Methods and compositions for the generation and use of conformation-specific antibodies

Abstract

The present invention features methods and compositions for the generation and use of conformation-specific antibodies or fragments thereof.

What is claimed is: 
     
         1 - 65 . (canceled) 
     
     
         66 . A method of treating a subject with a disorder, wherein said disorder is associated with a deregulation of PPIase activity, said method comprising administering to said subject a pharmaceutical composition comprising a conformation-specific antibody or fragment thereof that specifically binds to the cis conformation of a Xaa-Pro motif of a polypeptide present in said subject, wherein said Xaa is serine or threonine and is phosphorylated, and said antibody or fragment thereof binds to the cis conformation of said Xaa-Pro motif of said polypeptide with at least 10- to 100-fold reater affinit than to the trans conformation of said Xaa-Pro motif of said polypeptide, any and wherein said conformation-specific antibody is administered in amount sufficient to treat said disorder. 
     
     
         67 - 69 . (canceled) 
     
     
         70 . The method of  claim 66 , wherein said PPIase is Pin1. 
     
     
         71 . The method of  claim 66 , wherein said method further comprises administering an additional therapeutic agent. 
     
     
         72 . The method of  claim 71 , wherein said additional therapeutic agent is a chemotherapeutic agent. 
     
     
         73 . The method of  claim 66 , wherein said disorder is a cell proliferation disorder or a neurological disorder, 
     
     
         74 . The method of  claim 73 , wherein said cell proliferation disorder is cancer. 
     
     
         75 . The method of  claim 73 , wherein said disorder is a neurological disorder. 
     
     
         76 . The method of  claim 66 , wherein said disorder is asthma. 
     
     
         77 . The method of  claim 66 , wherein said disorder is a microbial infection. 
     
     
         78 . The method of  claim 66 , wherein said disorder is aging or an aging-related disorder. 
     
     
         79 - 91 . (canceled) 
     
     
         92 . The method of  claim 71 , wherein said additional therapeutic agent is an anti-inflammatory agent. 
     
     
         93 . The method of  claim 71 , wherein said additional therapeutic agent is PPIase inhibitor. 
     
     
         94 . The method of  claim 93 , wherein said additional therapeutic agent is an agent for the treatment of neurological disorders. 
     
     
         95 . The method of  claim 74 , wherein said cancer is selected from the group consisting of prostate cancer, squamous cell cancer, small-cell lung cancer, non-small-cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, vulval cancer, thyroid cancer, hepatic carcinoma, gastric cancer, and melanoma. 
     
     
         96 . The method of  claim 75 , wherein said neurological disorder is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, Parkinson's disease, multiple sclerosis, muscular dystrophy, corticobasal degeneration, dementia pugilistica, Down's syndrome, frontotemporal dementias, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease, progressive supranuclear palsy, subacute sclerosing panencephalistis, epilepsy, vascular dementia, age-related dementia, head trauma, stroke, neurofibromatosis, Lewy body disease, amyotrophic lateral sclerosis, peripheral neuropathies, and macular degeneration. 
     
     
         97 . The method of  claim 66 , wherein said polypeptide is a PPIase substrate. 
     
     
         98 . The method of  claim 97 , wherein said PPIase substrate is a Pin1 substrate. 
     
     
         99 . The method of  claim 98 , wherein said Pin1 substrate is NIMA, RAB4, CDC25, WEE1, PLK1, MYT1, CDC27, CENP-F, Incenp, RBP1, NHERF-1, KRMP1, CK2, TopoIIα, DAB2, p54nrb, SiI, EMI1, cyclin D1, Ki67, c-Myc, cyclin E, c-Jun, β-catenin, Cf-2, NF-κB, RAF1, c-Fcs, RARα, AIB1/SRC-3, HBx, STAT3, p53, Bcl-2, p73, BimEL, p66Shc, CHE1, tau, amyloid precursor protein (APP), APP fragment, synphilin-1, gephyrin, MCL1, NFAT, AUF1, IRF3, BTK, SIN3-RPD3, or hSpt5. 
     
     
         100 . The method of  claim 66 , wherein said antibody is a monoclonal antibody. 
     
     
         101 . The method of  claim 66 , wherein said antibody is a humanized antibody.