Publications

Neurology, Neuroimmunology & Neuroinflammation:

Nasal Foralumab for the Treatment of Progression Independent of Relapses in Patients With Nonactive Secondary Progressive Multiple Sclerosis

Abstract:
Ten patients with nonactive secondary progressive MS (naSPMS) that continued to progress on B-cell therapy were treated with nasal anti-CD3 (foralumab) for a minimum of 6 months in an open-label study. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), MS Functional Composite, Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test, and Low Contract Visual Acuity. MRI and microglial translocator protein (TSPO)-PET imaging with [F-18]PBR06 were conducted. Serum and CSF proteomic biomarkers and single-cell RNA sequencing of blood were performed to evaluate foralumab-induced immunomodulation. The end points of our study were safety, clinical effects, microglial signal, and immune measures.

Figure 1 TSPO-PET Signal Response to Foralumab Treatment in 2 Patients
Reduced TSPO-PET signal after nasal foralumab treatment. Individualized pGALP z-score maps for patients EA6 (A) and EA1 (B) superimposed on respective patient’s T1-weighted MRI demonstrate decreased PET abnormalities after treatment at 3 months (middle row) and 6 months (bottom row) as compared with baseline (top row). Hotter colors represent a higher z-score value and cooler colors represent a lower z-score value as determined by the GALP 2.0 pipeline. (C and D) White matter and global PET scores at baseline and on treatment. Decreased voxel-wise average [F-18]PBR06-PET mGALP z-scores (GALP 3.0) in white matter (C) and global (D) regions of interest after nasal foralumab treatment for 3 months and 7.5 months (mean duration of treatment at last available PET follow-up visit). GALP = Glial activity load on PET.

Clinical Nuclear Medicine:

Dampening of Microglial Activation With Nasal Foralumab Administration in Moderate Alzheimer’s Disease Dementia

Abstract:
A 78-year-old man with moderate Alzheimer disease (AD)
dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.

Image Source: Singhal T et al. Dampening of Microglial Activation with Nasal Foralumab Administration in Moderate Alzheimer’s Disease Dementia. Clinical Nuclear Medicine 2025 May 13. doi: 10.1097/RLU.0000000000005955. Online ahead of print.

Nature Neuroscience:

Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10 dependent Treg–microglia crosstalk 

Abstract:
Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (Treg cells) that migrated to the brain and closely contacted microglia. Treg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing Treg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury.

PNAS:

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19 

Significance
Activated T cells play an important role in the complications following COVID-19 infection. Anti-CD3 monoclonal antibody (mAb) binds to the T cell receptor and dampens inflammation by modulating T cell function. We show here that nasal administration of a fully human anti-CD3 Mab (Foralumab) modulates T cell inflammatory responses in COVID-19 by suppressing effector features in multiple T cell subsets, an effect also seen in subjects with multiple sclerosis. Immunomodulation by nasal anti-CD3 mAb represents a novel avenue for treatment of inflammatory human diseases.

PNAS

Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer’s disease

Significance
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques, neurofibrillary tangles, and microglial activation. Therapies targeting amyloid beta have shown positive effects in subjects with AD. Nasal anti-CD3 has been shown to treat animals with a progressive form of experimental autoimmune encephalomyelitis, a model for multiple sclerosis, by inducing regulatory T cells that dampen microglial inflammation in the brain. Here, we show that nasal anti-CD3 also ameliorates disease in a murine model of AD by targeting microglial activation in the brain independent of amyloid beta deposition. These studies identify a unique approach to treat Alzheimer’s disease that could also be given in combination with anti amyloid therapy.

Frontiers 

Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects

Conclusion:

These findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases. 

Frontiers 

Treatment of six non-active secondary progressive MS with nasal anti-CD3 monoclonal
antibody (foralumab): safety, biomarker, and disability outcomes

Conclusion:
Nasal foralumab is a novel, non-toxic immunomodulatory treatment for non-active SPMS. We report a total of 6 patients on foralumab: 2 patients completed over 12 months
of therapy, and an additional 4 patients were treated for 6 months with no severe TRAEs. All 6 patients experienced improvement in at last one clinical measure (EDSS,
pyramidal score or MFIS), and 5/6 showed improvement on microglial PET imaging at 6 months. 10 patients in total will be treated under the expanded access program and
a multi-center placebo controlled double-blind phase 2 trial is underway.