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 - 54 . (canceled) 
     
     
         55 . A method of treating a disease related to or caused by cellular senescence in a mammal comprising administering to the mammal a pharmaceutical composition comprising: (a) a humanized antibody or antibody fragment thereof, wherein the humanized antibody or antibody fragment thereof specifically binds to a senescent cell; and (b) a pharmaceutically acceptable carrier. 
     
     
         56 . The method of  claim 55 , wherein the humanized antibody or antibody fragment thereof specifically binds to a senescent cell-specific peptide, polypeptide, or glycoprotein on the senescent cell. 
     
     
         57 . The method of  claim 56 , wherein the senescent cell-specific peptide, polypeptide, or glycoprotein is expressed on a cell surface of the senescent cell. 
     
     
         58 . The method of  claim 57 , wherein the senescent cell-specific peptide, polypeptide, or glycoprotein is a senescent cell-specific antigen comprising an amino acid sequence set forth in any one of SEQ ID NOS:11-23. 
     
     
         59 . The method of  claim 55 , wherein the humanized antibody of the antibody fragment thereof is coupled to a therapeutic agent. 
     
     
         60 . The method of  claim 59 , wherein the therapeutic agent is a cytotoxic agent. 
     
     
         61 . The method of  claim 55 , wherein the disease is a cancer, an age-related disease, or a tobacco-related disease. 
     
     
         62 . The method of  claim 61 , wherein the age-related disease is selected from the group consisting of cardiovascular disease, cerebrovascular disease, osteoarthritis, benign prostatic hypertrophy, and Alzheimer's disease. 
     
     
         63 . The method of  claim 61 , wherein the tobacco-related disease is selected from the group consisting of emphysema, aortic aneurysms, esophageal cancer, peripheral vascular disease, cardiac diastolic dysfunction, aortic aneurysm, and squamous cell cancer. 
     
     
         64 . A method for inducing apoptosis in a senescent cell in a mammal comprising administering to the mammal a pharmaceutical composition comprising (a) a humanized antibody or antibody fragment thereof, wherein the humanized antibody or antibody fragment thereof specifically binds to the senescent cell; and (b) a pharmaceutically acceptable carrier. 
     
     
         65 . The method of  claim 64 , wherein the humanized antibody or antibody fragment thereof specifically binds to a senescent cell-specific peptide, polypeptide, or glycoprotein. 
     
     
         66 . The method of  claim 65 , wherein the senescent cell-specific peptide, polypeptide, or glycoprotein is expressed on a cell surface of the senescent cell. 
     
     
         67 . The method of  claim 66 , wherein the senescent cell-specific peptide, polypeptide, or glycoprotein is a senescent cell-specific antigen comprising an amino acid sequence set forth in any one of SEQ ID NOS:11-23. 
     
     
         68 . The method of  claim 64 , wherein the humanized antibody or the antibody fragment that is administered to the mammal is coupled to a therapeutic agent. 
     
     
         69 . The method of  claim 68 , wherein the therapeutic agent is a cytotoxic agent. 
     
     
         70 . The method of  claim 64 , wherein the senescent cell is a senescent lung cell, a senescent breast cell, a senescent colon cell, a senescent prostate cell, a senescent gastric cell, a senescent hepatic cell, a senescent ovarian cell, a senescent esophageal cell, a senescent bronchial epithelial or stromal cell, a senescent skin epithelial or stromal cell, a senescent glial cell, or a senescent vascular endothelial or stromal cell. 
     
     
         71 . The method of  claim 64 , wherein the humanized antibody or antibody fragment thereof comprises (a) amino acid sequence selected from any one of SEQ ID NOS:1-3 in a complementarity determining region; or (b) an amino acid sequence at least 90% identical to the amino acid sequence selected from any one of SEQ ID NOS:1-3 in a complementarity determining region. 
     
     
         72 . A method for depleting senescent cells from donor cells, a donor tissue, or a donor organ, said method comprising (a) contacting the donor cells, the donor tissue, or the donor organ with a humanized antibody or antibody fragment thereof, wherein the humanized antibody or antibody fragment thereof specifically binds to a senescent cell; and (b) administering the donor cells, the donor tissue, or the donor organ to the mammal prior to, concurrent with, or subsequent to the step of contacting. 
     
     
         73 . The method of  claim 72 , wherein the humanized antibody or antibody fragment thereof is administered to the mammal prior to, concurrent with, or subsequent to administration of the donor cells, the donor tissue, or the donor organ to the mammal. 
     
     
         74 . The method of  claim 72 , wherein the humanized antibody or antibody fragment thereof contacting the donor cells, tissue, or organ is coupled to a therapeutic agent. 
     
     
         75 . A pharmaceutical composition comprising:
 (a) a humanized antibody or antibody fragment thereof coupled to a therapeutic agent, wherein the humanized antibody or antibody fragment thereof specifically binds to a senescent cell-specific peptide, polypeptide, or glycoprotein, and wherein the therapeutic agent is capable of killing a senescent cell; and   (b) a pharmaceutically acceptable carrier.   
     
     
         76 . The pharmaceutical composition of  claim 75 , wherein the humanized antibody or antibody fragment thereof comprises (a) an amino acid sequence selected from any one of SEQ ID NOS:1-3 in a complementarity determining region; or (b) an amino acid sequence at least 90% identical to the amino acid sequence selected from any one of SEQ ID NOS:1-3 in a complementarity determining region. 
     
     
         77 . The pharmaceutical composition of  claim 75 , wherein the senescent cell-specific peptide, polypeptide, or glycoprotein is a senescent cell-specific antigen comprising an amino acid sequence set forth in any one of SEQ ID NOS:11-23,