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

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.

A Randomized Phase I Study of the Anti‐Interleukin‐33 Antibody Tozorakimab in Healthy Adults and Patients With Chronic Obstructive Pulmonary Disease

“…Despite the lower exposure observed in Japanese participants compared with non‐Japanese participants in phase I, no differences were found for target engagement in the serum for these 2 cohorts. Following multiple doses administered q2w, a slight accumulation of tozorakimab was noted based on the trough concentration, which was consistent with the estimated half‐life of the drug 13 …”

“…In an exploratory analysis, local target engagement was confirmed in nasal MLF samples through a numerical increase in the levels of the IL‐33/tozorakimab complex and a decrease in levels of both free IL‐33 red and IL‐33 ox . The relative levels of different forms of IL‐33 were consistent with the mechanism of action of tozorakimab and indicated that it prevented the formation of IL‐33 ox in patients with COPD 13 . Tozorakimab significantly reduced the serum levels of the COPD‐associated inflammatory cytokines IL‐5 and IL‐13, 25 confirming reductions in inflammatory biomarkers downstream of the IL‐33–ST2 pathway.…”

“…Indeed, early phase clinical studies suggest that anti‐IL‐33 and anti‐ST2 monoclonal antibodies may be effective for the treatment of IL‐33‐driven respiratory diseases 18,19 . To our knowledge, tozorakimab is the first anti‐IL‐33 antibody reported to inhibit both the IL‐33 red –ST2 and IL‐33 ox –RAGE/EGFR signaling pathways and may offer a mechanism of action that is distinct from other therapies that only target the IL‐33–ST2 signaling pathway 13,29,30 …”

“…Activation of the IL‐33–ST2 pathway typically leads to the increased production of type 2 inflammatory cytokines and the infiltration of inflammatory cells into airways 10,11 . There is emerging evidence that suggests IL‐33–ST2 can also drive type 1 inflammation 10,12,13 . Oxidized IL‐33 (IL‐33 ox ) binds to the receptor for advanced glycation end products (RAGE) in a complex with the epidermal growth factor receptor (EGFR) and regulates airway epithelial remodeling and mucus secretion 14 …”

“…Tozorakimab is a novel high‐affinity human immunoglobulin G1 monoclonal antibody that potently neutralizes IL‐33. Tozorakimab prevents IL‐33 red signaling via the ST2 pathway and prevents the formation of IL‐33 ox , thereby also reducing signaling via the distinct RAGE/EGFR pathway 13 . This phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK) profile, and immunogenicity of single and repeated doses of tozorakimab in healthy adults with a history of atopy, patients with mild COPD, and healthy Japanese adults.…”