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New Immune Biomarkers of Multiple Sclerosis Discovered in Study of Anti-CD3 Antibody Foralumab
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Key Takeaways
- Foralumab, an intranasal anti-CD3 monoclonal antibody, modulates immune pathways in na-SPMS, reducing microglial inflammation and maintaining clinical stability.
- Key immune biomarkers identified include FoxP3 regulatory cells, central memory T cells, monocytes, and naïve B cells, linked to na-SPMS progression.
Treatment with foralumab, an anti-CD3 monoclonal antibody, led to the discovery of several biomarkers known to be associated with antigen presentation, interferon responses, and other regulatory immune mechanisms.
Tanuja Chitnis, MD
In an expanded access (EA) program testing the effects of foralumab (Tiziana Life Sciences), an investigational anti-CD3 monoclonal antibody, researchers have identified several key immune biomarkers that play a role in progression of non-active secondary progressive multiple sclerosis (na-SPMS). Among these modulated biomarkers were FoxP3 regulatory cells (Tregs), CD4+ and CD8+ central memory T cells, CD14+ and CD14- monocytes, and naïve B cells.1
Foralumab, an intranasally-administered monoclonal antibody, is designed to stimulate T regulatory cells among patients with na-SPMS. In the EA program, the study used single-cell RNA sequencing of peripheral blood samples collected before and at 3 and 6 months after drug administration, uncovering gene expression changes linked to nasal foralumab. These changes were associated with reduced microglial brain inflammation, as confirmed by advanced microglial inflammation, as confirmed by advanced microglial PET scans in the same patients.
Based on the announcement from Tiziana, there are currently 10 patients with na-SPMS who have been dosed the open-label intermediate sized EA program. Recently, the FDA allowed an additional 20 patients to be enrolled in this program, increasing the cohort to a total of 30 patients. Of note, patients with na-SPMS who were not eligible for the ongoing phase 2a trial (NCT06292923) assessing the treatment, initiated in November 2023, were considered for this EA program.
"We are excited to announce this breakthrough in understanding how nasal foralumab induces immune modulation in patients with Secondary Progressive MS,” principal investigator Tanuja Chitnis, MD, an associate neurologist at Brigham and Women’s Hospital, said in a statement.1 "These findings highlight the potential of nasal foralumab in modulating critical immune pathways and offer new insights into its clinical effects. This discovery represents a pivotal step toward personalized treatment strategies for MS. We look forward to submitting these data to a peer reviewed journal.”
READ MORE: Differences in Gray Matter Structure May Help Distinguish Multiple Sclerosis From NMOSD
Earlier this month, Tiziana announced the publication of a review article demonstrating foralumab’s potential in the treatment of various neurological diseases, including MS, Alzheimer disease, amyotrophic lateral sclerosis, and Parkinson disease. The review explored the role of microglia, monocytes, and T cells in the pathogenesis of these disorders, emphasizing their potential as shared therapeutic targets. It also highlighted the microbiome as an emerging target for indirectly modulating the immune system.Additionally, it examined immune-based therapeutic approaches under development, showcasing how treatments designed for one neurological disease.2,3
At the 2024 American Academy of Neurology (AAN) Annual Meeting, significant findings from the open-label EA program showed that foralumab treatment reduced microglial activation and maintained clinical stability in patients with na-SPMS and progression independent of relapses (PIRA). At 3- and 6-month follow-ups, 83% (5 of 6) of treated patients showed reduced (F-18)PBR06-PET signals in multiple brain regions, indicating decreased microglial activity. Patients also demonstrated stable Expanded Disability Status Scale (EDSS) scores and improvements in the Modified Fatigue Impact Scale (MFIS). Investigators plan a double-blind, placebo-controlled, dose-ranging study using (F-18)PBR06-PET as a primary endpoint.4
In the study, a voxel-by-voxel z-score mapping approach was used and sum of z-scores in voxels with z-values of more than 2 were calculated. In addition to the 6 patients, the study also included 2 patients with na-SPMS with PIRA who underwent a test and a retest (F-18)PBR06-PET scan. In the foralumab-treated group, white matter z-scores were reduced by 26%-36% at 3 and 6 months, which was at least 4-5-times higher compared to the 6% variability observed in the test-retest group (PET effect size estimate at 3 months, 1.4).
"The observed clinical stabilization and microglial PET findings are supported by these new biomarker discoveries, providing compelling evidence of nasal foralumab's biological effects," Howard Weiner, chairman of Tiziana’s Scientific Advisory Board and co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, said in a statement.1 "The identification of these biomarkers not only strengthens our understanding of the treatment’s mechanism but also establishes a framework for monitoring its efficacy in future trials and may establish a framework for monitoring a patient’s response to foralumab treatment."
