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

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.

1 . An agent comprising a peptide, polypeptide, antibody, or fragment thereof comprising an amino acid sequence set forth in any one of SEQ ID NOs:1-3 and 5-8 or a peptide, polypeptide, antibody, antibody fragment, or small molecule capable of specifically binding to an antigen comprising an amino acid sequence having at least 20 amino acids with at least 80% sequence identity to any one of the amino acid sequences set forth in SEQ ID NOS:11-23. 
     
     
         2 . (canceled) 
     
     
         3 . The agent of  claim 1 , wherein said antigen comprises any one of the amino acid sequences set forth in SEQ ID NOS:11-23. 
     
     
         4 . The agent of  claim 1 , further comprising one or more of a detectable label, a therapeutic agent, a chelating agent, or a linker moiety. 
     
     
         5 - 13 . (canceled) 
     
     
         14 . The agent of  claim 4 , wherein said therapeutic agent is a cytotoxic agent. 
     
     
         15 - 18 . (canceled) 
     
     
         19 . The agent of  claim 1 , wherein said agent specifically binds to a senescent cell. 
     
     
         20 . The agent of  claim 19 , wherein said senescent cell comprises a senescent lung, breast, colon, prostate, gastric, hepatic, ovarian, esophageal, or bronchial epithelial or stromal cell, a senescent skin epithelial or stromal cell; a senescent glial cell; or a senescent vascular endothelial or stromal cell. 
     
     
         21 . A method of imaging a senescent cell-containing region in a mammal in vivo, said method comprising the steps of:
 (a) administering to said mammal the agent of  claim 1  and a detectable label;   (b) allowing said agent to bind senescent cells and allowing unbound agent to be cleared from the body of said mammal; and   (c) obtaining an image of said senescent cell-containing region.   
     
     
         22 - 24 . (canceled) 
     
     
         25 . A method of predicting cancer risk in a mammal, said method comprising the steps of:
 (a) administering to said mammal the agent of  claim 1  and a detectable label;   (b) predicting an elevated cancer risk in said mammal by detecting binding of said agent to a senescent cell of said mammal.   
     
     
         26 - 27 . (canceled) 
     
     
         28 . A method of treating or preventing disease in a mammal, said method comprising administering to said mammal the agent of  claim 14 . 
     
     
         29 - 32 . (canceled) 
     
     
         33 . A method of treating or preventing disease in a mammal, said method comprising administering to said mammal a nucleic acid molecule encoding a cytotoxic agent and the agent of  claim 1 . 
     
     
         34 - 40 . (canceled) 
     
     
         41 . A method for identifying a peptide or polypeptide capable of detecting senescent cells comprising the steps of:
 (a) culturing cells to produce senescent cells;   (b) exposing said senescent cells to a phage peptide library;   (c) recovering said senescent cells and phage from said phage peptide library bound to said senescent cells;   (d) eluting and amplifying said bound phage to produce amplified phage;   (e) repeating steps (a)-(d) one or more times; and   (f) recovering a peptide or polypeptide expressed by said amplified phage that is capable of detecting senescent cells.   
     
     
         42 . (canceled) 
     
     
         43 . A method for making an antibody or antibody fragment capable of specifically binding to a senescent cell-specific antigen, said method comprising the steps of:
 (a) administering a polypeptide comprising at least 20 amino acids comprising at least 80% amino acid sequence identity to any one of the amino acid sequences set forth in SEQ ID NOS:11-23 to a mammal;   (b) allowing said mammal to generate a humoral immune response to said polypeptide; and   (c) isolating from said mammal an antibody or antibody fragment that binds said polypeptide with a dissociation constant of less than 10 −7  M.   
     
     
         44 . The method of  claim 43 , wherein said mammal is a mouse, hamster, rat, guinea pig, chicken, goat, sheep, cow, horse, non-human primate, or human. 
     
     
         45 - 46 . (canceled) 
     
     
         47 . A method of cellular therapy comprising administering to a mammal in need thereof the agent of  claim 1  prior to, concurrent with, or following administration of a cellular therapeutic. 
     
     
         48 . (canceled) 
     
     
         49 . A method of cellular therapy comprising contacting the agent of  claim 1  to a donor cell, tissue, or organ prior to, concurrent with, or following administration of said cell, tissue, or organ to a mammal. 
     
     
         50 - 53 . (canceled) 
     
     
         54 . A kit comprising:
 (a) the agent of  claim 1 ; and   (b) one or more of a detectable label, a therapeutic agent, a chelating agent, or a linker moiety.