Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo‐controlled, double‐blind, dose‐escalation study

McBride, Jacqueline; Jiang, Jenny; Abbas, Alexander R.; Morimoto, Alyssa; Li, Jing; Maciuca, Romeo; Townsend, Michael J.; Wallace, Daniel J.; Kennedy, William P.; Drappa, Jörn

doi:10.1002/art.34632

Cited by 169 publications

(109 citation statements)

References 61 publications

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“…Current medical efforts are focused on the development of antibody-based drugs (sifalimumab, rontalizumab, etc.) for neutralizing IFNAR1 in patients with diverse inflammatory/ autoimmune syndromes (61,62). Our data suggest that a similar strategy could be potentially envisioned for relieving IFN-mediated pancreatotoxicity in patients with Wolcott-Rallison or patients who receive PERK inhibitors for treating tumors (22)(23)(24) and prion-mediated neurogenerative disorders (25).…”

Section: Discussionmentioning

confidence: 86%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERKdeficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.T umor microenvironment-associated deficit in oxygen and nutrients activate numerous pathways that aid cancer and tumor stroma cells by increasing their ability to survive, withstand anticancer therapies, and ultimately select for more aggressive and viable clones capable of metastasizing (1). Activation of the unfolded protein response (UPR) plays a central role in these processes (2). Three branches of this response include stimulation of activating transcription factor-6 and activation of two kinases, inositol requiring enzyme 1α/β and the eukaryotic translation initiation factor 2-alpha kinase 3 [also termed double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, or pancreatic endoplasmic reticulum kinase (PERK)]. The latter kinase contributes to phosphorylation of the eukaryotic translation initiation factor 2-alpha and controls the rate of global translation and noncanonical induction of specific proteins that help cope with stress (reviewed in ref. 2).Among three main UPR pathways, signaling through PERK has received the most attention for its central role in cancer (3-6). Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7-12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16-18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20, 21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22-24). Furthermore, some of these inhibitors can protect against the prion-...

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Section: Discussionmentioning

confidence: 86%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although IFN-a plays a critical role in antiviral responses, multiple lines of evidence suggest that abnormal upregulation of IFN-a contributes to the progression of SLE. To date, a number of approaches are being evaluated in the clinic by targeting IFN-a, including the administration of anti-IFN-a Ab in lupus patients (26). Besides biological therapy, an orally available selective small-molecule IFN-a antagonist will be highly desirable.…”

Section: Discussionmentioning

confidence: 99%

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

Cai¹,

Xu²,

Kim³

et al. 2014

The Journal of Immunology

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Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor.

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“…Administration of monoclonal antibodies against the IFNα pathway results in decreases in RNA expression from IFN‐inducible genes in whole blood from SLE patients 24, 25, 26, but change in IFN‐associated serum protein levels has not been reported. In the present study, we describe the immunologic impact of the first clinical experience of IFNγ blockade in SLE patients.…”

mentioning

confidence: 99%

Blockade of Interferon‐γ Normalizes Interferon‐Regulated Gene Expression and Serum CXCL10 Levels in Patients With Systemic Lupus Erythematosus

Welcher

Boedigheimer

Kivitz

et al. 2015

Arthritis & Rheumatology

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ObjectiveTo assess the safety and immunologic impact of inhibiting interferon‐γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).MethodsTwenty‐six patients with mild‐to‐moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously.ResultsSimilar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose‐dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood. The list of impacted genes overlapped with that identified by stimulating human whole blood with IFNγ and with those gene sets reported in the literature to be differentially expressed in SLE patients. Serum levels of IFNγ‐induced chemokines, including IFNγ‐inducible protein 10 (IP‐10), were found to be elevated at baseline in SLE patients as compared to healthy volunteers. In contrast to previously reported results from studies using type I IFN–blocking agents, treatment with AMG 811 led to dose‐related reductions in the serum levels of CXCL10 (IP‐10).ConclusionThe scope and nature of the biomarkers impacted by AMG 811 support targeting of IFNγ as a therapeutic strategy for SLE.

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Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo‐controlled, double‐blind, dose‐escalation study

Cited by 169 publications

References 61 publications

Type I interferons mediate pancreatic toxicities of PERK inhibition

Type I interferons mediate pancreatic toxicities of PERK inhibition

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

Blockade of Interferon‐γ Normalizes Interferon‐Regulated Gene Expression and Serum CXCL10 Levels in Patients With Systemic Lupus Erythematosus

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