Methods of assessing the risk of developing progressivemultifocal leukoencephalopathy in patients treated withvla-4 antagonists

Natalizumab a monoclonal antibody is associated with the risk of progressive multifocal leukoencephalopathy (PML), an infection caused by the John Cunningham (JC) virus. The inventors explored the hypothesis that bacteria should be involved in the onset of PML in connection to the HLA-DR haplotype in multiple sclerosis (MS) patients. Thus 625 MS patients starting Natalizumab therapy from the BIONAT study were followed prospectively. Among those patients, 12 developed a PML. Outside the BIONAT cohort, we included nine additional MS patients with PML who had been referred to our center. For each patient, blood metagenomics sequencing and sequencing-based typing for HLA-DRB1*15:01 ancestral haplotype were determined. HLA-DRB1*15:01 haplotype carriers show a protection against PML (p=0.03). Among blood taxa, at genus level, Phyllobacterium was only significantly associated in HLA-DRB1*15:01 haplotype carriers with an inflammatory marker (p<0.0001) as opposed to HLA-DRB1*15:01 haplotype negative where no significant correlation was observed. Among the patients with no HLA-DRB1*15:01 haplotype, we showed a positive association (p=0.02) between the abundance of Phyllobacterium and PML whereas no significant association was observed in patients with HLA-DRB1*15:01 haplotype. JC positive virus patients with no HLA-DRB1*15:01 haplotype and a level of Phylobacterium in blood >2% have an odds ratio of 4.55 (95% confidence intervals 1.82-11.37; p=0.001) of developing or having PML under NTZ treatment. In conclusion, the inventors showed a relation between the HLA-DRB1*15:01 haplotype, the circulating microbiota and the risk of PML. The interaction between blood microbiota and the HLA-DRB1*15:01 haplotype may play a role in the virulence of the viruses.

Keywords: Natalizumab, progressive multifocal leukoencephalopathy (PML), multiple sclerosis (MS) patients, HLA-DR haplotype, Microbiota
Patent Application number: EP21305115.4 on 29/01/2021
and
PCT/EP2022/052085 on 28/01/2022

Reference:

BIO19385-D1

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Pierre MAZOT
Pierre MAZOT
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Patent filling date: 2021-01-29

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