A Comparative Analysis of Acute-phase Proteins as Inflammatory Biomarkers in Preclinical Toxicology Studies: Implications for Preclinical to Clinical Translation

Watterson, Claire; Lanevschi, Anne; Horner, Judith; Louden, Calvert

doi:10.1177/0192623308329286

Cited by 31 publications

(16 citation statements)

References 28 publications

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“…Elevated CRP and fibrinogen are consistent with activating the IL22 pathway in liver hepatocytes, and elevated REG3A is consistent with activating the IL22 pathway in intestinal and pancreatic acinar epithelial cells . In contrast to the cynomolgus monkeys, rats did not exhibit increases in CRP and fibrinogen levels as rats utilize a different acute‐phase response than monkeys . Results from the monkey studies demonstrated that serum REG3A levels were increased, and correlated with UTTR1147A drug levels.…”

Section: Discussionmentioning

confidence: 73%

“…5,25,26 In contrast to the cynomolgus monkeys, rats did not exhibit increases in CRP and fibrinogen levels as rats utilize a different acute-phase response than monkeys. 23 REG3A, partially protected against weight loss and mortality in IL22−null mice infected with Citrobacter rodentium. 5 As with the skin findings, these transient dose-dependent elevations in acutephase proteins as well as in REG3A were observed in human clinical trials.…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Nonclinical safety assessment of a human interleukin‐22FC IG fusion protein demonstrates in vitro to in vivo and cross‐species translatability

Lee¹,

Zhong²,

Pai

et al. 2018

Pharmacology Res & Perspec

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Although Interleukin‐22 (IL‐22) is produced by various leukocytes, it preferentially targets cells with epithelial origins. IL‐22 exerts essential roles in modulating various tissue epithelial functions, such as innate host defense against extracellular pathogens, barrier integrity, regeneration, and wound healing. Therefore, IL‐22 is thought to have therapeutic potential in treating diseases associated with infection, tissue injury or chronic tissue damage. A number of in vitro and in vivo nonclinical studies were conducted to characterize the pharmacological activity and safety parameters of UTTR1147A, an IL‐22 recombinant fusion protein that links the human cytokine IL‐22 with the Fc portion of a human immunoglobulin. To assess the pharmacological activity of UTTR1147A, STAT3 activation was evaluated in primary hepatocytes isolated from human, cynomolgus monkey, minipig, rat, and mouse after incubation with UTTR1147A. UTTR1147A activated STAT3 in all species evaluated, demonstrating that all were appropriate nonclinical species for toxicology studies.The nonclinical safety profile of UTTR1147A was evaluated in rats, minipigs, and cynomolgus monkeys to establish a safe clinical starting dose for humans in Phase I trials and to support clinical intravenous, subcutaneous and/or topical administration treatment regimen. Results demonstrate the cross‐species translatability of the biological response in activating the IL‐22 pathway as well as the translatability of findings from in vitro to in vivo systems. UTTR1147A was well tolerated in all species tested and induced the expected pharmacologic effects of epidermal hyperplasia and a transient increase in on‐target acute phase proteins. These effects were all considered to be clinically predictable, manageable, monitorable, and reversible.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 95%

Nonclinical safety assessment of a human interleukin‐22FC IG fusion protein demonstrates in vitro to in vivo and cross‐species translatability

Lee¹,

Zhong²,

Pai

et al. 2018

Pharmacology Res & Perspec

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“…50 ATF6 has been linked to acute-phase-response, a broad immunological process associated with infiltration and activation of inflammatory cells and production of inflammatory mediators. 51 Cleavage of ATF6 leads to transcriptional activation of a set of acute-phase proteins such as C-reactive protein (CRP), which is a well-known marker of systemic inflammatory response. CRP can cause elevated expression of MCP-1 receptor and thus contribute to inflammation.…”

Section: Er Stress In Inflammationmentioning

confidence: 99%

Inflammation, Endoplasmic Reticulum Stress, Autophagy, and the Monocyte Chemoattractant Protein-1/CCR2 Pathway

Kolattukudy

Niu

2012

Circulation Research

217

148

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Numerous inflammatory cytokines have been implicated in the pathogenesis of cardiovascular diseases. Monocyte chemoattractant protein (MCP)-1/CCL2 that is expressed by mainly inflammatory cells and stromal cells such as endothelial cells, and its expression is upregulated following pro-inflammatory stimuli and tissue injury. MCP-1 can function as a traditional chemotactic cytokine and also regulates gene transcription. The recently discovered novel zinc-finger protein, called MCPIP (MCP-1-induced protein), which initiates a series of signaling events that causes oxidative and endoplasmic reticulum (ER) stress, leading to autophagy that can result in cell death or differentiation depending on the cellular context. After briefly reviewing the basic processes involved in inflammation, ER stress and autophagy, the recently elucidated role of MCP-1 and MCPIP in inflammatory diseases is reviewed. MCPIP was found to be able to control inflammatory response by inhibition of NFκB activation via its deubiquitinase activity or by degradation of mRNA encoding a set of inflammatory cytokines via its RNase activity. The potential inclusion of such a novel deubiquitinase in the emerging anti-inflammatory strategies for the treatment of inflammation related diseases such as cardiovascular diseases and type 2 diabetes is briefly discussed.

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“…Nothing can be done to change the molecular properties of the drug at that time. On the other hand, animal results do not always translate to humans accurately, due to several factors, including species differences and genetic variability 84. Contemporary in silico approaches to ADR prediction concentrate on docking studies and Structure–Activity Relationship (SAR)/QSAR models for the identification of structural features with ADR propensity 85,86.…”

Section: Discussionmentioning

confidence: 99%

Drug repurposing and adverse event prediction using high‐throughput literature analysis

Deftereos

Andronis

Friedla

et al. 2011

WIREs Mechanisms of Disease

103

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Drug repurposing is the process of using existing drugs in indications other than the ones they were originally designed for. It is an area of significant recent activity due to the mounting costs of traditional drug development and scarcity of new chemical entities brought to the market by bio-pharmaceutical companies. By selecting drugs that already satisfy basic toxicity, ADME and related criteria, drug repurposing promises to deliver significant value at reduced cost and in dramatically shorter time frames than is normally the case for the drug development process. The same process that results in drug repurposing can also be used for the prediction of adverse events of known or novel drugs. The analytics method is based on the description of the mechanism of action of a drug, which is then compared to the molecular mechanisms underlying all known adverse events. This review will focus on those approaches to drug repurposing and adverse event prediction that are based on the biomedical literature. Such approaches typically begin with an analysis of the literature and aim to reveal indirect relationships among seemingly unconnected biomedical entities such as genes, signaling pathways, physiological processes, and diseases. Networks of associations of these entities allow the uncovering of the molecular mechanisms underlying a disease, better understanding of the biological effects of a drug and the evaluation of its benefit/risk profile. In silico results can be tested in relevant cellular and animal models and, eventually, in clinical trials.

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A Comparative Analysis of Acute-phase Proteins as Inflammatory Biomarkers in Preclinical Toxicology Studies: Implications for Preclinical to Clinical Translation

Cited by 31 publications

References 28 publications

Nonclinical safety assessment of a human interleukin‐22FC IG fusion protein demonstrates in vitro to in vivo and cross‐species translatability

Nonclinical safety assessment of a human interleukin‐22FC IG fusion protein demonstrates in vitro to in vivo and cross‐species translatability

Inflammation, Endoplasmic Reticulum Stress, Autophagy, and the Monocyte Chemoattractant Protein-1/CCR2 Pathway

Drug repurposing and adverse event prediction using high‐throughput literature analysis

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