A Clinical Study to Test the Safety, Exposure, and Pharmacodynamic Markers of CSL311 in Subjects With Mild-to-moderate Asthma and in Healthy Volunteers

This is a phase 1, first-in-human (FIH), multi-center, randomized, double-blind, placebo-controlled study of CSL311 in patients with mild-to-moderate asthma. The primary objective of this study is to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of CSL311.

开始日期2019-11-28

申办/合作机构

CSL Behring LLC

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2024-03-01·Journal of Allergy and Clinical Immunology

Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade

Article

作者: Bozinovski, Steven ; Wilson, Nick ; Cildir, Gökhan ; Keam, Simon P ; Vlahos, Ross ; Toubia, John ; Yip, Kwok Ho ; Pant, Harshita ; Hercus, Timothy R ; Wang, Hao ; Kral, Anita C ; Wark, Peter ; Owczarek, Catherine ; Tumes, Damon J ; Nichol, Kristy ; Lopez, Angel F

BACKGROUNDPatients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation.OBJECTIVETo determine the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease.METHODSβc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling.RESULTSβc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung.CONCLUSIONSβc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

2022-08-01·Respirology

Targeting the human β_c receptor inhibits inflammatory myeloid cells and lung injury caused by acute cigarette smoke exposure

Article

作者: Lopez, Angel F. ; Owczarek, Catherine M. ; Wilson, Nick ; Wang, Hao ; Vlahos, Ross ; Bozinovski, Steven ; Fung, Nok Him

AbstractBackground and objectiveChronic obstructive pulmonary disease (COPD) is a devastating disease commonly caused by cigarette smoke (CS) exposure that drives tissue injury by persistently recruiting myeloid cells into the lungs. A significant portion of COPD patients also present with overlapping asthma pathology including eosinophilic inflammation. The βc cytokine family includes granulocyte monocyte‐colony‐stimulating factor, IL‐5 and IL‐3 that signal through their common receptor subunit βc to promote the expansion and survival of multiple myeloid cells including monocytes/macrophages, neutrophils and eosinophils.MethodsWe have used our unique human βc receptor transgenic (hβcTg) mouse strain that expresses human βc instead of mouse βc and βIL3 in an acute CS exposure model. Lung tissue injury was assessed by histology and measurement of albumin and lactate dehydrogenase levels in the bronchoalveolar lavage (BAL) fluid. Transgenic mice were treated with an antibody (CSL311) that inhibits human βc signalling.ResultshβcTg mice responded to acute CS exposure by expanding blood myeloid cell numbers and recruiting monocyte‐derived macrophages (cluster of differentiation 11b+ [CD11b+] interstitial and exudative macrophages [IM and ExM]), neutrophils and eosinophils into the lungs. This inflammatory response was associated with lung tissue injury and oedema. Importantly, CSL311 treatment in CS‐exposed mice markedly reduced myeloid cell numbers in the blood and BAL compartment. Furthermore, CSL311 significantly reduced lung CD11b+ IM and ExM, neutrophils and eosinophils, and this decline was associated with a significant reduction in matrix metalloproteinase‐12 (MMP‐12) and IL‐17A expression, tissue injury and oedema.ConclusionThis study identifies CSL311 as a therapeutic antibody that potently inhibits immunopathology and lung injury caused by acute CS exposure.

2022-04-01·Journal of Investigative Dermatology1区 · 医学

Targeting the Human βc Receptor Inhibits Contact Dermatitis in a Transgenic Mouse Model

1区 · 医学

Article

作者: Pant, Harshita ; Grimbaldeston, Michele A ; Ramshaw, Hayley S ; Wilson, Nicholas J ; Vairo, Gino ; Yip, Kwok Ho ; McKenzie, Duncan ; Chao, Jessica ; Röder, Joachim ; Maxwell, Mhairi ; Tumes, Damon J ; Hercus, Timothy R ; Fong, Jia Hong ; Owczarek, Catherine M ; Kraushaar, Timo ; Alhamdoosh, Monther ; Raquet, Elmar ; Monaghan, Katherine ; Zeglinski, Kathleen ; McClure, Barbara J ; Hammet, Andrew ; Lopez, Angel F

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (β_c) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit β_c, a property that has made β_c an attractive target to simultaneously inhibit these cytokines. However, the species specificity of β_c has precluded testing of inhibitors of human β_c in mouse models. To overcome this problem, we developed a human β_c receptor transgenic mouse strain with a hematopoietic cell‒specific expression of human β_c instead of mouse β_c. Human β_c receptor transgenic cells responded to mouse GM-CSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of ACD. Similarly, Il3^-/- mice developed ACD pathology comparable with that of wild-type mice. Importantly, the blocking anti-human β_c antibody CSL311 strongly suppressed ear pinna thickening and histopathological changes typical of ACD and reduced accumulation of neutrophils, mast cells, and eosinophils in the skin. These results show that GM-CSF and IL-5 but not IL-3 are major mediators of ACD and define the human β_c receptor transgenic mouse as a unique platform to test the inhibitors of β_c in vivo.

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