Anti-CD20 monoclonal antibody therapy represents a major advance in treating relapsing multiple sclerosis (MS) in adult patients, reducing relapse risk and mitigating disability progression.

These monoclonal antibody therapies deplete circulating B cells by targeting CD20, a surface marker expressed on pre-B cells, naïve B cells and memory B cells.

A review article in CNS Drugs, “Clinical Perspectives on the Molecular and Pharmacological Attributes of Anti-CD20 Therapies for Multiple Sclerosis,” details the molecular and pharmacological differences and attributes of the four anti-CD20 monoclonal antibodies currently used, approved, or in late-stage clinical trials. The review offers clinical perspectives on the differences between them.

The article was co-authored by Michael L. Sweeney, M.D., a neurologist with Norton Children’s Neuroscience Institute, affiliated with the UofL School of Medicine, and an assistant professor at the University of Louisville.

The review applies only to adult patients. Pediatric MS B-cell therapy trials are underway.

Four anti-CD20 monoclonal antibody treatments reviewed

• Rituximab is a murine-human chimeric monoclonal antibody approved for a number of oncological and rheumatological indications. It was the first anti-CD20 monoclonal antibody and has been used off-label for MS for both relapsing remitting and primary progressive MS. The dosing for MS is the same regimen approved for rheumatoid arthritis: two 1000-milligram intravenous infusions two weeks apart followed by 1000-milligram infusions every six months. Premedication is required before each dose.
• Ocrelizumab is a humanized monoclonal antibody and was the first anti-CD20 monoclonal approved for MS. It is indicated for treatment of both relapsing and primary progressive MS. Ocrelizumab is administered intravenously at a dose of 300 milligrams over >5 hours in the first two doses, with subsequent doses of 600 milligrams over > 3.5 hours every six months. Premedication prior to each dose is recommended to mitigate systemic reactions.
• Ofatumumab, the first subcutaneously administered B-cell depleting therapy, is a fully human monoclonal antibody approved more recently in the United States for treatment of relapsing forms of MS. Ofatumumab is a self-administered, 20-milligram monthly injection after four weekly doses. No premedication is required.
• Ublituximab is a murine-human chimeric monoclonal antibody in late-stage development for the treatment of MS. It is administered intravenously. The Phase 3 trials used a 150-milligram dose administered over four hours, followed by a 450-milligram dose over one hour two weeks later and every 24 weeks up to week 96. Premedication was required before each infusion.

Rituximab and ocrelizumab target an almost identical epitope. Ofatumumab and ublituximab target different epitopes. The main mechanisms of action for anti-CD20 monoclonal antibodies are thought to be antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Rituximab and ofatumumab both rely more on complement-dependent cytotoxicity, while ocrelizumab and ublituximab exhibit higher levels of antibody-dependent cellular cytotoxicity.

MS dose regimens for these four monoclonal antibodies result in a near total depletion of circulating B cells. However, blood levels of B cells do not necessarily reflect the extent of B cell depletion within the tissues. Also, it’s unclear whether this extent of depletion of circulating B cells is necessary for an effective treatment.

Rates of B cell reconstitution offer indirect evidence of the extent of tissue depletion.

In a clinical trial for rituximab, circulating B cells were nearly completely depleted beginning in week 2 and sustained through week 24. They were reconstituted to 30.7-34.5% of baseline by week 48 following the last dose.

With clinical trials for ocrelizumab, B-cell levels increased to the baseline or the lower limit of normal within 2 1/2 years of the last infusion. Studies of ocrelizumab in rheumatoid arthritis suggest more infusions are not associated with longer time to B-cell repletion.

Time to B-cell repletion was faster with ofatumumab than other anti-CD20 monoclonal antibodies, with more than half of patients reaching the low level of normal 24 to 36 weeks after the discontinuation of treatment.

In a Phase 2 study of ublituximab, B-cell depletion persisted pre-dose at weeks 24 and 48. Data from a Phase 3 trial is expected to provide additional data on B-cell depletion and reconstitution.

Longer-term studies of these four therapies are underway and will provide additional information about their safety and effectiveness over time.

Dr. Sweeney’s recently published research

Read more at Pubmed.gov