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

被引：58

作者：

England, Elizabeth ^{[1
]}

Rees, D. Gareth ^{[1
]}

Scott, Ian Christopher ^{[2
]}

Carmen, Sara ^{[1
]}

Chan, Denice T. Y. ^{[1
]}

Huntington, Catherine Chaillan E. ^{[1
]}

Houslay, Kirsty F. ^{[3
]}

Erngren, Teodor ^{[4
]}

Penney, Mark ^{[5
]}

Majithiya, Jayesh B. ^{[3
]}

Rapley, Laura ^{[3
]}

Sims, Dorothy A. ^{[6
]}

Hollins, Claire ^{[3
]}

Hinchy, Elizabeth C. ^{[3
]}

Strain, Martin D. ^{[1
]}

Kemp, Benjamin P. ^{[1
]}

Corkill, Dominic J. ^{[7
]}

May, Richard D. ^{[3
]}

Vousden, Katherine A. ^{[1
]}

Butler, Robin J. ^{[1
]}

Mustelin, Tomas ^{[8
]}

Vaughan, Tristan J. ^{[1
]}

Lowe, David C. ^{[1
]}

Colley, Caroline ^{[1
]}

Cohen, E. Suzanne ^{[3
]}

机构：

[1] AstraZeneca, Biol Engn, R&D, Cambridge, England

[2] AstraZeneca, Translat Sci & Expt Med Res & Early Dev, BioPharmaceut R&D, Resp & Immunol, Cambridge, England

[3] AstraZeneca, Res & Early Dev, Resp & Immunol, BioPharmaceut R&D,Biosci Asthma & Skin Immun, Cambridge, England

[4] AstraZeneca, BioPharmaceut R&D, Res & Early Dev, Resp & Immunol,Drug Metab & Pharmacokinet, Gothenburg, Sweden

[5] AstraZeneca, Early Oncol DMPK, Oncol R&D, Cambridge, England

[6] AstraZeneca, Res & Early Dev, Resp & Immunol, BioPharmaceut R&D,Biosci Asthma & Skin Immun, Gaithersburg, MD USA

[7] AstraZeneca, Res & Early Dev, Resp & Immunol, BioPharmaceut R&D,Biosci In Vivo,Resp & Immunol, Cambridge, England

[8] Univ Washington, Dept Med, Div Rheumatol, Seattle, WA USA

来源：

SCIENTIFIC REPORTS | 2023年 / 13卷 / 01期

关键词：

MONOCLONAL-ANTIBODY; PHASE; 2A; AFFINITY; INTERLEUKIN-33; CYTOKINE; BINDING; CELLS; GENERATION; PROTEIN; ASSOCIATION;

D O I：

10.1038/s41598-023-36642-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(red)) and oxidized IL-33 (IL-33(ox)) 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(7) 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-33(red) and a fast association rate (8.5 x 10(7) 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-33(red) and IL-33(ox) signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

引用

页数：15

共 71 条

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