MUC1 Based Glycolipopeptide Vaccine with Adjuvant

Abstract

Provided herein are liposomal glycolipopeptidic vaccine formulations comprising an adjuvant and an immunogen for immunotherapy and/or treatment of cancer.

1 - 18 . (canceled) 
     
     
         19 . 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 comprising:
 (a) a peptide comprising at least two copies of a core tandem repeat:   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   TSAPDTRPAPGSTAPPAHGV, 
                 
             
                
                
               
            
           
         
         or a sequence at least 85% identical to SEQ ID NO: 1, or linear permutations thereof;
 wherein
 S and T are independently, at each occurrence, optionally substituted with a cancer-associated carbohydrate epitope Te; 
 
 
         (b) a lipopeptide covalently attached to (a) having the formula:
   H 2 N-( aa   1 )*( aa   2 )*( aa   3 )-OH 
 wherein
 aa 1  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 2  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 3  is independently, at each occurrence, selected from L or G; 
 * independently, at each occurrence, represents a lipid covalently attached to an amino acid residue; 
 
 
         (c) 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 −0; 
           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(O)(O)(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 
         (d) one or more carrier lipids. 
       
     
     
         20 . The method of  claim 19 , 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. 
     
     
         21 . The method of  claim 19 , further comprising measuring an immune response in the individual. 
     
     
         22 . The method of  claim 21 , wherein measuring the immune response in the treated individual comprises measuring T-cell proliferation in the individual. 
     
     
         23 . The method of  claim 21 , wherein measuring the immune response in the treated individual comprises measuring antibody production in the individual. 
     
     
         24 . The method of  claim 19 , wherein the vaccine composition is administered by an intramuscular, intravenous, subcutaneous, intranodal, intratumoral, intraperitoneal, intradermal injection or by an implanted pump. 
     
     
         25 . The method of  claim 19 , wherein the individual is treated with cyclophosphamide, daclizumab or imatinib prior to treatment with the vaccine formulation of claim  1 . 
     
     
         26 . 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 comprising:
 (a) a peptide comprising at least two copies of a core tandem repeat:
 TSAPDTRPAPGSTAPPAHGV, (SEQ ID NO: 1) 
   or a sequence at least 85% identical to SEQ ID NO: 1, or linear permutations thereof;
 wherein
 S and T are independently, at each occurrence, optionally substituted with a cancer-associated carbohydrate epitope Te; 
 
   (b) a lipopeptide covalently attached to (a) having the formula:
   H 2 N-( aa   1 )*( aa   2 )*( aa   3 )-OH 
 wherein
 aa 1  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 2  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 3  is independently, at each occurrence, selected from L or G; 
 * independently, at each occurrence, represents a lipid covalently attached to an amino acid residue; 
 
   (c) 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(O)(O)(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 
       
       
         
           
           
               
               
           
         
         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 
         (d) one or more carrier lipids. 
       
     
     
         27 . The method of  claim 26 , wherein the method further comprises measuring T-cell proliferation in the individual. 
     
     
         28 . The method of  claim 26 , wherein the method further comprises measuring antibody production in the individual. 
     
     
         29 . A method of treating a disease, disorder or condition associated with hypoglycosylated MUC1 in an individual comprising administering to an individual having hypoglycosylated MUC1, for a period of time, a liposomal vaccine formulation of claim  1  comprising:
 (a) a peptide comprising at least two copies of a core tandem repeat: 
 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   TSAPDTRPAPGSTAPPAHGV, 
                 
             
                
                
               
            
           
         
         or a sequence at least 85% identical to SEQ ID NO: 1, or linear permutations thereof;
 wherein
 S and T are independently, at each occurrence, optionally substituted with a cancer-associated carbohydrate epitope Te; 
 
 
         (b) a lipopeptide covalently attached to (a) having the formula:
   H 2 N-( aa   1 )*( aa   2 )*( aa   3 )-OH 
 wherein
 aa 1  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 2  is independently, at each occurrence, selected from S, T, K, R or C; 
 aa 3  is independently, at each occurrence, selected from L or G; 
 * independently, at each occurrence, represents a lipid covalently attached to an amino acid residue; 
 
 
         (c) 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(O)(O)(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 
       
       
         
           
           
               
               
           
         
         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 
         (d) one or more carrier lipids. 
       
     
     
         30 . The method of  claim 29 , wherein the hypoglycosylated MUC1 in the individual is associated with a cancer. 
     
     
         31 . The method of  claim 19 , 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). Other suitable phospholipids further include 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. 
     
     
         32 . The method of  claim 19 , wherein (b) is attached to the carboxy terminus of (a). 
     
     
         33 . The method of  claim 19 , wherein (a)+(b) and (c) are in a weight (a)+(b):weight (c) ratio of from about 1:10 to about 10:1. 
     
     
         34 . The method of  claim 19 , wherein Te is, independently at each occurrence, selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a T-hapten. 
     
     
         35 . The method of  claim 19 , 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.   
     
     
         36 . The method of  claim 19 , wherein at least one strongly lipophilic group is one of the structures set forth below 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 19 , 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. 
       
     
     
         38 . The method of  claim 19 , wherein the adjuvant has one of the structures set forth below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . The method of  claim 19 , wherein the peptide is substituted with at least 6 Te. 
     
     
         40 . The method of  claim 19 , wherein the peptide comprises H 2 N-TSAPDT(Tn)RPAPGS(Tn)T(Tn)APPAHGVTSAPDT(Tn)RPAPGS(Tn)T(Tn)APPAHGVS*S*L-OH
 (SEQ ID NO: 2) wherein Tn represents GalNAcα1.   
     
     
         41 . The method of  claim 19 , wherein the adjuvant is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method of  claim 19 , wherein the method further comprises administering an anti-cancer agent. 
     
     
         43 . The method of  claim 19 , wherein the method further comprises administering an anti-cancer therapy, radiotherapy, immunotherapy, hormone therapy, surgery or gene therapy.