Killing B cells

Svenningsson A, Bergman J, Dring A, Vågberg M, Birgander R, Lindqvist T, Gilthorpe J, Bergenheim T.Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally.
Neurol Neuroimmunol Neuroinflamm. 2015 Feb 26;2(2):e79. doi: 10.1212/NXI.0000000000000079. eCollection 2015 Apr.

OBJECTIVE:We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year post-treatment.
METHODS: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2-3 months.
RESULTS:The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period.
CONCLUSIONS: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments.

An Ommaya reservoir is an intraventricular (into the ventricles) catheter system that can be used for the aspiration of cerebrospinal fluid or for the delivery of drugs (e.g. chemotherapy) into the cerebrospinal fluid. It consists of a catheter in one lateral ventricle attached to a reservoir implanted under the scalp. It is used to treat brain tumours, leucaemia/lymphoma or leptomeningeal disease by intrathecal drug administration. In the palliative care of terminal cancer, an Ommaya reservoir can be inserted for intracerebroventricular(ICV) injection of morphine.

In MS there is no real idea of what causes MS.

One idea is that it is due to the B cell. In Britain and Italy there are a group of Pathologists that think that MS is caused by B cell responses within the CNS. So some people want to deliver drugs into the CNS. When things are delivered to the spinal cord they tend to be removed because the drainage of the CNS is down the spinal cord. But by pulling in the ventricles then the flow is down and stuff should bathe the brain. It then escapes and gets into the blood. Which is interesting,
In this study they put a B cell depleting agent in because in studies in PPMS it has been shown that people with gadolinium enhancing lesions respond to treatment. This means that depleting B cells is beneficial in relapsing MS and in PPMS with relapsing disease (about 25% of people) respond. But in PPMSers without blood brain barrier breakdown the antibody can’t get into the brain and so it doesn’t work. So the answer is to put antibody into the brain and then deplete the B cells directly. Will this stop PPMS? I hope so but I am not convinced that such B cell activity is the substrate for PPMS. If you look in MS lesions only a few groups have link progression to B cells. Most people do not,

Rituximab will not kill plasma cells that make antibodies so oligoclonal bands will not disappear.

Will this approach approach stop the MS?

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