A Review of Innovative Therapies for Systemic Lupus Erythematosus

Mar 02,2023

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by high levels of autoantibodies in the patient's blood and various organs. The global SLE incidence and newly diagnosed population were estimated to be 5.14 (1.4 to 15.13) per 100,000 person-years and 400,000 people per year, respectively [1]. The SLE disease activity index (SLEDAI) can be used to evaluate and grade the disease activity over a spectrum of possible symptoms. Despite the fact that SLE has been studied for over a century, its pathogenesis remains unclear. Multiple studies point to genetic abnormalities, abnormalities in the endocrine system and immune system, and even some environmental factors as possible causes of SLE.


There is no cure for SLE, only treatments that alleviate symptoms. Current practice is to control lupus activity, improve symptoms, and stop organ damage. Nonsteroidal anti-inflammatory drugs (NSAIDs) or immunosuppressive therapies with short courses of corticosteroids are the most commonly used clinical treatments for SLE. It is worth noting that these therapies inevitably have side effects. For example, prednisone is one of the fastest acting and most effective drugs for the treatment of active lupus and for inflammation control, but it is associated with an increased risk of weight gain and infections. Furthermore, the frequency and severity of side effects rise along with the dosage of drugs required for maintenance therapy. As a result, additional research into the pathogenesis of SLE as well as development of novel therapies is needed.


Category of Innovative SLE Medication



Targeting innate immunity

Targeting adaptive immunity

CAR-T therapy

Others

Representative targets

BDCA2, IFNa, TLR7/8/9

CD20, CD19, BAFF/APRIL, 

CD40, CD40L; L12/IL23

CD19

JAKs, mTOR

Representative medication

Anifrolumab

Belimumab

Anti-CD19 CAR-T therapy

Jaktinib

Function

Type I interferon receptor antagonist (IFNAR1)

Inhibiting BAFF (B-cell activating factor)

Targeting CD19 to eliminate B cells

Blocking JAK/STAT signaling pathway

Status

Marketed

Marketed

Clinical trials ongoing

Phase III trail


Research into new treatments for SLE needs to be backed up by robust and extensive understanding of the immune system. The innate and adaptive immune systems both play critical role in the development of SLE. This involves immunological complexes comprised of antinuclear antibodies, activation of dendritic cells and auto-reactive T cells, and overproduction of autoantibodies released by activated B cells.


Innate immunity and SLE therapy

Type I interferons (IFN-I, notably including IFN-α and IFN-β) are a type of cytokines. IFN-I levels are positively correlated with higher disease activity index (SLEDAI) scores in 60%–80% of SLE patients. The innate immune cells produce IFN-I, which can aid the adaptive immune response. Furthermore, IFN-I can induce CD8+ T cell apoptosis via metabolic reprogramming, contributing to the pathophysiology of SLE[2].


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IFN-I production and signaling pathways[3]


Anifrolumab can bind to Interferon Alpha and Beta Receptor Subunit 1 (IFNAR1), inhibiting IFN-I production. Clinical trials demonstrated that anifrolumab reduces the severity of lupus erythematosus in patients. Anifrolumab has been available in the United States since July 2021 for the approved indication of moderate-to-severe SLE in adults, and it is now being evaluated in a Phase III clinical trial for SLE in China.

 

Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in the innate immune response and serve as a link between innate and adaptive immunity. TLRs rely on two pathways, NF-κB and IRFs (interferon-regulatory factors), to activate downstream signaling and stimulate cytokine and IFN-I production. Merck's enpatoran, a TLR 7/8 inhibitor currently undergoing Phase II clinical trials in China, is one example of a drug with rapid progress in development.

 

Adaptive immunity and SLE therapy

Evidence suggests that T cells from SLE patients are activated in vivo and aid autoreactive B cells. B cells and plasma cells (effector B cells), which release autoantibodies and inflammatory cytokines, respectively, play key roles in the pathogenesis of SLE. Thus the primary targets of current therapy development efforts aim at the adaptive immune system. Autoantibody overproduction triggers an inflammatory cascade response, resulting in organ damage.


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Pharmaceuticals targeting B cells in different developmental stages[4]


Directly eliminating B cells, modulating B cell function, inhibiting substances necessary for B cell growth and survival, and speeding up autoantibody clearance are therapeutic approaches targeting B cells. Belimumab, the world's first SLE-targeting biologic, is a specific inhibitor of B lymphocyte-stimulating factor (BLyS or BAFF) with a high affinity for soluble BLyS in serum, preventing BLyS from binding to receptors on B cells, inhibiting B cell proliferation and differentiation into plasma cells, and reducing autoantibody production by B cells. All in all, B cells and plasma cells are critical in the pathogenesis of SLE. Therapeutic targets aiming at B cells also include CD19, CD20, and CD40.

 

CAR-T therapy and SLE

While CAR-T cell therapy has shown amazing success in oncology, its application to treat autoimmune diseases is still in its infancy. Prof. Georg Schett's team at the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) published "Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus" in the journal Nature Medicine in September 2022. This study showed that all five patients with refractory SLE who were treated with CAR-T therapy improved, and none of the patients experienced a relapse during the 17-month follow-up period, achieving drug-free alleviation[5]. Carl H. June, the father of CAR-T, praised this work in a review paper published in Cell on November 23, 2022. 


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Anti-CD19 CAR-T therapy treating SLE[6]


Although significant progress has been made in understanding and treating SLE, there is still a long way to go before clinical demands are adequately satisfied and the disease's complicated pathology is fully addressed. We anticipate the creation of more effective medications and therapies for SLE as technology and research continue to develop.

 

Animal models are essential for pharmaceutical development and mechanistic exploration. GemPharmatech assists in the discovery and development of novel drugs for SLE and has developed multiple SLE research mouse models to provide preclinical in vivo pharmacodynamic services.


Suggested SLE-related mouse models

B6-Trex1-KO mice

B6-hBAFF mice

3′–5′ DNA nucleic acid exonuclease (TREX1) knockout mice exhibit defective double-stranded DNA degradation, elevated anti-dsDNA levels, and increased IFN-I expression.

Appropriate for innate immunity-related SLE research.

Human-derived B-cell activating factor (BAFF) was randomly inserted into the genome of B6 mice, resulting in increased BAFF expression as well as remarkably high anti-dsDNA levels and B-cell levels.

Suitable for research on B-cell-mediated SLE treatment.

Pristane-induced SLE model

Immune reconstituted model

Pristane triggers inflammation and stimulates the immune response. It can be used with genetically humanized mice for induction modeling and evaluation of target-specific drugs.

Reconstituted mice with human immune system can be used to assess the efficacy of CAR-T cell therapy.


Reference:

[1] Tian J, Zhang D, Yao X, et al. Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study. Annals of the Rheumatic Diseases Published Online First: 14 October 2022. doi: 10.1136/ard-2022-223035

[2] Buang, N., Tapeng, L., Gray, V. et al. Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus. Nat Commun. 2021 Mar 31;12(1):1980.

[3] Rönnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus. 2008 May;17(5):394-9.

[4] Parodis I, Stockfelt M, Sjöwall C. B Cell Therapy in Systemic Lupus Erythematosus: From Rationale to Clinical Practice. Front Med (Lausanne). 2020 Jul 9;7:316

[5] Schett G, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132

[6] Jin X, Han Y, Wang JQ, Lu L. CAR-T cell therapy: new hope for systemic lupus erythematosus patients. Cell Mol Immunol. 2021 Dec;18(12):2581-2582.