Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

Abstract

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung.

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

“…As shown in Figure 8C, these studies highlight a modest IL-13Rα2 signal in lungs from normal individuals, most of which was intracellular. In keeping with the literature (32,33), an enhanced IL-13Rα2 signal, some of which was localized to cell membranes, was seen in the samples from the IPF patients ( Figure 8C). In contrast, in HPS lungs IL-13Rα2 was expressed at lower levels, and the cytoplasmic pool was readily noted but the membrane pool could not be detected ( Figure 8C).…”

Modulation of pulmonary fibrosis by IL-13Rα2

“…They found that IL-13R␣2 deficiency resulted in decreased survival, increased granuloma size, and increased liver fibrosis (19). Recently, Murray et al have elegantly demonstrated that targeting IL-13 directly with tralokinumab also attenuates fibrosis and epithelial damage, highlighting the importance of targeting this ligand/receptor complex (21).…”

Idiopathic Pulmonary Fibrosis: Molecular Endotypes of Fibrosis Stratifying Existing and Emerging Therapies

“…Usually, it promotes IgE class switching and inhibits inflammatory cytokine production, and, more recently, it was discovered that IL-13 is a regulator of the ECM and plays a role in inducing tissue fibrosis in schistosomiasis and asthma. Its overexpression has a direct pro-fibrotic action in animal models [95] and, on the other hand, its downregulation inhibits the development of fibrosis [96,97]. Wilson and Wynn [98] demonstrated that an elevation in IL-13 level is involved in lung fibrosis, and several studies showed higher levels of this cytokine in lungs of IPF patients [99,100].…”

“…Wilson and Wynn [98] demonstrated that an elevation in IL-13 level is involved in lung fibrosis, and several studies showed higher levels of this cytokine in lungs of IPF patients [99,100]. These findings correlate directly with the rate of disease progression [97] and inversely with percent predicted FVC and D LCO [100]. IL-13 pro-fibrotic activity works in synergy with IL-4 [96], but its role is controversial.…”