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Systemic lupus erythematosus

Disease ID:1037
Name:Systemic lupus erythematosus
Associated with:6 targets
27 immuno-relevant ligands
Description
SLE is a complex autoimmune disease that is characterised by inflammation of various connective tissues, and symptoms include dermatitis, arthritis, inflammation of the kidneys (glomerulonephritis), vasculitis, inflammation of the tissue surrounding the heart, and seizures. It is caused by the production of autoantibodies against widely expressed nuclear, cytoplasmic, and cell surface molecules. Extracellular RNA in the circulation in combination with the presence of autoantibodies potently stimulates interferon production and immune system activation.
Database Links
Disease Ontology: DOID:9074
OMIM: 152700
Orphanet: ORPHA536

Targets

CXCR5
References:  20
TLR7
TLR9
CIITA
NLRP1
cytotoxic T-lymphocyte-associated protein 4 (CD152)

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
fenebrutinib
Immuno Disease Comments: Phase 2 clinical candidate for SLE (see NCT02908100).
Clinical Use: GDC-0853 has reached Phase 2 clinical trial in patients with rheumatoid arthritis (RA: see NCT02833350), and Phase 1 in patients with resistant B-cell lymphoma or chronic lymphocytic leukemia (CLL). | View clinical data
iberdomide
Immuno Disease Comments: Phase 2 clinical candidate for SLE- see NCT03161483
Clinical Use: CC-220 is being evaluated in clinical trials for systemic lupus erythematosus (SLE; Phase 2), and for relapsed and refractory multiple myeloma (alone or in combination with (Phase 1/2). | View clinical data
Bioactivity Comments: CC-220 binds cereblon with higher affinity than or [23]. | View biological activity
rontalizumab
Immuno Disease Comments: Failed Phase 2 clinical candidate for SLE.
Clinical Use: Clinical development was discontinued after a failure to show efficacy in a Phase 2 clinical trial (NCT00962832) in patients with systemic lupus erythematosus (SLE) [14]. | View clinical data
Bioactivity Comments: Rontalizumab is broadly neutralizing of IFN-αs but not other Type I interferons [2]. | View biological activity
sifalimumab 10,16
Immuno Disease Comments: Targets the dysregulated type I interferon system in SLE. Phase 2 clinical candidate with studies e.g. NCT00979654 and NCT01283139 completed, and showing positive outcomes. Development discontinued for SLE in 2015.
Clinical Use: Sifalimumab reached Phase 2 clinical trial in patients with SLE. Results from NCT01283139 were promising, and although no efficacy of safety failures were reported [16], development of sifalimumab was discontinued for strategic business reasons in 2015. | View clinical data
brentuximab vedotin
Immuno Disease Comments: Ex Phase 2 clinical candidate for adults with SLE- trial NCT02533570 was terminated
Clinical Use: Brentuximab vedotin is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma [24] and systemic anaplastic large cell lymphoma. Several clinical trials are evaluating the combination of brentuximab vedotin with immune checkpoint inhibitors, to assess any synergistic effects as a result of dual targeting. Checkpoint inhibitors being investigated in this way include and (both anti-PD-1), and (anti-CTLA4). Brentuximab vedotin + pembrolizumab (NCT02684292) and brentuximab vedotin + nivolumab (NCT03138499) are both Phase 3 studies in patients with relapsed/refractory classical Hodgkin's lymphoma.

Expanded approvals:
In November 2017, the FDA approved brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, following review of results from the Phase 3 ALCANZA trial (NCT01578499) [6]. In March 2018, the FDA approved the use of brentuximab vedotin for the treatment of patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy. This expansion was based on results from the ECHELON-1 clinical trial (NCT01712490) [5,39]. November 2018 saw further expansion of approval for the use of brentuximab vedotin plus chemotherapy for adult patients who are newly diagnosed with CD30-expressing peripheral T-cell lymphomas. | View clinical data
Bioactivity Comments: Detailed information contained in the covering patent [7] describes in vitro and in vivo activity of the invention, which supports its anti-CD30 action. However, no affinity data is provided for the interaction between the antibody and its molecular target. | View biological activity
CEP-37440
Immuno Disease Comments: Phase 2 clinical candidate for SLE- see NCT03252587
Clinical Use: CEP-37440 has completed Phase 1 clinical trial as an oncology candidate (see NCT01922752). | View clinical data
Bioactivity Comments: CEP-37440 inhibits ALK-driven cell proliferation with an IC50 of 22nM, and FAK-driven cells with an IC50 of 82nM [25]. | View biological activity
evobrutinib
Immuno Disease Comments: Phase 2 clinical candidate for SLE- see NCT02975336
Clinical Use: Evobrutinib is being evaluated in Phase 2 clinical trials for rheumatoid arthritis, systemic lupus erythematosus and relapsing-remitting multiple sclerosis. A full list of evobrutinib trials registered with ClinicalTrials.gov is available by clicking here. | View clinical data
Bioactivity Comments: Evobrutinib exhibits high selectivity for BTK over the EGFR and other Tec family kinases. This profile suggests that evobrutinib is likely to have a reduced potential for off-target related adverse effects compared to existing less selective BTK inhibitors like . The improved selectivity profile and reduced propensity to cause adverse side-effects means that evobrutinib is suitable for evaluation in non-oncology indications. In contrast, the serious side-effects profile of ibrutinib precludes its evaluation in diseases other than life-threatening cancers. | View biological activity
lenabasum
Immuno Disease Comments: Phase 2 clinical candidate for SLE- see NCT03093402
Clinical Use: Ajulemic acid (research code JBT-101) is being evaluated as a treatment for systemic lupus erythematosus (SLE) in Phase 2 clinical trial NCT03093402.
It was also more effective in reducing chronic neuropathic pain than placebo in a Phase 2 clinical trial [15]. | View clinical data
azathioprine
Immuno Disease Comments: Approved drug for SLE.
Clinical Use: Used to reduce organ rejection in transplant patients and to treat autoimmune diseases such as rheumatoid arthritis, Crohn's disease, lupus erythematosus and ulcerative colitis. | View clinical data
Bioactivity Comments: Azathioprine is reported to inhibit peptidylarginine deiminase 4 (PADI4), albeit with very low in vitro affinity [18]. PADI enzymes catalyze the hydrolytic deimination of protein arginine to produce protein citrulline and ammonia [13] and cause chromatin decondensation. Dysregulated PADI4 activity may be involved in cancer progression as it is overexpressed in many malignant tumours, where enhanced chromatin decondensation is involved in promoting pluripotency and stem cell maintenance. | View biological activity
prednisolone
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including SLE.
Clinical Use: This drug used as an antiinflammatory or immunosuppressive agent and is indicated for the treatment of various inflammatory pathologies, including acute asthma, suppression of inflammatory and allergic disorders, ulcerative colitis, Crohn's disease, idiopathic thrombocytopenic purpura, rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus and chronic obstructive pulmonary disease (COPD). | View clinical data
flurbiprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including SLE.
Clinical Use: Flurbiprofen is approved to treat the pain and inflammation associated with rheumatic diseases and other musculoskeletal disorders, as well as dysmenorrhoea, migraine and as postoperative analgesia. | View clinical data
APRIL 4
Immuno Disease Comments: Investigational therapeutics targeting APRIL are under development- e.g. the fusion peptide atacicept for various autoinflammatory conditions, including SLE.
BAFF 19
Immuno Disease Comments: BAFF is a drug target for SLE, as evidenced by the approval of the anti-BAFF mAb belimumab for the treatment of SLE.
belimumab
Immuno Disease Comments: Approved drug for SLE.
Clinical Use: Approved as an adjunctive treatment for systematic lupus erythematosus (SLE) [21]. The original formulation of belimumab was administered intravenously. In July 2017, a new self-injectable subcutaneous formulation of belimumab for the treatment of adult patients with active, autoantibody‑positive SLE was FDA approved, which allows patients to self-administer their medicine at home rather than going to medical facilities to receive their i.v. infusions.
Additional indications being evaluated with belimumab include vasculitis (Phase 3), and myaesthenia gravis and transplant rejection (both Phase 2). | View clinical data
tabalumab
Immuno Disease Comments: Tabalumab was a clinical candidate therapeutic for SLE.
Clinical Use: Tabalumab progressed to Phase 3 clinical evaluation in patients with SLE [33] and rheumatoid arthritis, but trials in these conditions were terminated due to an observed lack of efficacy. Click here to link to ClinicalTrials.gov. complete list of tabalumab studies. | View clinical data
Bioactivity Comments: In patent US7317089 a KD for the interaction between antibody 4A5-3.1.1-B4 and human TNFSF13B is reported as 38µM [17]. However, this appears to be a very low affinity, considering the patent abstract suggests a requirement for the KD to be <10nM. We have therefore entered the 10nM figure in the interaction table below. | View biological activity
epratuzumab
Immuno Disease Comments: Epratuzumab is being investigated for antiinflammatory actions in SLE.
Clinical Use: Epratuzumab is an investigational immunotherapy in Phase 3 clinical trial for the treatment of systemic lupus erythematosus (SLE; failure to show efficacy reported in [3]) [27], relapsed acute lymphoblastic leukemia (ALL) and relapsed/refractory, aggressive non-Hodgkin's lymphoma (NHL). Click here to link to ClinicalTrials.gov's full listing of registered epratuzumab trials. | View clinical data
Bioactivity Comments: We have been unable to find a publicly available binding affinity for interaction between epratuzumab and CD22. However, this interaction as the primary mmoa is supported in the published literature [26,31]. | View biological activity
anifrolumab
Immuno Disease Comments: Approved therapy for SLE.
Clinical Use: Anifrolumab was progressed to clinical development for SLE and for scleroderma. First approval was granted by the FDA in August 2021, for the indication of moderate to severe systemic lupus erythematosus (SLE) in patients who are receiving standard therapy. | View clinical data
Bioactivity Comments: Anifrolumab inhibits the antiproliferative effect of IFNω on Daudi cells with an EC50 value of 0.3nM [1]. | View biological activity
elotuzumab
Immuno Disease Comments: CS1 expression is elevated in patients with SLE suggesting that CS1-targeted inhibition may be effective in this condition.
Clinical Use: Following evaluation in Phase 3 clinical trial for MM, which tested various combinations of , or ± elotuzumab [34,37], the US FDA approved the elotuzumab/lenalidomide/dexamethasone combination in late 2015. Use is indicated for MM patients who have received one to three prior therapies.
In the European Union elotuzumab has had orphan drug designation since August 2012, for the treatment of MM. | View clinical data
Bioactivity Comments: The biological activity of elotuzumab has been well characterised [12,32]. We have tagged the primary molecular target, providing data from patent US7709610 [38]. | View biological activity
vobarilizumab
Immuno Disease Comments: Phase 2 clinical candidate for SLE (see NCT02437890).
Clinical Use: Vobarilizumab (as research code ALX-0061) has reached Phase 2 clinical trial. See NCT02437890 (SLE) and NCT02518620 (RA) as examples. | View clinical data
Bioactivity Comments: Binding affinity (KD) for human serum albumin is 22nM [35]. | View biological activity
deflazacort
Immuno Disease Comments: Approved corticosteroid that can be prescribed for SLE.
Clinical Use: Deflazacort can be prescribed for many inflammatory conditions including asthma, rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis, idiopathic thrombocytopenic purpura, polymyalgia rheumatica, systemic lupus erythematosus and ulcerative colitis. More recently approved by the FDA as a treatment for Duchenne muscular dystrophy [11]. | View clinical data
Bioactivity Comments: In vitro binding to rat kidney, thymus and liver glucocorticoid receptors is reported in [22]. | View biological activity
blisibimod 8
Immuno Disease Comments: Blisibimod is an investigational SLE agent.
Clinical Use: Click here to link to the full list of blisibimod trials registered with ClinicalTrials.gov. | View clinical data
atacicept 4
Immuno Disease Comments: Atacicept was in clinical development for the treatment of SLE.
Clinical Use: Atacicept was investigated for clinical efficacy in a range of autoimmune conditions e.g. SLE [9], rheumatoid arthritis [36] and optic neuritis (a demyelinating inflammation of the optic nerve) [30]. These trials have largely been unsuccessful., however Vera Therapeutics believe it may have potential for IgA nephropathy (based on results from Merck's trial NCT02808429 in patients with kidney disease IgA nephropathy), and as of January 2021 they were planning on taking atacicept forward for this indication. | View clinical data
Bioactivity Comments: WO2002094852 provides binding data for BAFF but not for APRIL, ZNTF4 and ZNTF2 respectively in this patent [28]. | View biological activity
metformin 29
Immuno Disease Comments: Metformin is being evaluated as an adjunct to conventional immunosuppressants in patients with SLE, to determine if it reduces disease flares- see Phase 4 clinical trial NCT02741960
Clinical Use: Used in the management of non-insulin dependent type 2 diabetes as an adjunct to diet and exercise. Also used in the management of polycystic ovary syndrome (PCOS).
Metformin is combined with in Invokamet®, (also marketed as Vokanamet®) the first fixed-dose combination of an SGLT2 inhibitor with metformin to be approved (by the US FDA, 2014). Later in 2014, the US FDA approved a second SGLT2/metformin drug, Xigduo XR®, which contains (as dapagliflozin propanediol monohydrate PubChem CID 56841155) and metformin hydrochloride. The first approval of a metformin-containing drug mixture by the EMA was for Avandamet (rosiglitazone plus metformin), although this drug was later withdrawn from the market. Avandamet has been superceeded by newer and more effective anti-diabetes combination drugs. | View clinical data
Bioactivity Comments: As the molecular mechanism of metformin is incompletely understood we have not tagged a primary drug target. | View biological activity
RSLV-132
Immuno Disease Comments: RSLV-132 has progressed to Phase 2 clinical evaluation in SLE patients- see NCT03247686
Clinical Use: RSLV-132 has been advanced to clinical evaluations in autoinflammatory conditions. It has been entered into a clinical study to determine efficacy in patients with long-COVID. | View clinical data
BIIB059
Immuno Disease Comments: Clinical lead for SLE and CLE.
Clinical Use: BIIB059 has progressed to Phase 2 clinical evaluation as a monotherapy in patients with SLE and active CLE. | View clinical data
dapirolizumab pegol
Immuno Disease Comments: Clinical candidate for the treatment of SLE.
Clinical Use: Dapirolizumab pegol (CDP7657) has progressed to Phase 3 evaluation for SLE. | View clinical data
elsubrutinib
Immuno Disease Comments: Clinical candidate for SLE
Clinical Use: Elsubrutinib has progressed to Phase 2 evaluations to determine efficacy in trial subjects with rheumatoid arthritis or systemic lupus erythematosus. | View clinical data

References

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