Ocrelizumab

Overview

Ocrelizumab (trade name Ocrevus) is a humanized monoclonal antibody (mAb) for the treatment of CD20-expressing tumors. The Fc engineered Ocrelizumab has overlapping epitopes with rituximab, but shows less immunogenicity and increased antibody-dependent cell-mediated cytotoxicity (ADCC) effect. Therefore, ocrelizumab is considered to be more effective and better-tolerated than rituximab. It is now being evaluated in phase III clinical trials in patients with relapsing-remitting multiple sclerosis (RRMS).

ADCC Enhancement Technology for Ocrelizumab

Ocrelizumab is a novel Fc-engineered anti-CD20 mAb developed to meet the needs of a new therapiy with higher activity on CD20-positive cancers. Compared to the classical rituximab, Ocrelizumab IgG1 shows increased binding to FcγR, greater ADCC potency, and a maximum cytotoxicity than rituximab replacement with the wild-type Fc domain.

Fig.1 Fc-optimized ocrelizumab vs rituximab.

Mechanism of Action of Ocrelizumab

Ocrelizumab is a mAb derived from a parent antibody—rituximab. Ocrelizumab and rituximab bind to the same epitope of CD20 and exhibit similar affinity, tumor orientation, effector cell-independent, anti-tumor cell proliferation activity in breast cancer cells in vitro. Fc-engineered Ocrelizumab is thought to have therapeutic activity against CD20-positive tumors because of:

(A) Binding to CD20 on the surface of B cells to activate complement cascade and produce a membrane attack complex (MAC) that directly induces B cell cleavage by complement-mediated cytotoxicity (CDC).
(B) Interaction with NK cells via Fc receptor III (FcRIII), which results in ADCC effect.

Fig.2 Mechanisms of action of Ocrelizumab.

ADCC Activity

• Ocrelizumab depletes CD20⁺ T lymphocytes in peripheral blood of multiple sclerosis (MS) patients.

Ocrelizumab in Preclinical

Ocrelizumab efficiently consume peripherally immature and mature B cells. B cell complementation kinetics accelerates when active immunization, and the clinical effect of B cell depletion is depended on the experimental autoimmune encephalomyelitis (EAE) model used.

Ocrelizumab in Clinical Trial

• Ocrelizumab is used mostly on patients with Primary Progressive Multiple Sclerosis (PPMS) in the clinical settings. The figure below shows the prevalence and population of PPMS. Approximately 15% of total MS patients are diagnosed with PPMS and the MS market worth approximately $18 billion. We believe Ocrelizumab will have far more market share owing to its safety and effectiveness, if we keep researching on it.

• A phase II study screened 220 RRMS patients for recurrence for 3-years-periord after injection of ocrelizumab, and statistical results showed the recurrence rate remained low for these patients.

• In the phase 3 clinical trial of Ocrelizumab, 732 patients with PPMS underwent intravenous injection of ocrelizumab or placebo for a durance of least 120 weeks, and the total volume of hyperintense lesions on T2-weighted images was then investigated. Result shows on figure below.

Clinical Development Status

For more detailed information, please do not hesitate to contact us.

References

1. Antonio.; et al. B-Cell Therapies in Relapsing Remitting and Primary Progressive Multiple Sclerosis: A Short Clinical Review Spectrum of Disease Progression in Multiple Sclerosis. September 2016.
2. Mulero P.; et al. Ocrelizumab: a new milestone in multiple sclerosis therapy. Therapeutic Advances in Neurological Disorders. 2018, 11:175628641877302.
3. Montalban X.; et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. New England Journal of Medicine. 2017, 376(3):209-220.
4. Darius H.; et al. Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease. Proceedings of the National Academy of Sciences. 2018:201810470.