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Methods for cancer and immunotherapy using glutamine analogs

A technology for immunotherapy and cancer, applied in the direction of medical raw materials, drug combinations, and pharmaceutical formulations derived from mammals

Active Publication Date: 2021-09-28
JOHNS HOPKINS UNIVERSITY +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 analogs
  • Methods for cancer and immunotherapy using glutamine analogs
  • Methods for cancer and immunotherapy using glutamine analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0447] To study the effect of DON on cancer, the EL4 mouse lymphoma model was used, and it showed that DON can significantly inhibit the growth of lymphoma, indicating 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

[0449] image 3 DON was shown to suppress tumor-infiltrating regulatory T cells (Foxp3 + ) to opsonize B16 melanoma to be killed by immunotherapy.

Embodiment 3

[0451] Summarize

[0452] 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 the brain:plasma ratio was increased 10-fold compared to DON. This strategy may provide an avenue for the utilization of DON in GBM patients.

[0453] introduce

[0454] Glioblastoma multiforme (GBM) is the most common and...

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Abstract

The presently disclosed subject matter relates to metabolic reprogramming agents that reduce glutamine metabolism, glycolysis and / or fatty acid synthesis, pharmaceutical compositions comprising at least one, at least two or at least three metabolic reprogramming agents, and those agents and compositions for use as immunotherapy, and enhancing immunotherapy for the treatment of cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Nos. 62 / 199,381 and 62 / 199,566, filed July 31, 2015, the contents of each of which are incorporated herein 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/195A61K31/66A61K31/357A61K31/421A61K31/404A61K31/7076A61K31/52
CPCA61K31/7076A61K39/39558A61K45/06A61K31/42A61K31/664A61K31/683A61K31/685A61K31/7034A61K31/655A61P35/00A61K31/22A61K31/225A61K31/4045Y02A50/30A61K2239/38A61K39/4611A61K39/4621A61K39/46433A61K39/46434A61K2239/31A61K2300/00A61K31/223A61K38/05A61K39/39541
Inventor 芭芭拉·斯卢谢尔乔纳森·鲍威尔贾德森·恩格勒特罗伯特·利昂卢卡斯·特诺拉帕维尔·马杰尔安德烈·詹卡瑞克
Owner JOHNS HOPKINS UNIVERSITY
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