Conjugates and conjugating reagents

1. A conjugate of a protein or peptide conjugated to a therapeutic agent via a linker, in which the linker also includes a cyclodextrin, and in which the cyclodextrin is present as a pendant group which is tethered to the backbone of the linker, wherein the conjugate is represented schematically by the formula:

in which:

D represents said therapeutic agent,

F′ represents a group of formula I:

in which Pr represents said protein or peptide, each Nu represents a sulfur atom or amine group present in or attached to the protein or peptide, each of A and B independently represents a C 1-4 alkylene or alkenylene chain, and W′ represents a keto group —CO—, an ester group —O—CO—, a sulfone group —SO 2 —, or a group obtained by reduction of one of these groups; and CD represents said cyclodextrin.

2. A conjugate as claimed in claim 1 , in which the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

3. A conjugate as claimed in claim 1 , in which the cyclodextrin is bonded to the rest of the linker via the 3- or the 6-position of a cyclic glucose group.

4. A conjugate as claimed in claim 1 , in which the cyclodextrin is monocyclic.

5. A conjugate as claimed in claim 1 , in which the linker includes a portion

wherein AA represents a protease-specific amino acid sequence.

6. A conjugate as claimed in claim 1 , in which the protein or peptide is an antibody or an antibody fragment.

7. A conjugate as claimed in claim 1 , wherein the group of formula (I) is a group of formula (Ia):

8. A conjugate as claimed in claim 7 , wherein the group of formula (Ia) is a group of formula (Ib) or (Ic):

9. A conjugate as claimed in claim 1 , in which each Nu represents a sulfur atom present in a cysteine residue present in the protein or peptide.

10. A conjugate as claimed in claim 1 , which has the formula:

11. A process for the preparation of a conjugate as claimed in claim 1 , which comprises reacting a protein or peptide with a conjugating reagent comprising a therapeutic agent and a linker in which the linker also includes a cyclodextrin, and in which the cyclodextrin is present as a pendant group which is tethered to the backbone of the linker, wherein the conjugate reagent is represented schematically by the formula:

in which: D represents said therapeutic agent,

CD represents said cyclodextrin, and

F is capable of reacting with sulfur atom or amine group present in or attached to the protein or peptide and F represents a group of formula (II) or (II′):

in which W represents a keto group —CO, an ester group —O—CO—, or a sulfone group —SO 2 —;

each of A and B independently represents a C 1-4 alkylene, or alkenylene chain, m is 0 to 4, and

each L independently represents a leaving group selected from —SP, —OP, —SO 2 P, —OSO 2 P, —N + PR 2 R 3 , halogen, or —OØ, in which P represents a hydrogen atom, C 1-6 alkyl, phenyl, or C 1-6 alkyl-phenyl group, or is a group which includes a portion —(CH 2 CH 2 O) n — in which n is a number of two or more, and each of R 2 and R 3 independently represents a hydrogen atom, a C 1-4 alkyl group, or a group P, and Ø represents a substituted phenyl, group, containing at least one substituent selected from the group consisting of —CN, —NO 2 , —CF 3 , —CO 2 R a , —COH, —CH 2 OH, —COR a , —OR a , —OCOR a , —OCO 2 R a , —SR a , —SOR a , —SO 2 R a , —NR a COR a , —NR a CO 2 R a , —NO, —NHOH, —NR a OH, —CH═N—NR a COR a , —N + R a 3 , halogen, —CH≡CR a , and —C═CR a 2 in which each R a represents a hydrogen atom, C 1-6 alkyl, phenyl, or C 1-6 alkyl-phenyl group.

12. A pharmaceutical composition which comprises a conjugate as claimed in claim 1 together with a pharmaceutically acceptable carrier, and optionally together with a further active ingredient.

13. A conjugate as claimed in claim 1 , in which the therapeutic agent is an auristatin, a maytansinoid or a duocarmycin.