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General Description:

Ocrelizumab, identified by CAS number 637334-45-3, is a notable compound with significant therapeutic applications. Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of patients with primary progressive or relapsing forms of multiple sclerosis (MS). It is a second-generation recombinant humanized monoclonal IgG1 antibody that selectively targets B-cells that express the CD20 antigen. Compared to non-humanized CD20 antibodies such as , ocrelizumab is expected to be less immunogenic with repeated infusions, improving the benefit-to-risk profile for patients with MS. MS is a chronic, inflammatory, autoimmune disease of the central nervous system that leads to neurological disabilities and a significantly reduced quality of life. 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 . 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 . In phase 3 clinical trials of patients with PPMS, treatment with ocrelizumab led to lower clinical and MRI progression rates compared to placebo.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ocrelizumab undergoes metabolic processing primarily in: As with other antibodies, ocrelizumab is expected to undergo nonspecific catabolism and broken into smaller peptides and amino acids. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ocrelizumab are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ocrelizumab is an important consideration for its dosing schedule: The terminal elimination half-life of ocrelizumab was 26 days. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Ocrelizumab from the body primarily occurs through: 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. The peptides and amino acids produced by catabolism are recycled or used as an energy source. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Ocrelizumab is distributed throughout the body with a volume of distribution of: In a population pharmacokinetic estimate, the central volume of distribution of ocrelizumab was 2.78 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ocrelizumab is a critical factor in determining its safe and effective dosage: 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. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ocrelizumab exerts its therapeutic effects through: 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. Since ocrelizumab is a recombinant humanized antibody, it is expected to be less immunogenic than , 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. 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ocrelizumab functions by: 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. Therefore, by targeting CD20, ocrelizumab does not affect the concentration of IgG and IgM antibodies in blood or the cerebrospinal fluid. 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 . 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Ocrelizumab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Ocrelizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic and Immunomodulating Agents, Blood Proteins, CD20-directed Antibody Interactions, CD20-directed Cytolytic Antibody, Globulins, Immunoglobulins, Immunologic Factors, Immunomodulatory Agents, Immunoproteins, Immunosuppressive Agents, Proteins, Selective Immunosuppressants, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Ocrelizumab include:

• Molecular Weight: 145000.0
• Molecular Formula: C6494H9978N1718O2014S46