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

Abstract

T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 μg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7 + effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1 , and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7 , and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

Identification of Marker Genes in Infectious Diseases from ScRNA-seq Data Using Interpretable Machine Learning

“…We observed the downregulation of CD16 as a marker of severe COVID-19 (compared to mild COVID- 19). The protein encoded by this gene is an antibody Fc receptor.…”

“…This gene is responsible for encoding a cluster of proteins that collectively form the T cell receptors, which are crucial for activating T cells and promoting their cytotoxicity. Notably, upon inhibiting the expression of CD3 , a controlled inflammatory response was observed in the context of COVID-19 [ 19 ]. Thus, we theorize that the upregulation of CD3 that differentiated severe COVID-19 might have caused the cytotoxic effect of CD3+ T cells attacking infected host cells.…”

Respiratory delivery of passive immunotherapies for SARS-CoV-2 prophylaxis and therapy

“…in COVID-19. 43 I.n. administration (37 μg/nostril) of scFv76 2 h before and 4 h after infection, completely blocked infection by luciferase-expressing D614G S-pseudotyped virus in hACE2-expressing transgenic mice, as deduced by the loss of luminescent signal; the same was true when 35 μg/nostril were administered to hamsters 2 h before and once daily for the 2 consecutive days post-infection.…”

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

“…Foralumab, a fully human anti-CD3 mAb, has been successfully given to human subjects and has demonstrated immune effects with minimal toxicity ( 26 ). A pilot trial in subjects with COVID-19 ( 27 , 28 ) and initial studies in subjects with progressive MS have shown positive effects. The results presented here provide the basis for testing nasal anti-CD3 in subjects with AD.…”

“…In studies most relevant to the treatment of AD by nasal anti-CD3, we found that nasal anti-CD3 treatment in a progressive model of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, dampened microglia and astrocyte inflammation in the CNS ( 22 ). Importantly, in human subjects, we have found that the nasal administration of a fully human anti-CD3 antibody (Foralumab) modulated immune responses when given to normal subjects ( 26 ) and showed positive effects in a pilot trial in subjects with COVID-19 with minimal toxicity ( 27 , 28 ). Given this and the importance of activated microglia in AD, we tested nasal anti-CD3 administration in the 3xTg mouse model of AD and found modulation of activated microglia, changes in gene expression patterns in the brain, and improved cognition independent of Aβ deposition.…”