A Dual Target-directed Agent against Interleukin-6 Receptor and Tumor Necrosis Factor α ameliorates experimental arthritis.

Youngkyun Kim,Hyerin Jung,Ji Hyeon Ju,Hyoju Yi,Seung Min Jung,Sung-Hwan Park,Narae Park,Juryun Kim,Yeri Alice Rim,Young Woo Park

doi:10.1038/srep20150

Abstract

A considerable proportion of patients with rheumatoid arthritis (RA) do not respond to monospecific agents. The purpose of our study was to generate a hybrid form of biologics, targeting tumor-necrosis factor alpha (TNFα) and interleukin-6 receptor (IL-6R), and determine its anti-arthritic properties in vitro and in vivo. A novel dual target-directed agent (DTA(A7/sTNFR2)) was generated by conjugating soluble TNF receptor 2 (sTNFR2) to the Fc region of A7, a new anti-IL-6R antibody obtained by screening the phage display human antibody library. DTA(A7/sTNFR2) inhibited the proliferation and migration of fibroblast-like synoviocytes from patients with RA (RA-FLS) more efficiently than single target-directed agents. DTA(A7/sTNFR2) also blocked osteoclastogenesis from bone marrow cells. The arthritis severity scores of the experimental arthritis mice with DTA(A7/sTNFR2) tended to be lower than those of mice with IgG, A7, or sTNFR2. Histological data suggested that DTA(A7/sTNFR2) is more efficient than single-target drugs in preventing joint destruction and bone loss. These results were confirmed in vivo using the minicircle system. Taken together, the results show that DTA(A7/sTNFR2) may be a promising therapeutic agent for the treatment of RA.

Highlights

A considerable proportion of patients with rheumatoid arthritis (RA) do not respond to monospecific agents
Etanercept, a soluble TNF receptor 2 (TNFR2) conjugated with human IgG Fc region, and tocilizumab, a fully humanized anti-IL-6 receptor antibody, are the typical biological drugs approved by the FDA to treat Rheumatoid arthritis (RA)
Pathogenesis, we designed a dual-target agent (DTA) against IL-6 receptor (IL-6R) and TNFα (Fig. 1a)

Summary

Introduction

A considerable proportion of patients with rheumatoid arthritis (RA) do not respond to monospecific agents. DTA(A7/sTNFR2) inhibited the proliferation and migration of fibroblast-like synoviocytes from patients with RA (RA-FLS) more efficiently than single target-directed agents. Histological data suggested that DTA(A7/sTNFR2) is more efficient than single-target drugs in preventing joint destruction and bone loss. These results were confirmed in vivo using the minicircle system. TNFα activates T-cells and induces T-cell infiltration and neoangiogenesis, and it leads to joint destruction by increasing proliferation of fibroblast-like synoviocytes (FLS) and formation of osteoclasts. Etanercept, a soluble TNF receptor 2 (TNFR2) conjugated with human IgG Fc region, and tocilizumab, a fully humanized anti-IL-6 receptor antibody, are the typical biological drugs approved by the FDA to treat RA. Binding to both the soluble IL-6 receptor (IL-6R) and the membrane bound IL-6R12, and its efficacy for the treatment of RA has been shown in many clinical trials[13,14,15]

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