Methods for cancer and immunotherapy using glutamine analogues, including don

A technology of immunotherapy and glutamine, applied in the direction of medical raw materials, drug combinations, and pharmaceutical formulas derived from mammals

Active Publication Date: 2018-07-31
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, specific inhibitors of only individual enzymes in these metabolic pathways have not proven to be effective because as the metabolism of the cell is reprogrammed to meet the very large energy demands of an abnormal, harmful or unhealthy state, in each metabolic pathway Multiple points of the

Method used

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  • Methods for cancer and immunotherapy using glutamine analogues, including don
  • Methods for cancer and immunotherapy using glutamine analogues, including don
  • Methods for cancer and immunotherapy using glutamine analogues, including don

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0455] To study the effect of DON on cancer, the EL4 mouse lymphoma model was used, and it showed that DON can significantly inhibit lymphoma growth, suggesting that bone marrow-derived tumors may be very sensitive to DON ( figure 1 ). However, DON had a modest effect on inhibiting the growth of melanomas that were not bone marrow-derived tumors ( figure 2 ).

Embodiment 2

[0457] image 3 DON was shown to suppress tumor-infiltrating regulatory T cells (Foxp3 + ) to opsonize B16 melanoma to be killed by immunotherapy.

Embodiment 3

[0459] Summarize

[0460] The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON, 1) showed strong anticancer efficacy in preclinical and clinical studies but was discontinued due to significant systemic toxicity its development. Here, we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a mouse glioblastoma model, despite observed toxicity. To increase the therapeutic index of DON, we used a prodrug strategy to increase its brain delivery and limit systemic exposure. Although these bipartite prodrugs exhibit rapid metabolism in mouse plasma, several bipartite prodrugs provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM_DON-isopropyl ester) was evaluated in monkeys, where it showed a 10-fold increase in the brain:plasma ratio compared to DON. This strategy may provide an avenue for the utilization of DON in GBM patients.

[0461] introduce

[0462] Glioblastoma multiforme (GBM) is the most...

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PUM

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Abstract

The presently disclosed subject matter relates to metabolic reprogramming agents that decrease glutamine metabolism, glycolysis, and fatty acid synthesis, pharmaceutical compositions comprising at least one, at least two, or at least three metabolic reprogramming agents, and the use of those agents and compositions for treating metabolic reprogramming disorders, such as immune disorders (e.g., autoimmune diseases), inflammatory diseases, and transplant rejection, pathologies due to CNS inflammation due to infection and not involving infection, and neurodegenerative disorders.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Nos. 62 / 199,381 and 62 / 199,566, filed July 31, 2015, the contents of each of which are hereby incorporated by reference in their entirety. Background technique [0003] A cell may, under certain conditions, undergo a metabolic profile ranging from requiring less activity of certain metabolic pathways to meet the energy needs of the cell to requiring greater activity of these metabolic pathways or enhanced activity of other metabolic pathways to meet its energy needs Metabolic conversion of the metabolic profile required. For example, cells under certain conditions may undergo a transition towards increased glycolysis and away from oxidative phosphorylation (OXPHOS). Although glycolysis provides less adenosine triphosphate (ATP) than oxidative phosphorylation, it has been proposed that aerobic glycolysis allows for the production of substrates necessary for t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/195A61K31/66A61K31/357A61K31/421A61K31/404A61K31/7076A61K31/52
CPCA61K31/7076A61K39/39558A61K45/06A61K31/42A61K31/664A61K31/683A61K31/685A61K31/7034A61K35/17A61K31/655A61P35/00A61K31/22A61K31/225A61K31/4045Y02A50/30A61K2300/00A61K31/223A61K38/05A61K39/39541
Inventor 芭芭拉·斯卢谢尔乔纳森·鲍威尔
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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