US2015274847A1PendingUtilityA1

Antibody toxin conjugates

48
Assignee: NOVO NORDISK ASPriority: Jul 25, 2003Filed: Apr 1, 2015Published: Oct 1, 2015
Est. expiryJul 25, 2023(expired)· nominal 20-yr term from priority
Inventors:Shawn DefreesZhi-Guang Wang
C12N 9/96C07K 19/00B82Y 5/00A61K 47/60A61K 47/6855A61K 47/6849A61K 47/6811A61K 47/6899A61K 47/6839A61K 47/6889A61K 47/6851A61K 47/6843
48
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Claims

Abstract

The present invention provides conjugates formed between toxins and sugars and toxins and peptides, such as antibodies. In an exemplary embodiment, a toxin-sugar construct is conjugated to an antibody through an intact glycosyl linking group.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound having the formula:
   Ab-G-L-T   wherein
 Ab is an antibody; 
 G is an intact glycosyl linking group covalently joining Ab to L; 
 L is a bond or a spacer moiety covalently joining G to T; and 
 T is a toxin. 
   
     
     
         2 . The compound according to  claim 1 , wherein said linker moiety is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl moieties. 
     
     
         3 . The compound according to  claim 2 , wherein said linker moiety comprises a poly(ethylene glycol) moiety. 
     
     
         4 . The compound according to  claim 1 , wherein L has the formula: 
       
         
           
           
               
               
           
         
         wherein
 L 1  is a bond or a linker moiety covalently joining S to A; 
 A is an amplifier moiety; and 
 L 2  is a bond or a spacer moiety covalently adjoining A to T. 
 
       
     
     
         5 . The compound according to  claim 4 , wherein said amplifier moiety is a polyamine moiety. 
     
     
         6 . The compound according to  claim 5 , wherein said polyamine moiety is a dendrimer. 
     
     
         7 . The compound according to  claim 4 , having the formula:
   Ab-G-(PEG) m -(toxin) n      wherein
 PEG is a straight- or branched-chain poly(ethylene glycol); 
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         8 . The compound according to  claim 4 , having the formula:
   Ab-G-L 1 -(dendrimer) m -(L 2 -toxin) n      wherein
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         9 . The compound according to  claim 4 , having the formula:
   Ab-G-(L 1 ) m -(toxin) n      wherein
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         10 . The compound according to  claim 1 , having the formula:
   Ab-G-X 1 -PEG-X 2 -AX 3 —(CH 2 ) a —Z—(CH 2 ) b —X 4 -T) n  
   wherein
 X 1 , X 2  and X 4  are linking groups and are members selected from the group consisting of O, S, NH, (CH 2 ) q —NH, NH—(CH 2 ) q , NH—C(O)—O, O—C(O)—NH, (CH 2 ) q —NH—C(O)—O, O—C(O)—NH—(CH 2 ) q , C(O)—O, O—C(O), (CH 2 ) q —NH—C(O), C(O)—NH—(CH 2 ) q , NH—C(S), and C(S)—NH 
 and wherein
 A is an amplifier moiety; 
 Z is a bond cleaved by a metabolic/physiological process; 
 n is an integer from 1 to 1,000; 
 a is an integer from 1 to 10; 
 b is an integer from 1 to 10; and 
 q is an integer from 0 to 20. 
 
   
     
     
         11 . The compound according to  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         at least one of R 1 , R 2 , R 3 , R 4 , R 5 , is: 
       
       
         
           
           
               
               
           
         
         wherein 
         r is an integer from 1 to 2,500; 
         Z 1  is selected from the group consisting of O, S, and NH; 
         Z 2  is selected from the group consisting of NH, and NH—(CH 2 ) q ; and
 X 1 , X 2  and X 3  are linking groups and are members selected from the group consisting of O, S, NH, (CH 2 ) q —NH, NH—(CH 2 ) q , NH—C(O)—O, O—C(O)—NH, (CH 2 ) q —NH—C(O)—O, O—C(O)—NH—(CH 2 ) q , C(O)—O, O—C(O), (CH 2 ) q —NH—C(O), C(O)—NH—(CH 2 ) q , NH—C(S), and C(S)—NH 
 wherein
 n is an integer from 1 to 1,000; and 
 q is an integer from 0 to 20. 
 
 
       
     
     
         12 . The compound according to  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein
 X 1 , X 2  and X 4  are linking groups and are members selected from the group consisting of O, S, NH, (CH 2 ) q —NH, NH—(CH 2 ) q , NH—C(O)—O, O—C(O)—NH, (CH 2 ) q —NH—C(O)—O, O—C(O)—NH—(CH 2 ) q , C(O)—O, O—C(O), (CH 2 ) q —NH—C(O), C(O)—NH—(CH 2 ) q , NH—C(S), and C(S)—NH 
 
         wherein
 n is an integer from 1 to 1,000; and 
 q is an integer from 0 to 20. 
 
       
     
     
         13 . The compound according to  claim 12 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound having the formula:
   S-L-T   wherein
 S is a nucleotide sugar 
 L is a bond or a spacer moiety covalently joining S to T; and 
 T is a toxin moiety. 
   
     
     
         15 . The compound according to  claim 14 , wherein said spacer moiety is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl moieties. 
     
     
         16 . The compound according to  claim 15 , wherein said spacer moiety comprises a poly(ethylene glycol) moiety. 
     
     
         17 . The compound according to  claim 14 , wherein L has the formula: 
       
         
           
           
               
               
           
         
         wherein
 L 1  is a bond or a spacer moiety covalently joining S to A; 
 A is an amplifier moiety; and 
 L 2  is a bond or a spacer moiety covalently joining A to T. 
 
       
     
     
         18 . The compound according to  claim 17 , wherein said amplifier moiety is a polyamine moiety. 
     
     
         19 . The compound according to  claim 18 , wherein said polyamine moiety is a dendrimer. 
     
     
         20 . The compound according to  claim 17 , having the formula:
   S-(PEG) m -(toxin) n      wherein
 PEG is a straight- or branched-chain poly(ethylene glycol); 
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         21 . The compound according to  claim 17 , having the formula:
   S-L 1 -(dendrimer) m -(L 2 -toxin) n      wherein
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         22 . The compound according to  claim 17 , having the formula:
   S-(L 1 ) m -(toxin) n      wherein
 m is an integer from 1 to 6; and 
 n is an integer from 1 to 1,000. 
   
     
     
         23 . The compound according to  claim 22 , having the formula:
   Sugar-X 1 -PEG-X 2 -AX 3 —(CH 2 ) a —Z—(CH 2 ) b —X 4 -T) n  
   wherein
 X 1 , X 2  and X 3  are linking groups and are members selected from the group consisting of O, S, NH(CH 2 ) q —NH, NH—(CH 2 ) q , NH—C(O)—O, O—C(O)—NH, (CH 2 ) q —NH—C(O)—O, O—C(O)—NH—(CH 2 ) q , C(O)—O, O—C(O), (CH 2 ) q —NH—C(O), C(O)—NH—(CH 2 ) q , NH—C(S), and C(S)—NH 
 and wherein
 A is an amplifier moiety; 
 Z is a bond cleaved by a metabolic/physiological process; 
 n is an integer from 1 to 1,000; 
 a is an integer from 1 to 10; 
 b is an integer from 1 to 10; and 
 q is an integer from 0 to 20. 
 
   
     
     
         24 . The compound according to  claim 14 , having the formula: 
       
         
           
           
               
               
           
         
         wherein
 X 1 , X 2  and X 3  are linking groups and are members selected from the group consisting of O, S, NH(CH 2 ) q —NH, NH—(CH 2 ) q , NH—C(O)—O, O—C(O)—NH, (CH 2 ) q —NH—C(O)—O, O—C(O)—NH—(CH 2 ) q , C(O)—O, O—C(O), (CH 2 ) q —NH—C(O), C(O)—NH—(CH 2 ) q , NH—C(S), and C(S)—NH 
 
         wherein
 q is an integer from 0 to 20. 
 
       
     
     
         25 . The compound according to  claim 24 , having the formula:

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