Following the approval of ocrelizumab for progressive MS, it stands to reason that alemtuzumab will also be similarly active
However, the tortoise is yet to set off and the Hare has crossed the finished line. So should the tortoise start the race?
This is the dilema for Sanofi Genzyme and whether they should do a progressive MS trial.
Of the highly active treatments it has the most liberal licence and would be a natural choice to use as the bottom layer on which to layer other treatments, as it is an induction (pulsed immune reconstitution therapy) therapy.
However have they left it too late?
I also think ocrelizumab is an induction therapy, but this has not been formally reported.
However if this is indeed shown and ocrelizumab is as active as alemtuzumab, who will want to take alemtuzumab as it's use is asssocatiated with autoimmune side effects and ocrelizumab will have been made safer, as repeated CD20 depletion for every will at sometime mean infection).
Likewise if cladribine is used in progressive and it works like ocrelizumab. Again it means it will be hard to deveop alemtuzumab unless it is substantially better.
It maybe, but we wont know unless it is tested.
However, in gearing up to go into progressive MS, you may want animal data to support your hunch to do a trial in humans.
So in this study they look at the effect of a CD52 depleting drug in a model that is called a "B cell dependent EAE" model.
Which has B cell rich aggregates..which are probaly all EAE models if you wait long enough and look in the right places.
These are really models that are sub-optimaitised to make B cells look important either by a bit of antigen presentation by B cells or by the production of antibodies, which will augement the subclinical T cell disease to become clinically apparent.
If they inject at disease onset there is a positive effect, presumably because the anti CD52 kills the T cells causing the disease but if they wait for months after the attack there is no clinical effect. This is not surprising because the clinical attack has caused axonal loss and the antibody can't raise the dead (nerves). However it kills the B cells in the CNS. This is interesting because that implies the CD52 antibody gets into the brain. This may not happen much in humans (but if it does then does it kill B cell follicles?) as antibody penetration is still low in MS and alemtuzumab does not appear to impact on the oligoclonal bands. If it does get in, it may have an advantage as CD20 is not expressed by antibody-secreting B cells and with rituzimab the B cell response in the CNS is not adequately targeted.
Simon M, Ipek R, Homola GA, Rovituso DM, Schampel A, Kleinschnitz C, Kuerten S.Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis. J Neuroinflammation. 2018 Aug 11;15(1):225
BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable.
METHODS: We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA.
RESULTS: Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment.
CONCLUSION:Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.
COI: I have had support from Genzyme and Merck but this not relevant. I have heard of an answer to the "will they won't they" but it is not my place to say. If they will....come back in 3-5 years for the answer and it may be another treatment option.
Labels: Alemtuzumab