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Effectiveness determination marker in disease treatment by pd-1 signal inhibitor

A technology of PD-1 and signal inhibition, applied in the direction of disease diagnosis, allergic diseases, medical preparations containing active ingredients, etc.

Pending Publication Date: 2019-07-09
KYOTO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is also true that about half of patients show non-responsiveness

Method used

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  • Effectiveness determination marker in disease treatment by pd-1 signal inhibitor
  • Effectiveness determination marker in disease treatment by pd-1 signal inhibitor
  • Effectiveness determination marker in disease treatment by pd-1 signal inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Meth A (Cell Resource Center for Biomedical Research) and RENCA (American Type Culture Collection), which are sensitive to PD-1 inhibitory antibody treatment, and non-sensitive CT26 (American Type Culture Collection) BALB / c mice (Charles River Laboratories Japan) were inoculated with WEHI (American Type Culture Collection), and PD-L1 antibody (1-111A, produced by our laboratory, 150ug / ml). On the second day from the last administration, CD8+ T cells in the accessory lymph nodes were isolated, and the oxygen consumption of mitochondria was measured using XF96 Extracellular Flux analyzer (Seahorse Biosciences). And based on it, ATP turnover is calculated. show the result in figure 1 .

[0129] C57BL / 6N mice (Charles River Laboratories Japan) will be inoculated with MC38 (Dr. Jim Allison), non-sensitive LLC (American Type Culture Collection) sensitive to PD-1 inhibitory antibody treatment, 5 days later The PD-L1 antibody (1-111A, produced by our laboratory, 150ug / ml) ...

Embodiment 2

[0132] Extraction from wild-type C57BL / 6N mice (Charles River Laboratories Japan) and PD using a methanol / chloroform / water mixture - / - The serum recovered from mice (Immunity 11, 141-151 (1999).; Science 291, 319-322 (2001).; Nat. Med. 9, 1477-1483 (2003).) generated methoxylamine derivatives thing. After separation of metabolites using a methylpolysiloxane nonpolar column, the concentrations of TCA cycle-related metabolites were determined using mass spectrometry. In PD-1 - / - In mice, serum TCA cycle-related metabolites tended to decrease. show the result in image 3 .

[0133] C57BL / 6N mice were administered with PD-L1 antibody (1-111A, produced by our laboratory, 200ug) or control IgG (Bio X Cell) three times a day, and the serum levels related to the TCA cycle were determined by GC-MS. The concentration of metabolites. show the result in Figure 4 . When PD-L1 antibody is administered, metabolites related to TCA cycle in serum tend to decrease. This is considered ...

Embodiment 3

[0136] Mitochondrial activation is associated with cellular activation. In the activation of cells, mTOR signaling plays an important function. Mitochondria are also known to be activated for the mTOR pathway, and T-bet, which is important for Th1-type immunity, is also known to be activated.

[0137] Therefore, using the CD8+ T cells obtained in Example 1, the T-bet activity before and after treatment was compared.

[0138] The accessory lymph node cells used in Example 1 were stained with anti-CD8 antibody (BioLegend) and anti-T-bet antibody (BioLegend), and anti-EOMES antibody (eBioscience), and CD8+T cells were gated and compared in PD-L1 antibody The expression of T-bet and EOMES before and after administration. show the result in Figure 5 .

[0139] It is known that the expression of T-bet increases after antibody administration in the treatment of highly sensitive cancer. On the other hand, EOMES, which performs a different function from T-bet, increased regardles...

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Abstract

Provided is a marker that determines effectiveness prior to or in an early stage of disease treatment with a PD-1 signal inhibitor. A biomarker that can serve as an indicator of metabolic change related to T-cell mitochondrial activity and / or T-cell activation in a subject is used as a biomarker for predicting or determining the effectiveness of treatment with a PD-1 signal inhibitor. The following can be used as the indicator: intestinal flora-related metabolites in serum or plasma; energy metabolism-related metabolites in serum or plasma; amino acid metabolism-related metabolites and / or derivatives thereof in serum or plasma; oxygen consumption level and / or ATP turnover rate in peripheral CD8+ cells; amino acids in T-cells; and T-bet in peripheral CD8+ cells.

Description

technical field [0001] The invention relates to a marker for judging the effectiveness of a PD-1 signal inhibitor in disease treatment. Background technique [0002] According to the results of clinical trials in recent years, it has been clarified that anti-PD-1 antibody therapy is more effective than conventional standard therapy in various cancers [Non-Patent Documents 1-3]. Compared with traditional immunotherapy, the response rate of PD-1 antibody therapy is 20-30% alone, and 60-70% when used in combination. However, it is also true that about half of the patients showed non-responsiveness. Little is known about why these patients do not respond to PD-1 antibody therapy. [0003] prior art literature [0004] non-patent literature [0005] Non-Patent Document 1: Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 373: 1627-1639, 2015. [0006] Non-Patent Document 2: Hamanishi J, Mandai ...

Claims

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Application Information

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IPC IPC(8): C12Q1/02A61K39/395A61K45/00A61P35/00A61P37/04A61P43/00G01N33/68
CPCA61K39/395A61K45/00A61P35/00A61P37/04A61P43/00C12Q1/02G01N33/68G01N33/574G01N33/6812G01N2333/70532G01N2800/52G01N2570/00C12Q1/008A61P31/00C07K16/2818C07K16/2827G01N33/492G01N33/5011G01N33/6872G01N2800/7028
Inventor 本庶佑茶本健司松田文彦奥野恭史西多妮亚·弗格勒尚
Owner KYOTO UNIV
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