Treatment With OPN-305, a Humanized Anti–Toll-Like Receptor-2 Antibody, Reduces Myocardial Ischemia/Reperfusion Injury in Pigs

Arslan, Fatih; Houtgraaf, Jaco H.; Keogh, Brian; Kazemi, Kushan; Jong, Renate de; McCormack, William; O’Neill, Luke A. J.; McGuirk, Peter; Timmers, Leo; Smeets, Mirjam B.; Akeroyd, Lars; Reilly, Mary; Pasterkamp, Gérard; Kleijn, Dominique P.V. de

doi:10.1161/circinterventions.111.967596

Cited by 97 publications

(67 citation statements)

References 34 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, it was reported that inhibition of TLR2 with T2.5 protected against angiotensin II-induced cardiac fibrosis by attenuating macrophage recruitment and the inflammatory response in the heart. The humanized anti-TLR2 monoclonal antibody OPN305 has shown promising results for the prevention of myocardial ischemia/reperfusion injury (Arslan et al, 2012). OPN305 is able to block both TLR2/1-and TLR2/6-mediated signaling, reducing TLR2-mediated proinflammatory cytokine production.…”

Section: A Toll-like Receptor Signaling Inhibitionmentioning

confidence: 99%

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

2015

View full text Add to dashboard Cite

Section: A Toll-like Receptor Signaling Inhibitionmentioning

confidence: 99%

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

2015

View full text Add to dashboard Cite

“…Dysregulated TLR2 signaling has been implicated in numerous diseases (e.g., sepsis, atherosclerosis, tumor metastasis, ischemia/reperfusion injury) (11)(12)(13)(14). Several inhibitors of TLR2 signaling have been developed (15)(16)(17)(18)), yet none is licensed for human use. A better understanding of the Toll/IL-1 receptor resistance (TIR) domain interactions involved in TLR2 signaling could lead to novel therapeutic agents.…”

mentioning

confidence: 99%

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

Mistry¹,

Laird²,

Schwarz³

et al. 2015

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

136

View full text Add to dashboard Cite

Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C 16 H 15 NO 4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors.small molecule inhibitor | BB loop | TLR2 pocket | CADD T oll-like receptors (TLRs) are type I transmembrane receptors that detect conserved "pathogen-associated molecular patterns" from microbes, as well as host-derived "danger-associated molecular patterns" (1). TLR2 heterodimerizes with TLR6 or TLR1 to recognize diacyl lipopeptides or triacyl lipopeptides, respectively (2, 3), present in gram-positive and gram-negative bacteria (4-9).Ligand engagement of TLR2/1 or TLR2/6 activates the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway (i.e., nuclear translocation of NF-κB, activation of MAPKs), resulting in production of proinflammatory cytokines (10). Dysregulated TLR2 signaling has been implicated in numerous diseases (e.g., sepsis, atherosclerosis, tumor metastasis, ischemia/reperfusion injury) (11)(12)(13)(14). Several inhibitors of TLR2 signaling have been developed (15-18), yet none is licensed for human use. A better understanding of the Toll/IL-1 receptor resistance (TIR) domain interactions involved in TLR2 signaling could lead to novel therapeutic agents.Both TLRs and adapter proteins contain a cytoplasmic TIR domain that mediates homotypic and heterotypic interactions ...

show abstract

“…For example OPN-301, a novel anti-TLR2 monoclonal antibody, was shown to reduce infarct size and preserve cardiac function and geometry when administered before reperfusion in a mouse MI model [34]. Importantly, the same group recently reported development of a clinical-grade humanised anti-TLR2 antibody (OPN-305) and showed similar benefit in pigs after myocardial ischemia/reperfusion injury [153]. These data suggest that OPN-305 may have potential as an adjunctive for reperfusion therapy in MI patients.…”

Section: Therapeutic Approaches To Target Damp Pathwaysmentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

166

124

View full text Add to dashboard Cite

Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

show abstract

Treatment With OPN-305, a Humanized Anti–Toll-Like Receptor-2 Antibody, Reduces Myocardial Ischemia/Reperfusion Injury in Pigs

Abstract: Background-Toll-like receptor (TLR)-

Cited by 97 publications

References 34 publications

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Contact Info

Product

Resources

About