Details

Autor(en) / Beteiligte

• England, Elizabeth
• Rees, D Gareth
• Scott, Ian Christopher
• Carmen, Sara
• Chan, Denice T Y
• Chaillan Huntington, Catherine E
• Houslay, Kirsty F
• Erngren, Teodor
• Penney, Mark
• Majithiya, Jayesh B
• Rapley, Laura
• Sims, Dorothy A
• Hollins, Claire
• Hinchy, Elizabeth C
• Strain, Martin D
• Kemp, Benjamin P
• Corkill, Dominic J
• May, Richard D
• Vousden, Katherine A
• Butler, Robin J
• Mustelin, Tomas
• Vaughan, Tristan J
• Lowe, David C
• Colley, Caroline
• Cohen, E Suzanne

Titel

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

Ist Teil von

• Scientific reports, 2023-06, Vol.13 (1), p.9825-9825, Article 9825

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-33 ) and oxidized IL-33 (IL-33 ) 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 10  M  s , 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-33 and a fast association rate (8.5 × 10  M  s ), 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-33 and IL-33 signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.