Preclinical development of CAT‐354, an IL‐13 neutralizing antibody, for the treatment of severe uncontrolled asthma

Abstract

BACKGROUND AND PURPOSEIL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development.EXPERIMENTAL APPROACHIn vitro the potency, specificity and species selectivity of CAT-354 was assayed in TF-1 cells, human umbilical vein endothelial cells and HDLM-2 cells. The ability of CAT-354 to modulate disease-relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT-354 was tested on human IL-13-induced air pouch inflammation in mice, ovalbumin-sensitization and challenge in IL-13 humanized mice and antigen challenge in cynomolgus monkeys.KEY RESULTSCAT-354 has a 165 pM affinity for human IL-13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL-13. CAT-354 did not neutralize human IL-4. In vitro CAT-354 functionally inhibited IL-13-induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT-354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia.CONCLUSIONS AND IMPLICATIONSCAT-354 is a potent and selective IL-13-neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.

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

“…To determine whether the IL-13 generated by human fibroblasts contributed to the lung remodeling, SCID mice were treated with tralokinumab from Days 35 to 63 after the injection of the human fibroblasts from a patient who showed rapidly progressive disease ( Figures 5D-5M). Although human IL-13 can signal via murine IL-13 receptors (31), tralokinumab only targets human IL-13 and has no neutralizing capacity on mouse IL-13 (31), indicating that these data are a consequence of inhibiting IPF fibroblast-derived human IL-13. At Day 63 after human fibroblast administration, the immunoneutralization of IL-13 reduced alveolar wall, airway epithelium, and basement membrane thickening, as observed in trichrome-stained lung sections ( Figures 5D-5F).…”

Reduction of eotaxin production and eosinophil recruitment by pulmonary autologous macrophage transfer in a cockroach allergen-induced asthma model

“…47) following activation via IL-4R␣ (58), which is also known to be involved in the development of an alternatively activated phenotype via signals mediated by both IL-4 and IL-13 (13, 32, 38, 52). As we have shown, CRA induces significant production of IL-4 and IL-13 by lung cells, and, although the precise cellular source of these cytokines remains undefined, it is known that they both play a role in upregulating eotaxin production (34,36,58). Whereas the reduction of IL-4 and IL-13 was not accompanied by a corresponding decrease in eotaxin 2 levels in vitro, reduction in both eotaxin 1 and 2 was seen in the BAL fluid and whole lung homogenate in vivo; this observation serves to expose the limitations of a solely in vitro approach.…”

“…Significant eosinophil influx is observed in the CRA-induced asthma model (Fig. 1, B and C), and both IL-4 and -13 are known to positively influence eotaxin production (34,36,58). In vitro production of eotaxin 1 and 2 is observed, but the picture is complex (Fig.…”

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“…Tralokinumab is a humanized monoclonal antibody to IL-13. May RD et al [40] used tralokinumab to treat 194 patients with moderate and severe BA. A moderate improvement in lung function and a reduced use of adrenoceptor agonists was noted.…”