Non-linear self-immolative linkers and conjugates thereof

1. A linker-drug compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein V 1 is a conditionally-cleavable or conditionally-transformable moiety, which can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process;

Z is a cytotoxic drug comprising a phenolic hydroxyl group through which Z is attached to the linker;

n is 0, 1, 2, or 3; and

m is 0 or 1.

2. The compound according to claim 1 , wherein Z is

wherein R 1 , R 2 , and R 3 are independently selected from H, OH, SH, NH 2 , N 3 , NO 2 , NO, CF 3 , CN, C(O)NH 2 , C(O)H, C(O)OH, halogen, R a , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , OS(O)R a , OS(O) 2 R a , OS(O)OR a , OS(O) 2 OR a , OR a , NHR a , N(R a )R b , + N(R a )(R b )R c , P(O)(OR a )(OR b ), OP(O)(OR a )(OR b ), SiR a R b R c , C(O)R a , C(O)OR a , C(O)N(R a )R b , OC(O)R a , OC(O)OR a , OC(O)N(R a )R b , N(R a )C(O)R b , N(R a )C(O)OR b , N(R a )C(O)N(R b )R c , and a water-soluble group, wherein

R a , R b , and R c are independently selected from H and optionally substituted (CH 2 CH 2 O) aa CH 2 CH 2 X 1 R a1 , C 1-15 alkyl, C 1-15 heteroalkyl, C 3-15 cycloalkyl, C 1-15 heterocycloalkyl, C 5-15 aryl, or C 1-15 heteroaryl, wherein aa is selected from 1 to 1000, X 1 is selected from O, S, and NR b1 , and R b1 and R a1 are independently selected from H and C 1-3 alkyl, one or more of the optional substituents in R a , R b , and/or R c optionally being a water-soluble group, two or more of R a , R b , and R c optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles.

3. The compound according to claim 2 , wherein Z is

4. The compound according to claim 3 , wherein R 1 is selected from H, methyl and methoxy.

5. The compound according to claim 4 , wherein Z is

6. The compound according to claim 1 , wherein V 1 is selected from valylalanine, valyllysine, valylcitrulline, phenylalanyllysine, and alanylphenylalanyllysine, each of which may optionally be capped.

7. The compound according to claim 1 , selected from

8. An antibody-drug conjugate comprising the compound according to claim 1 conjugated to an antibody or an antigen-binding fragment thereof through a cysteine residue of the antibody or the antigen-binding fragment.

9. The antibody-drug conjugate according to claim 8 , wherein the compound is site-specifically conjugated to an antibody or antigen-binding fragment thereof through an engineered cysteine at one or more positions of said antibody or antigen-binding fragment selected from

heavy chain 40, 41 and 89 (according to Kabat numbering);

heavy chain 152, 153, 155, 171, 247, 297, 339, 375 and 376 (according to Eu numbering); and

light chain 40, 41, 165 and 168 (according to Kabat numbering).

10. The antibody-drug conjugate according to claim 9 , wherein the compound is site-specifically conjugated to an antibody or antigen-binding fragment thereof through an engineered cysteine at one or more positions of said antibody or antigen-binding fragment selected from

heavy chain 40, 41 and 89 (according to Kabat numbering); and

light chain 40 and 41 (according to Kabat numbering).

11. The antibody-drug conjugate according to claim 8 , wherein said antibody-drug conjugate is a compound of formula (III)

wherein Antibody is an antibody or antigen-binding fragment thereof;

n is 0, 1, 2 or 3;

y represents an average DAR of from 1 to 6; and

R is selected from

12. The antibody-drug conjugate according to claim 8 , wherein the antibody or the antigen-binding fragment binds to an antigen target selected from the group consisting of annexin A1, CA242, CD19, CD22, CD30, CD33, CD37, CD38, CD44, CD47, CD56, CD70, CD74, CD79, CD115, CD123, CD138, CD203c, CD303, CD333, CEACAM, CLL-1, c-MET, Cripto, DLL3, EGFR, EPCAM, EphA2, EphB3, ETBR, FAP, FcRL5, FGFR3, FOLR1, GCC, GPNMB, HER2, HMW-MAA, integrin, Lewis A like carbohydrate, Lewis Y, LIV1, mesothelin, MN, MUC1, MUC16, NaPi2b, Nectin-4, PSMA, SLC44A4, STEAP-1, 5T4 antigen, Tag72, tissue factor, TF-Ag, TROP2, and VLA.

13. A pharmaceutical composition comprising the antibody-drug conjugate according to claim 8 and one or more pharmaceutically acceptable excipients.

14. The compound according to claim 1 , wherein Z is a duocarmycin derivative or a CBI dimer derivative.

15. The compound according to claim 1 , wherein Z is a duocarmycin derivative.

16. The compound according to claim 1 , wherein V 1 comprises a di-, tri-, or tetra-peptide that is bonded to the linker via its C-terminal side, and optionally is capped on the N-terminal side by an amine blocking group or a water-soluble group.

17. The compound according to claim 2 , wherein V 1 is selected from valylalanine, valyllysine, valylcitrulline, phenylalanyllysine, and alanylphenylalanyllysine, each of which may optionally be capped.

18. The compound according to claim 3 , wherein V 1 is selected from valylalanine, valyllysine, valylcitrulline, phenylalanyllysine, and alanylphenylalanyllysine, each of which may optionally be capped.

19. The compound according to claim 5 , wherein V 1 is selected from valylcitrulline and valylalanine, each of which may optionally be capped.

20. The antibody-drug conjugate according to claim 11 , wherein the antibody or the antigen-binding fragment binds to an antigen target selected from the group consisting of annexin A1, CA242, CD19, CD22, CD30, CD33, CD37, CD38, CD44, CD47, CD56, CD70, CD74, CD79, CD115, CD123, CD138, CD203c, CD303, CD333, CEACAM, CLL-1, c-MET, Cripto, DLL3, EGFR, EPCAM, EphA2, EphB3, ETBR, FAP, FcRL5, FGFR3, FOLR1, GCC, GPNMB, HER2, HMW-MAA, integrin, Lewis A like carbohydrate, Lewis Y, LIV1, mesothelin, MN, MUC1, MUC16, NaPi2b, Nectin-4, PSMA, SLC44A4, STEAP-1, 5T4 antigen, Tag72, tissue factor, TF-Ag, TROP2, and VLA.