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Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Natalizumab Serum Concentration as Potential Biomarkers for Pharmacodynamics and Treatment Response of Patients with Multiple Sclerosis Receiving Natalizumab

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Abstract

Background

Natalizumab (NTZ) is an established treatment for highly active, relapsing-remitting multiple sclerosis. In the context of rare progressive multifocal leukoencephalopathy and extended interval dosing as a treatment option, biomarkers for treatment monitoring are required. Natalizumab serum concentration (NTZ SC) and soluble vascular cell adhesion molecule 1 (sVCAM-1) concentration were shown to change on treatment with NTZ. We aimed to investigate whether NTZ SC and sVCAM-1 could be suitable pharmacodynamic markers and whether they could predict disease activity on NTZ, improving the concept of personalized multiple sclerosis treatment.

Methods

In a retrospective study at the Medical University of Innsbruck, Austria, we identified patients treated with NTZ and chose samples longitudinally collected during routine follow-ups for the measurement of NTZ SC and sVCAM-1 by an enzyme-linked immunosorbent assay. We correlated these with clinical and demographic variables and clinical outcomes. Furthermore, we analyzed the stability of NTZ SC and sVCAM-1 during treatment.

Results

One hundred and thirty-seven patients were included. We found a strong negative correlation between NTZ SC and sVCAM-1. Both showed significant associations with body mass index, infusion interval, sample age, and anti-drug-antibodies. Natalizumab serum concentration was reduced in extended interval dosing, but not sVCAM-1. Only sVCAM-1 showed a weak association with relapses during treatment, while there was no association with disease progression. Both NTZ SC and sVCAM-1 showed a wide inter-individual distribution while levels in single patients were stable on treatment.

Conclusions

Soluble vascular cell adhesion molecule 1 is a suitable pharmacodynamic marker during treatment with NTZ, which is significantly reduced already after the first dose, remains stable in individual patients even on extended interval dosing, and strongly correlates with NTZ SC. Because of the high inter-individual range, absolute levels of sVCAM-1 and NTZ SC are difficult to introduce as treatment monitoring biomarkers in order to predict disease activity in single patients.

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Authors and Affiliations

  1. Department of Neurology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria

    Michael Auer, Angelika Bauer, Antonia Oftring, Dagmar Rudzki, Harald Hegen, Franziska Di Pauli, Klaus Berek, Anne Zinganell, Markus Reindl & Florian Deisenhammer

  2. Department of Neurology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Wien, Austria

    Gabriel Bsteh & Thomas Berger

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Corresponding author

Correspondence to Michael Auer.

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Funding

There was no funding for this research.

Conflict of interest

Michael Auer received speaker honoraria and/or travel grants from Biogen, Merck, Novartis, and Sanofi Genzyme. Angelika Bauer, Antonia Oftring, and Dagmar Rudzki report no conflicts of interest. Harald Hegen has participated in meetings sponsored by and has received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, and Teva, and received honoraria for consulting from Biogen, Celgene, Novartis, and Teva. Gabriel Bsteh has participated in meetings sponsored by and received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme, and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis. Franziska Di Pauli has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Celgene, and Roche. Klaus Berek has participated in meetings sponsored by and received travel funding from Roche, Biogen, and Teva. Anne Zinganell has participated in meetings sponsored by and received speaking honoraria or travel funding from Biogen, Merck, Sanofi-Genzyme, and Teva. Thomas Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, and Teva. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Sanofi Aventis, and Teva and for participation in clinical trials in MS sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, and Teva). Markus Reindl reports no conflicts of interest relating to the present article. Florian Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Merck, Novartis, Roche, and Sanofi-Genzyme. His institution received scientific grants from Biogen and Sanofi-Genzyme.

Ethics approval

The study was approved by the Ethics Committee of the Medical University of Innsbruck, Austria (approval number 1341/2020).

Consent to participate

For storage of samples, patients had to sign a written informed consent for the use of excess material for scientific purposes at the time of sampling.

Consent for publication

Not applicable.

Code availability

Not applicable.

Availability of data and material

Data are available upon reasonable request from the corresponding author.

Authors’ contributions

MA: study concept and design, patient recruitment, acquisition and interpretation of data, statistical analysis, drafting of manuscript. AB: performance of assays, acquisition of data, critical revision of manuscript for intellectual content. AO: performance of assays, acquisition and interpretation of data, critical revision of manuscript for intellectual content. DR: performance of assays, acquisition of data, critical revision of manuscript for intellectual content. HH: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. GB: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. FDP: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. KB: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. AZ: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. TB: patient recruitment, acquisition of data, critical revision of manuscript for intellectual content. MR: performance of assays, acquisition of data, critical revision of manuscript for intellectual content. FD: study concept and design, patient recruitment, acquisition of data, interpretation of data, critical revision of manuscript for intellectual content, supervision. All authors have read and approve the final submitted version of the manuscript and agree to be accountable for the work.

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Auer, M., Bauer, A., Oftring, A. et al. Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Natalizumab Serum Concentration as Potential Biomarkers for Pharmacodynamics and Treatment Response of Patients with Multiple Sclerosis Receiving Natalizumab. CNS Drugs 36, 1121–1131 (2022). https://doi.org/10.1007/s40263-022-00953-x

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