Ocrevus reduces B-cells’ diversity, but not T-cells’, in relapsing MS
Depletion was most evident in the subset of cells responsible for making IgM antibodies
Long-term treatment with Ocrevus (ocrelizumab) doesn’t change the diversity of T-cells — those needed to mount effective immune responses against foreign pathogens — in people with relapsing multiple sclerosis (MS) patients, a small study shows.
Consistent with its mechanism of B-cell depletion, however, Ocrevus did reduce the molecular diversity of B-cells and of the antibodies they produced. The researchers also found certain B-cell subsets that were particularly resistant or susceptible to Ocrevus-mediated depletion.
“Persistence of a highly diverse T-cell repertoire suggests that aspects of adaptive immunity remain intact despite extended [Ocrevus] therapy,” the researchers wrote in “Effect of Ocrelizumab on B- and T-Cell Receptor Repertoire Diversity in Patients With Relapsing Multiple Sclerosis From the Randomized Phase III OPERA Trial,” which was published in Neurology- Neuroimmunology & Neuroinflammation.
Developed by Genentech, a Roche company, Ocrevus reduces the risk of relapses and disability progression in relapsing MS. The antibody therapy is designed to destroy B-cells by targeting the CD20 protein at their surface, but data has shown it can reduce T-cells’ inflammatory activity too.
Both are immune cell types that participate in the inflammatory attack that drives MS. They’re also involved in adaptive immunity — immune responses that attack and destroy invading pathogens and prevent future disease by remembering foreign invaders.
While Ocrevus’ impact on B-cells is well studied, not as much is known about its effects on T-cells. In particular, it’s unknown if it reduces the diversity of T-cells and therefore the number of foreign invaders these cells can remember and fight.
To explore that, researchers in the U.S. examined blood samples from eight patients with relapsing MS who participated in OPERA I (NCT01247324), one of the Phase 3 clinical trials that supported the drug’s approval for relapsing forms of MS.
Effects of Ocrevus on B-cells
Four patients received Ocrevus in the two-year OPERA trial and its open-label extension. The other four initially received Rebif (interferon beta-1a), an under-the-skin medication, in the main trial and then switched to Ocrevus in the extension. Patients were followed for up to 39 months, or more than three years.
The molecular diversity of T-cells was analyzed by sequencing their T-cell receptors. Each T-cell contains receptors that recognize a single target and the binding between the receptor and its target activates the cell to trigger an immune attack.
The diversity of helper and cytotoxic T-cell repertoires remained unchanged with Ocrevus, results showed. Cytotoxic T-cells are a type of inflammatory cell capable of killing other cells. Helper T-cells are essential for the adaptive immune response, aiding the activity of other immune cells, including antibody-producing B-cells.
As expected, all B-cell populations dropped significantly after treatment and re-emerged after 60 weeks.
Their depletion resulted in a reduction in their diversity, particularly in the subset of cells responsible for making IgM antibodies. IgMs are the first circulating antibodies to appear in response to being exposed to a disease-causing agent and usually indicate an ongoing infection. IgGs are the most abundant circulating antibody and are produced at a later stage of the infection.
There was no obvious relationship between B-cell diversity and minor infections or MS relapses, however.
The impact of Ocrevus on specific B-cell subsets depended on which genes were responsible for variable antibodies and B-cell repertoires. Cells that relied on the V gene IGHV3-23 were more likely to persist after treatment, while those carrying the IGHV1-69 gene were more likely to be depleted.
Previous work has shown IGHV1-69 is enriched in naïve B-cells (those that haven’t yet encountered their specific target), whereas IGHV3-23 is generally more prevalent in memory B-cells and antibody-producing B-cells that have already been exposed to their target.
“This may suggest that antigen-experienced B cells are more likely to persist after OCR treatment,” the researchers wrote, adding their study sheds light on “[Ocrevus’] immunologic effects and adaptive immunity’s resilience.” They said more research in larger populations could confirm the findings and determine how changes in B- and T-cell repertoires impact clinical efficacy and safety.
The study was funded by Roche, the National MS Society, and the National Institutes of Heath’s National Institute of Neurological Disorders and Stroke.