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

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

  • Sci Rep. 2023 Jun 17;13(1):9825. doi: 10.1038/s41598-023-36642-y.
Elizabeth England # 1,  D Gareth Rees # 1,  Ian Christopher Scott # 2,  Sara Carmen 1,  Denice T Y Chan 1,  Catherine E Chaillan Huntington 1,  Kirsty F Houslay 3,  Teodor Erngren 4,  Mark Penney 5,  Jayesh B Majithiya 3,  Laura Rapley 3,  Dorothy A Sims 6,  Claire Hollins 3,  Elizabeth C Hinchy 3,  Martin D Strain 1,  Benjamin P Kemp 1,  Dominic J Corkill 7,  Richard D May 3,  Katherine A Vousden 1,  Robin J Butler 1,  Tomas Mustelin 8,  Tristan J Vaughan 1,  David C Lowe 1,  Caroline Colley 1,  E Suzanne Cohen # 9
Affiliations

Affiliations

  • 1 Biologics Engineering, R&D, AstraZeneca, Cambridge, UK.
  • 2 Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 3 Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 4 Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 5 Early Oncology DMPK, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 6 Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 7 Bioscience In Vivo, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 8 Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA.
  • 9 Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. suzanne.cohen@astrazeneca.com.
  • # Contributed equally.
PMID: 37330528 DOI: 10.1038/s41598-023-36642-y
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 × 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z