MMP-SENSITIVE TAXANE PRODRUG
The present invention harnesses the differential expression of membrane-type matrix metalloproteinases (MT-MMPs) between human solid tumours and normal tissues to provide a systemically inactive prodrug which is selectively activated at the tumour micro-environment. The present invention provides a prodrug which is a conjugate of a taxane and a selective MT-MMP cleavable delivery vehicle.
1 . A conjugate comprising a taxane linked directly or indirectly via a linker moiety to a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-aa1-Gly-Hof-aa2-aa3-, wherein each of aa1, aa2 and aa3 is any amino acid.
2 . The conjugate according to claim 1 , wherein the taxane is selected from paclitaxel, docetaxel or cabazitaxel.
3 . The conjugate according to claim 1 or 2 , wherein the taxane is paclitaxel.
4 . The conjugate according to any one of claims 1 to 3 , wherein the linker moiety is a self-immolative linker.
5 . The conjugate according to claim 4 , wherein the self-immolative linker is selected from para-amino benzoic acid (PAB),
6 . The conjugate according to any one of the preceding claims, wherein aa1 is selected from Cit and Arg.
7 . The conjugate according to any one of the preceding claims, wherein aa1 is Cit.
8 . The conjugate according to any one of the preceding claims, wherein aa2 is selected from Tyr, Asp, Ala, Ser, Asn, Pro, Leu.
9 . The conjugate according to any one of the preceding claims, wherein aa2 is Tyr.
10 . The conjugate according to any one of the preceding claims, wherein aa3 is selected from Leu and Asn.
11 . The conjugate according to any one of the preceding claims, wherein aa3 is Leu.
12 . The conjugate according to any one of the preceding claims, wherein the MT-MMP cleavage site has the amino acid sequence
-Arg-Ser-Cit-Gly-Hof-Tyr-Leu-,
-Arg-Ser-Cit-Gly-Hof-Asn-Tyr-, or
-Arg-Ser-Arg-Gly-Hof-Tyr-Leu-.
13 . The conjugate according to any one of the preceding claims, wherein the peptide comprises one or more amino acids at one or both ends of the MT-MMP cleavage site.
14 . The conjugate according to any one of the preceding claims further comprising a capping group on the peptide to prevent non-specific degradation of the peptide.
15 . The conjugate according to claim 5 , wherein the capping group is selected from simple sugars, D-amino acids, proline imino acids, aromatics, aliphatics, fluorescein, or fluorescein derivatives, (e.g. that derived from fluorescein isothiocycante (FITC)), PEG and PEG derivatives.
16 . The conjugate according to any one of the preceding claims further comprising a spacer between the peptide and the capping group.
17 . The conjugate according to any one of the preceding claims further comprising a spacer between the linker moiety and the peptide.
18 . The conjugate according to claim 16 or 17 , wherein the spacer is selected from an amino acid, a non-natural amino acid, optionally beta-Ala, a succinyl group,
19 . The conjugate according to any one of the preceding claims, wherein the taxane is linked directly or indirectly via a linker moiety to the C-terminus of the peptide.
20 . The conjugate according to any one of the preceding claims, wherein the capping group is at the N-terminus of the peptide.
21 . The conjugate according to any one of the preceding claims, wherein the conjugate comprises paclitaxel linked via PAB to the C-terminus of the peptide comprising -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- and having the capping group FITC group at the N-terminus and having the spacer group beta-Ala between the peptide and the capping group.
22 . A conjugate comprising paclitaxel linked directly or indirectly via a PAB linker moiety to a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu-, and having an FITC capping group.
23 . A conjugate comprising Y-LX, wherein
Y is a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-aa1-Gly-Hof-aa2-aa3-,
wherein each of aa1, aa2 and aa3 is any amino acid,
L is a linker moiety, and
X is a taxane, each of Y, L and X as defined in any of claims 1 to 21 .
24 . A conjugate comprising C-Y-L-X, wherein
Y is a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-aa1-Gly-Hof-aa2-aa3-,
wherein each of aa1, aa2 and aa3 is any amino acid,
L is a linker moiety, and
X is a taxane,
C is a capping group, each of C, Y, L, X as defined in any of claims 1 to 21 .
25 . A conjugate comprising C-a-Y-L-X, wherein
Y is a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-aa1-Gly-Hof-aa2-aa3-,
wherein each of aa1, aa2 and aa3 is any amino acid,
L is a linker moiety, and
X is a taxane,
C is a capping group
a is a spacer, each of C, a, Y, L X as defined in claims 1 to 21 .
26 . A conjugate comprising C-a-Y-a-L-X, wherein
Y is a peptide comprising a membrane type matrix metalloproteinase (MT-MMP) cleavage site having the amino acid sequence -Arg-Ser-aa1-Gly-Hof-aa2-aa3-,
wherein each of aal aa2 and aa3 is any amino acid,
L is a linker moiety, and
X is a taxane,
C is a capping group
a is a spacer, each of C, a, Y, L X as defined in claims 1 to 21 .
27 . A pharmaceutical formulation comprising a conjugate according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier, diluent or excipient.
28 . The conjugate according to any one of claims 1 to 26 for use in medicine.
29 . The conjugate according to any one of claims 1 to 26 for use in treating cancer.
30 . The conjugate for the use of claim 29 wherein the cancer is a malignancy of epithelial, endodermal or mesenchymal origin, optionally wherein
a)the cancer is a carcinoma and preferably wherein the carcinoma is selected from cervix, prostate, breast, nose, head and neck, oral cavity, esophagus, stomach, liver, pancreas, colon, ovary, urinary bladder or lung, preferably non-small cell lung carcinoma, or
b)the cancer is a sarcoma, and preferably wherein the sarcoma is selected from bone, cartilage, adipose tissue, smooth muscle, skeletal muscle, nerve sheath, blood vessels, mesothelium and gastrointestinal stroma sarcoma.
31 . The conjugate for the use of claim 29 , wherein the cancer is prostate cancer.
32 . A method of treating a cancer in a subject, comprising administering a therapeutically effective amount of conjugate according to claim 1 to a subject in need thereof.
33 . A method according to claim 32 , wherein the cancer is selected from the group consisting of a malignancy of epithelial, endodermal or mesenchymal origin, optionally wherein
a)the cancer is a carcinoma and preferably wherein the carcinoma is selected from cervix, prostate, breast, nose, head and neck, oral cavity, esophagus, stomach, liver, pancreas, colon, ovary, urinary bladder or lung, preferably non-small cell lung carcinoma, or
b)the cancer is a sarcoma, and preferably wherein the sarcoma is selected from bone, cartilage, adipose tissue, smooth muscle, skeletal muscle, nerve sheath, blood vessels, mesothelium and gastrointestinal stroma sarcoma.
34 . A method according to claim 32 , wherein the cancer is a prostate cancer.