Immunotherapy for Autoimmune Diseases: Systemic Lupus Erythematosus

Immunotherapy for Autoimmune Diseases: Systemic Lupus Erythematosus: Review

Systemic lupus erythematosus (SLE) is an autoimmune syndrome that poses significant challenges in diagnosis and treatment. Novel immunotherapies with different mechanisms of action that are currently under development include biologic agents targeting co-stimulatory molecules, cytokines or their receptors and signaling molecules and B cells, cell-based therapy and peptide therapy.

Immunotherapy for autoimmune diseases: FDA approved medicine for systemic lupus erythematosus
Belimumab: Belimumab is a fully human monoclonal antibody that binds BAFF, which is a survival factor that regulates B cell differentiation, maturation and antibody production, and is the first ever FDA approved biologics in the treatment of systemic lupus erythematosus.

Immunotherapy for autoimmune diseases: Targeting co-stimulatory molecules for systemic lupus erythematosus
Anti-CD28: Lulizumab is a Vκ light chain domain antibody that targets human CD28 receptor and is linked to a polyethylene glycol platform allowing extension of its half-life in vivo. Phase II trial evaluating its safety and efficacy over 24 weeks in the treatment of SLE has shown preliminary encouraging results (NCT02265744).
Anti-CD40L: CD40-CD40L binding is pivotal in bridging innate and adaptive immune responses. A recent trial on Dapirolizumab Pegol (CDP7657), a monovalent Fab antibody fragment against CD40L linked to PEGylated platform was shown to be safe in early phase I study.
ICOS/ICOSL blockade: Upon activation, T cells express the inducible costimulator (ICOS) which binds to its ligand, ICOSL or also called B7-related peptide-1 (B7RP-1), expressed on B cells promoting B cell maturation and autoantibody production. Humanized IgG2 anti-ICOSL blocking antibody (AMG557) was shown to be safe in phase I trial in active SLE patients with cutaneous and articular presentations.

Immunotherapy for autoimmune diseases: Targeting cytokine or cytokine receptor for systemic lupus erythematosus
As a result of the aberrant immune regulation in SLE patients, many pro- and anti-inflammatory cytokines such as IL-10, IL-12, IL-18 and those involved in the IL-23/IL-17 pathway and IL-33/ST2 axis were found to be elevated in patient serum and the levels were higher in those who had active disease. Cytokines or their receptors emerge as biologic targets to novel therapy.
IL-10: A humanized neutralizing anti-IL10 monoclonal antibody (BT-063) has entered Phase II clinical trial for treatment of SLE (NCT02554019).
IFN-α: Sifalimumab, a human anti-IFN-α monoclonal antibody, demonstrated suppression of type I IFN gene signature in treated patients and has shown preliminary safety and tolerability in early phase I trial.
IFN-γ: Anti-IFN-γ antibody (AMG 811) was tested in phase I trial on SLE patients with discoid lupus. Although AMG 811 was biologically active with dose-dependent modulation of expression of genes associated with IFN-γ signaling, the study was terminated as it was not found to meet the efficacy endpoint
(NCT01164917).
TWEAK: Phase I trial of TWEAK-blocking monoclonal antibody (BIIB023) was shown to be safe and tolerable in patients with rheumatoid arthritis. However, a phase II trial in patients with lupus nephritis has been terminated due to failure to show clinical response (NCT01499355)

Immunotherapy for autoimmune diseases: B cell targeting therapy for systemic lupus erythematosus
The BAFF axis: The PEARL-SC study, a Phase II trial on Blisibimod, a human BAFF-binding antibody, demonstrated reduction in B cells, improvement in serological activity and SRI response.
Anti-CD22: Epratuzumab is a humanized monoclonal antibody that targets CD22 leading to their internalization and phosphorylation. Epratuzumab causes partial B cell depletion and targets preferentially naïve and transitional B cells.
B cell tolerogen: LJP 394 (abetimus sodium) was developed based on the scientific rationale of using B cell tolerogen as preventive therapy in SLE patients. However, LJP-394 in phase III clinical trial (ASPEN) was terminated early with lack of efficacy in delaying renal and major SLE flare (NCT00089804).

Immunotherapy for autoimmune diseases: Signaling molecules inhibitor for systemic lupus erythematosus
Ibrutinib is a novel Btk-targeting inhibitor and has shown reduction in anti-dsDNA antibody level and proteinuria in murine lupus model.

Immunotherapy for autoimmune diseases: Cell-based therapy for systemic lupus erythematosus
Haematopoietic stem cell transplantation: HSC transplantation that replaces existing bone marrow with healthy stem cells appears a promising strategy in the treatment of SLE aiming for immune reconstitution.
Mesenchymal stem cells transplantation: Transplantation of allogeneic bone marrow-derived MSCs and umbilical cord blood-derived MSCs have been examined in open-label studies in SLE patients with severe refractory disease and active lupus nephritis.
Tolerogenic dendritic cells: In human SLE, monocyte-derived DCs were shown to acquire tolerogenicity in co-culture with iC3b-opsonized apoptotic cells but in low efficiency.
Ex vivo expanded Treg: It remains controversial in regard to differences in number of circulating Treg and Treg function in SLE patients compared to normal controls[110]. Some reported reduced levels whereas others reported no difference in their circulating Treg compared to healthy subjects.

Immunotherapy for autoimmune diseases: Peptide therapy for systemic lupus erythematosus
Peptide immunotherapy has been studied by several groups as a novel strategy in the treatment of SLE. The scientific rationale of using peptide therapy lies with its high specificity in regard to the induction of peripheral tolerance to achieve immune
homeostasis and may theoretically offer more favourable efficacy to side effect profile.
Spliceosomal peptide: An open-label phase II trial on P140 peptide in moderately active SLE showed well tolerance and significant improvement in SLEDAI at week 12.
Peptide derived from anti-DNA antibody: The pConsensus is a 15-mer peptide derived from the VH regions of anti-DNA antibodies derived from BWF1 mice. Pre-clinical studies on oral administration of D-amino acid form of this peptide in BWF1 mice showed significantly lower proteinuria and serum anti-dsDNA antibody with prolonged survival.
Together with good scientific rationale and advanced biological engineering techniques, optimization of clinical trial design, patient selection and disease outcome measures are essential to demonstrate the clinical efficacy and safety of these agents.

Immunotherapy for Autoimmune Diseases: Systemic Lupus Erythematosus: Reference

MOK M Y et al. Recent advances and current state of immunotherapy in systemic lupus erythematosus[J]. Expert Opinion on Biological Therapy, 2016 (just-accepted).