Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer?Reddy V, Dahal LN, Cragg MS, Leandro M.Drug Discov Today. 2016 Aug;21(8):1330-8.
In Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE), B-cell depletion therapy using rituximab results in variable clinical responses between individuals, which likely relates to variable B-cell depletion in the presence of immune defects. Outcomes in clinical trials with other type I anti-CD20 mAbs, ocrelizumab and ofatumumab, are comparable to rituximab. A mechanistically different type II mAb, obinutuzumab (OBZ), with greater capacity for B-cell depletion, has recently entered clinical trials in SLE. Here we consider whether type II anti-CD20 mAbs will provide mechanistic advantages to overcome the disease-related immune defects in autoimmune diseases such as SLE
I say EAE is a T cell-mediated disease and you say “NSS”. Why does this matter? Well it matters when you are trying to understand what ocrelizumab, rituximab and ofatumumab do.
People treat EAE with anti-CD20 B cell depleting antibodies and then convince themselves and you that the results are significant. Rituximab was a first generation antibody, whereas they made a number of second generation antibodies, one of those is ocrelizumab developed for MS. Obinutuzumab is another humanised anti-CD20 antibody, but is approved for use in cancer. My experience is that anti-CD20 B cell depletion does very little. I would say this is alos seen in most peoples work, even when they try and convince themselves that something is occurring.
However, based on their mechanisms-of-action, CD20 monoclonal antibodies (mAbs) are grouped into Type I [complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)] and Type II [programmed cell death (apoptosis) and ADCC] mAbs.
It is claimed that MP4 which is a mixture of myelin basic protein and proteolipid protein induces a B cell mediated EAE. However, it is bound to be a T cell=mediated EAE that is suboptimal and augmented with by B cell activity.
They treated mice with anti-CD20 antibodies and they did nothing. Not surprising in my mind (a) They were given to late to do any thing and (b) even if they had treated at a time when it could do something, I suspect that they wouldn’t.
The important thing is that they try to suggest that obinutizumab protects axons….so this could mean that ocrelizumab is neuroprotective. Maybe it does but the figures are not compelling because they do not reflect the disease that is seen clinically. The clinical picture shows the animals have significant residual disability but the histology shows essentially no damage. Therefore, there has been cherry-picking. They look at neurofilament levels in the blood and so no decrease
Obinutuzumab-Induced B Cell Depletion Reduces Spinal Cord Pathology in a CD20 Double Transgenic Mouse Model of Multiple Sclerosis.Breakell T, Tacke S, Schropp V, Zetterberg H, Blennow K, Urich E, Kuerten S.Int J Mol Sci. 2020 Sep 18;21(18):E6864. doi: 10.3390/ijms21186864.
B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in a B cell-dependent mouse model of MS. Double transgenic huCD20xHIGR3 (CD20dbtg) mice, which express human CD20, were immunised with the myelin fusion protein MP4 to induce experimental autoimmune encephalomyelitis (EAE). Both light and electron microscopy were used to assess myelination and axonal pathology in mice treated with OBZ during chronic EAE. Furthermore, the effects of the already established murine anti-CD20 antibody 18B12 were assessed in C57BL/6 wild-type (wt) mice. In both models (18B12/wt and OBZ/CD20dbtg) anti-CD20 treatment significantly diminished the extent of spinal cord pathology. While 18B12 treatment mainly reduced the extent of axonal pathology, a significant decrease in demyelination and increase in remyelination were additionally observed in OBZ-treated mice. Hence, the data suggest that OBZ could have neuroprotective effects on the CNS, setting the drug apart from the currently available type I anti-CD20 antibodies.