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Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease

a technology of senescence cells and senescence, which is applied in the field of detection and treatment of cancer, age-related diseases, tobacco-related diseases, etc., can solve the problems of cellular senescence, increased cancer incidence and severity, and questionable whether replicative senescence actually contributes to aging or age-related symptoms in vivo, so as to reduce the size of tumors or the number, slow or prevent the growth of cancer cells, and stabilize the effect of cancer

Inactive Publication Date: 2015-06-04
UNITY BIOTECHNOLOGY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048]By “therapeutic agent” is meant any compound that is used in the detection, diagnosis or treatment of disease. Such compounds may be naturally-occurring, modified, or synthetic. A therapeutic agent may be, for example, an agent that causes apoptosis or necrosis of a cell (e.g., a senescent cell) in an organism (e.g., a mammal, such as a human), thereby reducing the number of such cells in the organism. Therapeutic agents that reduce the number of senescent cells in an organism may be, e.g., alkylating agents, antibiotics, antimetabolites, hormonal agonists or antagonists, anti- or pro-apoptotic agents, immunomodulators, or supplementary potentiating agents.
[0049]By “treating, stabilizing, or preventing cancer” is meant causing a reduction in the size of a tumor or in the number of cancer cells, slowing or preventing an increase in the size of a tumor or in cancer cell proliferation, increasing the disease-free survival time between the disappearance of a tumor or other cancer and its reappearance, preventing an initial or subsequent occurrence of a tumor or other cancer, or reducing an adverse symptom associated with a tumor or other cancer. In a desired embodiment, the percent of tumor or cancerous cells surviving the treatment is at least 20, 40, 60, 80, or 100% lower than the initial number of tumor or cancerous cells, as measured using any standard assay, such as those described herein. Desirably, the decrease in the number of tumor or cancerous cells induced by administration of a compound of the invention is at least 2, 5, 10, 20, or 50-fold greater than the decrease in the number of non-tumor or non-cancerous cells. Desirably, the methods of the present invention result in a decrease of 20, 40, 60, 80, or 100% in the size of a tumor or number of cancerous cells as determined using standard methods. Desirably, at least 20, 40, 60, 80, 90, or 95% of the treated subjects have a complete remission in which all evidence of the tumor or cancer disappears. Desirably, the tumor or cancer does not reappear after more than 5, 10, 15, or 20 years.

Problems solved by technology

Whether replicative senescence actually contributes to aging or age-related symptoms in vivo is questionable on the basis of theoretical estimates of the number of cell divisions that occur in vivo and the absence of strong empirical evidence.
Generally speaking, agents that damage DNA can cause cellular senescence.
This view is supported by experiments in mice showing that p53 knockout results in increased cancer incidence and severity.

Method used

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  • Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease
  • Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease
  • Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease

Examples

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example 1

Discovery of Agents that Bind Senescent Cells

Phage Selection Technique

[0134]Normal skin cell line CCD-1070Sk was obtained from American Type Culture Collection (Bethesda, Md.). The cells were grown in Eagle's Minimal Essential medium with Earle's BSS, 2 mM L-glutamine, 1.0 mM Sodium pyruvate, 0.1 mM nonessential amino acids and 1.5 g / L sodium bicarbonate supplemented with 10% fetal bovine serum.

[0135]Cells were sub-cultured every 4-5 days till they became senescent. Cell senescence was confirmed by senescence-associated beta-galactosidase staining

[0136]An M13 phage peptide library, Ph.D.-12, was obtained from New England BioLabs (Beverly, Mass.), which displays random 12-mer peptides.

[0137]For the selection step for round 1, an aliquot (10 μL) of the Ph.D.-12 complete phage library was incubated with 5×105 cells of senescent fibroblasts in 1 mL PBS / 0.5% BSA for ˜3.5 hours at room temperature with slow shaking on Lab-Quake. At the end of the incubation, the cells were pelleted in a m...

example 2

Human Study to Test the Prognostic Use of a Senescent Cell Binding Agent Labeled with a Radioisotope; Using a Senescent Cell Detecting Radiotracer to Predict Cancer Risk

[0141]This study is designed to show that noninvasive, in vivo imaging of senescent cell content can be used to predict cancer risk in smokers. Six-hundred subjects will be enrolled. Eighty percent of these subjects will be smokers; twenty percent will be nonsmokers. Subjects less than 18 years of age, subjects with a history of cancer, and pregnant subjects will be excluded. The anticipated mean age of study subjects is 55 years. Each study subject will undergo scintigraphic imaging using a radio-labeled peptide of the invention (SEQ ID NO:1) as the radiopharmaceutical. The radiopharmaceutical will be prepared by reacting peptide-gly-gly-gly-ser-DTPA with 111-In chloride. Each study subject will receive an intravenously administered dose of 5 mCi of 111-In labeled peptide. Anterior and posterior whole body planar im...

example 3

Using Senescent Cell Binding Agents Coupled to Cytotoxic Agents to Eliminate Senescent Cells: Effect on Subsequent Development of Cancer

[0142]The purpose of this study is to show that elimination of some senescent cells from an organism using the agents of the invention (e.g., peptides, polypeptides, proteins, small molecules, antibodies, or antibody fragments that target senescent cells) will reduce the risk of subsequently developing cancer. For example, a senescent cell binding peptide. (SEQ ID NO:1) will be conjugated to a cytotoxic peptide having the sequence KFAKFAKKFAKFAKKFAKFAK (SEQ ID NO:4; Leuschner and Hansel, Biology of Reproduction 73:860-865) via an amino acid linker sequence (e.g., a linker sequence selected from GGGC (SEQ ID NO:9), GGGS (SEQ ID NO:10), and GG) at the C terminus of the senescent cell binding peptide. Study subjects will consist of 60 BALB / c mice, mean age 6 mo which includes 30 experimental animals and 30 controls. Experimental animals will receive an...

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Abstract

Disclosed are agents (e.g., peptides, polypeptides, proteins, small molecules, antibodies, and antibody fragments that target senescent cells) and methods of their use for imaging senescent cells in vivo and for treating or preventing cancer, age-related disease, tobacco-related disease, or other diseases and disorders related to or caused by cellular senescence in a mammal. The methods include administering one or more of the agents of the invention to a mammal, e.g., a human. The agents, which specifically bind to senescent cells, can be labeled with a radioactive label or a therapeutic label, e.g., a cytotoxic agent.

Description

STATEMENT REGARDING SEQUENCE LISTING[0001]The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 200201—401D1_SEQUENCE_LISTING.txt. The text file is 70.5 KB, was created on Nov. 29, 2014, and is being submitted electronically via EFS-Web.FIELD OF THE INVENTION[0002]This invention relates to compositions and methods for the detection and treatment of cancer, age-related diseases, tobacco-related diseases, and other diseases and disorders related to or caused by cellular senescence.BACKGROUND OF THE INVENTION[0003]The definition of cellular senescence has undergone some revision since the phenomenon was described by Leonard Hayflick as cessation of replication of cultured human cells after a finite number of population doublings (Hayflick et al., Exp. Cell Res. 37:585-621, 1961). Senescent cells remain metabolic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48A61K49/00A61K51/08
CPCA61K47/48246A61K49/0056A61K51/08A61K51/088G01N33/57492G01N2800/50A61K47/64A61K47/6803A61K47/6849A61K47/6851A61K51/1027A61K38/10A61K38/16A61K38/168G01N33/5005A61K35/12C07K16/28C07K2317/24C07K2317/73A61K2039/505C07K2317/76A61K49/0004C07K14/00C07K2317/92C12N15/1037C12N15/86C12N2710/10043G01N33/5032
Inventor SQUIRES, SHAYNE
Owner UNITY BIOTECHNOLOGY INC
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