# US 10,765,648 B2 · iNKT cell modulators and methods of using the same

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- Number: US 10,765,648 B2
- Document ID: US10765648B2
- Status: Granted
- Kind: B2
- Application number: 16/387,322
- Filed: 2019-04-17
- Published: 2019-12-12
- Granted: 2020-09-08
- Earliest claimed: 2011-11-30
- Assignees: Ludwig Institute for Cancer Research
- Applicants: Ludwig Institute for Cancer Research
- Inventors: Vincenzo Cerundolo; Gurdyal S. Besra; Liam R. Cox
- Web page: https://patentgrep.com/patent/US10765648B2

## CPC

- A61K 31/16: Amides, e.g. hydroxamic acids
- A61J 1/14: Details; Accessories therefor (A61J7/00 takes precedence; openers B65D, B67B7/00)
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 39/0011: {Cancer antigens}
- A61K 39/001106: {Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4}
- A61K 39/001119: {Receptors for interleukins [IL]}
- A61K 39/001124: {CD20}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07C 233/18: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/30: from tumour cells
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Disclosed herein are α-galactosylceramide (α-GalCer) analogs and compositions thereof, methods of activating invariant Natural Killer T (iNKT) cells using said analogs, methods of treating diseases by activating iNKT cells using said analogs, and combination therapy of said analogs.

## Claims

### Claim 1

A method of activating a natural killer T (NKT) cell in a human subject with ovarian cancer, the method comprising administering to a subject with ovarian cancer a composition comprising a compound, in an amount effective to activate the NKT cells, wherein the compound has a structure:
wherein n is 1, 2, or 3;
or a salt, ester, solvate, or hydrate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein n is 1.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound has a structure:
wherein n is 1, 2, or 3;
or a salt, ester, solvate, or hydrate thereof.

### Claim 4 (depends on 3)

The method according to claim 3, wherein n is 1, and wherein the composition further comprises a pharmaceutically acceptable carrier.

### Claim 5 (depends on 4)

The method according to claim 4, further comprising administering to the subject a second therapeutic selected from the group consisting of a chemotherapeutic agent, a biological response modifying agent, and an immunotherapeutic agent.

### Claim 6 (depends on 5)

The method of claim 5, wherein the second therapeutic comprises an immunotherapeutic that comprises a cancer vaccine, a cancer antigen, or a polynucleotide that comprises a nucleotide sequence that encodes a cancer antigen.

### Claim 7 (depends on 6)

The method of claim 6, wherein the second therapeutic comprises a cancer antigen that comprises at least one member selected from one or more of (a) MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, MAGE-A13, GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-1, RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), tyrosinase, brain glycogen phosphorylase, Melan-A, MAGE-C1, MAGE-C2, NY-ESO-1, LAGE-1, SSX-1, SSX-2(HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1, CT-7, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, Lage-1, NA-88, /Lage-2, SP17, and TRP2-Int2, (MART-I), gp100 (Pmel 17), TRP-1, TRP-2, MAGE-1, MAGE-3, p15(58), CEA, NY-ESO (LAGE), SCP-1, Hom/Mel-40, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, and TPS; and (b) immunogenic fragments that comprise an epitope of any of the foregoing antigens.

### Claim 8 (depends on 5)

The method of claim 5, wherein the second therapeutic comprises at least one chemotherapeutic agent selected from the group consisting of aspirin, sulindac, curcumin, alkylating agents; nitrosoureas, ethylenimines/methylmelamine; alkyl sulfonates, folic acid analogs, pyrimidine analogs, purine analogs, antimitotic drugs, epipodophylotoxins, antibiotics, and enzymes.

### Claim 9 (depends on 5)

The method of claim 5, wherein the second therapeutic comprises at least one agent selected from the group consisting of interferon-alpha, IL-2, G-CSF, GM-CSF, platinum coordination complexes, anthracenediones, substituted urea, methylhydrazine derivatives, adrenocortical suppressants, hormones, hormone antagonists, adrenocorticosteroid antagonists, kinase inhibitors, histone deacetylase inhibitors, methylation inhibitors, proteasome inhibitors, monoclonal antibodies, oxidants, anti-oxidants, telomerase inhibitors, BH3 mimetics, ubiquitin ligase inhibitors, stat inhibitors, and receptor tyrosine kinase inhibitors.

### Claim 10 (depends on 5)

The method of claim 5, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are administered simultaneously.

### Claim 11 (depends on 10)

The method of claim 10, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are co-formulated.

### Claim 12 (depends on 5)

The method of claim 5, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are administered sequentially.

### Claim 13

A method of treating a subject suffering from ovarian cancer comprising administering to the subject a composition comprising a compound, or a salt, ester, solvate, or hydrate thereof, in an amount effective to treat the cancer, wherein the compound has a structure:
wherein n is 1, 2, or 3.

### Claim 14 (depends on 13)

The method of claim 13, wherein n=1, and wherein the subject is human.

### Claim 15 (depends on 13)

The method of claim 13 further comprising administering to the subject a second therapeutic selected from the group consisting of a chemotherapeutic agent, a biological response modifying agent, and an immunotherapeutic agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the second therapeutic comprises an immunotherapeutic that comprises a cancer vaccine, a cancer antigen, or a polynucleotide that comprises a nucleotide sequence that encodes a cancer antigen.

### Claim 17 (depends on 16)

The method of claim 16, wherein the second therapeutic comprises a cancer antigen that comprises at least one member selected from one or more of (a) MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, MAGE-A13, GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-1, RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), tyrosinase, brain glycogen phosphorylase, Melan-A, MAGE-C1, MAGE-C2, NY-ESO-1, LAGE-1, SSX-1, SSX-2(HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1, CT-7, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomeras, GnTV, Herv-K-mel, Lage-1, NA-88, /Lage-2, SP17, and TRP2-Int2, (MART-I), gp100 (Pmel 17), TRP-1, TRP-2, MAGE-1, MAGE-3, p15(58), CEA, NY-ESO (LAGE), SCP-1, Hom/Mel-40, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, and TPS; and (b) immunogenic fragments that comprise an epitope of any of the foregoing antigens.

### Claim 18 (depends on 15)

The method of claim 15, wherein the second therapeutic comprises at least one chemotherapeutic agent selected from the group consisting of aspirin, sulindac, curcumin, alkylating agents nitrosoureas, ethylenimines/methylmelamine, alkyl sulfonates, folic acid analogs, pyrimidine analogs, purine analogs, antimitotic drugs, epipodophylotoxins, antibiotics, and enzymes.

### Claim 19 (depends on 15)

The method of claim 15, wherein the second therapeutic comprises at least one agent selected from the group consisting of interferon-alpha, IL-2, G-CSF and GM-CSF, platinum coordination complexes anthracenediones, substituted urea, methylhydrazine derivatives, adrenocortical suppressants, hormones, hormone antagonists, adrenocorticosteroid antagonists, kinase inhibitors, histone deacetylase inhibitors, methylation inhibitors, proteasome inhibitors, monoclonal antibodies, oxidants, anti-oxidants, telomerase inhibitors, BH3 mimetics, ubiquitin ligase inhibitors, stat inhibitors, and receptor tyrosine kinase inhibitors.

### Claim 20 (depends on 15)

The method of claim 15, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are administered simultaneously.

### Claim 21 (depends on 15)

The method of claim 15, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are co-formulated.

### Claim 22 (depends on 15)

The of claim 15, wherein the second therapeutic and the compound, salt, ester, solvate, or hydrate thereof are administered sequentially.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the composition comprises a lipid-based formulation of the compound.

### Claim 24 (depends on 13)

The method according to claim 13, wherein the composition comprises a lipid-based formulation of the compound.

### Claim 25 (depends on 8)

The method of claim 8, wherein the second therapeutic comprises at least one chemotherapeutic agent selected from the group consisting of mechlor-ethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine), busulfan, dacarbazine (DTIC), methotrexate, trimetrexate, 5-fluorouracil, fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2′-difluorodeoxycytidine, 6-mercaptopurine, 6-thioguanine, azathioprine, 2′-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA), paclitaxel, vinblastine (VLB), vincristine, vinorelbine, taxotere, estramustine, estramustine phosphate, etoposide, teniposide, actimomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycinC, actinomycin; and L-asparaginase.

### Claim 26 (depends on 9)

The method of claim 9, wherein the second therapeutic comprises at least one agent selected from the group consisting of interferon-alpha, IL-2, G-CSF, and GM-CSF, cisplatin, carboplatin, mitoxantrone, hydroxyurea, N-methylhydrazine (MIH), procarbazine, mitotane (o,p′-DDD), aminoglutethimide; prednisone, dexamethasone, aminoglutethimide, progestin, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estrogen, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, gonadotropin-releasing hormone analogs, leuprolide, flutamide, imatinib mesylate, and erlotinib.

### Claim 27 (depends on 18)

The method of claim 18, wherein the second therapeutic comprises at least one chemotherapeutic agent selected from the group consisting of mechlor-ethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine), busulfan, dacarbazine (DTIC), methotrexate, trimetrexate, 5-fluorouracil, fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2′-difluorodeoxycytidine, 6-mercaptopurine, 6-thioguanine, azathioprine, 2′-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA), paclitaxel, vinblastine (VLB), vincristine, vinorelbine, taxotere, estramustine, estramustine phosphate, etoposide, teniposide, actimomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycinC, actinomycin; and L-asparaginase.

### Claim 28 (depends on 19)

The method of claim 19, wherein the second therapeutic comprises at least one agent selected from the group consisting of interferon-alpha, IL-2, G-CSF, and GM-CSF, cisplatin, carboplatin, mitoxantrone, hydroxyurea, N-methylhydrazine (MIH), procarbazine, mitotane (o,p′-DDD), aminoglutethimide; prednisone, dexamethasone, aminoglutethimide, progestin, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estrogen, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, gonadotropin-releasing hormone analogs, leuprolide, flutamide, imatinib mesylate, and erlotinib.