Compositions and methods for cancer immunotherapy
The invention relates to immunotherapeutic compounds and to methods for stimulating an immune response in a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer or the compounds of the invention can be administered as a prophylactic to a subject individual to prevent or delay the development of cancer.
1. A method for inducing an immune response in a subject individual, the method comprising the steps of: administering to the individual one or more anti-cancer antibodies and administering to the individual a compound of formula (I)
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-4 alkyl-C(O)— or —C(O)—C 1-4 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl —O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl - NH—C(O)C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxyl or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more group selected from the group consisting of hydroxy, halo, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 , X 2 , Y 1 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(f)
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino; or
(g)
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)NH—, —O—C(O)O—, —NH—C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —, wherein n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from the group consisting of —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH), where R 8 is a C 1-4 alkyl, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 , where R 9 is a C 1-4 alkyl;
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation;
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof;
wherein said immune response results in stabilizing a tumor by preventing or slowing the growth of an existing cancer, preventing the spread of a tumor or of metastases, reducing tumor size, preventing the recurrence of treated cancer, eliminating cancer cells not killed by earlier treatments, or preventing or delaying the development of cancer in said individual;
wherein the one or more anti-cancer antibodies is trastuzumab and the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or amorphous solid thereof.
2. The method of claim 1 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered at about the same time.
3. The method of claim 1 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered separately.
4. The method of claim 1 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered to a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer.
5. The method of claim 4 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically in combination with a surgical procedure to remove or reduce the size of a cancer tumor, radiation therapy, chemotherapy, and/or ablation therapy.
6. The method of claim 4 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically to stabilize a tumor by preventing or slowing the growth of the existing cancer, to prevent the spread of a tumor or of metastases, to reduce the tumor size, to prevent the recurrence of treated cancer, or to eliminate cancer cells not killed by earlier treatments.
7. The method of claim 1 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered prophylactically to the subject individual to prevent or delay the development of cancer.
8. The method of claim 1 , wherein the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the pharmaceutically acceptable salt of ER 804057 is E6020
10. A method for increasing the therapeutic efficacy of an anti-cancer antibody in a subject individual, the method comprising the steps of: administering to the individual one or more anti-cancer antibodies and administering to the individual a compound of formula (I)
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)— or —C(O)—C 1-14 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl -O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl -NH—C(O)C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxyl or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more group selected from the group consisting of hydroxy, halo, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 , X 2 , Y 1 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(f)
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino; or
(g)
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)NH—, —O—C(O)O—, —NH—C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —,
wherein n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from the group consisting of —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH), where R 8 is a C 1-4 alkyl, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 , where R 9 is a C 1-4 alkyl;
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation;
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof
wherein the increased therapeutic efficacy of the one or more anti-cancer antibodies results in stabilizing a tumor by preventing or slowing the growth of an existing cancer, preventing the spread of a tumor or of metastases, reducing tumor size, preventing the recurrence of treated cancer, eliminating cancer cells not killed by earlier treatments, or preventing or delaying the development of cancer in said individual;
wherein the one or more anti-cancer antibodies is trastuzumab and the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or amorphous solid thereof.
11. The method of claim 10 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered at about the same time.
12. The method of claim 10 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered separately.
13. The method of claim 10 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered to a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer.
14. The method of claim 13 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically in combination with a surgical procedure to remove or reduce the size of a cancer tumor, radiation therapy, chemotherapy, and/or ablation therapy.
15. The method of claim 13 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically to stabilize a tumor by preventing or slowing the growth of the existing cancer, to prevent the spread of a tumor or of metastases, to reduce the tumor size, to prevent the recurrence of treated cancer, or to eliminate cancer cells not killed by earlier treatments.
16. The method of claim 10 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered prophylactically to the subject individual to prevent or delay the development of cancer.
17. The method of claim 10 , wherein the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the pharmaceutically acceptable salt of ER 804057 is E6020
19. A method for treating or preventing cancer in a subject individual, the method comprising the steps of administering to the individual one or more anti-cancer antibodies and administering to the individual a compound of formula (I)
wherein:
R 1 is:
(a) —C(O)—;
(b) —C(O)—C 1-14 alkyl-C(O)— or —C(O)—C 1-14 alkenyl-C(O)—;
wherein the —C 1-14 alkyl- or —C 1-14 alkenyl- is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyldioxy, C 1-5 alkylamino, carboxy, C 1-6 alkoxycarbonyl, C 1-6 carbamoyl, C 1-6 acylamino, and/or (aryl)C 1-6 alkyl; and
wherein the aryl moiety of the (aryl)C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyamino, C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C 1-6 alkoxy, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkylamino-C(O)—C 1-6 alkyl-C(O)—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C 1-6 alkyl-O—C 1-6 alkyl, —O—C 1-6 alkyl-NH—C(O)C 1-6 alkyl-C(O)OH, and/or —O—C 1-6 alkyl-NH—C(O)C 1-6 alkyl-C(O)—C 1-6 alkyl;
(c) a C 2 to C 15 straight or branched chain alkyl group optionally substituted with one or more hydroxyl or alkoxy groups; or
(d) —C(O)—C 6-12 aryl-C(O)— wherein the aryl is optionally substituted with one or more group selected from the group consisting of hydroxy, halo, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy groups;
a and b are each independently 0, 1, 2, 3 or 4;
a′ and b′ are independently 2, 3, 4, 5, 6, 7 or 8;
d and e are each independently 1, 2, 3, 4, 5 or 6;
d′ and e′ are each independently 0, 1, 2, 3 or 4;
d″ and e″ are each independently 0, 1, 2, 3 or 4;
T is oxygen or sulfur;
X 1 , X 2 , Y 1 and Y 2 are each independently null, oxygen, NH, —N(C(O)C 1-4 alkyl)-, or —N(C 1-4 alkyl)-;
W 1 and W 2 are each independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently:
(a) C 2 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(b) C 2 to C 20 straight chain or branched chain alkenyl, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(c) C 2 to C 20 straight chain or branched chain alkoxy, which is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(d) —NH—C 2-20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(e) —C(O)—C 2-20 straight chain or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more groups selected from the group consisting of oxo, halo, hydroxy and alkoxy groups;
(f)
Z is O or NH; and M and N are each independently C 2 to C 20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, or acylamino; or
(g)
R 8 is C 1-6 straight or branched chain alkyl or C 2-6 straight or branched chain alkenyl or alkynyl;
R 9 and R 10 are independently selected from the group consisting of
(i) C 1 to C 20 straight chain or branched chain alkyl, which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy; and
(ii) C 2 to C 20 straight chain or branched chain alkenyl or alkynyl which is optionally substituted with one or more groups selected from the group consisting of halo, oxo, hydroxy and alkoxy;
G 1 , G 2 , G 3 , G 4 and G 5 are each independently oxygen, methylene, —NH—, thiol, —N(C 1-4 alkyl)-, —N[C(O)—C 1-4 alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)NH—, —O—C(O)O—, —NH—C(O)—NH—, —C(O)NH—, —C(O)N(C 1-4 alkyl), aryl, and —S(O) n —, wherein n is 0, 1, or 2;
or G 1 R 2 , G 2 R 4 , G 3 R 5 and/or G 4 R 7 may together be a hydrogen atom or hydroxyl;
Z 1 and Z 2 are each independently selected from the group consisting of —OP(O)(OH) 2 , —P(O)(OH) 2 , —OP(O)(OR 8 )(OH), where R 8 is a C 1-4 alkyl, —OS(O) 2 OH, —S(O) 2 OH—, —CO 2 H, —OB(OH) 2 , —OH, —CH 3 , —NH 2 , and —N(R 9 ) 2 , where R 9 is a C 1-4 alkyl;
R 12 is H or a C 1-4 straight or branched alkyl; and
M is independently selected from a hydrogen atom and a pharmaceutically acceptable cation;
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, amorphous solid thereof, or any combination thereof;
wherein said administering results in stabilizing a tumor by preventing or slowing the growth of an existing cancer, preventing the spread of a tumor or of metastases, reducing tumor size, preventing the recurrence of treated cancer, eliminating cancer cells not killed by earlier treatments, or preventing or delaying the development of cancer in said individual;
wherein the one or more anti-cancer antibodies is trastuzumab and the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or amorphous solid thereof.
20. The method of claim 19 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered at about the same time.
21. The method of claim 19 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered separately.
22. The method of claim 19 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered to a subject individual at risk for developing cancer, diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer.
23. The method of claim 22 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically in combination with a surgical procedure to remove or reduce the size of a cancer tumor, radiation therapy, chemotherapy, and/or ablation therapy.
24. The method of claim 22 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered therapeutically to stabilize a tumor by preventing or slowing the growth of the existing cancer, to prevent the spread of a tumor or of metastases, to reduce the tumor size, to prevent the recurrence of treated cancer, or to eliminate cancer cells not killed by earlier treatments.
25. The method of claim 19 , wherein the one or more anti-cancer antibodies and the compound of formula (I) are administered prophylactically to the subject individual to prevent or delay the development of cancer.
26. The method of claim 19 , wherein the compound of formula (I) is ER 804057 and/or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 , wherein the pharmaceutically acceptable salt of ER 804057 is E6020