US2011269943A1PendingUtilityA1

Radiolabeled annexins

62
Assignee: UNIV WASHINGTONPriority: Jul 26, 1996Filed: Jun 28, 2010Published: Nov 3, 2011
Est. expiryJul 26, 2016(expired)· nominal 20-yr term from priority
Inventors:Sudhakar KasinaJohn M. RenoAlan R. FritzbergJonathan Tait
A61K 47/54A61K 51/087C07K 14/4721A61K 47/547A61K 51/088C07K 1/13A61P 9/00A61K 2123/00C07K 7/06A61K 47/549
62
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Claims

Abstract

Radiolabeled annexin and modified annexin conjugates useful for imaging vascular thrombi are described. Methods for making and using such radiolabeled annexin conjugates are also provided.

Claims

exact text as granted — not AI-modified
1 . A conjugate comprising:
 a modified annexin, wherein the modification provides an accessible sulfhydryl group; and   a hexose moiety recognized by a mammalian liver receptor, wherein the hexose moiety is conjugated to the annexin.   
     
     
         2 . The conjugate of  claim 1 , wherein the hexose moiety comprises a cluster containing at least three hexose residues connected in a branched configuration, and wherein the cluster is conjugated via a single point of attachment to the annexin. 
     
     
         3 . The conjugate of  claim 2 , wherein the hexose residues are independently selected from the group consisting of galactose, mannose, mannose 6-phosphate, N-acetylglucosamine, pentamannosyl phosphate, glucose, N-galactosamine, N-acetylgalactosamine, thioglycosides of galactose, D-galactosides and glucosides. 
     
     
         4 . The conjugate of  claim 3 , wherein the hexose residue is N-acetylgalactosamine, and wherein the cluster comprises: 
       
         
           
           
               
               
           
         
         wherein X is H or CH 3 . 
       
     
     
         5 . The conjugate of  claim 1  or  4 , wherein the annexin is annexin V. 
     
     
         6 . The conjugate of  claim 5 , wherein the amino acid at position 316 of the annexin is mutated to serine. 
     
     
         7 . The conjugate of  claim 5 , wherein the modification of the annexin comprises an amino acid extension at the N-terminus, the amino acid extension comprising the accessible sulfhydryl group. 
     
     
         8 . The conjugate of  claim 7 , wherein the extension comprises at least about ten amino acids. 
     
     
         9 . The conjugate of  claim 7 , wherein the extension comprises at least about six amino acids. 
     
     
         10 . The conjugate of  claim 1  wherein the accessible sulfhydryl group is provided by cysteine. 
     
     
         11 . The conjugate of  claim 7 , wherein the accessible sulfhydryl group is provided by cysteine. 
     
     
         12 . The conjugate of  claim 1  or  11 , wherein the conjugate further comprises a diagnostic radionuclide complexed directly to the modified annexin. 
     
     
         13 . The conjugate of  claim 12 , wherein the radionuclide is selected from the group consisting of F-18, Cu-64, Ga-67, Ga-68, Re-186, Re-188, 1-123, I-125, Cu-67, Tc-99m, Tc-94, Ru-95 and In-111. 
     
     
         14 . The conjugate of  claim 13 , wherein the radionuclide is technetium-99m. 
     
     
         15 . A conjugate comprising:
 a modified annexin, wherein the modification provides an accessible sulfhydryl group;   a hexose moiety recognized by a mammalian liver receptor; and   a N x S y  chelating compound, wherein the hexose moiety is conjugated to the modified annexin directly or via the chelating compound and the chelating compound is conjugated to the modified annexin directly or via the hexose moiety.   
     
     
         16 . The conjugate of  claim 15 , wherein the hexose moiety comprises a cluster containing at least three hexose residues, connected in a brandied configuration, and wherein the cluster is conjugated via a single point of attachment to the annexin. 
     
     
         17 . The conjugate of  claim 16 , wherein the hexose residues are independently selected from the group consisting of galactose, mannose, mannose 6-phosphate, N-acetylglucosamine, pentamannosyl phosphate, glucose, N-galactosamine, N-acetylgalactosamine, thioglycosides of galactose, D-galactosides and glucosides. 
     
     
         18 . The conjugate of  claim 17 , wherein the hexose residue is N-acetylgalactosamine. 
     
     
         19 . The conjugate of  claim 15  or  18 , wherein the annexin is annexin V. 
     
     
         20 . The conjugate of  claim 19 , wherein the amino acid at position 316 of the annexin is mutated to serine. 
     
     
         21 . The conjugate of  claim 19 , wherein the modification of the annexin comprises an amino acid extension at the N-terminus, the amino acid extension comprising the accessible sulfhydryl group. 
     
     
         22 . The conjugate of  claim 21 , wherein the extension comprises at least about ten amino acids. 
     
     
         23 . The conjugate of  claim 21 , wherein the extension comprises at least about six amino acids. 
     
     
         24 . The conjugate of  claim 15 , wherein the accessible sulfhydryl group is provided by cysteine. 
     
     
         25 . The conjugate of  claim 21 , wherein the accessible sulfhydryl group is provided by cysteine. 
     
     
         26 . The conjugate of  claim 15  or  25 , wherein the N x S y  chelating compound comprises an N 2 S 2  chelating compound. 
     
     
         27 . The conjugate of  claim 26 , wherein the chelating compound has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein T is H, CH 3  or bears a functional group and n is 0 or 1. 
     
     
         28 . The conjugate of  claim 16  or  27 , wherein the cluster comprises: 
       
         
           
           
               
               
           
         
       
       wherein X is H or CH 3 . 
     
     
         29 . The conjugate of  claim 28 , wherein the conjugate has the following configuration:
 cluster-modified annexin V-chelating compound.   
     
     
         30 . The conjugate of  claim 28 , wherein the conjugate has the following configuration:
 chelating compound-cluster-modified annexin V.   
     
     
         31 . The conjugate of  claim 28 , wherein the conjugate further comprises a cleavable linker between the chelating compound and cluster. 
     
     
         32 . The conjugate of  claim 31 , wherein the cleavable linker is selected from the group consisting of monosaccharides, polysaccharides, polyamino acids, hydroxyakyl acrylamides, polyethylene glycol based hydrophilic polymers, biodegradable polymers containing an ether or ester linkage, dextran or hemisuccinyl esters. 
     
     
         33 . The conjugate of  claim 32 , wherein the conjugate has the following configuration:
 chelating compound-cleavable linker-cluster-modified annexin V.   
     
     
         34 . The conjugate of any one of  claims 15 ,  28  and  32 , further comprising a radionuclide complexed by the chelating compound, wherein the radionuclide is selected from the group consisting essentially of F-18, Cu-64, Ga-67, Ga-68, Re-186, Re-188, 1-123, I-125, Cu-67, Tc-99m, Tc-94, Ru-95 and In-111. 
     
     
         35 . The conjugate of  claim 34 , wherein the radionuclide is technetium-99m. 
     
     
         36 . A conjugate comprising:
 an annexin; and   an esterase-sensitive N x S y  chelating compound conjugated to the annexin.   
     
     
         37 . The conjugate of  claim 36 , wherein the annexin is annexin V. 
     
     
         38 . The conjugate of  claim 37 , wherein the N x S y  chelating compound is the N 3 S chelating compound. 
     
     
         39 . The conjugate of  claim 38 , wherein the N 3 S chelating compound is of the following formula: 
       
         
           
           
               
               
           
         
         wherein R is ethoxyethyl and R 1  is tetraflurophenyl. 
       
     
     
         40 . The conjugate of  claim 36  or  39 , further comprising a diagnostic radionuclide complexed by the chelating compound. 
     
     
         41 . The conjugate of  claim 40 , wherein the radionuclide is selected from the group consisting essentially of F-18, Cu-64, G4-67, Ga-68, Re-186, Re-188, I-123, 1-125, Cu-67, Tc-99m, Tc-94, Ru-95 and In-111. 
     
     
         42 . The conjugate of  claim 41 , wherein the radionuclide is technetium-99m. 
     
     
         43 . The conjugate of  claim 36 , wherein the conjugate further comprises a hexose moiety recognized by a mammalian liver receptor, and wherein the hexose moiety is conjugated to the annexin directly or via the chelating compound and the chelating compound is conjugated to the annexin directly or via the hexose moiety. 
     
     
         44 . A conjugate comprising:
 an annexin multimer;   a hexose moiety recognized by a mammalian liver receptor; and   a N x S y  chelating compound, wherein the hexose moiety is conjugated to the multimer directly or via the chelating compound and the chelating compound is conjugated to the multimer directly or via the hexose moiety.   
     
     
         45 . The conjugate of  claim 44 , wherein the hexose moiety comprises a cluster containing at least three hexose residues, connected in a branched configuration, and wherein the cluster is conjugated at a single point of attachment to the multimer. 
     
     
         46 . The conjugate of  claim 45 , wherein the hexose residues are independently selected from the group consisting of galactose, mannose, mannose 6-phosphate, N-acetylglucosamine, pentamannosyl phosphate, glucose, N-galactosamine, N-acetylgalactosamine, thioglycosides of galactose, D-galactosides and glucosides. 
     
     
         47 . The conjugate of  claim 46 , wherein the hexose residue is N-acetylgalactosamine. 
     
     
         48 . The conjugate of  claim 44  or  47 , wherein the annexin is annexin V. 
     
     
         49 . The multimer of  claim 44 , wherein the multimer comprises two or more modified annexin molecules which are linked by disulfide bonds between one or more of the accessible sulfhydryl groups on the respective annexins. 
     
     
         50 . The multimer of  claim 44 , wherein the multimer is a dimer. 
     
     
         51 . The conjugate of  claim 44  or  48 , wherein the N x S y  chelating compound is an N 2 S 2  chelating compound. 
     
     
         52 . The conjugate of  claim 51 , wherein the N 2 S 2  chelating compound is of the following formula: 
       
         
           
           
               
               
           
         
       
       and wherein T is H, CH 3  or bears a functional group and n is 0 or 1. 
     
     
         53 . The conjugate of  claim 52 , wherein the cluster comprises: 
       
         
           
           
               
               
           
         
       
       wherein X is H or CH 3 . 
     
     
         54 . The conjugate of  claim 53 , wherein the conjugate has the following configuration:
 cluster-multimer-chelating compound.   
     
     
         55 . The conjugate of  claim 53 , wherein the conjugate has the following configuration:
 chelating compound-cluster-multimer.   
     
     
         56 . The conjugate of  claim 53 , wherein the conjugate further comprises a linker between the chelating compound and cluster. 
     
     
         57 . The conjugate of  claim 56 , wherein the cleavable linker is selected from the group consisting of monosaccharides, polysaccharides, polyamino acids, hydroxyakyl acrylamides, polyethylene glycol based hydrophilic polymers, biodegradable polymers containing an ether or ester linkage, dextran or hemisuccinyl esters. 
     
     
         58 . The conjugate of  claim 57 , wherein the conjugate has the following configuration:
 chelating compound-cleavable linker-multimer.   
     
     
         59 . The conjugate of  claim 44  or  53 , wherein the conjugate further comprises a diagnostic radionuclide complexed by the chelating compound. 
     
     
         60 . The conjugate of  claim 59 , wherein the radionuclide is selected from the group consisting essentially of F-18, Cu-64, Ga-67, Ga-68, Re-186, Re-188, I-123, 1-125, Cu-67, Tc-99m, Tc-94, Ru-95, and In-111. 
     
     
         61 . The conjugate of  claim 60 , wherein the radionuclide is technetium-99m. 
     
     
         62 . A conjugate comprising:
 a modified annexin, wherein the modification provides an accessible sulfhydryl group; and   a N x S y  chelating compound conjugated to the annexin.   
     
     
         63 . A conjugate comprising:
 a modified annexin, wherein the modification provides an accessible sulfhydryl group; and   an esterase-sensitive N x S y  chelating compound conjugated to the annexin.   
     
     
         64 . A conjugate comprising:
 an annexin multimer; and   a N x S y  chelating compound conjugated to the annexin.   
     
     
         65 . A conjugate comprising:
 an annexin multimer; and   an esterase-sensitive N x S y  chelating compound conjugated to the annexin.

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