as I expect ocrelizumab to get a licence for the treatment of relapsing MS, or
perhaps even active (relapsing & progressive) MS.
recent paper, which shifts the focus from the T cell onto the B cell and
notably the memory B cell subsets.
We have made an argument that active treatments act via
depletion of memory B cell subsets.
Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine;16:41-50.
cell subsets or even CD19 B cell numbers, based on data with alemtuzumab, but
does disease activity relate to memory B cell activity?
information that we know they have?
specific because the driving force for relapses and active disease is immune
activity coming from the blood into the CNS and it will be a small fraction of any immune subset we care to look at.
occur in the apparent relative absence of B cell activity in the blood so it will not be absolute, suggesting you do not need many of the wrong cells to trigger relapse.
constant B cell depletion increases your risk of infection
approach to reduce the risk: benefit?
antibody is active.
Can it work in MS?
correlate with peripheral blood memory B cell numbers and that they can be used
as a biomarker of when to retreat, as it is clear some people deplete for a few
months others for a few years.
Systemic Lupus Erythematosis
- Vital et al. Arthritis Rheum 2011 63: 14
Neuromyelitis Optica (NMO)
- Kim SH,et al. Arch Neurol 2011 68:1412
- Kim SH, et al. JAMA Neurol 2015: 72: 994
- Rosenthal M et al.Neurol Sci. 2017;373:335
- Leandro et al. 2006 Arthritis Rheum 54:613
- Iwata et al. J Rhheumatl 2011, 38:633
- Trouvin et al. 2015 , Clin Exp Immunol 180:11
Ideopathic Nephrotic Syndrome
- Colucci et al. J Am Soc 2016; 27:1811
- Lebrun et al. 2016, J Neuroimmunol 298:79
to be known by Devics MS. Is this the future way of using rituximab?
associated with an antibody against astrocytes and some of the treatments
promoting wellness in MS, make NMO worse. Likewise we know that some of the
issues important in the diseases above are also a problem of antibodies).
Therefore, it may be different in MS, but may be it won’t be.
but rather than religiously giving people rituximab treatment every 6 months,
they look at the CD19, CD27+ B cell numbers to provide an indication when to
retreat as their number seems to increase within about 4 months from the next
Don’t believe me that there is efficacy?
Look at the figure of before and after from Kim SH, Jeong IH, Hyun JW, Joung A, Jo HJ, Hwang SH, Yun S, Joo J, Kim HJ. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol. 2015;72(9):989-95. I think its impressive.
It is not perfect, but the number of relapses were reduced by 96%
from 2.4 (2 a year) to 0.1 (one every ten years). They administered another dose when the frequency of CD19+, CD27+ memory B cells within the CD19+ population reached 0.05% in the first two years and 0.1% in the second. This is reduced from normally about 20-30% of CD19 B cells (Switched =IgD- & Unswitched = IgD+) in the the healthy situation (click here. They should use absolute numbers per microlitre as it is more risky to use percentages).
In yet new another recent study
Cohen M, Romero G, Bas J, Ticchioni M, Rosenthal M, Lacroix R, Brunet C, Rico A, Pelletier J, Audoin B, Lebrun C. Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: Results from a bicentric study. Neurol Sci. 2017;373:335-338. Set a level at 0.05% and they could drop the infusions from every 6 months to 7.4 months with no loss of efficacy.
Could this be used in MS?
complement fixation or via antibody-dependent cellular cytotoxicity (ADCC). This
latter method of killing is used predominantly by alemtuzumab and ocrelizumab also, in fact ocrelizumab is more dependent on this than rituximab.
the antibody by an Fc Receptor.
Fc Receptor links to activity.
Kim et al. 2015 found factors that influenced depletion of the memory B cells and one factor was notably a variant of a gene FCGR3A (Fc receptor gamma 3A).
If there was a phenyalanine (F) amino acid at position 158 of the molecule compared to the usual valine (V) the receptor had a lower binding capacity for IgG (If you are heterozgous (F/V) or homozygous (F/F), there was a reduced response to (V/V) B cell depleting response. The residue at position 158 directly interacts with the lower hinge region of IgG1
If you had the F/F variant you depleted B cells less well and were at a greater risk of relapse.
What is going to happen in the PCORI (at the Karolinska Institute home of MS genetics in Sweden) study?
Surely they should be genotyped to link genotype with depletion/clinical efficacy.
This genotype can influence the efficacy of other IgG1 antibodies
What is it going to do with daclizumab and notably alemtuzumab (there is no influence with the cancer dose, but based on rituximab the influence of FCG3A is antibody dose-dependent) and ocrelizumab?
Currently CD19+, CD27+ and genotyping are not routine maybe they will be in the future