Nasal anti-CD3 mAb (Foralumab) dampens CD3+ T effector function and decreases NKG7 in COVID-19 through a mechanism involving GIMAP-7 and TGFb1

Abstract

T cells are present in early stages of the SARS-CoV-2 infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully humanized 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 RNA-sequencing and serum proteomics, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100ug/day) 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 function, 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 and TGF-b1 signaling, was downregulated in Foralumab treated individuals. TGFb1, GIMAP7 and NKG7 transcriptomic changes observed in Foralumab treated COVID-19 subjects was 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.