The first‐in‐human study of CNTO 7160, an anti‐interleukin‐33 receptor monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis

Abstract

To assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 7160, an anti-interleukin-33 receptor (IL-33R) monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis (AD). Methods: In Part 1 of this Phase I, randomized, double-blind, placebo-controlled study, healthy subjects (n = 68) received single ascending intravenous (IV) CNTO 7160 dose (0.001 to 10 mg/kg) or placebo. In Part 2, patients with mild asthma (n = 24) or mild AD (n = 15) received 3 biweekly IV CNTO 7160 doses (3 or 10 mg/kg) or placebo. Results: CNTO 7160 was generally well tolerated, with 1 serious adverse event of severe cellulitis reported (AD, CNTO 7160, 3 mg/kg). CNTO 7160 exhibited nonlinear PK (0.01-10 mg/kg). Mean clearance decreased with increasing dose (2.43 to 18.03 mL/d/kg). CNTO 7160 PK was similar between healthy subjects and patients with asthma or AD (3 or 10 mg/kg). Free sIL-33R suppression was rapid and dose dependent. Ex vivo inhibition of p38 phosphorylation of basophils was dosedependent (1-10 mg/kg) and sustained inhibition (≥75%) was observed at higher doses (3 or 10 mg/kg). PK/PD modelling and simulation suggests that 1 mg/kg IV every 2 weeks provides adequate systemic drug exposure for sustained inhibition of p38 phosphorylation of basophils. Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or AD). Conclusion: This first-inhuman study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD.

Discovery of small molecular inhibitors for interleukin-33/ST2 protein–protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations

“…An sST2-neutralizing monoclonal antibody has been introduced that can reduce inflammation and decrease acute graft-versus-host disease severity and mortality [ 23 ]. In particular, another anti-ST2 monoclonal antibody CNTO 7160 has been clinical studied in healthy subjects and patients with asthma or atopic dermatitis [ 24 ].…”

Biology of interleukin‑37 and its role in autoimmune diseases (Review)

“…Therefore, further elucidation of the mechanism by which IL-37 is involved in other AIDs is critical for the therapeutic use of this cytokine. Currently, clinical studies involving IL-18 inhibitors [glycogen synthase kinase 1070806( 109 ), ABT-325( 110 ), and rIL-18 binding protein ( 111 )] are underway, and a clinical study involving an IL-33 inhibitor (CNTO-7160) has commenced ( 112 ). IL-37 is considered to be an AID biomarker, a predictive factor, and a possible AID treatment.…”

Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases*

“…Atopic dermatitis 149,150 Uncertain b Allergic contact dermatitis 166 Irritant contact dermatitis 190 Rosacea 191 Psoriasis vulgaris 65,192,193 Pustular psoriasis 67 Mastocytosis 171 Systemic lupus erythematosus 194 Systemic sclerosis 195,196 Chronic spontaneous urticaria 197 Autoimmune blistering diseases 198 Behc ßet disease 199 genes (such as CCL2, CXCL1, CXCL2, Cxcl15 and vascular endothelial growth factor genes) in keratinocytes, in an autocrine manner. 62 Also, in a murine model, IL-33 induced psoriasis-like lesions through interaction with mastocytes and neutrophils.…”