Rationale for and clinical development of anti-fractalkine antibody in rheumatic diseases

ABSTRACT

Introduction: Rheumatic diseases are inflammatory diseases that damage target organs via multiple subsets of immune cells. Fractalkine (FKN) acts as chemoattractant as well as adhesion molecule. It contributes to the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases through multiple mechanisms: the migration of monocytes and cytotoxic effector T cells, the proliferation and activation of fibroblast-like synoviocytes, angiogenesis, and osteoclastogenesis. FKN has potential as a new therapeutic target, and clinical trials on anti-FKN monoclonal antibodies for RA are ongoing. FKN-targeted therapy has been developed and a humanized anti-FKN monoclonal antibody is currently being tested in phase 2 clinical trials.

Areas covered: This review summarizes accumulated evidence on the involvement of FKN in RA and other rheumatic diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, Sjögren’s syndrome (SS), osteoarthritis, and systemic vasculitis.

Expert opinion: A phase 1/2a clinical trial on anti-FKN demonstrated its safety, tolerability, and clinical efficacy. Anti-FKN therapy has potential in the treatment of atherosclerosis and interstitial lung diseases associated with RA. Based on recent findings, other rheumatic diseases, including SLE, polymyositis/dermatomyositis, and SS, may also be treated using anti-FKN therapy.

KEYWORDS:

• CX3CR1
• fractalkine
• polymyositis/dermatomyositis
• rheumatoid arthritis
• sjögren’s syndrome
• systemic lupus erythematosus
• systemic sclerosis
• systemic vasculitis

Article highlights

• Emerging evidence indicates the involvement of FKN in the pathogenesis of RA as well as other rheumatic diseases, including SLE, SSc, SS, PM/DM, OA, and systemic vasculitis.

• Based on multiple studies that examined the roles of FKN in RA, targeted therapy by an anti-FKN blocking antibody was developed and phase 1/2a clinical trials on RA confirmed its safety, tolerability, and clinical efficacy at 12 weeks.

• The FKN-CX3CR1 axis is also a potentially effective therapeutic target for atherosclerosis and interstitial lung fibrosis associated with RA, which is a complication of RA.

• However, accumulating evidence has shown the involvement of the FKN-CX3CR1 axis in the pathogenesis of other rheumatic diseases.

• Although further studies are needed, the targeting of FKN has potential in the treatment of rheumatic diseases.

This box summarizes key points contained in the article.

Declaration of interest

T Nanki has received research grants, consulting fees and/or speaking fees from Eisai Co., Ltd. KAN Research Institute Inc. which is a subsidiary of Eisai Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.