ROCKVILLE, MD, United States
ROCKVILLE, MD, United States

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Patent
Oncoimmune, Inc. | Date: 2016-08-11

The present invention relates to treating a hematologic cancer using a Hypoxia-Inducible Factor (HIF inhibitor). The invention also relates to inducing acute myeloid leukemia remission using the HIF inhibitor. The invention further relates to inhibiting a maintenance or survival function of a cancer stem cell (CSC) using the HIF inhibitor.


Chen G.-Y.,University of Michigan | Chen X.,University of California at Davis | King S.,Nationwide Childrens Hospital | Cavassani K.A.,University of Michigan | And 16 more authors.
Nature Biotechnology | Year: 2011

Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the t interaction of CD24 and SiglecG (SIGLEC10 in human). Here we use an intestinal perforation model of sepsis to show that microbial sialidases target the sialic acid-based recognition of CD24 by SiglecG/10 to exacerbate inflammation. Sialidase inhibitors protect mice against sepsis by a mechanism involving both CD24 and Siglecg, whereas mutation of either gene exacerbates sepsis. Analysis of sialidase-deficient bacterial mutants confirms the key contribution of disrupting sialic acid-based pattern recognition to microbial virulence and supports the clinical potential of sialidase inhibition for dampening inflammation caused by infection.


Toubai T.,University of Michigan | Hou G.,University of Michigan | Mathewson N.,University of Michigan | Liu C.,Florida College | And 12 more authors.
Blood | Year: 2014

Activation of sialic-acid - binding immunoglobulin-like lectin-G (Siglec-G) by non-infectious damage-associated molecular patterns controls innate immune responses. However, whether it also regulates T-cell - mediated adaptive immune responses is not known. Graft-versus-host reaction is a robust adaptive immune response caused by allogeneic hematopoietic cell transplantation that have been activated by antigen-presenting cells (APCs) in the context of damaged host tissues following allogeneic hematopoietic cell transplantation. The role of infectious and noninfectious pattern recognition receptor - mediated activation in the induction and aggravation of graft-versus-host disease (GVHD) is being increasingly appreciated. But the role of pathways that control innate immune responses to noninfectious stimuli in modulating GVHD has heretofore not been recognized. We report that Siglec-G expression on host APCs, specifically on hematopoietic cells, negatively regulates GVHD in multiple clinically relevant murine models. Mechanistic studies with various relevant Siglec-G and CD24 knockout mice and chimeric animals, along with rescue experiments with novel CD24 fusion protein demonstrate that enhancing the interaction between Siglec-G on host APCs with CD24 on donor T cells attenuates GVHD. Taken together, our data demonstrate that Siglec-G - CD24 axis, controls the severity ofGVHDand suggest that enhancing this interaction may represent a novel strategy for mitigating GVHD. © 2014 by The American Society of Hematology.


Li Y.,U.S. National Institutes of Health | Abu-Asab M.,U.S. National Institutes of Health | Su J.,Capital Medical University | Qiu P.,Oncoimmune, Inc. | And 6 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2015

Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT (n = 94), ET (n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced (P < 0.0001) similarly (P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h (P < 0.05), whereas ET decreased it progressively throughout (P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output (P < 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h (P < 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h (P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels (P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia. © 2015 American Physiological Society. All Rights Reseved.


Patent
Oncoimmune, Inc. | Date: 2011-04-28

Provided herein is a method of treating rheumatoid arthritis using a CD24 protein. The CD24 protein may include mature human or mouse CD24, as well as a N- or C-terminally fused portion of a mammalian immunoglobulin.


Patent
Oncoimmune, Inc. | Date: 2010-06-25

The present invention relates to treating a hematologic cancer using a Hypoxia- Inducible Factor (HIF inhibitor). The invention also relates to inducing acute myeloid leukemia remission using the HIF inhibitor. The invention further relates to inhibiting a maintenance or survival function of a cancer stem cell (CSC) using the HIF inhibitor.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 155.18K | Year: 2011

DESCRIPTION (provided by applicant): Sepsis is one of the top leading causes of deaths for Americans and it is responsible for approximately 200,000 deaths in US annually. Despite of the advance of antibiotics and medical treatment in general, there has been no reduction in severity and death associated with the disease. Since inflammation is the underlying cause of sepsis, the lack of progress in sepsis treatment suggests major gaps in understanding the root cause of inflammation associated with infection.A major breakthrough in immunology is the identification of pathogen-associated molecular pattern (PAMP) as the root cause of inflammation. However, PAMP alone does not explain sepsis as controlling infection, which should remove PAMP, is insufficient tocure sepsis. Another source of inflammation is tissue damage-associated molecular pattern (DAMP). We have recently demonstrated that host response to DAMP is controlled by CD24-Siglec 10/G interaction. Our preliminary data provided herein demonstrated thatsepsis is associated with disruption of CD24-Siglec 10 interaction and polybacterial sepsis in the mouse can be effectively treated by sialidase inhibitors. Here we propose to use rational drug design and a novel enzymo-chemical synthesis strategy to produce sialidase inhibitors for the treatment of sepsis, as detailed in two specific aims. Specifically, we will produce new sialidase inhibitors through the rational drug design and our novel enzymochemical strategy. Then we will use cecal ligation and puncture (CLP) model to test the therapeutic efficacy of the novel sialidase inhibitors. As proof of concept, the successful completion of this proposal will not only sustain bacterial sialidase as the therapeutic target for sepsis, but also provide new and effective prototype drugs for further development. PUBLIC HEALTH RELEVANCE: Sepsis is the tenth leading cause of deaths for Americans as it is responsible for approximately 200,000 deaths in US annually. Despite of the advance of antibiotics and medical treatment in general, there has been no reduction in severity and death associated with the disease. The ultimate goal of this application is to develop a novel and effective treatment for sepsis by targeting on the bacterial sialidase.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.15K | Year: 2011

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is among the most common autoimmune diseases. The current treatment for RA is mainly by targeting tumor-necrosis factor (TNF). Despite the remarkable efficacy, significant portion of RA patients are not responsive to this class of drugs. Therefore, there is an urgent need to develop therapeutic that can complement existing therapeutic biologics. Recently, it has been suggested that danger (or damage)-associated molecular patterns (DAMPs), a group of intracellular component released from necrotic cells, such as HMGB1 and HSP70, may be involved in the pathogenesis of RA. In consistency with this notion, partial inhibition of collagen-induced arthritis was achieved by administration of anti-HMGB1 mAb. These data support the notion that tissue destruction by autoreactive cells can form a vicious cycle of chronic inflammation, as is the case of RA. However, it appears that the impact of anti-HMGB1 antibodies remains modest. The relatively minor effectsare to be expected as multiple DAMPs are expected to be released during autoimmune tissue damage. On the other hand, we have recently identified that CD24-Siglec 10 mediate a negatively regulatory pathway that selective regulates host response to DAMP 1.Since the CD24 binds to multiple DAMPs, including HMGB1, HSP70, HSP90 and nucleolin, it is conceivable that CD24 fusion proteins can be explored for therapy of RA. As the proof of concept, we have shown that CD24Fc, a fusion protein consisting extracellular domain of human CD24 and the Fc of human IgG1, protected mice against RA induced by a cocktail of anti-collagen antibodies. Based on this exciting observation, we will use collagen-induced arthritis (CIA) model, the gold standard for clinical developmentof RA drug, to confirm the therapeutic effect of CD24Fc and compare CD24Fc with Enbrel, the clinically used soluble receptor for TNFa. In addition, we will establish an in vitro model to demonstrate the mode of action of the CD24Fc, as detailed in two specific aims. Specifically, we will establish the therapeutic effect of CD24Fc using CIA model and determine whether the therapeutic efficacy of CD24Fc can be used in combination with TNFa antagonist to increase therapeutic efficacy. Then we will determine the CD24 expression in DC and macrophages among the inflammatory cells and identify the population that produces inflammatory cytokine. We will also test whether CD24Fc inhibit the production of inflammatory cytokines on these cells. The completion of thisproposal will not only substantiate the therapeutic potential of CD24Fc, but also provide a mechanism of action for CD24Fc and facilitate the down-stream drug development. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is among the most common autoimmune diseases and it affects 0.5-1% of humans. Despite the remarkable efficacy of the current therapies that mostly target on TNF-alpha, significant portion of RA patients are not responsive to these treatments. The ultimate goal of this application is to develop a novel biological therapeutics, namely CD24Ig Fc fusion protein, by targeting danger (or damage)-associated molecular patterns (DAMPs), which was recently been demonstrated to be involved in the pathogenesis of Rheumatoid arthritis.


Oncoimmune, Inc. | Entity website

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PubMed | Capital Medical University, Oncoimmune, Inc. and U.S. National Institutes of Health
Type: Comparative Study | Journal: American journal of physiology. Heart and circulatory physiology | Year: 2015

Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT (n = 94), ET (n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced (P < 0.0001) similarly (P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h (P 0.05), whereas ET decreased it progressively throughout (P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output (P 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h (P 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h (P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels (P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia.

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