US2007274981A1PendingUtilityA1

Fibroblast Growth Factor Receptor-1 Inhibitors and Methods of Treatment Thereof

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Assignee: IMCLONE SYSTEMS INCPriority: Oct 16, 2003Filed: Oct 18, 2004Published: Nov 29, 2007
Est. expiryOct 16, 2023(expired)· nominal 20-yr term from priority
Inventors:Haijun SunJuqun ShenJames R. Tonra
A61P 43/00A61P 3/06A61P 9/12A61P 3/10A61P 7/02A61P 9/10A61P 9/00A61P 9/14A61P 37/04A61P 25/02A61P 29/00A61P 3/04A61P 3/00A61P 35/00A61P 27/02A61P 25/26A61P 25/00A61P 31/00A61P 19/06A61P 11/00A61P 1/18A61P 13/10A61P 1/16A61P 17/00A61P 13/12A61P 17/02A61P 19/02A61P 15/08C07K 2317/55C07K 16/2863A61K 31/00C07K 2317/73A61K 45/06C07K 2317/76A61K 2039/505C07K 2317/56C07K 2317/565
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Claims

Abstract

The present invention is directed to an antibody or fragments thereof that are specific for a fibroblast growth factor receptor (FGFR)-1(IIIb), FGFR-1(IIIc), and/or FGFR-4. Also, provided herein, are vectors and host cells comprising the nucleic acids encoding those antibodies. The present invention further provides methods of antagonizing FGFR-1 or FGFR-4 as a treatment for obesity, diabetes, or a condition related thereto, and methods of reducing food intake.

Claims

exact text as granted — not AI-modified
1 . A purified antibody, or fragment thereof, which specifically binds to a fibroblast growth factor receptor (FGFR)-1(IIIb), FGFR-1(IIIc), or FGFR-4(IIIc).  
     
     
         2 . The antibody of  claim 1 , wherein the antibody, or fragment thereof, binds to an extracellular domain of fibroblast growth factor receptor FGFR-1(IIIb), FGFR-1(IIIc), or FGFR-4(IIIc) and neutralizes activation of the receptor.  
     
     
         3 . The antibody of  claim 1 , wherein the antibody, or fragment thereof, inhibits binding of a ligand of FGFR-1(IIIb), FGFR-1(IIIc), or FGFR-4(IIIc) to its receptor.  
     
     
         4 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.  
     
     
         5 . The antibody of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least 70% homology to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.  
     
     
         6 . The antibody of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 80% homology to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.  
     
     
         7 . The antibody of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 90% homology to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.  
     
     
         8 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody comprises a sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14.  
     
     
         9 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least 70% homology to SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14.  
     
     
         10 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 80% homology to SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14.  
     
     
         11 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 90% homology to SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14.  
     
     
         12 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody comprises a sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.  
     
     
         13 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least 70% homology to SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.  
     
     
         14 . The antibody of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 80% homology to SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.  
     
     
         15 . The antibody of any of claims  1 - 3 , wherein at least one complementarity-determining region (CDR) of the antibody, or fragment thereof, comprises a sequence with at least about 90% homology to SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.  
     
     
         16 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence of SEQ ID NO:7 or a light chain variable region sequence of SEQ ID NO:8.  
     
     
         17 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 70% homology to SEQ ID NO:7 or a light chain variable region sequence with at least about 70% homology to SEQ ID NO:8.  
     
     
         18 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 80% homology to SEQ ID NO:7 or a light chain variable region sequence with at least about 80% homology to SEQ ID NO:8.  
     
     
         19 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 90% homology to SEQ ID NO:7 or a light chain variable region sequence with at least about 90% homology to SEQ ID NO:8.  
     
     
         20 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence of SEQ ID NO:15 or a light chain variable region sequence of SEQ ID NO:16.  
     
     
         21 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 70% homology to SEQ ID NO:15 or a light chain variable region sequence with at least about 70% homology to SEQ ID NO:16.  
     
     
         22 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 80% homology to SEQ ID NO:15 or a light chain variable region sequence with at least about 80% homology to SEQ ID NO:16.  
     
     
         23 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 90% homology to SEQ ID NO:15 or a light chain variable region sequence with at least about 90% homology to SEQ ID NO:16.  
     
     
         24 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence of SEQ ID NO:23 or a light chain variable region sequence of SEQ ID NO:24.  
     
     
         25 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 70% homology to SEQ ID NO:23 or a light chain variable region sequence with at least about 70% homology to SEQ ID NO:24.  
     
     
         26 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 80% homology to SEQ ID NO:23 or a light chain variable region sequence with at least about 80% homology to SEQ ID NO:24.  
     
     
         27 . The antibody of any of claims  1 - 3 , wherein the antibody comprises at least a heavy chain variable region sequence with at least about 90% homology to SEQ ID NO:23 or a light chain variable region sequence with at least about 90% homology to SEQ ID NO:24.  
     
     
         28 . An isolated nucleic acid encoding the antibody of any of claims  4 - 27   
     
     
         29 . An expression vector comprising the nucleic acid of  claim 28  operably linked to a control sequence.  
     
     
         30 . A host cell comprising the expression vector of  claim 29 .  
     
     
         31 . A method of producing an antibody comprising culturing the host cell of  claim 30  under conditions permitting expression of the antibody.  
     
     
         32 . The method of  claim 31 , wherein the method further comprises purifying the antibody.  
     
     
         33 . A pharmaceutical composition comprising the antibody of any of claims  1 - 27  and a pharmaceutically acceptable carrier.  
     
     
         34 . A method of identifying a fibroblast growth factor receptor (FGFR)-1(IIIb), FGFR-1(IIIc), or FGFR-4(IIIc) specific antibody, or fragment thereof, comprising: 
 providing a library of antibody fragments,    screening the library for the antibody that is specific for FGFR-1(IIIb) and/or FGFR-1(IIIc) or the antibody specific for FGFR-1(IIIc) and/or FGFR-4, and    purifying the antibody that is specific for FGFR-1(IIIb) and/or FGFR-1(IIIc) or the antibody specific for FGFR-1(IIIc) and/or FGFR-4.    
     
     
         35 . The method of  claim 34 , wherein the screening of the library comprises 
 providing an affinity matrix having the FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 bound to a solid support,    contacting the affinity matrix with the library of antibody fragments, and    separating the antibody fragments that bind to the affinity matrix from the antibody fragments that do not bind the affinity matrix.    
     
     
         36 . Am antibody identified using the method of  claim 34  or  35 .  
     
     
         37 . A method of treating obesity or an obesity related condition comprising administering to a mammal in need thereof a therapeutically effective amount of a FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 antagonist.  
     
     
         38 . A method of treating diabetes or a diabetes related condition comprising administering to a mammal in need thereof a therapeutically effective amount of a FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 antagonist.  
     
     
         39 . A method of reducing food intake or a condition affected by reducing food intake comprising administering to a mammal in need thereof a therapeutically effective amount of a FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 antagonist.  
     
     
         40 . The method of any of claims  37 - 39 , wherein the condition is hypertension.  
     
     
         41 . The method of any one of claims  37 - 39 , wherein the condition is cardiovascular disease.  
     
     
         42 . The method of any of claims  37 - 39 , wherein said method reduces body mass index.  
     
     
         43 . The method of any of claims  37 - 39 , wherein said method reduces serum triglycerides.  
     
     
         44 . The method of any of claims  37 - 39 , wherein said method alters leptin levels.  
     
     
         45 . The method of any of claims  37 - 39 , wherein said method inhibits angiogenesis.  
     
     
         46 . The method of any of claims  37 - 39 , wherein said method alters energy metabolism.  
     
     
         47 . The method of any of claims  37 - 39 , wherein said method alters the Respiratory Exchange Ratio.  
     
     
         48 . The method of any of claims  37 - 39 , wherein said method has an FGFR-1 or FGFR-4 pathway related anorexic effect.  
     
     
         49 . The method of any of claims  37 - 39 , wherein the antagonist is a biological molecule.  
     
     
         50 . The method of  claim 49 , wherein the biological molecule is an antibody or fragment thereof.  
     
     
         51 . The method of  claim 50 , wherein the antibody is an antibody of any of claims  1 - 7 .  
     
     
         52 . The method of any of claims  37 - 39 , wherein the antagonist is a small molecule that blocks FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 signaling.  
     
     
         53 . The method of claim  37 - 39 , wherein the FGFR-1 antagonist binds FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 internally.  
     
     
         54 . The method of claim  37 - 39 , wherein the FGFR-1 antagonist inhibits FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 phosphorylation.  
     
     
         55 . The method of claim  37 - 39 , wherein the FGFR-1 antagonist inhibits binding of ATP to FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4.  
     
     
         56 . The method of claim  37 - 39 , wherein the FGFR-1 antagonist competes with ATP for FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4.  
     
     
         57 . The method of claim  37 - 39 , wherein the FGFR-1 antagonist inhibits FGFR-1(IIIb), FGFR-1(IIIc), and/or FGFR-4 tyrosine kinase activity.  
     
     
         58 . The method of any of claims  52 - 57 , wherein the small molecule comprises pyrimido-pyridine derivative A or B, SU-6668, PD-173074, SU-5402, CHIR-258, or PD-166285.  
     
     
         59 . The method of any of claims  37 - 58 , wherein the mammal is a human.

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