Recently, it has been noted that the formation of advanced glycation end products (AGE) and their receptor (RAGE) play an important role in activation of pro-inflammatory states and are involved in numerous pathologic situations.
AGEs result from non-enzymatic glycation and glycoxidation of proteins and lipids. The increased formation and accumulation of AGEs has been reported in such pathophysiological areas such as diabetes, renal failure, aging and inflammation, as well as Alzheimer's disease. The pool of AGEs in vivo reflects not only their endogenous formation, but also their accumulation from exogenous sources including the consumption of foods rich in AGEs and from smoking. During the past two decades, numerous receptors for AGEs have been identified on multiple cell types: endothelial cells, leucocytes, macrophages, mesothelial cells and neuronal cells. The most characterized AGE receptor to-date is RAGE, which is a member of the immunoglobulin super family.
It has been demonstrated that administration of recombinantly produced extracellular domain of RAGE [soluble RAGE (sRAGE)] can block AGE/RAGE interaction, and can lead, for example, to early intense inflammatory response to the excision wound, which promotes better granulation tissue and thus causes early blunting of inflammatory response. Such response can result overall for example, to better wound healing. Further, sRAGE, acting in principle as a decoy receptor, can reduce ischemic organ damage following myocardial infarction or ischemic stroke. In human studies, circulating endogenous sRAGE has been identified as a potential biomarker where decreased levels have been seen in vascular disease states affecting vascular health and function, including coronary artery disease (CAD), hypertension, vascular dementia, atherothrombotic stroke, nonalcoholic steatohepatitis and the diabetic state (type 1 and type 2 diabetes).
Recent studies have also demonstrated a marked increase in the level of advanced glycation end products (AGEs) in the plasma, skin and amyloid fibrils of hemodialysis (HD) patients, with the implication that therapeutic that increased sRAGE would be therapeutically beneficial. Importantly, sRAGE can be used as a biomarker for such inflammatory, renal and other disorders, where low sRAGE can predict a poor outcome. This can be important for candidates in need of an organ or other transplant, and such patients may be required to have an elevated level of sRAGE to become eligible for e.g., such a transplantation procedure. Further, obese, and to some extent, overweight patients may be at a higher risk of such inflammatory and/or renal diseases, and it may be desirable for such patients to lose weight as well as increase sRAGE. Further, patients with established inflammatory microvascular diseases such as that which occurs in diabetes may be at increased risk of poor tissue repair including wound healing, and it may be desirable for such patients to increase sRAGE in order to improve microvascular function.
Adiponectin is an adipocyte-derived, 30 kDa protein that circulates in plasma and has been shown to have multiple functions (see, e.g., Idorn, et al., Transplant Intl. 2012, 25, 1194). A correlation is believed to exist between low adiponectin plasma levels and risk of kidney failure, likelihood of successful kidney transplant, and likelihood of getting kidney stones (see, e.g., Idorn, et al., Transplant Intl. 2012, 25, 1194; Lin et al., Diabetes Care 2007, 30 239; and Fujii et al., PLOS 2013, 8, e61343). High molecular weight adiponectin, which is properly folded, is believed to have the highest relative potency on the adiponectin receptor.
Thrombomodulin is a surface glycoprotein that neutralizes thrombin clotting activity and accelerates thrombin-catalyzed activation of protein C (see, e.g., Takano et al., Blood 1996, 76, 2024). Thrombomodulin levels are believed to be associated with vascular inflammation and chronic renal disease (see, e.g., Takano et al., Blood 1996, 76, 2024; Takahashi et al, Am. J. Hematol. 1992, 41, 32; and Califano et al., Eur. Rev. Med. Pharm. Sci. 2000, 4, 59).
There is an on-going need for agents that increase sRAGE and/or increase adiponectin levels and/or decrease thrombomodulin levels and can be used to treat indications such as renal disease.