Recent developments in biologic therapies for the treatment of patients with systemic lupus erythematosus

Carreira, Pedro; Isenberg, David

doi:10.1093/rheumatology/key064

Cited by 19 publications

(18 citation statements)

References 21 publications

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“…However, their use was linked to the development of thromboembolic events due to the engagement of CD40L on platelets with subsequent platelet activation [18]. The use of modified anti-CD40L Abs, such as anti-CD40L pegylated Fab fragments, which do not activate platelets, were further explored for their ability to reduce autoimmunity [19][20][21]. Recent clinical data, however, suggest that their use may not be efficient in treating SLE [22].…”

Section: Introductionmentioning

confidence: 99%

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

2021

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Background CD40-CD40L is a key co-stimulatory pathway for B cell activation. As such, its blockade can inhibit pathogenic B cell responses in autoimmune diseases, such as Sjogren’s syndrome (SjS) and systemic lupus erythematosus (SLE). In this study, we examined the in vitro effects of KPL-404, a humanized anti-CD40 monoclonal antibody (Ab), on primary human B cells derived from either healthy donors (HD) or autoimmune patients and compared them to the effects of G28-5, a partially antagonistic anti-CD40 antibody. Methods PBMCs from HD or SjS and SLE patients were cultured in high-density cell cultures in the presence of IgG4 isotype control or anti-CD40 Abs KPL-404 or G28-5. Cells were stimulated with anti-CD3/CD28 cross-linking reagent ImmunoCult (IC) to induce CD40L-CD40-mediated B cell responses. B cell proliferation and activation, measured by dilution of proliferation tracker dye and the upregulation of CD69 and CD86, respectively, were assessed by flow cytometry. Anti-CD40 Ab cell-internalization was examined by imaging flow cytometry. Cytokine release in the PBMC cultures was quantified by bead-based multiplex assay. Results KPL-404 binds to CD40 expressed on different subsets of B cells without inducing cell depletion, or B cell proliferation and activation in in vitro culture. Under the same conditions, G28-5 promoted proliferation of and increased CD69 expression on otherwise unstimulated B cells. KPL-404 efficiently blocked the CD40L-CD40-mediated activation of B cells from HD at concentrations between 1 and 10 μg/ml. Treatment with KPL-404 alone did not promote cytokine production and blocked the production of IFNβ in healthy PBMC cultures. KPL-404 efficiently blocked CD40L-CD40-mediated activation of B cells from patients with SjS and SLE, without affecting their anti-IgM responses or affecting their cytokine production. Consistent with the differences of their effects on B cell responses, KPL-404 was not internalized by cells, whereas G28-5 showed partial internalization upon CD40 binding. Conclusions Anti-CD40 mAb KPL-404 showed purely antagonistic effects on B cells and total PBMCs. KPL-404 inhibited CD40L-CD40-mediated B cell activation in PBMC cultures from both healthy controls and autoimmune patients. These data support the therapeutic potential of CD40 targeting by KPL-404 Ab for inhibiting B cell responses in SjS and SLE.

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Section: Introductionmentioning

confidence: 99%

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

2021

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“…The approaches of these therapeutic agents vary, from targeting B cell-selective cell surface molecules (such as CD22 or CD20), to inhibiting B cell survival by targeting cytokines and signalling molecules (such as B cell activating factor (BAFF), IL-6, IL-17 and IL-21), to interfering with B cell antigen presentation by targeting co-stimulatory molecules (such as CD40-CD40 ligand (CD40L) interactions and inducible T cell costimulator (ICOS)-ICOS ligand (ICOSL) interactions). Many of these therapies, including rituximab (an anti-CD20 monoclonal antibody (mAb)) 11 , epratuzumab (an anti-CD22 mAb), abatacept (which stops APCs from interacting with T cells via CD80 and CD86) and tabalumab (an anti-BAFF mAb), have not shown a statistically significant benefit in clinical trials for SLE, reviewed recently 12 Rituximab and belimumab (an anti-BAFF mAb), are the biologic drugs most commonly used to treat SLE in clinical practice. The results of a large number of open-label studies of rituximab 11 and the encouraging data from national registries 12,13 were sufficient for both the ACR 14 and EULAR 15 to recommend rituximab as a treatment for lupus nephritis, and for the National Health Service (NHS) England to sanction its use in difficult-to-treat patients 16 .…”

Section: [H1] Current Use Of Biologic Therapymentioning

confidence: 99%

“…Many of these therapies, including rituximab (an anti-CD20 monoclonal antibody (mAb)) 11 , epratuzumab (an anti-CD22 mAb), abatacept (which stops APCs from interacting with T cells via CD80 and CD86) and tabalumab (an anti-BAFF mAb), have not shown a statistically significant benefit in clinical trials for SLE, reviewed recently 12 Rituximab and belimumab (an anti-BAFF mAb), are the biologic drugs most commonly used to treat SLE in clinical practice. The results of a large number of open-label studies of rituximab 11 and the encouraging data from national registries 12,13 were sufficient for both the ACR 14 and EULAR 15 to recommend rituximab as a treatment for lupus nephritis, and for the National Health Service (NHS) England to sanction its use in difficult-to-treat patients 16 . For example, in the Lupus Clinic at University College Hospital, London, ~140 patients have been treated with rituximab since 2000 owing to inefficacy of treatment or adverse events following immunosuppression with steroids, azathioprine, mycophenolate mofetil (MMF) or cyclophosphamide (D.A.I.…”

Section: [H1] Current Use Of Biologic Therapymentioning

confidence: 99%

New therapies for systemic lupus erythematosus — past imperfect, future tense

2019

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The failure of many new, mostly biologic, drugs to meet their primary endpoints in double-blind clinical trials in patients with systemic lupus erythematosus (SLE) has caused a profound sense of disappointment among both physicians and patients. Arguably, the success of B cell depletion with rituximab in open-label clinical trials, the approval of belimumab (which blocks the B cell activating factor (BAFF)) for use in patients with lupus nephritis in the USA and in difficult-to-treat patients with SLE in the UK, and the recognition that clinical trial design can be improved has given some cause for hope. However, changes to therapies in current use and the development of new approaches are urgently needed. The results of the latest studies investigating the use of several new approaches to treat SLE are discussed in this Review, including: fully humanized anti-CD20 and anti-CD19 monoclonal antibodies; inhibition of protein tyrosine kinase BTK; CD40 ligand blockade;interfering with the presentation of antigen to autoreactive T cells using a peptide approach; a receptor decoy approach using an analogue of Fcɣ receptor IIB; dual blockade of IL-12 and IL-23; and inhibition of Janus kinases.

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“…Immune activation of B cells requires the interaction of costimulatory signals with T cells, especially CD40/40L, CD28, Inducible T cell co-stimulator ligand (ICOSL), and CD80/CD86. Blocking this pathway indirectly inhibits the proliferation and activation of B cells and down-regulates autoantibody production, thus achieving a therapeutic effect ( 48 , 49 ).…”

Section: Targeting Costimulatorsmentioning

confidence: 99%

A Comprehensive Review of Biological Agents for Lupus: Beyond Single Target

Yang

Zhao

et al. 2020

Front. Immunol.

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Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cells. Due to its complex pathogenesis, the effectiveness of traditional treatment methods is limited. Many patients have developed resistance to conventional treatment or are not sensitive to steroid and immunosuppressant therapy, and so emerging therapeutic antibodies have become an alternative and have been shown to work well in many patients with moderate and severe SLE. This review summarizes the biological agents that are in the preclinical and clinical trial study of SLE. In addition to the various monoclonal antibodies that have been studied for a long time, such as belimumab and rituximab, we focused on another treatment for SLE, bispecific antibodies (BsAbs) such as tibulizumab, which simultaneously targets multiple pathogenic cytokines or pathways. Although the application of BsAbs in cancer has been intensively studied, their application in autoimmune diseases is still in the infant stage. This unique combined mechanism of action may provide a novel therapeutic strategy for SLE.

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Recent developments in biologic therapies for the treatment of patients with systemic lupus erythematosus

Cited by 19 publications

References 21 publications

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

New therapies for systemic lupus erythematosus — past imperfect, future tense

A Comprehensive Review of Biological Agents for Lupus: Beyond Single Target

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