8395
Nasal Anti-CD3 Monoclonal Antibody (Foralumab) Reduces PET Microglial Activation and Blood Inflammatory Biomarkers in a Patient with Non-Active Secondary Progressive MS
There are no effective treatments for non-active secondary progressive MS (SPMS), which is mediated by compartmentalized CNS inflammation, including activated microglia. We found that nasal anti-CD3 suppressed disease in a chronic EAE model by dampening microglia and astrocyte inflammation. Nasal anti-CD3 does not enter the bloodstream or the brain. Anti-CD3 has been given intravenously and orally to humans, but never nasally. A dose-finding study of a fully human anti-CD3 intranasal monoclonal antibody (Foralumab) in healthy volunteers dosed at 10ug, 50ug and 250ug for 5 consecutive days, found the drug to be safe with immune effects seen at the 50ug dose. We also treated COVID patients with 100ug of intranasal Foralumab for 10 consecutive days, which was well-tolerated and exhibited positive effects on blood markers and lung inflammation.
Objectives:
To determine if nasal Foralumab has a therapeutic effect on a patient with non-active SPMS, under the approval of an expanded access IND.
Methods:
EA1 is 61 year old male with non-active SPMS for over 20 years. Despite treatment with anti-CD20 (ocrelizumab) for 2 years, he continued to progress clinically. Treatment was initiated in May 2021 and has continued for 6 months with a 7-week washout period after 3 months. Treatment occurs in 3-week cycles with intranasal Foralumab 50ug/day administered 3x/week for 2 weeks followed by rest period for 1 week. At the start of each cycle, EA1 repeats clinical and neurological assessments, and imaging is repeated every 3 months.
Results:
To date, there have been no adverse reactions, local irritation, or laboratory abnormalities in response to treatment. Clinically, symptom progression has subsided. The patient is feeling more stable, subjectively, and has noted improvement in lower extremity strength. EDSS, pyramidal motor score and timed 25-foot walk (T25FW) have stabilized or improved. SDMT and 9HPT were stable during treatment. Microglial activation as measured by [F-18] PBR06 PET scan was significantly reduced 3 months after the start of nasal Foralumab, and this reduction was sustained after 7-week washout and at 6 months. Serum protein measurements of cytokines were performed in batch by the Olink assay. Measures of Th1 cytokines IFN-γ and IL-18 were reduced after initiating nasal Foralumab, consistent with results in pre-clinical models. Pro-inflammatory cytokines IL-1ß and IL-6 were also reduced. Cellular immune studies showed an increase in CD8 naïve cells and a decrease in CD8 effector cells and an alteration in gene expression, as measured by single cell RNA sequencing.
Conclusions:
Nasal Foralumab in a non-active SPMS patient treated over a 6-month period reduced microglial activation on [F-18]PBR06 PET imaging, decreased levels of proinflammatory cytokines, and had positive clinical effects. Additional patients are currently being treated with nasal Foralumab at the Brigham MS Center.