Monoclonal antibodies targeting interleukins for systemic lupus erythematosus: updates in early clinical drug development

ABSTRACT

Introduction

The advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In systemic lupus erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs.

Areas covered

In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis.

Expert opinion

An unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.

KEYWORDS:

• Systemic lupus erythematosus
• Monoclonal antibodies
• interleukins
• anifrolumab
• belimumab
• interferon
• IL-2
• clinical trials

Article highlights

• B cell activating factor (BAFF) and the related cytokine APRIL, are important regulators of B cell survival and maturation, with studies linking their dysregulation to autoimmunity development. The anti-BAFF monoclonal antibody (mAb) belimumab is the first approved biological therapy in SLE. Telitacicept is a fusion protein targeting both BAFF and APRIL undergoing phase III evaluation. Ianalumab is an anti-BAFF receptor also acting as B cell-depleting therapy and is undergoing phase III evaluation.

• Dysregulation of Type I IFN pathway has been linked to SLE development, leading to the development of several related biological drugs. Anifrolumab is an anti-type I IFN receptor mAb recently approved for the treatment of non-renal SLE. IFNα-kinoids are bioengineered molecules which are able to induce an autoimmune response targeting IFNα, thus inhibiting its action. A phase III clinical trial for IFNα-kinoids was announced in 2018, but never started.

• The ‘IL 23-Th17-IL17’ axis has been shown to play a role in SLE inflammation, particularly in lupus nephritis. However, trials involving Ustekinumab and Secukinumab in SLE have been unsuccessful. Guselkumab, an anti-IL23 mAb, is undergoing a phase II clinical trial in lupus nephritis.

• Treg dysfunction has been shown to be a prominent feature of SLE. Low doses of IL2 have been shown to be able to selectively induce Treg expansion in translational studies as well as in phase I clinical trials for several autoimmune diseases. Several IL-2 analogues are now undergoing phase II evaluation in SLE.

• Several other mAbs are under development targeting CXCR5, IL6, IL-21 and IL-10.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.