Proof of Mechanism for Anti-Interleukin-33 Antibody Tozorakimab in a Phase 1 Study in Healthy Adults and Patients with Chronic Obstructive Pulmonary Disease

Scott, Ian; Killick, Helen; Newcombe, P.; White, N.; Williams, A.; Reid, F.; Pandya, H.; Cohen, S.; Kell, C.; Gavala, M.; Singh, Trevor Hansel Acknowledgments: Dave

doi:10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a2397

Cited by 4 publications

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“…Oxidation of IL-33 limits its ST2-dependent activities [21]; however, recent data has demonstrated that IL-33 ox can signal via RAGE-EGFR on airway epithelial cells in vitro and induces a COPD-associated epithelial phenotype [22]. Consistent with the large structural difference between IL-33 red and IL-33 ox [21], we showed in the present study that tozorakimab is unable to directly neutralize IL-33 Tozorakimab has completed phase 1 clinical evaluation, in which it was shown to be well-tolerated with no safety concerns in healthy subjects and patients with mild COPD (NCT03096795) [56,57]. Building on the pre-clinical pharmacology studies described here, pharmacodynamic biomarker analyses from a phase 1 study suggest that tozorakimab reduced biomarkers of inflammation, including serum IL-5, IL-13 and blood eosinophils in patients with mild COPD [57].…”

Section: C>ssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

“…Tozorakimab has completed phase 1 clinical evaluation, in which it was shown to be well-tolerated with no safety concerns in healthy subjects and patients with mild COPD (NCT03096795) [56,57]. Building on the pre-clinical pharmacology studies described here, pharmacodynamic biomarker analyses from a phase 1 study suggest that tozorakimab reduced biomarkers of inflammation, including serum IL-5, IL-13 and blood eosinophils in patients with mild COPD [57]. Tozorakimab is currently being investigated in multiple inflammatory diseases including a phase 3 study in acute respiratory failure (NCT05624450); phase 2 (NCT04631016) and phase 3 (NCT05166889 and NCT05158387) trials in COPD and phase 2 studies in asthma (NCT04570657) and diabetic kidney disease (NCT04170543).…”

Section: Discussionmentioning

confidence: 99%

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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

Rees

Scott

et al. 2023

Preprint

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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 107M−1s−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-33redand a fast association rate (8.5 × 107M−1s−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 increasingin vitroepithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33redand IL-33oxsignalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

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Section: C>ssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

Rees

Scott

et al. 2023

Preprint

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“…Lastly, tozorakimab is a novel dual-pharmacology mAb that inhibits IL-33 activity via both the ST2 and receptor for advanced glycation end-products–epidermal growth factor receptor complex signalling pathways [ 177 ]. Tozorakimab reduced biomarkers of inflammation, including serum IL-5, IL-13 and blood eosinophils, in a phase 1 study [ 178 ] and is being evaluated in a phase 2 study in patients with asthma ( ClinicalTrials.gov : NCT04570657). Although the impact of these mAbs on airway remodelling has not yet been assessed in clinical studies, IL-33 blockade prevented exacerbations in a mouse model of chronic airway inflammation by blunting persistent inflammation and remodelling [ 179 ].…”

Section: Targeting the Epithelium And Epithelial Cytokines To Modify ...mentioning

confidence: 99%

Airway remodelling in asthma and the epithelium: on the edge of a new era

Varricchi,

Brightling,

Grainge

et al. 2024

Eur Respir J

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Asthma is a chronic, heterogeneous disease of the airways, often characterised by structural changes known collectively as airway remodelling. In response to environmental insults, including pathogens, allergens and pollutants, the epithelium can initiate remodellingviaan inflammatory cascade involving a variety of mediators that have downstream effects on both structural and immune cells. These mediators include the epithelial cytokines thymic stromal lymphopoietin (TSLP), interleukin 33 and interleukin 25, which facilitate airway remodelling through cross-talk between epithelial cells and fibroblasts, and between mast cells and airway smooth muscle cells, as well as through signalling with immune cells like macrophages. The epithelium can also initiate airway remodelling independently of inflammation in response to the mechanical stress present during bronchoconstriction. Furthermore, genetic and epigenetic alterations to epithelial components are believed to influence remodelling. Here, we review recent advances in our understanding of the roles of the epithelium and epithelial cytokines in driving airway remodelling, facilitated by developments in genetic sequencing and imaging techniques. We also explore how new and existing therapeutics that target the epithelium and epithelial cytokines could modify airway remodelling.

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“…A second dose of tozorakimab 300 mg was administered on day 15 if the patient was receiving invasive mechanical ventilation. The tozorakimab dose rationale for patients with COVID-19 was based on results of a tozorakimab phase 1 study in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) [23,24]. The SoC was based on appropriate guidelines in place at the time of each patient's participation, and consequently evolved over time.…”

Section: Drug Administrationmentioning

confidence: 99%

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2

Wilkinson,

De Soyza,

Carroll

et al. 2023

ERJ Open Res

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BackgroundIncreased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020–001736-95).MethodsACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg+standard of care [SoC] or SoC alone. The primary endpoint was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other endpoints included death or respiratory failure, mortality, intensive care unit (ICU) admissions by day 29 and safety. Serum IL-33/soluble ST2 (sST2) complex was measured by high sensitivity immunoassay.ResultsEfficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively [hazard ratio 0.96 (80% confidence interval [CI] 0.70–1.31), one-sided p=0.33]). Tozorakimab was well tolerated, and the odds ratio for risk of death or respiratory failure with treatmentversusSoC was 0.55 ([80% CI 0.27–1.120], p=0.26), whilst the odds ratio was 0.31 (80% CI 0.09–1.06) in patents with high baseline serum IL-33/sST2.ConclusionsOverall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

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Proof of Mechanism for Anti-Interleukin-33 Antibody Tozorakimab in a Phase 1 Study in Healthy Adults and Patients with Chronic Obstructive Pulmonary Disease

Cited by 4 publications

References 0 publications

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

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

Airway remodelling in asthma and the epithelium: on the edge of a new era

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2

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