Nasal administration of anti-CD3 mAb (Foralumab) downregulates <i>NKG7</i> and increases <i>TGFB1</i> and <i>GIMAP7</i> 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. <i>CCL5,</i> <i>IL32,</i> <i>CST7,</i> <i>GZMH,</i> <i>GZMB,</i> <i>GZMA,</i> <i>PRF1</i>, and <i>CCL4</i> gene expression were downregulated in T cells and <i>CASP1</i> 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 <i>TGFB1</i> gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene <i>GIMAP7</i> in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. <i>TGFB1,</i> <i>GIMAP7</i>, and <i>NKG7</i> 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.