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

England, E.; Rees, D. G.; Scott, I. C.; Carmen, S.; Chan, D. T. Y.; Huntington, C. E. C.; Houslay, K. F.; Erngren, T.; Penney, M.; Majithiya, J. B.; Rapley, L.; Sims, D. A.; Hollins, C.; Hinchy, E. C.; Strain, M. D.; Kemp, B. P.; Corkill, D. J.; May, R. D.; Vousden, K. A.; Butler, R. J.; Mustelin, T.; Vaughan, T. J.; Lowe, D. C.; Colley, C.; Cohen, E. S.

doi:10.1101/2023.02.28.527262

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bioRxiv · 10.1101/2023.02.28.527262

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

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Abstract

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.

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England, E., Rees, D. G., Scott, I. C., Carmen, S., Chan, D. T. Y., Huntington, C. E. C., Houslay, K. F., Erngren, T., Penney, M., Majithiya, J. B., Rapley, L., Sims, D. A., Hollins, C., Hinchy, E. C., Strain, M. D., Kemp, B. P., Corkill, D. J., May, R. D., Vousden, K. A., Butler, R. J., Mustelin, T., Vaughan, T. J., Lowe, D. C., Colley, C., Cohen, E. S.. 2023-03-01. 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. https://doi.org/10.1101/2023.02.28.527262

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