Methods and compositions for treating cancer

A therapeutic composition and composition technology, applied in the field of cancer treatment and composition, capable of solving problems such as exhausted T cells, decreased lymphocytes in mice, and off-target effects

Pending Publication Date: 2020-04-17
UNIVERSITY OF CHICAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First, there are still significant obstacles to the implementation of siRNA drugs for cancer therapy, including poor cellular uptake, instability under physiological conditions, off-target effects, and possible immunogenicity (Dominska and Dykxhoorn, J Cell Sci., 2010; Jackson and Linsley et al., Nat Rev Drug Discov., 2010; Moschos et al., Bioconjug Chem., 2007)
Second, since CD95 is critical for the survival, proliferation and activation of T cells, deletion of CD95 in T cells results in lymphopenia in mice (Hao et al., J. Exp. Med., 2004; Krammer., Nature, 2000 ), this approach may deplete T cells and suppress anti-tumor immunity, leading to undesirable side effects

Method used

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  • Methods and compositions for treating cancer
  • Methods and compositions for treating cancer
  • Methods and compositions for treating cancer

Examples

Experimental program
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Effect test

Embodiment 1

[0172] ways to treat cancer

[0173] Human PMNs broadly and selectively kill cancer cells. Human peripheral blood neutrophils (PMN) were isolated from healthy donors and incubated in serum-free DMEM to collect its secreted factors (PMN medium). (A-B) Human or murine cancer cells (A) or healthy cells (b) were incubated with PMN medium or control serum-free DMEM (control medium) for 24 hours. Cell viability was assessed by calcein AM staining. (C) Human or murine cancer cells were treated with PMN medium or control medium for 6 hours. Caspase 3 / 7 activity was detected by luminescence assay and cell surface annexin V staining was assessed by flow cytometry. The results showed that PMN medium induced the death of cancer cells through apoptosis. *, p<0.05, Student's t-test (Figure 1).

[0174] Human neutrophil-adapted medium kills a variety of cancer cells. Human peripheral blood neutrophils were isolated from healthy donors. Cells were seeded in serum-free DMEM, and neutrop...

Embodiment 2

[0185] Degradation of CD95 and Cancer Therapy

[0186] The catalytic activity of ELANE is required for its selective killing of cancer cells. (Fig. 5A) Purified native ELANE or PMN medium was treated with PMSF (100 nM) or α-1-antitrypsin (A1AT; 42 nM) for 30 min, and the loss of ELANE catalytic activity was confirmed by chromogenic substrate assay. Killing assays were performed by treating MDA-MB-231 cells for 24 h and assessed by calcein AM staining. (FIG. 5B) ELANE activity in PMN medium was measured by chromogenic substrate activity assay, and PMN-killing effect on MDA-MB-231 cells exposed to PMN medium for 4 hours was measured by calcein AM staining. The results showed that the catalytic activity of ELANE in PMN medium was linearly correlated (linearly) with the cancer cell killing ability of PMN medium from nine healthy donors. *, p<0.05, Student's t-test.

[0187] ECP is a type II allosteric activator of ELANE catalytic activity. (FIG. 7A) 1OnM ELANE was incubated wi...

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Abstract

Embodiments are directed to: (i) neutrophil secreted factors that have the capacity to kill a broad range of cancer cells without affecting the viability of non-cancer cells. Two neutrophil killing factors have been identified by the inventors: (1) eosinophil cationic protein (ECP) and (2) neutrophil elastase (ELANE); or (ii) therapeutic compositions that include CD95 degrading polypeptide components and methods of treating cancer with the same.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 520325, filed June 15, 2017, and U.S. Provisional Patent Application No. 62 / 610711, filed December 27, 2017, the entire contents of which are hereby incorporated by reference Incorporated into this article. technical field [0003] Some embodiments relate generally to biology, medicine, and cancer treatment. Some aspects relate to protein compositions having protein or polypeptide components that are toxic to various cancer cells. Other aspects relate to protein compositions having or delivering CD95-degrading protein or polypeptide components. Background technique [0004] Precision medicine, medical care aimed at optimizing the efficiency or therapeutic benefit of specific patient populations through the use of genetic or molecular profiling, has gained enormous traction in the treatment of cancer. Identifying specific genomic abnormali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/48A61P35/00A61K38/46
CPCA61K38/48A61P35/00A61K38/465A61K38/54C12Y304/21037C12Y301/26003
Inventor 莱芙·贝克尔崔畅
Owner UNIVERSITY OF CHICAGO
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