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:

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

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

Target	Actions	Organism
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 (C_max) was 212 mcg/mL. Following intravenous infusion of two 300 mg doses separated by 14 days every 6 months in patients with PPMS, C_max 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.

Drug	Interaction
Integrate drug-drug interactions in your software
Abatacept	Ocrelizumab may increase the immunosuppressive activities of Abatacept.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Ocrelizumab.
Adalimumab	Ocrelizumab may increase the immunosuppressive activities of Adalimumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ocrelizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Ocrelizumab is combined with Aducanumab.
Aldesleukin	Ocrelizumab may increase the immunosuppressive activities of Aldesleukin.
Alefacept	The risk or severity of adverse effects can be increased when Alefacept is combined with Ocrelizumab.
Alemtuzumab	Ocrelizumab may increase the immunosuppressive activities of Alemtuzumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Ocrelizumab.
Allogeneic processed thymus tissue	The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Ocrelizumab.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Ocrevus	Solution	30 mg / mL	Intravenous	Hoffmann La Roche	2017-09-21	Not applicable
Ocrevus	Injection, solution, concentrate	300 mg	Intravenous	Roche Registration Gmb H	2020-12-16	Not applicable
Ocrevus	Injection	300 mg/10mL	Intravenous	Genentech, Inc.	2017-03-28	Not applicable
Ocrevus	Injection, solution, concentrate	300 mg	Intravenous	Roche Registration Gmb H	2020-12-16	Not applicable

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

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]
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]
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]
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]
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]
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]
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]
FDA Press Announcements: FDA approves new drug to treat multiple sclerosis [Link]
FDA Approved Drug Products: OCREVUS (ocrelizumab) injection for intravenous use [Link]

External Links

KEGG Drug: D05218
PubChem Substance: 347911266
RxNav: 1876366
Wikipedia: Ocrelizumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Multiple Sclerosis	1
4	Active Not Recruiting	Treatment	Relapsing Multiple Sclerosis (RMS)	1
4	Active Not Recruiting	Treatment	Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Completed	Treatment	Multiple Sclerosis	1
4	Recruiting	Basic Science	Clinically Isolated Syndrome (CIS) / Relapsing Multiple Sclerosis (RMS)	1
4	Recruiting	Other	Clinically Isolated Syndrome (CIS) / Multiple Sclerosis	2
4	Recruiting	Prevention	Multiple Sclerosis / Radiologically Isolated Syndrome (RIS)	1
4	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Recruiting	Treatment	Multiple Sclerosis	2
4	Recruiting	Treatment	Relapsing Multiple Sclerosis (RMS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	300 mg/10mL
Injection, solution, concentrate	Intravenous	300 mg
Injection, solution, concentrate	Intravenous; Parenteral	300 MG
Solution	Intravenous	30 mg / mL
Injection, solution, concentrate		300 mg/10ml
Solution, concentrate	Intravenous	30 mg

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. B-lymphocyte antigen CD20

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

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]
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]
FDA Approved Drug Products: OCREVUS (ocrelizumab) injection for intravenous use [Link]

Drug created at October 20, 2016 21:08 / Updated at December 01, 2022 11:27

Ocrelizumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References