Mechanism of Action of Ocrelizumab
Ocrelizumab is a humanized monoclonal antibody that selectively binds to CD20, a cell surface antigen present on pre-B and mature B lymphocytes, resulting in B-cell depletion through antibody-dependent cellular cytolysis (ADCC) and complement-mediated lysis (CML). 1
Primary Mechanism
- Ocrelizumab targets CD20-expressing B cells, which are key pathogenic cells in multiple sclerosis, leading to their selective depletion from circulation 2, 1
- The drug binds to the CD20 antigen on the surface of B lymphocytes, triggering two main cytotoxic pathways 1:
- Antibody-dependent cellular cytolysis (ADCC)
- Complement-mediated lysis (CML)
Pharmacodynamic Effects
- CD19+ B-cell counts in blood are reduced by 14 days after ocrelizumab administration, with CD19+ assays used because ocrelizumab interferes with CD20 assays 1
- B-cell depletion is profound and sustained, with median time for B-cell recovery to baseline or lower limit of normal being 72 weeks (range 27-175 weeks) after the last infusion 1
- Within 2.5 years after the last infusion, 90% of patients had B-cell counts return to either baseline or lower limit of normal 1
Beyond B-Cell Depletion
Ocrelizumab also depletes CD20-expressing T cells, which constitute approximately 18.4% of all CD20+ cells in MS patients and represent a highly activated cell population 3. This dual targeting may contribute to the drug's therapeutic efficacy beyond simple B-cell depletion 3.
Additional Immunomodulatory Effects
- Ocrelizumab treatment modulates the BAFF-APRIL system by enhancing BAFF levels and reducing the endogenous soluble receptor sTACI in both serum and CSF 4
- Reduction of sTACI (a decoy for APRIL) may enhance local APRIL activity, potentially promoting regulatory IgA+ plasma cells and astrocytic IL-10 production, which could contribute to the drug's anti-inflammatory effects 4
- The formation of sTACI-BAFF complexes occurs following treatment, representing a novel immunomodulatory mechanism distinct from simple B-cell depletion 4
Clinical Relevance
While the precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis remains incompletely understood, the presumed mechanism involves selective CD20+ B-cell depletion, addressing a key pathogenic component of MS pathophysiology 2, 1.