased when Ofatumumab is combined with Asfotase alfa.
AtezolizumabThe risk or severity of adverse effects can be increased when Ofatumumab is combined with Atezolizumab.
AtoltivimabThe risk or severity of adverse effects can be increased when Ofatumumab is combined with Atoltivimab.
Additional Data Available
  • Extended Description
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  • Severity
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  • Evidence Level
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  • Action
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Food Interactions
No interactions found.

Products

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International/Other Brands
Kesimpta (Novartis)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ArzerraInjection, solution20 mg/1mLIntravenousGlaxosmithkline Inc2011-07-222017-08-31US flag
ArzerraSolution100 mgIntravenousNovartis2012-08-132019-03-01Canada flag
ArzerraInjection, solution20 mg/1mLIntravenousNovartis Pharmaceuticals Corporation2016-02-01Not applicableUS flag
ArzerraInjection20 mg/1mLIntravenousGlaxosmithkline Inc2009-10-262012-03-31US flag
ArzerraInjection, solution20 mg/1mLIntravenousNovartis Pharmaceuticals Corporation2016-02-01Not applicableUS flag
ArzerraSolution1000 mgIntravenousNovartis2012-08-132019-03-01Canada flag
KesimptaInjection, solution20 mg/0.4mLSubcutaneousNovartis Pharmaceuticals Corporation2009-10-26Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
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    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
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    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XC10 — Ofatumumab
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
M95KG522R0
CAS number
679818-59-8

References

General References
  1. Lin TS: Ofatumumab: a novel monoclonal anti-CD20 antibody. Pharmgenomics Pers Med. 2010;3:51-9. Epub 2010 May 10. [PubMed:23226042]
  2. Glennie MJ, French RR, Cragg MS, Taylor RP: Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007 Sep;44(16):3823-37. [PubMed:17768100]
  3. Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [PubMed:28653357]
  4. Zhang B: Ofatumumab. MAbs. 2009 Jul-Aug;1(4):326-31. doi: 10.4161/mabs.1.4.8895. Epub 2009 Jul 1. [PubMed:20068404]
  5. Ogura M, Hatake K, Tobinai K, Uchida T, Suzuki T, Terui Y, Yokoyama M, Maruyama D, Mori M, Jewell RC, Katsura K, Hotta T: Phase I study of ofatumumab, a human anti-CD20 antibody, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Jpn J Clin Oncol. 2013 May;43(5):466-75. doi: 10.1093/jjco/hyt022. Epub 2013 Feb 28. [PubMed:23456745]
  6. FDA Approved Drug Products: ARZERRA (ofatumumab) injection, for intravenous use [Link]
  7. Novartis announces FDA and EMA filing acceptance of ofatumumab, a novel B-cell therapy for patients with relapsing forms of multiple sclerosis (RMS) [Link]
  8. Arzerra (ofatumumab) FDA Approval History - Drugs.com [Link]
  9. FDA Approved Drug Products: KESIMPTA (ofatumumab) injection [Link]
KEGG Drug
D09314
PubChem Substance
347910355
RxNav
712566
ChEMBL
CHEMBL1201836
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ofatumumab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (153 KB)
MSDS
Download (92 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma1
3CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)2
3CompletedTreatmentLeukemias1
3CompletedTreatmentLymphoma, Large-Cell, Diffuse1
3CompletedTreatmentRelapsed or Refractory Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma1
3CompletedTreatmentRelapsing Multiple Scelrosis1
3CompletedTreatmentRelapsing Multiple Sclerosis (RMS)1
3Enrolling by InvitationTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma1
3Not Yet RecruitingTreatmentRelapsing Multiple Sclerosis (RMS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous20 mg/1mL
Injection, solutionIntravenous20 mg/1mL
SolutionIntravenous100 mg
SolutionIntravenous1000 mg
Injection, solutionIntravenous100 mg
Injection, solutionIntravenous1000 mg
Injection, solutionSubcutaneous20 mg/0.4mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8337847No2012-12-252028-11-25US flag
US8975282No2015-03-102032-07-28US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Liquid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Mhc class ii protein complex binding
Specific Function
This protein may be involved in the regulation of B-cell activation and proliferation.
Gene Name
MS4A1
Uniprot ID
P11836
Uniprot Name
B-lymphocyte antigen CD20
Molecular Weight
33076.99 Da
References
  1. Dorner T, Burmester GR: New approaches of B-cell-directed therapy: beyond rituximab. Curr Opin Rheumatol. 2008 May;20(3):263-8. doi: 10.1097/BOR.0b013e3282f5e08d. [PubMed:18388516]
  2. Glennie MJ, French RR, Cragg MS, Taylor RP: Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007 Sep;44(16):3823-37. [PubMed:17768100]
  3. Du J, Yang H, Guo Y, Ding J: Structure of the Fab fragment of therapeutic antibody Ofatumumab provides insights into the recognition mechanism with CD20. Mol Immunol. 2009 Jul;46(11-12):2419-23. doi: 10.1016/j.molimm.2009.04.009. Epub 2009 May 8. [PubMed:19427037]

Drug created on March 19, 2008 10:44 / Updated on November 27, 2020 08:19

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