Ocrelizumab

Identification

Summary

Ocrelizumab is a CD20 specific monoclonal antibody used to treat relapsing remitting multiple sclerosis.

Brand Names
Ocrevus
Generic Name
Ocrelizumab
DrugBank Accession Number
DB11988
Background

Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of patients with primary progressive or relapsing forms of multiple sclerosis (MS).9 It is a second-generation recombinant humanized monoclonal IgG1 antibody that selectively targets B-cells that express the CD20 antigen.2 Compared to non-humanized CD20 antibodies such as rituximab, ocrelizumab is expected to be less immunogenic with repeated infusions, improving the benefit-to-risk profile for patients with MS.1,7

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that leads to neurological disabilities and a significantly reduced quality of life.8 Most patients with MS experience episodes of relapses with worsening function, followed by recovery periods or remissions. Primary progressive multiple sclerosis (PPMS) accounts for 10-15% of the overall population of patients with MS, and leads to the gradual worsening of neurologic disability from symptom onset, often without early relapses or remissions 3.

Developed by Genentech/Roche, ocrelizumab was approved by the FDA in March 2017 under the market name Ocrevus for intravenous injection. It was later approved by Health Canada in August 2017, making the drug the first available treatment for PPMS in both the US and Canada. In clinical trials of patients with relapsing forms of MS, treatment with ocrelizumab resulted in reduced relapse rates and reduced worsening of disability compared to interferon beta-1a.8 In phase 3 clinical trials of patients with PPMS, treatment with ocrelizumab led to lower clinical and MRI progression rates compared to placebo.3

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6494H9978N1718O2014S46
Protein Average Weight
145000.0 Da (Approximate, glycosylated)
Sequences
>CDR L1 sequence (SEQ ID 1)
RASSSVSYMH
>CDR L2 sequence (SEQ ID 2)
APSNLAS
>CDR L3 sequence (SEQ ID 3)
QQWSFNPPT
>CDR H1 sequence (SEQ ID 4)
GYTFTSYNMH
>CDR H2 sequence (SEQ ID 5)
AIYPGNGDTSYNQKFKG
>CDR H3 sequence (SEQ ID 6)
VVYYSNSYWYFDV
>Variable light chain sequence (SEQ ID 7)
DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPLIYAPSNLASGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQWSFNPPTFGQGTKVEIKR
>Variable heavy chain sequence (SEQ ID 8)
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSY
NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTV
SS
>Light chain amino acid sequence (SEQ ID 9)
DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPLIYAPSNLASGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQWSFNPPTFGQGTKVEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Heavy chain amino acid sequence (SEQ ID 10)
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSY
NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Heavy chain amino acid sequence (SEQ ID 11)
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSY
NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
References:
  1. Manfrini, M. (2022). Methods for treating multiple sclerosis with ocrelizumab (U.S. Patent No. US 2022/0064320 A1). U.S. Patent and Trademark Office. [Link]
Download FASTA Format
Synonyms
  • Ocrelizumab
  • Ocrelizumab (genetical recombination)
  • rhuMAb 2H7
External IDs
  • PR-070769
  • PR070769
  • R-1594
  • RG-1594
  • RO4964913

Pharmacology

Indication

Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Ocrelizumab is also indicated for the treatment of primary progressive MS in adults.9

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofClinically isolated syndrome (cis)••••••••••••••••••••••••••
Management ofPrimary progressive multiple sclerosis••••••••••••••••••••••••••
Management ofRelapsing multiple sclerosis••••••••••••••••••••••••••
Management ofRelapsing remitting multiple sclerosis (rrms)••••••••••••••••••••••••••
Management ofActive secondary progressive multiple sclerosis (spms)••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Since ocrelizumab interferes with the CD20 assay, CD19+B-cells are used to assess B-cell counts after treatment. Fourteen days following infusion, a reduction in CD19+B-cell counts was observed. In clinical studies, B-cell counts rose above the lower limit of normal (LLN) or baseline counts between infusions of ocrelizumab at least once in 0.3% to 4.1% of patients. In a clinical study involving 51 patients, the time for B-cell counts to return to baseline or LLN ranged from 27 to 125 weeks, with a median time of 72 weeks after the last infusion. Within 2.5 years after the last infusion, B-cell counts returned to either baseline or LNN in 90% of patients treated with ocrelizumab.9

Since ocrelizumab is a recombinant humanized antibody, it is expected to be less immunogenic than rituximab, a chimeric antibody. Compared to the ocrelizumab pivotal trial, a rituximab phase II trial had a higher proportion of anti-drug antibodies, suggesting greater immunogenicity. However, caution should be exercised since these studies used different assay methods, and the association between anti-drug antibody development and infusion reactions has not been fully elucidated.5 The use of ocrelizumab can cause infusion reactions, and lead to a higher risk of respiratory tract infections and viral infections. Cases of progressive multifocal leukoencephalopathy (PML) and immune-mediated colitis have been reported in patients treated with ocrelizumab. Also, an increased risk of malignancy may exist.9

Mechanism of action

Ocrelizumab is a recombinant humanized antibody that targets CD20, a glycosylated phosphoprotein expressed on the surface of different types of B-cells. CD20 can be found on pre-B cells, naïve and memory B-cells, and it is not expressed on hematopoietic stem B-cells, pro-B cells (precursors), or differentiated plasma cells.2,3 Therefore, by targeting CD20, ocrelizumab does not affect the concentration of IgG and IgM antibodies in blood or the cerebrospinal fluid.2

B-cells contribute to the pathogenesis of multiple sclerosis (MS) through the activation of proinflammatory T-cells and the secretion of proinflammatory cytokines. Also, B-cells may differentiate into plasma cells that produce autoantibodies directed against myelin, leading to the complement-mediated attack on the myelin sheath 2. By targeting CD20, ocrelizumab specifically depletes B-cells. While the exact mechanism of ocrelizumab leading to B-cell depletion is unknown, there are several proposed mechanisms. It has been suggested that upon cell surface binding to CD20-expressing B-cells, ocrelizumab promotes antibody-dependent cellular cytotoxicity and complement-mediated cell lysis while preserving the capacity for B-cell reconstitution and preexisting humoral immunity.2,3,4

TargetActionsOrganism
AB-lymphocyte antigen CD20
antagonist
antibody
Humans
Absorption

Ocrelizumab displays a two-compartment pharmacokinetic model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of ocrelizumab was 3,510 mcg/mL per day. Following the intravenous infusion of maintenance doses of 600 mg every 6 months in relapsing MS patients, the mean peak plasma concentration of ocrelizumab (Cmax) was 212 mcg/mL. Following intravenous infusion of two 300 mg doses separated by 14 days every 6 months in patients with PPMS, Cmax was 141 mcg/mL. Ocrelizumab follows linear and dose proportional pharmacokinetics between 400 mg and 2000 mg.9

Volume of distribution

In a population pharmacokinetic estimate, the central volume of distribution of ocrelizumab was 2.78 L.9

Protein binding

Not Available

Metabolism

As with other antibodies, ocrelizumab is expected to undergo nonspecific catabolism and broken into smaller peptides and amino acids.

Route of elimination

Monoclonal antibodies (mAb) such as ocrelizumab are too large to be filtered by the kidneys, and therefore, not eliminated in urine under normal conditions. If antibody fragments of low molecular weight are filtered, they are usually reabsorbed and metabolized in the proximal tubule.6 The peptides and amino acids produced by catabolism are recycled or used as an energy source.

Half-life

The terminal elimination half-life of ocrelizumab was 26 days.9

Clearance

The constant clearance of ocrelizumab was 0.17 L/day, while the initial time-dependent clearance was 0.05 L/day. Peripheral volume and inter-compartment clearance were 2.68 L and 0.29 L/day, respectively.9

Adverse Effects
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Toxicity

Toxicity information regarding ocrelizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as immune-mediated colitis.9 Symptomatic and supportive measures are recommended. The carcinogenic and mutagenic potentials of ocrelizumab have not been evaluated. In monkeys given three loading doses of 15 or 75 mg/kg intravenously, followed by weekly doses of 20 or 100 mg/kg for 8 weeks (2-10 times the recommended human dose), ocrelizumab did not have effects on reproductive organs. No reproductive effects were detected on the estrus cycle of female monkeys given the same ocrelizumab regimen.9

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
AbataceptOcrelizumab may increase the immunosuppressive activities of Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ocrelizumab.
AdalimumabOcrelizumab may increase the immunosuppressive activities of Adalimumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ocrelizumab.
AducanumabThe risk or severity of adverse effects can be increased when Ocrelizumab is combined with Aducanumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OcrevusSolution30 mg / mLIntravenousHoffmann La Roche2017-09-21Not applicableCanada flag
OcrevusInjection, solution, concentrate300 mgIntravenousRoche Registration Gmb H2020-12-16Not applicableEU flag
OcrevusInjection300 mg/10mLIntravenousGenentech, Inc.2017-03-28Not applicableUS flag
OcrevusInjection, solution, concentrate300 mgIntravenousRoche Registration Gmb H2020-12-16Not applicableEU flag

Categories

ATC Codes
L04AA36 — Ocrelizumab
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
A10SJL62JY
CAS number
637334-45-3

References

Synthesis Reference

Manfrini, M. (2022). Methods for treating multiple sclerosis with ocrelizumab (U.S. Patent No. US 2022/0064320 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/a3/24/be/d30651ed8b7f68/US20220064320A1.pdf

General References
  1. McGinley MP, Moss BP, Cohen JA: Safety of monoclonal antibodies for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017 Jan;16(1):89-100. Epub 2016 Oct 31. [Article]
  2. Sorensen PS, Blinkenberg M: The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2016 Jan;9(1):44-52. doi: 10.1177/1756285615601933. [Article]
  3. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21. [Article]
  4. Florou D, Katsara M, Feehan J, Dardiotis E, Apostolopoulos V: Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab. Brain Sci. 2020 Oct 20;10(10). pii: brainsci10100758. doi: 10.3390/brainsci10100758. [Article]
  5. Mancinelli CR, Rossi N, Capra R: Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology. Ther Clin Risk Manag. 2021 Jul 30;17:765-776. doi: 10.2147/TCRM.S282390. eCollection 2021. [Article]
  6. 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]
  7. Alcala C, Quintanilla-Bordas C, Gascon F, Sempere AP, Navarro L, Carcelen-Gadea M, Landete L, Mallada J, Canizares E, Belenguer A, Carratala S, Dominguez JA, Perez-Miralles FC, Gil-Perotin S, Gasque R, Cubas L, Castillo J, Casanova B: Effectiveness of rituximab vs. ocrelizumab for the treatment of primary progressive multiple sclerosis: a real-world observational study. J Neurol. 2022 Jul;269(7):3676-3681. doi: 10.1007/s00415-022-10989-0. Epub 2022 Feb 2. [Article]
  8. FDA Press Announcements: FDA approves new drug to treat multiple sclerosis [Link]
  9. FDA Approved Drug Products: OCREVUS (ocrelizumab) injection for intravenous use [Link]
  10. FDA Approved Drug Products: OCREVUS® (ocrelizumab) injection, for intravenous use (Jan 2024) [Link]
KEGG Drug
D05218
PubChem Substance
347911266
RxNav
1876366
Wikipedia
Ocrelizumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingBasic ScienceClinically Isolated Syndrome (CIS) / Relapsing Multiple Sclerosis (RMS)1
4Active Not RecruitingOtherClinically Isolated Syndrome (CIS) / Multiple Sclerosis1
4Active Not RecruitingTreatmentMultiple Sclerosis1
4Active Not RecruitingTreatmentRelapsing Multiple Sclerosis (RMS)1
4Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous300 mg/10mL
Injection, solution, concentrateIntravenous300 mg
Injection, solution, concentrateIntravenous; Parenteral300 MG
SolutionIntravenous30 mg / mL
SolutionIntravenous300.000 mg
Injection, solution, concentrate300 mg/10ml
Solution, concentrateIntravenous30 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. McGinley MP, Moss BP, Cohen JA: Safety of monoclonal antibodies for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017 Jan;16(1):89-100. Epub 2016 Oct 31. [Article]
  2. Florou D, Katsara M, Feehan J, Dardiotis E, Apostolopoulos V: Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab. Brain Sci. 2020 Oct 20;10(10). pii: brainsci10100758. doi: 10.3390/brainsci10100758. [Article]
  3. FDA Approved Drug Products: OCREVUS (ocrelizumab) injection for intravenous use [Link]

Drug created at October 20, 2016 21:08 / Updated at January 27, 2024 05:09