Lessons Learned From the Clinical Trials of Novel Biologics and Small Molecules in Lupus Nephritis

Furie, Richard; Toder, Kiley; Zapantis, Ekaterini

doi:10.1016/j.semnephrol.2015.08.012

Cited by 25 publications

(17 citation statements)

References 41 publications

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“…For instance, IFNβ is an effective therapy for multiple sclerosis patients and IFNα has been approved for the treatment of hepatitis B and C (76). In contrast, the blockade of the type I IFN receptor with anti-IFNAR, has been an attractive therapeutic for autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis, as these diseases are characterized by a profound IFN gene signature (77,78). However, difficulties in developing effective therapies that target the type I IFN system relies upon selecting the specific type I IFN to administer or block, and the timing of drug delivery, which can lead to opposing outcomes.…”

Section: Type I Ifn Treatment and The Prevention Of Bacterial Super-imentioning

confidence: 99%

The Impact of Type 1 Interferons on Alveolar Macrophage Tolerance and Implications for Host Susceptibility to Secondary Bacterial Pneumonia

Connolly

Hussell

2020

Front. Immunol.

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That macrophages adapt to environmental cues is well-established. This adaptation has had several reiterations, first with innate imprinting and then with various combinations of trained, tolerant, paralyzed, or primed. Whatever the nomenclature, it represents a macrophage that is required to perform very different functions. First, alveolar macrophages are one of the sentinel cells that flag up damage and release mediators that attract other immune cells. Next, they mature to support T cell priming and survival. Finally they are critical in clearing inflammatory immune cells by phagocytosis and extracellular matrix turnover components by efferocytosis. At each functional stage they alter intrinsic components to guide their activity. Training therefore is akin to changing function. In this mini-review we focus on the lung and the specific role of type I interferons in altering macrophage activity. The proposed mechanisms of type I IFNs on lung-resident alveolar macrophages and their effect on host susceptibility to bacterial infection following influenza virus infection.

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Section: Type I Ifn Treatment and The Prevention Of Bacterial Super-imentioning

confidence: 99%

The Impact of Type 1 Interferons on Alveolar Macrophage Tolerance and Implications for Host Susceptibility to Secondary Bacterial Pneumonia

Connolly

Hussell

2020

Front. Immunol.

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“…Some of B-cell targeted therapies are directed towards the surface molecules such as anti-CD20 (Rituximab and Ocrelizumab) and anti-CD22 (Epratuzumab) [120][121][122]. Others target the growth factors, BAFF and APRIL, such as Belimumab, Atacicept, Blisibimod and Tabalumab [123,124]. Also, immunoglobulin receptor antagonist (Abetimus sodium), anti-CD40L and proteasome antagonist (Bortezomib) have been tried in SLE [125][126][127].…”

Section: Interferons B Cells and Neutrophils: Innate And Adaptive Almentioning

confidence: 99%

Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus

Mohamed¹,

Gheita²

2018

JRAD

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Systemic lupus erythematosus (SLE) is clinically and immunologically heterogeneous with variable organ involvement, severity and therapeutic responses. B cells are known as mediators of disease manifestations. Therefore, disease control is targeted by inhibiting proliferation and inducing apoptosis of B cells via conventional cytotoxic drugs or newly developing biologics. However, the outcome of therapy is sometimes heterogeneous which further attracts to understand other immune mechanisms influencing B cell functions such as interferons (IFNs) cytokines and the innate cells, neutrophils. Successful management of SLE requires an understanding of how these factors interact, taking into consideration the patients' variations in these factors which might confer heterogeneity in disease outcome. In this review, it will be focused on the existing data in literature on the mutual influence between interferons, B cells and neutrophils in disease pathogenesis and the clinical impact in disease assessment and their potential blocking.

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“…Notably, a clinical trial is currently recruiting SLE patients (NCT02102594). Similarly, ixazomib (trade name Ninlaro®), which selectively and reversibly inhibits the proteasome subunit beta type-5 and it is used to treat multiple myeloma, is currently in phase I for the treatment of lupus nephritis (NCT02176486) [78]. …”

Section: Targeting the Nf-kb Pathwaymentioning

confidence: 99%

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Gadina

Gazaniga

Vian

et al. 2017

Journal of Autoimmunity

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Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

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Lessons Learned From the Clinical Trials of Novel Biologics and Small Molecules in Lupus Nephritis

Cited by 25 publications

References 41 publications

The Impact of Type 1 Interferons on Alveolar Macrophage Tolerance and Implications for Host Susceptibility to Secondary Bacterial Pneumonia

The Impact of Type 1 Interferons on Alveolar Macrophage Tolerance and Implications for Host Susceptibility to Secondary Bacterial Pneumonia

Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

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