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May, R. D.

Publications and source records attributed to May, R. D..

2 recordsLinked to original sources
bioRxiv2023

Patient phenotypes and their relation to TNFα signaling and immune cell composition in critical illness and autoimmune disease

RationaleTNF inhibitors have shown promise in reducing mortality in hospitalized COVID-19 patients; one hypothesis explaining the limited clinical efficacy is patient heterogeneity in the TNF pathway. MethodsWe evaluated the effect of TNF inhibitors in a mouse model of LPS-induced acute lung injury. Using machine learning we attempted predictive enrichment of TNF signaling in patients with either ARDS or sepsis. We examined biological factors that drive heterogeneity in host responses to critical infection and their relation to clinical outcomes. ResultsIn mice, LPS induced TNF-dependent neutrophilia, alveolar permeability and endothelial injury. In humans, TNF pathway activation was significantly increased in peripheral blood of patients with critical illnesses and associated with the presence of mature neutrophils across critical illnesses and several autoimmune conditions. Machine learning using a gene signature separated patients into 5 phenotypes; one was a hyper-inflammatory, interferon-associated phenotype enriched for increased TNF pathway activation and conserved across critical illnesses and autoimmune diseases. Cell subset profiles segregated severely ill patients into neutrophil-subset-dependent groups that were enriched for disease severity, demonstrating the importance of neutrophils in the immune response in critical illness. ConclusionsTNF signaling and mature neutrophils are associated with a hyper-inflammatory phenotype of patients, shared across critical illness and autoimmune disease. This phenotyping provides a personalized medicine hypothesis to test anti-TNF therapy in severe respiratory illness. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/564631v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1e25724org.highwire.dtl.DTLVardef@c708bcorg.highwire.dtl.DTLVardef@10e7531org.highwire.dtl.DTLVardef@3014b8_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2023

Tozorakimab (MEDI3506): a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products - epidermal growth factor receptor (RAGE-EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M-1 s-1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 x 107 M-1 s-1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

immunology↗