Compositions for treating a disease or condition associated with abnormal angiogenesis

Abstract

The present invention provides methods of treating (including preventing) a disease or condition associated with abnormal angiogenesis in a subject include administering a therapeutically effective amount of an AA targeting compound of the invention to the subject. The AA targeting compounds comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody.

What is claimed is: 
     
         1 . A compound of the formula:
   R 1 -[AA targeting agent]-R 2      wherein R 1  is CH 3 , C(O)CH 3 , C(O)CH 3 , C(O)CH 2 CH 3 , C(O)CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 3 , C(O)CH 2 CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 2 CH 3 , C(O)C 6 H 5 , C(O)CH 2 CH 2 (CH 2 CH 2 O) 1-5 Me, dichlorobenzoyl (DCB), difluorobenzoyl (DFB), pyridinyl carboxlate (PyC) or amido-2-PEG, an amino protecting group, a lipid fatty acid group or a carbohydrate; and   R 2  is OH, NH 2 , NH(CH 3 ), NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH(CH 3 )CH 3 , NHCH 2 CH 2 CH 2 CH 3 , NHCH(CH 3 )CH 2 CH 3 , NHC 6 H 5 , NHCH 2 CH 2 OCH 3 , NHOCH 3 , NHOCH 2 CH 3 , a carboxy protecting group, a lipid fatty acid group or a carbohydrate, and   wherein [AA targeting agent] comprises a peptide of the sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 193) 
                 
                 
               
                   R 1 -Q 1 x 2 Y 3 Q 4 x 5 L 6 D 7 x 8 x 9 D 10 x 11 x 12 x 13 x 14 x 15 x 16 F 17 x 18 x 19 Q 20 Q 21   
                 
                     
                 
                   G 22 -R 2   
                 
             
                
               
            
             
                
                
                
               
            
           
         
         wherein one of Q 1 , x 8 , x 9 , x 11 , x 12 , x 15 , x 16 , x 18 , x 19  or G 22  is a linking residue comprising a nucleophilic side chain covalently linkable to the combining site of an antibody directly or via an intermediate linker, the linking residue being selected from the group comprising K, R, Y, C, T, S, homologs of lysine, homocysteine, homoserine, Dap, and Dab, or the N-terminus or C-terminus, and 
         x 2  is selected from the group consisting of K, N, R, H, AcK, Nick, CbcK and the linking residue, and 
         x 5  is selected from the group consisting of P, hP, dhP, or BnHP, and 
         x 9  is selected from the group consisting of L, I, ThA, AcK and the linking residue, and 
         x 8  is selected from the group consisting of E and the linking residue, and 
         x 11  is selected from the group consisting of Q, N, C, K, AcK, Dab, Dap and the linking residue, and 
         x 12  is selected from the group consisting of L, HL, Nva, I, HchA, HF, ThA, and 
         x 13  is selected from the group consisting of L, HL, Nva, I, HchA, HF, ThA, and 
         x 14  is selected from the group consisting of aromatic residues and the linking residue, and 
         x 15  is selected from the group consisting of D and the linking residue, and 
         x 16  is selected from the group consisting of Q, N and the linking residue, and 
         x 18  is selected from the group consisting of M and the linking residue, and. 
         x 19  is selected from the group consisting of L, I and the linking residue. 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein the linking residue is selected from the group consisting of K, Y, T, Dap and Dab. 
     
     
         3 . A compound as claimed in  claim 1 , wherein the linking residue is K. 
     
     
         4 . A compound as claimed in  claim 1 , wherein the linking residue is located at one of x 9 , x 11 , x 12 , x 15 , x 16 , x 18  and x 19 . 
     
     
         5 . A compound as claimed in  claim 1 , wherein x 11  is the linking residue. 
     
     
         6 . A compound as claimed in  claim 1 , wherein
 x 2  is selected from the group consisting of K, N, and AcK, and   x 5  is selected from the group consisting of P, hP, and dhP, and   x 11  is selected from the group consisting of K, AcK, and   x 13  is selected from the group consisting of L, HL, Nva, I, and   x 14  is selected from the group consisting of F, Y, W, BPA, CF, NF, and x 16  is Q.   
     
     
         7 . A compound as claimed in  claim 1 , wherein x 2  is N. 
     
     
         8 . A compound as claimed in  claim 1 , wherein x 2  is AcK. 
     
     
         9 . A compound as claimed in  claim 1 , wherein x 5  is P. 
     
     
         10 . A compound as claimed in  claim 1 , wherein x 13  is L. 
     
     
         11 . A compound as claimed in  claim 1 , wherein x 14  is consisting of Y. 
     
     
         12 . A compound as claimed in  claim 1 , wherein x 9  is L. 
     
     
         13 . A compound as claimed in  claim 1 , wherein x 9  is AcK. 
     
     
         14 . A compound as claimed as claimed in  claim 1 , wherein the peptide comprises a sequence substantially homologous to one or more compounds selected from the group consisting of: SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, and SEQ ID NO:178. 
     
     
         15 . A peptide at least 90% homologous to a peptide selected from the group consisting of: SEQ ID NO: 22, SEQ ID NO: 34, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48 and SEQ ID NO: 64. 
     
     
         16 . A peptide according to  claim 15 , wherein at least 80% homologous to a peptide selected from the group consisting of: SEQ ID NO: 22, SEQ ID NO: 34, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48 and SEQ ID NO: 64. 
     
     
         17 . A peptide according to  claim 15 , wherein at least 70% homologous to a peptide selected from the group consisting of: SEQ ID NO: 22, SEQ ID NO: 34, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 48 and SEQ ID NO: 64. 
     
     
         18 . A peptide according to  claim 1 , selected from the group consisting of:
 R 1 -Q(AcK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -QNY QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEK D(AcK)T LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEK DET LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y Q(DHP)L DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y Q(HP)L DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT IYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEI DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT (HChA)YD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT (HF)YD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT (ThA)YD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT (Nva)YD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT (HL)YD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DE(AcK) DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT LFD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y Q(HP)L DE(ThA) DKT L(NO2F)D QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y Q(HP)L DE(ThA) DKT L(BPA)D QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y Q(HP)L DE(ThA) DKT L(CO2H)FD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DE(AcK) DKT L(NO2F)D QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DE(AcK) DKT LFD QFM LQQ G-R 2 ;   DCB-Q(AcK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   DFB-Q(AcK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   PyC-Q(AcK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   Amido 2-PEG-Q(AcK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(CIBnCarbamateK)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL D(Dab)T LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL D(Dap)T LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKT L(NO2F)D QFM LQQ G-R 2 ;   R 1 -QNY QPL DEL DKT L(BPA)D QFM LQQ G-R 2 ;   R 1 -QNY QPL DEL DKT L(CF)D QFM LQQ G-R 2 ;   R 1 -QNY QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(Nick)Y QPL DEL DKT LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DE(AcK) DKT L(CF)D QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DE(AcK) DK(OP)T LFD QFM LQQ G-R 2 ; wherein:   wherein R 1  is CH 3 , C(O)CH 3 , C(O)CH 3 , C(O)CH 2 CH 3 , C(O)CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 3 , C(O)CH 2 CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 2 CH 3 , C(O)C 6 H 5 , C(O)CH 2 CH 2 (CH 2 CH 2 O) 1-5 Me, dichlorobenzoyl (DCB), difluorobenzoyl (DFB), pyridinyl carboxlate (PyC) or amido-2-PEG, an amino protecting group, a lipid fatty acid group or a carbohydrate; and   R 2  is OH, NH 2 , NH(CH 3 ), NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH(CH 3 )CH 3 , NHCH 2 CH 2 CH 2 CH 3 , NHCH(CH 3 )CH 2 CH 3 , NHC 6 H 5 , NHCH 2 CH 2 OCH 3 , NHOCH 3 , NHOCH 2 CH 3 , a carboxy protecting group, a lipid fatty acid group or a carbohydrate.   
     
     
         19 . A peptide according to  claim 1 , selected from the group consisting of:
 R 1 -Q(AcK)Y QPL DELDKTLYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEL DKTLYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DELDKTL(NO2F)D QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEKDK(Ac)T LYD QFM LQQ G-R 2 ;   R 1 -Q(AcK)Y QPL DEK(Ac) DKLT LYD QFM LQQ G-R 2 ;   wherein   wherein R 1  is CH 3 , C(O)CH 3 , C(O)CH 3 , C(O)CH 2 CH 3 , C(O)CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 3 , C(O)CH 2 CH 2 CH 2 CH 3 , C(O)CH(CH 3 )CH 2 CH 3 , C(O)C 6 H 5 , C(O)CH 2 CH 2 (CH 2 CH 2 O) 1-5 Me, dichlorobenzoyl (DCB), difluorobenzoyl (DFB), pyridinyl carboxlate (PyC) or amido-2-PEG, an amino protecting group, a lipid fatty acid group or a carbohydrate; and   R 2  is OH, NH 2 , NH(CH 3 ), NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH(CH 3 )CH 3 , NHCH 2 CH 2 CH 2 CH 3 , NHCH(CH 3 )CH 2 CH 3 , NHC 6 H 5 , NHCH 2 CH 2 OCH 3 , NHOCH 3 , NHOCH 2 CH 3 , a carboxy protecting group, a lipid fatty acid group or a carbohydrate.   
     
     
         20 . A peptide of the formula:
   R 1 -Q(AcK)Y QPL DEK(Ac)DKLT LYD QFM LQQ G-R 2 ;   wherein
 R 1  is C(O)CH 3  and R 2  is NH 2 .