Antibody levels drop after alemtuzumab as infections occur…lessons for ocreliziumab use

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This study looks at the general antibody response after alemtuzumab and as you can see there is a tendency to go down. The authours suggest that these levels should be monitored in people requirng multiple infusions

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As a group you can see there is still massive overlap, but some individuals go a bit low and those with immunoglobulin (antibody) below normal limits are more likely to develop infections.

The study suggests that Cambridge were wrong because they didn’t find a reduction of anti-infection response and did not find that IgG levels dropped. In this study most people were above the lower limit of normal and so it is easy to see why it was suggested that there is no effect. However, we know that there are some antibodies that go up in essentially everybody treated with alemtuzumab and these are the anti-drug antibody response. So it is hard to generalise, but if you fail to have sufficient antibody in the system, this is an indication for a deficit in antibody production that may mean fighting infection is impaired.

It seems that CD52 is not particularly highly expressed on plasma cells ,which make antibodies and therefore the lost of IgA,IgM and IgG in perhaps not because of a direct effect on antibody-producing cells, but on the precursors for antibody producing cells (plasmablasts or maybe CD27, IgD negative memory cells) and with time and long-term depletion they go down an so after three cycles this drop may be more than with earlier cycles. I guess this is hardly surprising because alemtuzumab is working just like other B cell depleting agents and there is nothing new here. Indeed, this post is relevant to ocrelizumab treatment, where again plasma cells are not directly targeted but with time IgA, then IgM then IgG will be reduced and with that you start to see infections, as ProfG mentioned.

At baseline, 79% of all people tested exhibited positive oligoclonal bands in the CSF. At 12 and 24 months after therapy start, their percentage amounted to 75% and 71%, respectively. So for a few people the CNS antibodies go but for most people they don’t and so again is no different to CD20 depletion.

However there is a drop in the level of IgG in the spinal fluid

Sadly there is no insight of why this may be and as the authors think ” B-lymphocyte count typically normalizes within 6 months post-treatment”, there is probably no chance of the paper giving any real insight. However, you and I know (and surely even they know as the cite our paper-reference 18) that this thought of normal B cell activity is incorrect. We know the memory B/plasmablast components are wiped out for a few years and the feeling of normalisation is created by immature cells filling the blood. However, this may require some speculation to give an explanation and you know what scientists tend to do if they speculate (Neil from Inbetweeners 2 at SplashPlanet springs to mind).

Alemtuzumab therapy changes immunoglobulin levels in peripheral blood and CSF. Möhn N, Pfeuffer S, Ruck T, Gross CC, Skripuletz T, Klotz L, Wiendl H, Stangel M, Meuth SG. Neurol Neuroimmunol Neuroinflamm. 2019 Dec 11;7(2). pii: e654. doi: 10.1212/NXI.0000000000000654.

OBJECTIVE: The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects. To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels.

METHODS: Blood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug. Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF.

RESULTS:We observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab. Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice. Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith.

CONCLUSIONS: Our results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab-in particular when additional treatment courses are required-and to consider preventive action in critical cases.

Hypogammaglobulinemia in Multiple Sclerosis Patients Receiving Disease-Modifying Immunomodulatory Agents. DOI: https://doi.org/10.1016/j.jaci.2018.12.051

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