US2005037973A1PendingUtilityA1

Compounds and methods for cancer therapy

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Assignee: ADHEREX TECHNOLOGIES INCPriority: Dec 31, 1997Filed: Jul 6, 2004Published: Feb 17, 2005
Est. expiryDec 31, 2017(expired)· nominal 20-yr term from priority
Inventors:Orest W. BlaschukJames Matthew SymondsBarbara J. GourJ. Steven Alexander
C07K 14/705A61P 35/00C07K 14/47A61K 38/00
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PatentIndex Score
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Claims

Abstract

Methods for using modulating agents to enhance or inhibit occludin-mediated cell adhesion in a variety of in vivo and in vitro contexts are provided. Within certain embodiments, the modulating agents may be used for cancer therapy or to increase immune cell infiltration into tumors. The modulating agents comprise at least one occludin cell adhesion recognition sequence or an antibody or fragment thereof that specifically binds the occludin cell adhesion recognition sequence. Modulating agents may additionally comprise one or more cell adhesion recognition sequences recognized by other adhesion molecules. Such modulating agents may, but need not, be linked to a targeting agent, drug and/or support material.

Claims

exact text as granted — not AI-modified
1 . A method for enhancing the delivery of a drug to a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent and a drug, wherein said modulating agent comprises the sequence LYHY (SEQ ID NO:1), and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         2 . A method for enhancing the delivery of a drug to a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent and a drug, wherein said modulating agent comprises an antibody or fragment thereof that specifically binds to an occludin cell adhesion recognition sequence, and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         3 . A method according to  claim 1  or  claim 2 , wherein the tumor is selected from the group consisting of bladder tumors, ovarian tumors and melanomas.  
     
     
         4 . A method according to  claim 1  or  claim 2 , wherein said composition is administered to said tumor.  
     
     
         5 . A method according to  claim 1  or  claim 2 , wherein said composition is administered systemically.  
     
     
         6 . A method according to  claim 1 , wherein said modulating agent comprises a sequence selected from the group consisting of QYLYHYCVVD (SEQ ID NO:2), YLYHYCVVD (SEQ ID NO:12), LYHYCVVD (SEQ ID NO:13), QYLYHYC (SEQ ID NO:14), YLYHYC (SEQ ID NO:15), LYHYC (SEQ ID NO:16), QYLYHY (SEQ ID NO:17), YLYHY (SEQ ID NO:18),  CLYHYC  (SEQ ID NO:3),  CYLYHYC  (SEQ ID NO:40),  CQYLYHYC  (SEQ ID NO:41),  KQYLYHYD  (SEQ ID NO:42),  YLYHY  (SEQ ID NO:43),  QYLYHY  (SEQ ID NO:44),  KLYHYD  (SEQ ID NO:45) and derivatives of the foregoing sequences having one or more C-terminal, N-terminal and/or side chain modifications.  
     
     
         7 . A method according to  claim 1  or  claim 2 , wherein said modulating agent is linked to a targeting agent.  
     
     
         8 . A method according to  claim 1  or  claim 2 , wherein said modulating agent is linked to said drug.  
     
     
         9 . A method according to  claim 1  or  claim 2 , wherein said modulating agent further comprises one or more of: 
 (a) a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin, wherein said cell adhesion recognition sequence is separated from any LYHY (SEQ ID NO:1) sequence(s) by a linker; and/or    (b) an antibody or antigen-binding fragment thereof that binds to a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin.    
     
     
         10 . A method according to  claim 9 , wherein said cell adhesion recognition sequence comprises one or more sequences selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         11 . A method according to  claim 9 , wherein said antibody or antigen-binding fragment thereof binds to a cell adhesion recognition sequence comprising a sequence selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         12 . A method according to  claim 1  or  claim 2 , wherein said modulating agent and said drug are present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         13 . A method according to  claim 12 , wherein said pharmaceutical composition further comprises a modulator of cell adhesion comprising one or more of: 
 (a) a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin; and/or    (b) an antibody or antigen-binding fragment thereof that binds to a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin.    
     
     
         14 . A method according to  claim 13 , wherein said cell adhesion recognition sequence comprises one or more sequences selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         15 . A method according to  claim 13 , wherein said antibody or antigen-binding fragment thereof binds to a cell adhesion recognition sequence comprising a sequence selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         16 . A method for treating cancer in a mammal, comprising administering to a mammal a cell adhesion modulating agent, wherein said modulating agent comprises the sequence LYHY (SEQ ID NO:1), and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         17 . A method for treating cancer in a mammal, comprising administering to a mammal a cell adhesion modulating agent, wherein said modulating agent comprises an antibody or fragment thereof that specifically binds to an occludin cell adhesion recognition sequence, and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         18 . A method according to  claim 16  or  claim 17 , wherein said cancer is selected from the group consisting of carcinomas, leukemia and melanomas.  
     
     
         19 . A method according to  claim 16 , wherein said modulating agent comprises a sequence selected from the group consisting of QYLYHYCVVD (SEQ ID NO:2), YLYHYCVVD (SEQ ID NO:12), LYHYCVVD (SEQ ID NO:13), QYLYHYC (SEQ ID NO:14), YLYHYC (SEQ ID NO:15), LYHYC (SEQ ID NO:16), QYLYHY (SEQ ID NO:17), YLYHY (SEQ ID NO:18),  CLYHYC  (SEQ ID NO:3),  CYLYHYC  (SEQ ID NO:40),  CQYLYHYC  (SEQ ID NO:41),  KQYLYHYD  (SEQ ID NO:42),  YLYHY  (SEQ ID NO:43),  QYLYHY  (SEQ ID NO:44),  KLYHYD  (SEQ ID NO:45) and derivatives of the foregoing sequences having one or more C-terminal, N-terminal and/or side chain modifications.  
     
     
         20 . A method according to  claim 16  or  claim 17 , wherein said modulating agent is linked to a targeting agent.  
     
     
         21 . A method according to  claim 16  or  claim 17 , wherein said modulating agent further comprises one or more of: 
 (a) a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin, wherein said cell adhesion recognition sequence is separated from any LYHY (SEQ ID NO:1) sequence(s) by a linker; and/or    (b) an antibody or antigen-binding fragment thereof that binds to a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin.    
     
     
         22 . A method according to  claim 21 , wherein said cell adhesion recognition sequence comprises a sequence selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         23 . A method according to  claim 16  or  claim 17 , wherein said modulating agent is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         24 . A method according to  claim 16  or  claim 17 , wherein said pharmaceutical composition further comprises a modulator of cell adhesion comprising one or more of: 
 (a) a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin; and/or    (b) an antibody or antigen-binding fragment thereof that binds to a cell adhesion recognition sequence bound by an adhesion molecule other than an occludin.    
     
     
         25 . A method according to  claim 24 , wherein said cell adhesion recognition sequence comprises a sequence selected from the group consisting of HAV, NQK, NRN, NKD, EKD, ERD, RGD, DDK, EEY, EAQ, IYSY (SEQ ID NO:49), TSSY (SEQ ID NO:50), VTAF (SEQ ID NO:51) and VSAF (SEQ ID NO:52).  
     
     
         26 . A method for enhancing immune cell infiltration into a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent and a drug, wherein said modulating agent comprises the sequence LYHY (SEQ ID NO:1), and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         27 . A method for enhancing immune cell infiltration into a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent and a drug, wherein said modulating agent comprises an antibody or fragment thereof that specifically binds to an occludin cell adhesion recognition sequence, and wherein said modulating agent inhibits occludin-mediated cell adhesion.  
     
     
         28 . A method according to  claim 26  or  claim 27 , wherein the tumor is selected from the group consisting of bladder tumors, ovarian tumors and melanomas.  
     
     
         29 . A method according to  claim 26  or  claim 27 , wherein said composition is administered to said tumor.  
     
     
         30 . A method according to  claim 26  or  claim 27 , wherein said composition is administered systemically.  
     
     
         31 . A method according to  claim 26 , wherein said modulating agent comprises a sequence selected from the group consisting of QYLYHYCVVD (SEQ ID NO:2), YLYHYCVVD (SEQ ID NO:12), LYHYCVVD (SEQ ID NO:13), QYLYHYC (SEQ ID NO:14), YLYHYC (SEQ ID NO:15), LYHYC (SEQ ID NO:16), QYLYHY (SEQ ID NO:17), YLYHY (SEQ ID NO:18),  CLYHYC  (SEQ ID NO:3),  CYLYHYC  (SEQ ID NO:40),  CQYLYHYC  (SEQ ID NO:41),  KQYLYHYD  (SEQ ID NO:42),  YLYHY  (SEQ ID NO:43),  QYLYHY  (SEQ ID NO:44),  KLYHYD  (SEQ ID NO:45) and derivatives of the foregoing sequences having one or more C-terminal, N-terminal and/or side chain modifications.  
     
     
         32 . A method according to  claim 26  or  claim 27 , wherein said modulating agent is linked to a targeting agent.  
     
     
         33 . A method according to  claim 26  or  claim 27 , wherein said modulating agent and said drug are present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

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