Activated T cells are present in the early stages of SARS-CoV-2 infection, increasing their numbers over time. They have strong reactivity to the coronavirus proteins. Therefore, in addition to vaccination and antiviral strategies, dampening hyperactive T-cell responses is a goal of combatting COVID-19.

Foralumab is a fully human anti-CD3 monoclonal antibody. In a previous randomized pilot trial published in Frontiers of Immunology, Brigham and Women’s Hospital researchers found nasal administration of foralumab to outpatients with mild to moderate COVID-19 was associated with reductions in lung inflammation and two serum markers of inflammation, interleukin-6 and C-reactive protein.

In a follow-up study referring to the same trial, a Brigham team determined how nasal foralumab modulates inflammation using whole-genome cell transcriptomics and serum proteomics. They describes a potential novel avenue for treating not just COVID-19 but also autoimmune diseases.

Thais G. Moreira, PhD, Tanuja Chitnis, MD, Vijay Kuchroo, DVM, PhD, and Howard L. Weiner, MD, all of the Ann Romney Center for Neurologic Diseases in the Department of Neurology, and colleagues report in Proceedings of the National Academy of Sciences USA.

Methods

In the pilot trial previously reported, 12 patients received nasal foralumab (100 mcg/day) for 10 days and were compared with 16 patients who did not receive foralumab. In the current analysis, the researchers used serum proteomics and RNA sequencing to investigate immune changes in the treated patients, untreated patients, and seven healthy controls.

Results

Foralumab administration was associated with the following:

• Downregulation of effector function gene expression, including NKG7⁺, in multiple CD3+ T-cell subsets

• Downregulation of GIMAP7 gene expression—GTPases of immunity-associated proteins (GIMAPs) are reportedly associated with T-cell regulatory function

• Upregulation of TGFB1 gene expression in cell types with known effector functions that are not classical regulatory T cells

• Downregulation of Rho/ROCK1, a downstream pathway of GTPases signaling

• Increased secretion of brain-derived neurotrophic factor (BDNF), which has been associated with recovery in COVID-19

A Common Mechanism

The Brigham team previously observed the transcriptomic changes in NKG7, GIMAP7, and TGFB1 after administering foralumab to healthy volunteers and patients with multiple sclerosis. The interactions among these genes to affect immune activation have not been described before and may represent an important pathway for the maintenance of immune homeostasis.

The mechanism of action of nasal foralumab suggests the drug could be an adjunct therapy for COVID-19 and have long-term applications in other diseases involving immune dysfunction.