RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

Abstract

Introduction: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.

Methods: Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.

Results: In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.

Conclusion: RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).

Funding: AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.

Keywords: Asthma; IL-13; Respiratory.

Fig. 1

Anti-IL-13 antibody effects in the murine OVA-induced asthma model. Measurement of a AHR, b AMCase levels in the BALF, and c, d mucus production measured by Muc5ac ELISA and histologic assessment by PAS reactivity following administration of antibody 51D9 or 48D3 before OVA challenge. a–c Anti-mIL-13 antibodies that block binding of IL-13 to either IL-13Rα1 alone or both IL-13Rα1 and IL-13Rα2 similarly inhibit AHR and AMCase production, whereas blockade of IL-13Rα2 binding appears to be required for inhibition of mucus production. Pooled data from 3–4 studies; n = 10–30/data point. d Area of mucus-secreting epithelial cells visualized by PAS+ staining in OVA-challenged animals treated with either 51D9, 48D3, or dexamethasome. e Quantification of antibody levels in both serum and BALF of treated mice measured at the termination of the experiment. AHR airway hyperresponsiveness, AMCase acidic mammalian chitinase, ANOVA analysis of variance, BALF bronchoalveolar lavage fluid, Dex dexamethasone, ELISA enzyme-linked immunosorbent assay, IL interleukin, mIL-13 mouse IL-13, Muc5ac mucin 5ac, OVA ovalbumin, PAS periodic acid-Schiff, PBS phosphate-buffered saline, R receptor. *P < 0.05 by one-way ANOVA and the Dunnett posttest

Fig. 2

Lung gene expression analysis in murine OVA asthma models. a, left Hierarchical clustering of 361 probe sets showing at least twofold regulation (PBS treated vs OVA treated) with P ≤ 0.05 (the Student t test). a, right Highlight of cluster containing the most highly induced genes by OVA treatment, yet showing preferential normalization in response to 51D9. The positions of CLCA3 (the murine equivalent to human CLCA1) and Muc5ac, which were taken forward into human studies, are indicated. b Highly inducible mRNAs are particularly sensitive to dual receptor blockade. To highlight the effect of dual receptor blockade, the antibody response profile for each of the 20 mRNAs most highly induced in OVA-treated lungs compared with control lungs is indicated. Induced genes were defined as those upregulated at least threefold with P ≤ 0.01 using the Student t test. Values were normalized by subtraction of the PBS control. CLCA calcium-activated chloride channel regulator, IL interleukin, mRNA messenger RNA, Muc5ac mucin 5ac, OVA ovalbumin, PBS phosphate-buffered saline, R receptor

Fig. 3

RPC4046 serum concentration–time profiles in healthy participants and patients with asthma. Mean (SD) RPC4046 serum concentration following (a) a single IV infusion in healthy volunteers and asthma patients or (b) three weekly SC doses in patients with asthma (linear and log-linear [inset] scales). Arrows indicate SC injections. IV intravenous, SC subcutaneous

Fig. 4

Changes in a, b MUC5AC and c, d CLCA1 mRNA expression levels, in individuals with detectable expression at baseline (day 0), after 2 days of exposure to RPC4046 (all doses). Absolute values in a, c individual patients with asthma and b, d individual healthy subjects. CLCA calcium-activated chloride channel regulator, mRNA messenger RNA, MUC5AC mucin 5AC