Removing B cells
A medicine borrowed from cancer
Rituximab was developed to treat lymphoma by removing B cells, which carry a protein called CD20 on their surface. In the HERMES trial, published in 2008, it cut new inflammatory lesions in relapsing MS within weeks. Ocrelizumab, ofatumumab and ublituximab, all antibodies against CD20, went on to reduce relapses in large phase 3 trials against interferon beta or teriflunomide.
Rituximab itself was never submitted for approval in MS, but it is widely used in Sweden and Norway, and Nordic trials have compared it directly with approved medicines.
Where medicines act
Why the speed was a surprise
The cells that make antibodies, called plasma cells, do not carry CD20, so these medicines leave existing antibody levels largely in place. Yet the benefit appeared within weeks, too quickly to be explained by falling antibodies. B cells must therefore matter in other ways, by presenting targets to T cells and by releasing signals that drive inflammation.
What they taught researchers
Anti-CD20 medicines nearly stop relapses and new lesions in many people. Their effect on progression is smaller. Ocrelizumab slowed disability in primary progressive MS in the ORATORIO trial, while rituximab had missed its main goal in the earlier OLYMPUS trial in a similar group. Antibodies reach the brain poorly, so B cells that have already settled inside it, including the clusters in the membranes around the brain, are largely out of reach. This is part of the reason for testing CAR-T cells and other ways of removing B cells more completely, described in article 8.
Costs and trade-offs
Removing B cells for years raises the risk of some infections, and vaccines produce weaker responses while B cells are depleted.
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Key terms
- T cell
- A white blood cell that recognises a specific target and directs or carries out an immune attack.
- B cell
- A white blood cell that can present targets to T cells, release inflammatory signals and mature into antibody-making cells. Some B-cell-targeting medicines are highly effective MS treatments.
- Plasma cell
- An antibody-making cell derived from a B cell. Most plasma cells do not carry CD20, so anti-CD20 medicines do not directly target them.
- Lesion (plaque)
- An area of damage where myelin has been lost and the tissue scarred.
- Relapse (attack)
- New or worsening symptoms lasting at least 24 hours, without fever or infection to explain them.
- Anti-CD20
- Medicines that remove B cells by attaching to the CD20 protein on their surface, such as ocrelizumab and ofatumumab.
- Phase 1, 2 and 3
- The stages of testing in people: safety and dose, then an early sign of effect, then a large test of benefit.
References
- 1. Hauser et al. · HERMES. NEJM (2008)
- 2. Hauser et al. · OPERA. NEJM (2017)
- 3. Hauser et al. · ASCLEPIOS. NEJM (2020)
- 4. Steinman et al. · Ublituximab versus teriflunomide in relapsing multiple sclerosis (ULTIMATE). NEJM (2022)
- 5. Svenningsson et al. · Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis (RIFUND-MS). Lancet Neurology (2022)
- 6. Greenfield and Hauser (2018)
- 7. Montalban et al. · ORATORIO. NEJM (2017)
- 8. Hawker et al. · Rituximab in patients with primary progressive multiple sclerosis (OLYMPUS). Annals of Neurology (2009)
- 9. Magliozzi et al. · Meningeal B-cell follicles in secondary progressive multiple sclerosis. Brain (2007)
Next · Lesson 7 of 11
Calming and slowing immune cells
Teriflunomide, the fumarates, older immunosuppressants, and the ideas that made MS worse.
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