MUC1 based glycolipopeptide vaccine with adjuvant

1. A liposomal vaccine formulation comprising:

(a) a peptide comprising:

(SEQ ID NO: 2)

H 2 N-TSAPDT(Tn)RPAPGS(Tn)T(Tn)APPAHGVTSAPDT(Tn)

RPAPGS(Tn)T(Tn)APPAHGVS*S*L-OH

or a sequence at least 95% identical to SEQ ID NO: 2;

wherein

* independently, at each occurrence, represents a lipid covalently attached to an amino acid residue and Tn represents GalNAcα1;

(b) an adjuvant of Formula I:

wherein at least one of R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 is a strongly lipophilic group selected from the group consisting of

wherein X, X 1 , X 2 , and X 3 are independently —CO— or —CH 2 —;

Z is —NH— or —O;

k, m, and r are independently an integer of 0 to 30 inclusive,

n and q are independently an integer of 0 to 6 inclusive;

wherein Y 4 is a spacer selected from the group consisting of —O—, —S—, and —NH— wherein, at least one of Y 1 R 1 , Y 2 R 2 , Y 3 R 3 , Y 5 R 5 , Y 6 R 6 and Y 7 R 7 is a monovalent phosphate equivalent (MPE),

wherein each monovalent phosphate equivalent is, independently,

(a) —R′—C(O)OH where R′ is a substituted or unsubstituted alkyl group of 1-4 carbons, or

(b) selected independently from the group consisting of —OB(OH)OR, —OP(O)(OH)OR, —OS(0)(0)(OH)OR, and —OP(═O)(OH)—O—P(═O)(OH)OR,

 where R is hydrogen, or a substituted or unsubstituted alkyl group of 1-4 carbons, and if R is a substituted alkyl group, the substitutions are —OH or —NH 2 ,

wherein R 8 is selected from the group consisting of H, OH, OR 9 , a moiety which in combination with Y 8 forms a monovalent phosphate equivalent as previously defined, and a group (i)-(viii) as defined above; wherein R 9 is an alkyl or acyl group of 1 to 10 carbon length; and

wherein the glycosidic linkage is α or β;

or a pharmaceutically acceptable salt thereof;

or

an adjuvant of Formula II:

wherein at least one of R 1 , R 2 , R 3 , R 11 , R 12 and R 13 is a strongly lipophilic group selected from the group consisting of (i)-(viii) above;

wherein Y 4 is a spacer selected from the group consisting of —O—, —S—, and —NH— and

wherein at least one of Y 1 R 1 , Y 2 R 2 , Y 3 R 3 , Y 11 R 11 , Y 12 R 12 and Y 13 R 13 is independently a monovalent phosphate equivalent as previously defined;

wherein the following limitations apply to both (I) and (II) above:

Y 1 , Y 2 , Y 3 , Y 5 , Y 6 , Y 7 , Y 11 , Y 12 and Y 13 are spacers independently selected from the group consisting of —O—, —S—, and —NH—;

R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 11 , R 12 and R 13 are independently hydrogen,

a moiety which with the commonly numbered Y group forms monovalent phosphate equivalent as previously defined, or

a strongly lipophilic group selected from the group consisting of (i)-(viii) above;

the strongly lipophilic groups of said compound collectively provide at least two major carbon chains, and

the major carbon chains of said strongly lipophilic groups collectively provide at least 30 carbon atoms;

or a pharmaceutically salt thereof; and

(c) one or more carrier lipids.

2. The vaccine formulation of claim 1 , wherein the carrier lipid is selected from dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), phosphatidylcholine (PC; lecithin), phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylserine (PS) distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidyglycerol (DPPG), distearoylphosphatidyglycerol (DSPG), dipalmitoylphosphatidic acid (DPPA); dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidylserine (DPPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dipalmitoylphosphatidyethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearoylphosphatidylethanolamine (DSPE), or a pharmaceutically acceptable salt thereof, or combination thereof.

3. The vaccine formulation of claim 1 , wherein the lipid covalently attached to an amino acid residue is independently, at each occurrence, selected from myristoyl, palmitoyl, lauryl, stearoyl, decanoyl, and octanoyl chains, or a combination thereof.

4. The vaccine formulation of claim 1 , wherein

Y 4 is —O—;

Y 1 , Y 2 , and Y 7 are —O—;

Y 3 , Y 5 and Y 6 are independently —O— or —NH—;

R 1 , R 3 , R 5 and R 6 are independently hydrogen or a strongly lipophilic group selected from (i)-(viii);

at least one of R 1 , R 3 , R 5 , and R 6 is not hydrogen;

R 2 and R 7 are independently selected from the group consisting of H, —P(O)(OH) 2 , —SO 3 H, —P(O)(OH)(OCH 2 CH 2 NH 2 ) and —CH 2 COOH; and

R 8 is selected from the group consisting of H, OH, OSO 3 H, and OR 9 , wherein R 9 is an alkyl or acyl group of 1 to 10 carbon length.

5. The vaccine formulation of claim 1 , wherein at least one strongly lipophilic group is one of the structures set forth below

6. The vaccine formulation of claim 1 , wherein the adjuvant has the following structure:

wherein R 1 , R 3 , R 5 and R 6 are independently hydrogen or a lipophilic group selected from the group consisting of

wherein X, X 1 , X 2 , and X 3 are independently —CO— or —CH 2 ,—;

Z is —NH— or —O—;

k, m, and r are independently an integer of 0 to 30 inclusive,

n and q are independently an integer of 0 to 6 inclusive;

at least one of R 1 , R 3 , R 5 and R 6 is not hydrogen;

R 2 and R 7 are independently selected from the group consisting of H, —P(O)(OH) 2 , —SO 3 H, —P(O)(OH), (OCH 2 CH 2 NH 2 ), and —CH 2 COOH; and

R 9 is H, or an alkyl or acyl group of 1 to 10 carbon length.

7. The vaccine formulation of claim 1 , wherein the adjuvant has one of the structures set forth below:

8. A method for treating an individual suffering from or suspected to be suffering from a cancer that expresses a MUC1 tumor-associated antigen comprising administering to the individual in need thereof, for a period of time, a liposomal vaccine formulation of claim 1 .

9. The method of claim 8 , wherein the cancer is breast cancer, parotid gland cancer, gastric cancer, esophageal cancer, head and neck cancer, gall bladder cancer, hepatocellular cancer, thyroid cancer, endometrial cancer, multiple myeloma, acute myelogenous leukemia, acute/chronic lymphoblastic leukemia, hairy-cell leukemia, follicular lymphoma, multiple myeloma, plasmacytoma, diffuse large B-cell lymphoma, pancreatic cancer, colon cancer, prostate cancer, ovarian cancer, adenocarcinoma of the lung, squamous cell lung cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, urinary bladder cancer, or urinary tract cancer.

10. The method of claim 8 , further comprising measuring an immune response in the individual.

11. The method of claim 10 , wherein measuring the immune response in the treated individual comprises measuring T-cell proliferation in the individual.

12. The method of claim 10 , wherein measuring the immune response in the treated individual comprises measuring antibody production in the individual.

13. The method of claim 8 , wherein the vaccine composition is administered by an intramuscular, intravenous, subcutaneous, intranodal, intratumoral, intraperitoneal, intradermal injection or by an implanted pump.

14. The method of claim 8 , wherein the individual is treated with cyclophosphamide, daclizumab or imatinib prior to treatment with the vaccine formulation of claim 1 .

15. A method of inducing and/or sustaining a cellular and humoral immune response in an individual comprising administering to an individual, for a period of time, a liposomal vaccine formulation of claim 1 .

16. The method of claim 15 , wherein the method further comprises measuring T-cell proliferation in the individual.

17. The method of claim 15 , wherein the method further comprises measuring antibody production in the individual.

18. The vaccine formulation of claim 1 , wherein the carrier lipid is selected from DMPG, DPPC or a or a pharmaceutically acceptable salt thereof, or combination thereof.

19. The vaccine formulation of claim 1 , wherein the lipid covalently attached to an amino acid residue is, at each occurrence, a myristoyl chain.

20. The vaccine formulation of claim 1 , wherein the adjuvant has the following structure: