Viewing Multiple Sclerosis From the Bench and the Bedside
Material below is adapted from the SfN Short Course Multiple Sclerosis: From Bench to Bedside and Back Again, by Steven L. Hauser, MD. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
The connection between the type of immune cells called B-cells and multiple sclerosis (MS) was confirmed after unblinding a phase II clinical trial in 2006. The story of the challenges and successes that clinicians and researchers have faced in studying this connection reveals that coupling laboratory and clinical research can improve the efficacy of translational medicine.
MS is a disease in which the immune system attacks cells of the brain and spinal cord, yet symptoms observed in rodent models used in the 1970s likely came from problems with the peripheral nerves.
Eventually researchers generated a better animal model in small primates called marmosets (Callithrix jacchus) by injecting the animals with a type of immune cell capable of causing inflammation in the brain and antibodies that remove the protective covering myelin from nerve cells.
The antibodies associated with MS lesions in the marmosets were diverse, which suggested targeting just one was not likely to be effective. Scientists therefore decided to target B-cells, a type of immune cell that makes antibodies. In collaboration with Genentech, they began a trial of a drug named RTX, which is a monoclonal Ab (MAb) that binds a protein expressed on the surface of B-cells, CD20.
The trial consisted of a single course of RTX with an assessment of patient symptoms six months later. The researchers were surprised and puzzled to see positive clinical effects of RTX during this short trial. The speed with which the treatment worked suggested that it wasn’t the reduction of antibodies that was relevant to the disease, but rather something about the B-cells themselves.
In order to understand what was happening, the scientists considered all the functions of B-cells. In addition to producing antibodies, B-cells can serve as antigen-presenting cells. They can also shuttle antigens to other immune cells and secrete chemicals that influence the behavior of other immune cells or that generate a pro-inflammatory response, which happens especially in MS.
B-cells start their development in the bone marrow and from there proliferate and move into many niches in the body, including some protected areas of the central nervous system (CNS). The researchers predicted that targeting B-cell surface protein CD20 with RTX worked because it reduced numbers of circulating B-cells, which likely included memory B-cells that would otherwise return to the CNS to wreak havoc.
Based on regulatory hurdles and the looming end of the RTX patent, Genentech developed a new mAb to CD20 called ocrelizumab (OCR). OCR and RTX target different parts of CD20 and cause cell death via different pathways.
In a phase II trial of OCR, researchers observed effective reduction of clinical symptoms of MS. In phase III clinical trials, patients with relapsing MS displayed dramatic improvements on OCR, and it also caused improvements in patients with primary progressive MS, which had been previously considered untreatable.
Results from the clinical trials also showed disease lesions are reduced even when numbers of circulating B-cells come back up after treatment, suggesting that targeting CD20 might somehow reset the immune system.
It is also possible some of the beneficial effects are due to depletion of other immune cells that express CD20 on their cell surface. Following these results, the U.S. Food and Drug Administration approved OCR for the treatment of MS.
In the laboratory, researchers have since used the imperfect rodent models to show a reduction in B-cells is not always beneficial. In cases where B-cells play a regulatory rather than a pro-inflammatory function — for instance, depleting them can worsen neurological symptoms.
Identifying what role B-cells play and sorting them into populations could thus lead to more effective therapies. But as the entire history of B-cells and MS has shown, it is imperative to test ideas discovered in the lab in the clinic, as well as bring findings from the clinic to the bench for further investigation.