Ofatumumab

Identification

Summary

Ofatumumab is an anti-CD20 antibody used for the treatment of chronic lymphocytic leukemia (CLL) in selected patients with certain treatment histories and responsiveness to anticancer medications.

Brand Names

Arzerra, Kesimpta

Generic Name

Ofatumumab

DrugBank Accession Number

DB06650

Background

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

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

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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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Chronic lymphocytic leukemia	Regimen in combination with: Chlorambucil (DB00291)	••••••••••••		••••••••• •••••• •••••••••• ••• ••••••••••••••••• •••••••	•••••••••
Treatment of	Clinically isolated syndrome (cis)		••••••••••••	•••••		•••••••••
Treatment of	Refractory chronic lymphocytic leukemia		••••••••••••		•••••••••• •• ••••••••••• ••• •••••••••••	•••••••••
Treatment of	Relapsing multiple sclerosis (rms)		••••••••••••	•••••		•••••••••
Treatment of	Relapsing remitting multiple sclerosis (rrms)		••••••••••••	•••••		•••••••••

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

Target	Actions	Organism
AB-lymphocyte antigen CD20	antibody regulator	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 AUC_tau of 483 μg*h/mL and a mean steady-state C_max 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

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
Integrate drug-drug interactions in your software
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Ofatumumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Ofatumumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Ofatumumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ofatumumab.
Aducanumab	The risk or severity of adverse effects can be increased when Ofatumumab is combined with Aducanumab.

Food Interactions

No interactions found.

Products

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International/Other Brands

Kesimpta (Novartis)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Arzerra	Injection, solution	20 mg/1mL	Intravenous	Glaxosmithkline Inc	2011-07-22	2017-08-31
Arzerra	Injection, solution, concentrate	100 mg	Intravenous	Novartis Europharm Limited	2021-01-12	2019-05-10
Arzerra	Solution	1000 mg / 50 mL	Intravenous	Novartis	2012-08-13	2019-03-01
Arzerra	Injection, solution	20 mg/1mL	Intravenous	Novartis Pharmaceuticals Corporation	2016-02-01	Not applicable
Arzerra	Injection	20 mg/1mL	Intravenous	Glaxosmithkline Inc	2009-10-26	2012-03-31

Chemical Identifiers

UNII: M95KG522R0
CAS number: 679818-59-8

References

General References

Lin TS: Ofatumumab: a novel monoclonal anti-CD20 antibody. Pharmgenomics Pers Med. 2010;3:51-9. Epub 2010 May 10. [Article]
Glennie MJ, French RR, Cragg MS, Taylor RP: Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007 Sep;44(16):3823-37. [Article]
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. [Article]
Zhang B: Ofatumumab. MAbs. 2009 Jul-Aug;1(4):326-31. doi: 10.4161/mabs.1.4.8895. Epub 2009 Jul 1. [Article]
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. [Article]
FDA Approved Drug Products: ARZERRA (ofatumumab) injection, for intravenous use [Link]
Novartis announces FDA and EMA filing acceptance of ofatumumab, a novel B-cell therapy for patients with relapsing forms of multiple sclerosis (RMS) [Link]
Arzerra (ofatumumab) FDA Approval History - Drugs.com [Link]
FDA Approved Drug Products: KESIMPTA (ofatumumab) injection [Link]
FDA Approved Drug Products: KESIMPTA® (ofatumumab) injection, for subcutaneous use (Jan 2024) [Link]

External Links

KEGG Drug: D09314
PubChem Substance: 347910355
RxNav: 712566
ChEMBL: CHEMBL1201836
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Ofatumumab

FDA label

Download (153 KB)

MSDS

Download (92 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Relapsing Multiple Sclerosis (RMS)	1
4	Completed	Treatment	Chronic Lymphocytic Leukemia	1
4	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19) / Multiple Sclerosis	1
4	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19) / Relapsing Multiple Sclerosis (RMS)	1
4	Completed	Treatment	Relapsing Multiple Sclerosis (RMS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	20 mg/1mL
Injection, solution	Intravenous	20 mg/1mL
Injection, solution, concentrate	Intravenous
Injection, solution, concentrate	Intravenous	100 mg
Injection, solution, concentrate	Intravenous	1000 mg
Solution	Intravenous	100 mg / 5 mL
Solution	Intravenous	1000 mg / 50 mL
Injection, solution	Intravenous	100 mg
Injection, solution	Intravenous	1000 mg
Solution	Subcutaneous	20.000 mg
Solution		20 mg/0.4mL
Injection, solution		20 mg/0.4ml
Injection, solution	Subcutaneous	20 mg/0.4mL
Injection, solution	Subcutaneous	20 MG
Solution	Subcutaneous	20 mg / 0.4 mL
Solution	Subcutaneous	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8337847	No	2012-12-25	2028-11-25
US8975282	No	2015-03-10	2032-07-28

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. B-lymphocyte antigen CD20

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antibody
Regulator

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

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. [Article]
Glennie MJ, French RR, Cragg MS, Taylor RP: Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007 Sep;44(16):3823-37. [Article]
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. [Article]
Schnaiter A, Stilgenbauer S: Refractory chronic lymphocytic leukemia--new therapeutic strategies. Oncotarget. 2010 Nov;1(7):472-82. doi: 10.18632/oncotarget.101103. [Article]
Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A: Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel). 2021 Mar 5;7(3). pii: jof7030186. doi: 10.3390/jof7030186. [Article]

Drug created at March 19, 2008 16:44 / Updated at February 20, 2024 23:54

Ofatumumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References