Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis

Kirkham, Bruce; Chaabo, Khaldoun; Hall, Christopher; Garrood, Toby; Mant, Timothy; Allen, Edward D.; Vincent, Alexandra; Vasconcelos, Joana; Prevost, A. Toby; Panayi, G. S.; Corrigall, Valerie

doi:10.1093/rheumatology/kew287

Cited by 39 publications

(38 citation statements)

References 27 publications

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“…[23][24][25] In addition, HSP70 has been administered intravenously in patients with rheumatoid arthritis (RA). 29 The latter trial showed significantly prolonged remissions at the highest protein concentrations administered (5 and 15 mg), which suggested the induction of Treg, supporting the original hypothesis regarding the therapeutic action of HSP.…”

Section: Therapeutic Tolerancesupporting

confidence: 59%

Vaccination against autoimmune diseases moves closer to the clinic

Eden

2019

Human Vaccines & Immunotherapeutics

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Biologicals, e.g. TNF inhibitors, have improved dramatically the efficacy of medical interventions in autoimmune diseases, such as in rheumatoid arthritis (RA). However, although progressive inflammation can be halted in this way, no drug-free remissions or lasting cures are reached. For this to become real, therapies based on induction antigen-specific immune tolerance are sought. This review describes mechanisms of tolerance and the current possibilities for induction of therapeutic tolerance through antigen-specific vaccination approaches. And despite the fact that for various diseases the search for appropriate autoantigens is ongoing, pioneering studies are now already developed that use more broadly inflammation associated antigens. Through their capacity to preferentially induce regulatory T cells, heat shock proteins are an attractive source of such broadly inflammation associated antigens.

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Section: Therapeutic Tolerancesupporting

confidence: 59%

Vaccination against autoimmune diseases moves closer to the clinic

Eden

2019

Human Vaccines & Immunotherapeutics

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“…First-in-human trial Intravenous infusion of GRP78/BiP is safe in patients In 2006, Brownlie et al [362] reported that the prophylactic or therapeutic parenteral delivery of BiP ameliorates clinical and histological signs of inflammatory arthritis in mice. Ten years later, the first human clinical trial using intravenous BiP demonstrated that GRP78/ BiP is safe in patients with active rheumatoid arthritis and some patients had clinical and biological improvements [363]. In phase I/IIA RAGULA trial, 42 patients were screened, and 24 were randomized to receive either BiP or placebo.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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“…The multiple activities of BiP and its potential as a therapeutic agent for the management of inflammatory disease have been eloquently and comprehensively studied elsewhere (114). With respect to therapeutic potential, a Phase I/IIA clinical trial in 24 patients with rheumatoid arthritis Heat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators 11 | P a g e who received a 1-hour infusion of BiP (1, 5,or 15 mg) and who were followed up for 12 weeks has reported evidence of remission in patients receiving 5 and 15 mg doses (115) Returning to the 70 kDa family, the constitutive member Hsc70 appears to play a role in, arguably, the most important biological process for the survival of species, namely reproduction. Proteomic analysis of porcine oviductal fluid has revealed that epithelial cells in the oviductal lumen secrete several molecules in response to the presence of spermatozoa, most notable of which are heat shock (stress) proteins (HSPs) (116).…”

Section: Extracellular Cell Stress Proteins In Cancermentioning

confidence: 99%

Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

Pockley

Henderson

2017

Phil. Trans. R. Soc. B

101

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Contribution to a theme issue 'Heat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators' Keywords:Heat shock (stress) proteins, extracellular, immunity Author for correspondence:A. Graham Pockley, PhD e-mail: graham.pockley@ntu.ac.ukHeat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators 2 | P a g e Abstract Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory "danger signals" for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells.The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals / non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining / regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins therefore form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.Heat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators 3 | P a g e 1. Background 'Chance favours the prepared mind ' -Louis Pasteur (1822 -1895 The presence of additional new 'puffs' in the polytene chromosomes of cultured Drosophila larva which were induced following their incubation at an inadvertently high temperature and observed by Ferruccio Ritossa (25 th February 1936 -9 th January 2014) in the early 1960s was unexpected and puzzling. He realised the potential importance of this first evidence that stress can influence gene transcription and induce the synthesis of new proteins, yet found it surprisingly difficult to publish this discovery. It was eventually published in Experientia (1, 2).Ritossa's findings were extended and expanded upon during the next decade and by the mid-to-late 1960s it was clear that exposure of cells containing polytene chromosomes to a variety of environmental stressors resulted in the transcription of novel genes and, presumably, in the synthesi...

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Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis

Abstract: ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.

Cited by 39 publications

References 27 publications

Vaccination against autoimmune diseases moves closer to the clinic

Vaccination against autoimmune diseases moves closer to the clinic

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

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