Intrapulmonary Administration Of Polynucleotide Toll-Like Receptor 9 Agonists For Treating Cancer Of The Lung

A polynucleotide, therapeutic agent technology, used in therapy, radiation therapy, aerosol delivery, etc., can solve problems such as survival of patients with non-small cell lung cancer that do not improve

Inactive Publication Date: 2018-02-16
DYNAVAX TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the results of preclinical and phase II trials of polynucleotide TLR9 agonists were promising, polynucleotide TLR9 agonists did not imp

Method used

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  • Intrapulmonary Administration Of Polynucleotide Toll-Like Receptor 9 Agonists For Treating Cancer Of The Lung
  • Intrapulmonary Administration Of Polynucleotide Toll-Like Receptor 9 Agonists For Treating Cancer Of The Lung
  • Intrapulmonary Administration Of Polynucleotide Toll-Like Receptor 9 Agonists For Treating Cancer Of The Lung

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Isolation of human leukocytes and stimulation by polynucleotides

[0109] The activity of polynucleotide (PN) was evaluated in vitro by measuring the cytokines secreted by human peripheral blood mononuclear cells (PBMC) and isolated B cells.

[0110] Ficoll-Paque was used to separate PBMC from healthy human donor blood. Anti-CD19 microbeads (Miltenyi Biotec, Auburn, CA) were used to isolate B cells by positive selection from the buffy coat according to the manufacturer's instructions. For IFN-α induction, duplicate cultures of PBMC (2.5x10 6 Cells / mL) are incubated with increasing concentrations of polynucleotide for 24 hours. The IFN-α level in the cell culture supernatant was measured by ELISA (n=4 donors). For IL-6 induction, duplicate cultures of B cells (0.75x10 6 Cells / mL) are incubated with increasing concentrations of polynucleotide for 96 hours. The level of IL-6 in the cell culture supernatant was measured by ELISA (n=12 donors).

[0111] All polynucle...

Embodiment 2

[0114] Example 2: Evaluation of polynucleotides in mice

[0115] After intranasal administration of saline, D60-1, or D60-7 on a bi-weekly schedule, measurement of cytokines in mouse bronchoalveolar lavage fluid (BALF), histopathological score of lung tissue, and body weight changes To evaluate the activity of polynucleotide (PN) in vivo.

[0116] Saline or a polynucleotide TLR9 agonist at a dose of 1, 5, or 20 μg was administered to BALB / c mice (n=5 mice / group) via intranasal route in a volume of 50 μL to ensure delivery to the lungs. The mice were given intranasal treatment on days 0, 14, 28, and 42 for a total of four treatments. The mice are weighed twice a week. Twenty-four hours after the last (fourth) treatment, the mice were sacrificed and bronchoalveolar lavage was performed with saline to obtain eluate from the lower respiratory tract. Subsequently, the lung tissue was harvested and stored in 10% formalin for paraffin embedding, sectioning and staining with hematoxylin...

Embodiment 3

[0119] Example 3: Evaluation of polynucleotides in a mouse model of lung cancer

[0120] Polynucleotide (PN) activity is evaluated in vivo in several different mouse models of metastatic cancer that reaches the lung (Heppner et al., Breast Cancer Res. 2:331-334, 2000).

[0121] The cancer cells are injected subcutaneously (SC).

[0122] D60-7 and anti-PD-1 synergistically prolong the survival of mice bearing lung tumors

[0123] 4T1 breast cancer cells spontaneously metastasize from the subcutaneous space to the lung, liver, pancreas, bone and blood. About 10,000 4T1 cells were injected subcutaneously into BALB / c mice. Anti-PD-1 blocking antibody treatment was initiated 6 days later. The blocking antibody was administered by IP injections of 250 μg every 3 or 4 days for 5 weeks. The primary tumor was surgically removed on the 15th day. The polynucleotide TLR9 agonist D60-7 was administered intranasally in 50 μL saline at a dose of 10 μg, starting on day 16 and continuing for 3 wee...

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Abstract

The present disclosure relates to methods for treating cancer by intrapulmonary administration of a polynucleotide Toll-like receptor 9 agonist. The methods of the present disclosure are suitable fortreating primary cancer of the lung, as well as metastatic cancer to the lung and extra pulmonary cancers thereof. Additionally, the present disclosure provides polynucleotide Toll-like receptor 9 agonists with immune stimulatory and toxicity profiles suitable for intrapulmonary administration.

Description

[0001] Cross references to related applications [0002] This application requires the rights and interests of U.S. Provisional Application No. 62 / 276,767 filed on January 8, 2016, which is fully included by reference. This application also requires U.S. Provisional Application Nos. 62 / 169,309 and No. 62 / 169,321 filed on June 1, 2015, and U.S. Provisional Application Nos. 62 / 168,449 and 62 / 168,470 filed on May 29, 2015. . [0003] Submission of sequence table as ASCII text file [0004] no. Invention field [0005] The present disclosure relates to methods for the treatment of cancer by intrapulmonary administration of polynucleotide Toll-like receptor 9 agonists. The method of the present disclosure is suitable for treating primary cancer of the lung, as well as metastatic cancer that reaches the lung and its extrapulmonary cancer. In addition, the present disclosure provides polynucleotide Toll-like receptor 9 agonists with immunostimulatory and toxicity profiles suitable for int...

Claims

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Application Information

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IPC IPC(8): A61K31/7125A61K31/713A61P35/00A61P35/04
CPCA61K31/7125A61K31/713A61P35/00A61K39/39A61K9/00A61N5/00C07K14/435A61K2039/55511A61K2039/53A61K2039/543A61K2300/00A61K9/0073A61K45/06C12N15/113A61P35/04
Inventor C·吉杜奇R·L·柯夫曼
Owner DYNAVAX TECH CORP
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