Peptide-drug conjugates

Abstract

Peptide-drug conjugates comprising p-aminobenzyl carbamoyl or p-aminobenzolyl carbonate self-immolating linkers are disclosed. The peptide-drug conjugates comprise a peptide moiety that can be cleaved by cellular proteases, bound to the self-immolating linker, which linker is bound to a cytotoxic drug moiety. Upon cleavage of the peptide moiety, the linker self-immolates, releasing the cytotoxic drug in active form. Dimeric structures of the peptide drug conjugates comprising two molecules of cytotoxic drug per conjugate are also disclosed.

What is claimed is: 
     
         1 . A peptide-drug conjugate of Formula I:
   R-Y-Z-Asn-Linker-D  (Formula I)
   wherein   R comprises a substituent selected from the group consisting of
 i) an acyl group, a carbamoyl group, a sulfonyl group, phosphoryl group or an alkyl group derived from a C 1  to about C 20  linear, branched or alicyclic carboxylic acid, optionally substituted with from one to about five hydroxyl, amine, carboxyl, sulfonic, or phosphoryl groups, 
 ii) a peptide with one to about fifty L- or D-amino acid residues, and 
 iii) a polyethylene glycol with a molecular weight from 400 to about 40,000; 
   Y is an amino acid residue selected from the group consisting of Ala, Thr, Ser, Leu, Arg, Pro, Val, Tyr, Phe;   Z is an amino acid residue selected from the group consisting of Ala, Thr, Asn and Pro;   Asn is an asparagine residue;   Linker is a p-aminobenzyl carbamoyl moiety or a p-aminobenzyl carbonate moiety;   D is an anti-tumor drug moiety bonded to the Linker moiety, wherein the drug is selected from the group consisting of mitomycin, doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino-camptothecin, N 8 -acetyl spermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, cytarabine, etoposide, camptothecin, taxol, esperamicin, Podophyllotoxin, anguidine, vincristine, vinblastine, morpholine-doxorubicin, n-(5,5-diacetoxy-pentyl) doxorubicin, and derivatives thereof.   
     
     
         2 . A peptide-drug conjugate  claim 1 , wherein
 R comprises a substituent selected from the group consisting of
 i) an acyl group derived from a C1 to about C20 linear, branched or alicyclic carboxylic acid, optionally substituted with from one to about five hydroxyl, amine, carboxyl, sulfonic, or phosphoryl groups, 
 ii) a peptide with one to about fifty L-amino acid residues, and 
 iii) a polyethylene glycol with a molecular weight from 400 to about 40,000; 
   Y is an amino acid residue selected from the group consisting of Ala, Thr, Ser, Leu, Arg, Pro, Val, Tyr, Phe;   Z is an amino acid residue selected from the group consisting of Ala, Thr, Asn and Pro;   Asn is an asparagine residue;   Linker is a p-aminobenzyl carbamoyl moiety; and   D is an anti-tumor drug moiety, wherein the drug is selected from the group consisting of mitomycin and doxorubincin.   
     
     
         3 . A peptide drug conjugate of  claim 1 , wherein
 R comprises a substituent selected from the group consisting of
 i) an acyl group, a carbamoyl group, a sulfonyl group, phosphoryl group or an alkyl group derived from a C1 to about C20 linear, branched or alicyclic carboxylic acid, optionally substituted with from one to about five hydroxyl, amine, carboxyl, sulfonic, or phosphoryl groups, 
 ii) a peptide with one to about fifty L- or D-amino acid residues, and 
 iii) a polyethylene glycol with a molecular weight from 400 to about 40,000; 
   Y is an amino acid residue selected from the group consisting of Ala, Thr, Ser, Leu, Arg, Pro, Val, Tyr, Phe;   Z is an amino acid residue selected from the group consisting of Ala, Thr, Asn and Pro;   Asn is an asparagine residue;   Linker is a p-aminobenzyl carbonate moiety; and   D is an anti-tumor drug moiety bonded to the Linker moiety and wherein the drug is camptothecin.   
     
     
         4 . A peptide-drug conjugate of Formula II:
   D′-Linker-Asn-Z-Y-R′-Y-Z-Asn-Linker-D  (Formula II)
   Wherein D and D′ are cytotoxic drug moieties which are the same are different from one another and are independently selected from the group consisting of mitomycin, doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino-camptothecin, N8-acetyl spermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, cytarabine, etoposide, camptothecin, taxol, esperamicin, Podophyllotoxin, anguidine, vincristine, vinblastine, morpholine-doxorubicin, n-(5,5-diacetoxy-pentyl) doxorubicin, and derivatives thereof;   Linker is a p-aminobenzyl carbonate moiety or p-aminobenzyl carbonate moiety, wherein the linkers may be the same or different;   R′ comprises a substituent selected from the group consisting of
 i) a bis-functional group selected from an acyl group, a carbamoyl group, a sulfonyl group, phosphoryl group or an alkyl group derived from a C1 to about C20 linear, branched or alicyclic carboxylic acid, optionally substituted with from one to about five hydroxyl, amine, carboxyl, sulfonic, or phosphoryl groups, 
 ii) a peptide with one to about fifty L or D-amino acid residues, and 
 iii) a polyethylene glycol with a molecular weight from 400 to about 40,000; and 
   Y is an amino acid residue selected from the group consisting of Ala, Thr, Ser, Leu, Arg, Pro, Val, Tyr, Phe;   Asn is an asparagine residue; and   Z is an amino acid residue selected from the group consisting of Ala, Thr, Asn and Pro.   
     
     
         5 . A peptide-drug conjugate selected from the group consisting of
 Ala-Ala-Asn-PABC-mitomycin:   N α -succinamic acid-Ala-Ala-Asn-PABC-mitomycin:   N α -acetamide-Ala-Ala-Asn-PABC-mitomycin;   N α -butyramide-Ala-Ala-Asn-PABC-mitomycin;   N α -hexanamide-Ala-Ala-Asn-PABC-mitomycin;   Ala-Ala-Asn-PABC-doxorubicin;   N α -succinamic acid-Ala-Ala-Asn-PABC-doxorubicin;   N α -acetamide-Ala-Ala-Asn-PABC-doxorubicin;   N α -butyramide-Ala-Ala-Asn-PABC-doxorubicin;   N α -hexanamide-Ala-Ala-Asn-PABC-doxorubicin.   
     
     
         6 . A peptide-drug conjugate selected from the group consisting of
 N α -[-(2-amide-2-oxoethoxy) acetic acid]-Ala-Ala-Asn-PABC-mitomycin;   N α -[-((2-amide-2-oxoethoxy)(methyl) amino) acetic acid]-Ala-Ala-Asn-PABC-mitomycin;   N α -[-(2-amide-2-oxoethoxy) acetic acid]-Ala-Ala-Asn-PABC-doxorubicin; and   N α -[-((2-amide-2-oxoethoxy)(methyl) amino) acetic acid]-Ala-Ala-Asn-PABC-doxorubicin;   Ala-Ala-Asn-PABC-camptothecin;   N α -succinamic acid-Ala-Ala-Asn-PABC-camptothecin;   N α -[-(2-amide-2-oxoethoxy) acetic acid]-Ala-Ala-Asn-PABC-camptothecin; and   N α -[-((2-amide-2-oxoethoxy)(methyl) amino) acetic acid]-Ala-Ala-Asn-PABC-camptothecin.   
     
     
         7 . A peptide-drug conjugate selected from the group consisting of:
 N 1 -Ala-Ala-Asn-PABC-mitomycin, N 4 -Ala-Ala-Asn-PABC-doxorubicin-succinamide;   N 1 -Ala-Ala-Asn-PABC-mitomycin, N 5 -Ala-Ala-Asn-PABC-doxorubicin-bis(O α -acetamide;   N 1 -Ala-Ala-Asn-PABC-mitomycin, N 5 -Ala-Ala-Asn-PABC-doxorubicin-bis(N α -methyl)-acetamide;   N 1 -Ala-Ala-Asn-PABC-mitomycin, N 4 -Ala-Ala-Asn-PABC-camptothecin-succinamide;   N 1 -Ala-Ala-Asn-PABC-mitomycin, N 5 -Ala-Ala-Asn-PABC-camptothecin-bis(O α -acetamide; and   N 1 -Ala-Ala-Asn-PABC-mitomycin, N 5 -Ala-Ala-Asn-PABC-camptothecin-bis(N α -methyl)-acetamide.   
     
     
         8 . A pharmaceutical composition comprising at least one peptide-drug conjugate of  claim 1  and at least one pharmaceutically-acceptable carrier. 
     
     
         9 . The pharmaceutical composition of  claim 8 , packaged as one or more individual dosages. 
     
     
         10 . A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a peptide-drug conjugate of  claim 1 . 
     
     
         11 . A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a peptide-drug conjugate of  claim 2 . 
     
     
         12 . A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a peptide-drug conjugate of  claim 3 . 
     
     
         13 . A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a peptide-drug conjugate of  claim 4 . 
     
     
         14 . A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a pharmaceutical composition of  claim 8 .