Compositions and methods for the treatment of platinum-drug resistant cancer
VAR2CSA-drug conjugates for targeting and inhibiting the growth of cancer cells that have developed resistance to a platinum drug and the use of the conjugates in the treatment of platinum drug-resistant cancers. VAR2CSA-drug conjugates (VDCs) comprise a VAR2CSA polypeptide that is capable of binding to oncofetal chondroitin sulfate (ofCS) and one or more toxins having anti-cancer activity conjugated to the VAR2CSA polypeptide, either directly or via a linker.
1. A method of treating a platinum drug-resistant cancer in a subject comprising administering to the subject an effective amount of a VAR2CSA-drug conjugate (VDC), the VDC comprising:
a) a VAR2CSA polypeptide that specifically binds to oncofetal chondroitin sulfate (ofCS), and
b) one or more toxins having anti-cancer activity conjugated to the VAR2CSA polypeptide,
wherein the VAR2CSA polypeptide is a functional fragment of an extracellular portion of a native VAR2CSA protein, and wherein the functional fragment is between about 550 amino acids and about 1100 amino acids in length and comprises a sequential amino acid sequence of ID1 and DBL2Xb domains of the native VAR2CSA protein.
2. The method according to claim 1 , wherein the platinum drug is cisplatin, carboplatin or oxaliplatin.
3. The method according to claim 1 , wherein the cancer is bladder cancer, colon cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, testicular cancer, melanoma, head and neck cancer, endometrial cancer, ovarian cancer, adrenocortical cancer or non-Hodgkin lymphoma.
4. The method according to claim 3 , wherein the cancer is an advanced and/or metastatic cancer.
5. The method according to claim 1 , wherein the platinum drug-resistant cancer has an increased expression of CD44 as compared to a corresponding cancer that is not resistant to platinum-drugs.
6. The method according to claim 1 , wherein the platinum drug is cisplatin.
7. The method according to claim 1 , wherein the cancer is bladder cancer.
8. The method according to claim 6 , wherein the cancer is bladder cancer.
9. The method according to claim 7 , wherein the cancer is muscle invasive bladder cancer.
10. The method according to claim 1 , wherein the subject has undergone a prior treatment regimen comprising the platinum drug.
11. The method according to claim 10 , wherein the subject relapsed or progressed following the prior treatment regimen.
12. The method according to claim 1 , wherein the VDC is a compound of general formula (I):
V−[(L) n −(T) m ] p (I)
wherein
V is the VAR2CSA polypeptide;
L is a linker;
T is the toxin;
n is 0 or 1;
m is an integer between 1 and 8, and
p is an integer between 1 and 12.
13. The method according to claim 12 , wherein n is 1.
14. The method according to claim 13 , wherein m is 1.
15. The method according to claim 12 , wherein p is an integer from 1 to 10.
16. The method according to claim 14 , wherein p is an integer from 1 to 4.
17. The method according to claim 1 , wherein the extracellular portion of the native VAR2CSA protein has a sequence as set forth in SEQ ID NO:55 or 56.
18. The method according to claim 1 , wherein the VAR2CSA polypeptide comprises a sequential amino acid sequence of the ID1 and DBL2Xb domains and all or a N-terminal portion of an ID2a domain.
19. The method according to claim 1 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57.
20. The method according to claim 1 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in SEQ ID NO:57.
21. The method according to claim 1 , wherein the toxin is a microtubule polymerization inhibitor.
22. The method according to claim 1 , wherein the toxin is a hemiasterlin, an auristatin, a tubulysin, or an analogue or derivative thereof.
23. The method according to claim 1 , wherein the toxin is a compound of general formula (IV):
wherein:
R 26 is selected from optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
R 27 is selected from optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
R 16 and R 17 are each independently H or C 1-6 alkyl, and
R 18 is C 1-6 alkyl or SH, and
wherein the compound of general formula (IV) is conjugated to the VAR2CSA polypeptide via the R 26 substituent or the R 27 substituent.
24. The method according to claim 23 , wherein R 26 is optionally substituted alkyl or optionally substituted aryl.
25. The method according to claim 23 , wherein R 26 is optionally substituted phenyl or optionally substituted aralkyl.
26. The method according to claim 23 , wherein R 27 is optionally substituted aryl.
27. The method according to claim 24 , wherein R 27 is optionally substituted aryl.
28. The method according to claim 23 , wherein R 16 and R 17 are each independently H or methyl.
29. The method according to claim 23 , wherein R 18 is C 1 -C 6 alkyl.
30. The method according to claim 23 , wherein R 16 is H, and R 17 and R 18 are each methyl.
31. The method according to claim 24 , wherein the compound of general formula (IV) is a compound selected from Compounds 1, 3, 4, 5, 6, 7, 8, 9 and 10:
32. The method of claim 12 , wherein the VDC has the structure:
33. The method according to claim 12 , wherein n is 1 and L is a cleavable linker.
34. The method according to claim 33 , wherein L-T has the general formula (VI):
wherein:
Z is a functional group capable of reacting with a target group on the VAR2CSA polypeptide;
Str is a stretcher;
AA 1 and AA 2 are each independently an amino acid, wherein AA 1 -[AA 2 ] m forms a protease cleavage site;
X is a self-immolative group;
T is the toxin;
n is 0 or 1;
m is 1, 2 or 3, and
o is 0, 1 or 2.
35. The method according to claim 33 , wherein the VDC has the general formula (VIII):
wherein:
R 10 is selected from optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 11 —, —CSR 11 —, —OR 11 — and —NHR 11 —, wherein each R 11 is independently selected from optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
P 3 is the toxin or a portion of the toxin;
L 3 is the remaining portion of the linker, and
V is the VAR2CSA polypeptide.
36. A method of treating cancer in a subject who has received a prior treatment regimen comprising a platinum drug, the method comprising administering to the subject an effective amount of a VAR2CSA-drug conjugate (VDC), the VDC comprising:
a) a VAR2CSA polypeptide that specifically binds to oncofetal chondroitin sulfate (ofCS), and
b) one or more toxins having anti-cancer activity conjugated to the VAR2CSA polypeptide,
wherein the VAR2CSA polypeptide is a functional fragment of an extracellular portion of a native VAR2CSA protein, and wherein the functional fragment is between about 550 amino acids and about 1100 amino acids in length and comprises a sequential amino acid sequence of ID1 and DBL2Xb domains of the native VAR2CSA protein.
37. The method according to claim 36 , wherein the subject relapsed or progressed following the prior treatment regimen.
38. A method of inhibiting growth of a platinum drug-resistant tumor in a subject comprising administering to the subject an effective amount of a VAR2CSA-drug conjugate (VDC), the VDC comprising:
a) a VAR2CSA polypeptide that specifically binds to oncofetal chondroitin sulfate (ofCS), and
b) one or more toxins having anti-cancer activity conjugated to the VAR2CSA polypeptide,
wherein the VAR2CSA polypeptide is a functional fragment of an extracellular portion of a native VAR2CSA protein, and wherein the functional fragment is between about 550 amino acids and about 1100 amino acids in length and comprises a sequential amino acid sequence of ID1 and DBL2Xb domains of the native VAR2CSA protein.
39. A method of inhibiting the proliferation of platinum drug-resistant cancer cells comprising contacting the cells with an effective amount of a VAR2CSA-drug conjugate (VDC), the VDC comprising:
a) a VAR2CSA polypeptide that specifically binds to oncofetal chondroitin sulfate (ofCS), and
b) one or more toxins having anti-cancer activity conjugated to the VAR2CSA polypeptide,
wherein the VAR2CSA polypeptide is a functional fragment of an extracellular portion of a native VAR2CSA protein, and wherein the functional fragment is between about 550 amino acids and about 1100 amino acids in length and comprises a sequential amino acid sequence of ID1 and DBL2Xb domains of the native VAR2CSA protein.
40. The method according to claim 1 , wherein the functional fragment is between about 570 amino acids and about 1000 amino acids in length.
41. The method according to claim 1 , wherein the VAR2CSA polypeptide comprises the amino acid sequence as set forth in amino acids 1-969 of SEQ ID NO:58.
42. The method according to claim 36 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57.
43. The method according to claim 36 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in SEQ ID NO:57.
44. The method according to claim 36 , wherein the VAR2CSA polypeptide comprises the amino acid sequence as set forth in amino acids 1-969 of SEQ ID NO:58.
45. The method according to claim 38 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57.
46. The method according to claim 38 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in SEQ ID NO:57.
47. The method according to claim 38 , wherein the VAR2CSA polypeptide comprises the amino acid sequence as set forth in amino acids 1-969 of SEQ ID NO:58.
48. The method according to claim 39 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:29, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:53, SEQ ID NO:54 or SEQ ID NO:57.
49. The method according to claim 39 , wherein the VAR2CSA polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in SEQ ID NO:57.
50. The method according to claim 39 , wherein the VAR2CSA polypeptide comprises the amino acid sequence as set forth in amino acids 1-969 of SEQ ID NO:58.