Optimizing Natalizumab

Puñet-Ortiz J, Hervás-García JV, Teniente-Serra A, Cano-Orgaz A, Mansilla MJ, Quirant-Sánchez B, Navarro-Barriuso J, Fernández-Sanmartín MA, Presas-Rodríguez S, Ramo-Tello C, Martínez-Cáceres EM.Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis patients. Cytometry B Clin Cytom. 2017 Apr 5. doi: 10.1002/cyto.b.21527. [Epub ahead of print]

BACKGROUND:In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response.
METHODS:A multiparametric quantitative flow cytometry (QFCM) method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks.
RESULTS: Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing.
CONCLUSIONS: Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen

Natalizumab has one of the clearesst mechanisms of all the MS drugs. It works by binding to CD49d or very late antigen 4 or alpha 4 integrin (same thing different names) to block it binding to vascular cell adhession molecule. This gets up regulated at sites of inflammation and is use by white blood cells (T cells, Bcells and monocytes) to get into the inflammaed brain. Block this and they can’t get in. 

At the moment it is given every 4 weeks but is that too often or not often enough. 

I have met a few people who call it their “MS coke” as they get it an feel OK, but come week three they are having withdrawal symtpoms, which suggests to me that the effect is wearing off. 

 The simplest way to check this is to take white blood cells out of the blood and see if their CD49d is still blocked. If not maybe time for a top up, if it still is blocked maybe you can wait abit longer for the next dose. 

In this study they found 6 weekly worked OK, but receptor occupancy was reduced, which would argue that is is more likely to fail.

We have made a suggestion that by monitoring B cells in the blood you may get a biomarker, how often would you be willing to give blood?

In this study they do repeated bleeds to check for this and in this way they can personalise

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  • I have been on Tysabri for 11 years and seroconverted last year. After a brief hiatus I went on extended dosing. So far so good in terms of MRI activity. I have asked my neuro more than once if there is a way to determine what my optimal dosing schedule should be. His answer of course was not at this time. I already get my blood drawn quarterly to test for JCV antibodies so what is another vial. and it is so easy to give as they are starting the infusion.

    I do not take PML lightly, but have been so stable on Tysabri with no side effects it is hard to change. So any additional information on how to best maximize the therapy is music to my ears


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