HMGB1 antagonist treatment of acute lung injury

#The present invention is related to the use of HMGB1 antagonists in the treatment and/or prevention and/or inhibition of severe sepsis in mammals, e.g., humans, and pharmaceutical compositions for the same comprising HMGB1 antagonists in an effective amount to treat ab nd/or prevent and/or inhibit this condition.

#High mobility group box 1 (HMGB1) was first identified as a DNA-binding protein; it is translocated to the nucleus in healthy cells. (Baker, C., et al., Physical studies of the nonhistone chromosomal proteins HMG-U and HMG-2, Biochemistry, 1976, 15(8): p. 1645-9); (Bertheloot, D, HMGB1, IL-1alpha, IL-33 and S100 proteins: dual function alarmins, Cell Mol Immunol, 2016; Tsung, A., S. Tohme, and T. R. Billiar, High-mobility group box-1 in sterile inflammation, J Intern Med, 2014, 276(5): p. 425-43; Lotze, M. T. and K. J. Tracey, High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal, Nat Rev Immunol, 2005, 5(4): p. 331-42). Cellular damage, necrosis, or apoptotic cell fragments result in the passive release of HMGB1 into the extracellular space (Scaffidi, P., T. Misteli, and M. E. Bianchi, Release of chromatin protein HMGB1 by necrotic cells triggers inflammation, Nature, 2002, 418(6894): p. 191-5), which can recruit leukocytes to the site of an injury or infection. HMGB1 can also be secreted by monocytes, tissue macrophages, and other cell of the innate immune system when these cells are activated by pathogen-derived stimuli, exosomes, or pro-inflammatory cytokines (Andersson, U. and K. J. Tracey, HMGB1 is a therapeutic target for sterile inflammation and infection, Annu Rev Immunol, 2011, 29: p. 139-62; Bertheloot, D, HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins, Cell Mol Immunol, 2016). Depending upon its oxidation state and which of the multiple distinct receptors it interacts with, extracellular HMGB1 can trigger a variety of outcomes (reviewed in Bertheloot, D, HMGB1, IL-1alpha, IL-33 and S100 proteins: dual function alarmins, Cell Mol Immunol, 2016 and Harris, H. E., HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease, Nat Rev Rheumatol, 2012, 8(4): p. 195-202), including secretion of additional HMGB1. When this feed-forward loop becomes dysregulated, as in patients with sepsis, it can create a vicious cycle that stokes systemic inflammation by activating macrophages through the TLR4 receptor (Apetoh, L., et al., The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy, Immunol Rev, 2007, 220: p. 47-59; Apetoh, L., et al., Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy, Nat Med, 2007, 13(9): p. 1050-9; Fan, J., et al., Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: role of HMGB1-TLR4 signaling, J Immunol, 2007, 178(10): p. 6573-80; Tsung, A., et al., HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling, J Exp Med, 2007, 204(12): p. 2913-23; Tsung, A., et al., Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury, J Leukoc Biol, 2007, 81(1): p. 119-28).

#HMGB1 is a highly conserved protein that is central to the pathogenesis of sterile and pathogen-induced inflammation (Andersson, U., HMGB1 is a therapeutic target for sterile inflammation and infection, Annu Rev Immunol, 2011, 29: p. 139-62). Lethal organ failure and epithelial barrier failure without shock are driven by HMGB1. HMGB1 release is driven by a positive feedback loop that causes circulating HMGB1 levels generally to rise as disease progresses.

#—The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.—

#FIG. 1 is a graphical depiction of inflammation induced by HMGB1-partner molecule complexes.

#FIG. 2A is a graphical representation of the proportion of hospital stays in the United States that carried sepsis as a primary or secondary indication in 2009.

#In accordance with the above stated objects, it is shown that administration of a peptidomimetic small molecule that replaces terminal peptide bonds with azatide linkages (e.g., K883) to a subject(s) or patient(s) in need thereof, can prevent and/or inhibit and/or treat sepsis, ALI, bacterial and viral respiratory infections such as influenza and SARS-CoV-2 and/peripheral neuropathy, in particular DPN.

#The embodiments of the present invention, i.e. a rationally designed peptidomimetic small molecule, represent a huge advance in targeting HMGB1. Existing HMGB1 “inhibitors” either have numerous additional targets (e.g., glycyrrhizin) or only impinge on HMGB1 signaling indirectly (e.g., gabexate mesilate, a serine protease inhibitor). In contrast, the specificity of targeting distinct aspects of HMGB1 signaling allows the possibility of reducing systemic inflammation while preserving the immune system's response to pathogens. This selective approach represents a critical feature for treating patients who often have active systemic infections, one that currently available global immunosuppressive therapies lack. The specificity of targeting distinct aspects of HMGB1 signaling allows the possibility of ameliorating ALI through targeted immunosuppression, as well as the possibility of ameliorating bacterial and viral respiratory infections such as influenza and SARS-CoV-2. The specificity of targeting distinct aspects of HMGB1 signaling also allows the possibility of ameliorating neuropathic pain, and in particular DPN through targeted immunosuppression.

#HMGB1 has been implicated in driving the progression of sepsis by the twin observations that sepsis severity roughly tracks with levels of circulating HMGB1 (Wang, H., et al., HMG-1 as a late mediator of endotoxin lethality in mice, Science, 1999, 285(5425): p. 248-51; Gibot, S., et al., High-mobility group box 1 protein plasma concentrations during septic shock, Intensive Care Med, 2007, 33(8): p. 1347-53; Sunden-Cullberg, J., et al., Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with sepsis and septic shock, Crit Care Med, 2005, 33(3): p. 564-73) and that the presence of anti-HMGB1 autoantibodies correlates with improved outcomes (Barnay-Verdier, S., et al., Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock, Intensive Care Med, 2011, 37(6): p. 957-62). Experiments in rodents have confirmed that HMGB1-mediated signaling is central for precipitating the pathogenic inflammation that leads to mortality or other sequelae in sepsis survivors. Sepsis can be induced in rodents via the cecal ligation and puncture method; it is the preferred experimental model for sepsis because it recapitulates the progression of sepsis in humans (Dejager, L., et al., Cecal ligation and puncture: the gold standard model for polymicrobial sepsis?, Trends Microbiol, 2011, 19(4): p. 198-208). Briefly, cecal ligation and puncture surgery involves ligating the cecum to cause necrosis of the bowel and breaching the intestine and extruding a small amount of stool to establish an active, polymicrobial intra-abdominal infection. Similar to sepsis in humans, the survival rate is between 20% to 40% when untreated (Qin, S., et al., Role of HMGB1 in apoptosis-mediated sepsis lethality, J Exp Med, 2006, 203(7): p. 1637-42; Yang, H., et al., Reversing established sepsis with antagonists of endogenous high-mobility group box 1, Proc Natl Acad Sci USA, 2004, 101(1): p. 296-301) and survivors develop a persistent microcytic, hypochromic anemia (Valdes-Ferrer, S. I., et al., HMGB1 mediates anemia of inflammation in murine sepsis survivors, Mol Med, 2015). Remarkably, administering HMGB1-neutralizing antibodies, even as late as 24 hours post-injury, can counteract these symptoms attributed to blocking HMGB1-mediated release of pro-inflammatory cytokines.