B cell depletion with Antibodies.. Size matters?

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Last week we had a modeller try and predict how long to delay anti-CD20 to get a COVID-19 response. They not only did that but also made a prediction that the response may relate to B cell repopulation and made a prediction curve based on our data that we got from the phase II ocrelizumab study. ProfG made the point that by lumping studies on rituximab and ocrelizumab together the predictions may be a bit quick. So I had a look for some papers and the evidence is in Bar-Or et al. 2008. But, I came across a couple of papers that I had missed.

Could we see if the predictions are correct. I guess in the UK it is abit late to do these studies, but could maybe save them for vaccine round 3. I guess they could be done in places like Australia where the vaccination rate is low as are the risks of catching COVID-19. There it would be less of a risk to delay vaccination and one can be pacified by the emerging data that an anti-CD20 delay is safe at least for 3 months.

ProfG has argued that some people are being underdosed with ocrelizumab, this study (below) with largely rituximab also supports this argument. To play devils advocate, last week I threw in a paper suggesting that progression was related to waist size as a alternative. Whilst it could be dismissed, in the study below using rituximab, the doses were based on their size. Here they used (Body Surface Area) rather than Body Mass Index. The larger size people seem to repopulate their B cells quicker. Although some elements may be due to the way size is calculated. There are clearly more than just size that matters in determining what happens when you give antibody.

This may be relevant for the modellers, as it could suggests that larger size people may give a quicker COVID-19 vaccination response.

Ellwardt E, Ellwardt L, Bittner S, Zipp F. Monitoring B-cell repopulation after depletion therapy in neurologic patients. Neurol Neuroimmunol Neuroinflamm. 2018 ;5(4):e463.

Objective To determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients. Methods In this study, we determined the association of body surface area (BSA; calculated by body weight and height), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years). Results Patients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time. Conclusions B-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients’ BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.

“Although the efficacy of B-cell targeting therapies is closely linked to sufficient depletion, a considerable heterogeneity concerning monitoring and retreatment protocols complicates their use in clinical practice. The reappearance of B cells can be defined when CD19+ cells reach 1% of lymphocyte counts, which then leads to the next treatment cycle. However, some protocols use fixed time intervals (e.g., every 6 months in clinical trials for ocrelizumab) but also 2% or absolute lymphocyte counts such as 10 per μL for CD19+ cell monitoring. Clinical experience is that once patients reach 1%, they rapidly surpass 2% within days. As an alternative approach, monitoring of CD27+ memory B cells has been suggested as a sensitive marker after rituximab treatment”

This further suggests benefit can be obtained with precision treatment.

CD19+ B-cells’ repopulation rate significantly varied depending on the dosage applied leading to individualized application intervals (mean 9.73 ± 0.528 months). Low/absent CD19+ B-cell counts were associated with reduced ARR, EDSS, and GD+-MRI-lesions. Long-term B-cell-depleting therapy led to a transiently skewed CD4+/8+ T-cell ratio due to reduced CD4+ T-cells and absolute lymphocyte counts, which recovered after the second cycle.

I have also missed other studies

llrichmann, G., Bolz, J., Peschke, M. et al. Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders. J Neurol 266, 57–67 (2019). https://doi.org/10.1007/s00415-018-9092-4

Dosing with 250mg is low and B cell repopulate quickly

Objective: We evaluated the long-term depletion and repopulation rate of peripheral CD19+ B-cells as a potential surrogate for the clinical outcome, and whether it may serve for dosage and time-to-infusion decision making. Methods: We evaluated the CD19+ and CD4+/8+ T-cell counts in n = 153 patients treated with RTX (132 MS, 21 NMO/NMOSD). The dosages ranged from 250 to 2000 mg RTX. Depletion/repopulation rates of CD19+ B-cells as well as long-term total lymphocyte cell counts, were assessed and corroborated with EDSS, ARR (annualized relapse rate), MRI, and time to reinfusion. Results: CD19+ B-cells’ repopulation rate significantly varied depending on the dosage applied leading to individualized application intervals (mean 9.73 ± 0.528 months). Low/absent CD19+ B-cell counts were associated with reduced ARR, EDSS, and GD+-MRI-lesions. Long-term B-cell-depleting therapy led to a transiently skewed CD4+/8+ T-cell ratio due to reduced CD4+ T-cells and absolute lymphocyte counts, which recovered after the second cycle. Conclusion:Our data suggest that CD19+ B-cell repopulation latency may serve as surrogate marker for individualized treatment strategies in MS and NMO/NMOSD, which proved clinically equally effective in our cohort as evaluated by previous studies.

Despite the therapeutic effect being closely associated with the absence of CD19+ B-cells, we did not observe a correlation between B-cell counts at the time-point of reinfusion and clinical course or MRI outcome in patients in whom relapses did occur. This might be due to different proportion of progenitor CD19+ B-cells and mature B-cells after the first cycle of rituximab treatment. After replenishment of the B-cell compartment there are mainly naïve B-cells following repletion of circulating B-cells .CD27+ memory phenotype cells stay at significantly lower levels in peripheral blood

So no B cells is important to effective therapy, but just because you have B cells does not mean that disease will come back. This is not surprising because what comes back is not the same that was there before depletion. However this message is important when you hear that disease activity is unrelated to B cell numbers.

COI: Multiple but none relevant

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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9 comments

  • ”However this message is important when you hear that disease activity is unrelated to B cell numbers.” Is it related and what is the definition of underdosed?

  • “ Lack of B cell depletion and progression….” Are these two connected? Any published paper on this? What about lack of b cell depletion without progression or complete b cell depletion with progression, are they underdosed?
    “There are clearly more than just size that matters in determining what happens when you give antibody.” Of course, one of the main ones should be b cell counts at baseline. Size matters mainly in terms of blood volume.

  • A different size matter situation: Aducanumab how does it work to clear amyloid-β in the brain if antibodies are too large to cross BBB? (Neuro-degenarative so hopefully still on the topic..)

    • If you can remember the blog was closed becuase of a comment I made about this very antibody and the results it was producing, so I am not going there….Will it get NICEed?…I suppose beta interferon makers are used to Risk Sharing Schemes and the US cost is half that of an MS treatment shows us that costs are unrelated to the manufacturing costs….Does Wiki says how it works to answer your question…”Aducanumab analogue can cross the blood-brain barrier and engage its target efficiently, thus clearing beta amyloid toxicity”

      Will it work in phase IV. “Drugs approved under the FDA Accelerated Approval Program still need to be tested in clinical trials using endpoints that demonstrate clinical benefit, and those trials are known as phase 4 confirmatory trials. If the drug later proves unable to demonstrate clinical benefit to patients, the FDA may withdraw approval”

      ProfG predicted this approval would happen and gave me the reasons for that view a few years ago. I wont say what that was. Is this time to revoice or not?….maybe first to market encourages pharma to make the next better drug after all this is what happened with beta interferon and now you have twenty options and growing for MS. What happenned to the other similar antibodies will they be come out of mothballs to provide some competition? However it could make it difficult to do other studies. Anyway it is a alzheimers drug and this is an MS blog, but it will be another antibody to show us how much antibody gets in the brain. Rememeber the anti LINGO in MS it was 99.9 excluded and we were told it is the magic 0.1% that is all important….However where is the Anti-LINGO antibody now?

      file:///C:/Users/hmw275/Desktop/pharmaceuticals-13-00394.pdf
      William M. Pardridge. Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery 2020

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