CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study

Mastura Monif; Richard P Sequeira; Andrea Muscat; Sian Stuckey; Paul G Sanfilippo; Viet Minh; Naomi Loftus; Veronica Voo; Katherine Fazzolari; Melinda Moss; Vicki E Maltby; Ai-Lan Nguyen; Robb Wesselingh; Nabil Seery; Cassie Nesbitt; Josephine Baker; Chris Dwyer; Lisa Taylor; Louise Rath; Anneke Van der Walt; Mark Marriott; Tomas Kalincik; Jeannette Lechner-Scott; Terence J O'Brien; Helmut Butzkueven

doi:10.1016/j.clim.2024.110304

CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study

Clin Immunol. 2024 Aug:265:110304. doi: 10.1016/j.clim.2024.110304. Epub 2024 Jul 2.

Authors

Mastura Monif¹, Richard P Sequeira², Andrea Muscat², Sian Stuckey², Paul G Sanfilippo², Viet Minh³, Naomi Loftus⁴, Veronica Voo², Katherine Fazzolari⁵, Melinda Moss⁴, Vicki E Maltby⁶, Ai-Lan Nguyen⁷, Robb Wesselingh⁸, Nabil Seery⁸, Cassie Nesbitt⁹, Josephine Baker⁴, Chris Dwyer⁵, Lisa Taylor⁵, Louise Rath⁴, Anneke Van der Walt⁸, Mark Marriott¹⁰, Tomas Kalincik⁷, Jeannette Lechner-Scott⁶, Terence J O'Brien⁸, Helmut Butzkueven⁸

Affiliations

¹ Department of Neuroscience, Monash University, Melbourne, VIC, Australia; Department of Neurology, Melbourne Health, Melbourne, VIC, Australia; Department of Neurology, Alfred Health, Melbourne, VIC, Australia; Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia. Electronic address: Mastura.Monif@Monash.edu.
² Department of Neuroscience, Monash University, Melbourne, VIC, Australia.
³ Department of Neurology, Alfred Health, Melbourne, VIC, Australia; School of Nursing, Midwifery and Paramedicine, Australian Catholic University, Melbourne, VIC, Australia.
⁴ Department of Neurology, Alfred Health, Melbourne, VIC, Australia.
⁵ Department of Neurology, Melbourne Health, Melbourne, VIC, Australia.
⁶ John Hunter Hospital, Department of Neurology, New Lambton Heights, NSW, Australia; School of Medicine and Public Health, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW, Australia.
⁷ Department of Neurology, Melbourne Health, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
⁸ Department of Neuroscience, Monash University, Melbourne, VIC, Australia; Department of Neurology, Alfred Health, Melbourne, VIC, Australia.
⁹ Department of Neurology, Alfred Health, Melbourne, VIC, Australia; Department of Neurology, Barwon Health, Melbourne, VIC, Australia.
¹⁰ Department of Neurology, Melbourne Health, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Eastern Health, Melbourne, VIC, Australia.

PMID: 38964633
DOI: 10.1016/j.clim.2024.110304

Abstract

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

Keywords: Cladribine; Cytokines; Disease activity; Innate immunity; Monocytes; Multiple sclerosis; P2X7 receptor; Smouldering inflammation.

Publication types

Clinical Trial, Phase IV

MeSH terms

Adult
Cladribine* / pharmacology
Cladribine* / therapeutic use
Cytokines* / blood
Cytokines* / immunology
Female
Humans
Immunity, Innate* / drug effects
Immunosuppressive Agents / pharmacology
Immunosuppressive Agents / therapeutic use
Male
Middle Aged
Monocytes* / drug effects
Monocytes* / immunology
Multiple Sclerosis, Relapsing-Remitting* / blood
Multiple Sclerosis, Relapsing-Remitting* / drug therapy
Multiple Sclerosis, Relapsing-Remitting* / immunology
Prospective Studies
Receptors, Purinergic P2X7 / immunology
Young Adult

Substances

Cladribine
Cytokines
Receptors, Purinergic P2X7
Immunosuppressive Agents