Immunogenic compositions and methods of using the compositions for inducing humoral and cellular immune responses

• US 9,044,420 B2
• Filed: 04/06/2012
• Issued: 06/02/2015
• Est. Priority Date: 04/08/2011
• Status: Active Grant

• Current Assignee: Immune Design Corp. (Merck & Co., Inc.)
• Original Assignee: Immune Design Corp. (Merck & Co., Inc.)
• Inventors: Dubensky, Thomas W. Jr., Robbins, Scott H.
• Primary Examiner(s): Humphrey, Louise
• Application Number:
  US13/441,502
• Publication Number:
  US 20120328655A1
• Time in Patent Office: 1,152 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/001104 Epidermal growth factor receptors [EGFR]
• CPC Class Codes: A61K 39/001108 Platelet-derived growth factor receptors [PDGFR]
• CPC Class Codes: A61K 39/001109 Vascular endothelial growth factor receptors [VEGFR]
• CPC Class Codes: A61K 39/00111 Hepatocyte growth factor receptor [HGFR or c-met]
• CPC Class Codes: A61K 39/001149 Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR
• CPC Class Codes: A61K 39/001151 p53
• CPC Class Codes: A61K 39/001152 Transcription factors, e.g. SOX or c-MYC
• CPC Class Codes: A61K 39/001153 Wilms tumor 1 [WT1]
• CPC Class Codes: A61K 39/001156 Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]
• CPC Class Codes: A61K 39/001161 Caspases
• CPC Class Codes: A61K 39/001162 Kinases, e.g. Raf or Src
• CPC Class Codes: A61K 39/001164 GTPases, e.g. Ras or Rho
• CPC Class Codes: A61K 39/001168 Mesothelin [MSLN]
• CPC Class Codes: A61K 39/00117 Mucins, e.g. MUC-1
• CPC Class Codes: A61K 39/001171 : Gangliosides, e.g. GM2, GD2 or GD3
• CPC Class Codes: A61K 39/001172 : Sialyl-Thomson-nouvelle antigen [sTn]
• CPC Class Codes: A61K 39/001182 : Carcinoembryonic antigen [CEA]
• CPC Class Codes: A61K 39/001184 : Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
• CPC Class Codes: A61K 39/001186 : MAGE
• CPC Class Codes: A61K 39/001189 : PRAME
• CPC Class Codes: A61K 39/001191 : Melan-A/MART
• CPC Class Codes: A61K 39/001192 : Glycoprotein 100 [Gp100]
• CPC Class Codes: A61K 39/001193 : Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
• CPC Class Codes: A61K 39/001194 : Prostate specific antigen [PSA]
• CPC Class Codes: A61K 39/001195 : Prostate specific membrane antigen [PSMA]
• CPC Class Codes: A61K 39/12 : Viral antigens
• CPC Class Codes: A61K 39/245 : Herpetoviridae, e.g. herpes simplex virus
• CPC Class Codes: A61K 39/39 : characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2710/16634 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/15034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/16043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2810/609 : positive strand RNA viruses
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compositions and methods are provided herein for improved dual immunization strategies that induce in a subject an immune response that includes a humoral immune response and cellular immune response, both CD4 and CD8 T lymphocyte immune responses, thereby providing a complete adaptive immune response to one or more antigens. The methods described are therefore useful for treating and/or preventing (i.e., reducing the likelihood or risk of occurrence) different diseases, disorders, and conditions such as cancers and infectious diseases for which induction of both a humoral immune response and cellular immune response is desired and beneficial.

Claims

1. A method for priming and boosting a CD8 T cell immune response in a subject, the method comprising (a) administering to the subject at least one dose of a first immunogenic composition comprising (i) a lentiviral vector comprising a nucleotide sequence that encodes a first immunogen or an immunogenic fragment thereof, wherein the lentiviral vector is incorporated into a vector particle, wherein the vector particle comprises a lentiviral vector genome and an alpha virus envelope;

and (b) subsequently administering to the subject at least one dose of a second immunogenic composition comprising (i) at least the first immunogen or an immunogenic fragment thereof and (ii) a TRL4 agonist, thereby priming and boosting a CD8 T cell immune response specific for the first immunogen, wherein the TRL4 agonist is a compound of the following structure;

2. The method of claim 1, wherein (i) the first immunogenic composition further comprises a second adjuvant;

or (ii) the second composition further comprises an adjuvant;

or both (i) and (ii).

3. The method of claim 1, wherein at least two doses of the first immunogenic composition are administered or wherein at least two doses of the second immunogenic composition are administered.

4. The method of claim 1, wherein (a) two doses;

(b) three doses;

(c) four doses;

or (d) five doses of the first immunogenic composition are administered.

5. The method of claim 4, wherein two doses of the first immunogenic composition are administered prior to administration of the second immunogenic composition.

6. The method of claim 1, wherein the immune response induced by the method comprises a CD4 T cell immune response specific for the first immunogen.

7. The method of claim 1, wherein the second immunogenic composition further comprises a second immunogen or an immunogenic fragment thereof, and wherein the lentiviral vector further comprises a nucleotide sequence that encodes the second immunogen or an immunogenic fragment thereof, wherein the method induces an immune response specific for the second immunogen.

8. The method of claim 7 wherein the immune response induced by the method comprises a CD4 T cell response specific for the second immunogen.

9. The method of claim 1, wherein A1 is phosphate or phosphate salt, A2 is hydrogen, R1, R3, R5 and R6 are undecyl, and R2 and R4 are tridecyl.

10. The method of claim 9, wherein the compound is formulated in a stable oil-in-water emulsion.

11. The method of claim 2, wherein the first immunogen is (a) a tumor-associated antigen or (b) from an infectious microorganism selected from a virus, a bacterium, a fungus, and a parasite.

12. The method of claim 11, wherein the first immunogen is a tumor-associated antigen selected from a renal cell carcinoma antigen, a prostate cancer antigen, a mesothelioma antigen, a pancreatic cancer antigen, a melanoma antigen, a breast cancer antigen, a lung cancer antigen, and an ovarian cancer antigen.

13. The method of claim 11, wherein the first immunogen is selected from the group consisting of prostatic acid phosphatase, prostate specific antigen, NKX3.1, prostate specific membrane antigen, PRAME;

BAGE;

RAGE, Lage (also known as NY ESO

     1), SAGE, HAGE, GAGE, Plu-1, HASH-1, HasH-2, Cripto, Criptin, MART-1/Melan-A, gp100, gp75, mda-7, tyrosinase, tyrosinase-related protein, p53, Ras, c-Myc, A-Raf, B -Raf, and C- Raf, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE- A12, MART-1, BAGE, DAM-6, -10, GAGE-I, GAGE-2, GAGE-8, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7B, NA88-A, MART-I, MC1R, Gp100, PSM, TRP-1, TRP-2, ART-4, CAMEL, CEA, Cyp-B, hTERT, hTRT, iCE, MUC1, MUC2, PRAME, P15, RU1, RU2, SART-1, SART-3, Wilms'"'"' tumor antigen (WT1), AFP, μ

-catenin/m, Caspase-8/m, CEA, CDK-4/m, ELF2M, GnT-V, G250, HSP70-2M, HST-2, KIAA0205, MUM-I, MUM-2, MUM-3, Myosin/m, SART-2, TRP-2/INT2, 707-AP, Annexin II, CDC27/m, TPI/mbcr-abl, BCR-ABL, interferon regulatory factor 4 (IRF4), ETV6/AML, LDLR/FUT, Pml/RAR, Tumor-associated calcium signal transducer 1 (TACSTD

     1) TACSTD2, Epidermal Growth Factor receptor (EGFR and EGFRvIII), platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), integrin-linked kinase (ILK), STAT3, STAT5, STAT6, HIF-1, HIF-2, Nuclear Factor-Kappa B (NF-KB), Notchl-4, c-Met, mammalian targets of rapamycin (mTOR), WNT, PMSA, PR-3, MDM2, Mesothelin, renal cell carcinoma—

5T4, SM22-alpha, carbonic anhydrases I (CAI) and IX (CAIX) (also known as G250), STEAD, TEL/AML1, GD2, proteinase3, hTERT, sarcoma translocation breakpoints, EphA2, ML-IAP, EpCAM, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, ALK, androgen receptor, cyclin B1, polysialic acid, MYCN, RhoC, GD3, fucosyl GM1, mesothelian, PSCA, sLe, PLAC1, GM3, BORIS, Tn, GLoboH, NY-BR-1, RGs5, SART3, STn, PAX5, OY-TES 1, sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, B7H3, legumain, TIE2, PAGE4, MAD-CT-1, FAP, MAD-CT-2, and fos related antigen 1.

14. The method of claim 11, wherein the first immunogen is from a virus.

15. The method of claim 14, wherein the virus is Herpes Simplex Virus-2 (HSV-2).

16. The method of claim 15, wherein the first immunogen is HSV-2 UL19 polypeptide or HSV-2 gD polypeptide.

17. The method of claim 7, wherein each of the first immunogen and the second immunogen is a tumor-associated antigen.

18. The method of claim 17, wherein each of the first immunogen and the second immunogen is selected from a renal cell carcinoma antigen, a prostate cancer antigen, a mesothelioma antigen, a pancreatic cancer antigen, a melanoma antigen, a breast cancer antigen, a lung cancer antigen, and an ovarian cancer antigen.

19. The method according to claim 18, wherein each of the first immunogen and the second immunogen is selected from the group consisting of a prostate cancer antigen selected from prostatic acid phosphatase, prostate specific antigen, NKX3.1, o˜

prostate specific membrane antigen, PRAME;

BAGE;

RAGE, Lage (also known as NY ESO

     1), SAGE, HAGE, GAGE, Plu-1, HASH-1, HasH-2, Cripto, Criptin, MART-1/Melan-A, gp100, gp75, mda-7, tyrosinase, tyrosinase-related protein, p53, Ras, c-Myc, A-Raf, B-Raf, and C-Raf, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE- A12, MART-1, BAGE, DAM-6, -10, GAGE-I, GAGE-2, GAGE-8, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7B, NA88-A, MART-I, MC1R, Gp100, PSM, TRP-1, TRP-2, ART-4, CAMEL, CEA, Cyp-B, hTERT, hTRT, iCE, MUC1, MUC2, PRAME, P15, RU1, RU2, SART-1, SART-3, Wilms'"'"' tumor antigen (WT1), AFP, μ

-catenin/m, Caspase-8/m, CEA, CDK-4/m, ELF2M, GnT-V, G250, HSP70-2M, HST-2, KIAA0205, MUM-I, MUM-2, MUM-3, Myosin/m, SART-2, TRP-2/INT2, 707-AP, Annexin II, CDC27/m, TPI/mbcr-abl, BCR-ABL, interferon regulatory factor 4 (IRF4), ETV6/AML, LDLR/FUT, Pml/RAR, Tumor-associated calcium signal transducer 1 (TACSTD

     1) TACSTD2, Epidermal Growth Factor receptor (EGFR and EGFRvIII), platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), integrin-linked kinase (ILK), STAT3, STAT5, STAT6, HIF-1, HIF-2, Nuclear Factor-Kappa B (NF-κ

B), Notchl-4, c-Met, mammalian targets of rapamycin (mTOR), WNT, PMSA, PR-3, MDM2, Mesothelin, renal cell carcinoma—

5T4, SM22-alpha, carbonic anhydrases I (CAI) and IX (CAIX) (also known as G250), STEAD, TEL/AML1, GD2, proteinase3, hTERT, sarcoma translocation breakpoints, EphA2, ML-IAP, EpCAM, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, ALK, androgen receptor, cyclin B1, polysialic acid, MYCN, RhoC, GD3, fucosyl GM1, mesothelian, PSCA, sLe, PLAC1, GM3, BORIS, Tn, GLoboH, NY-BR-1, RGs5, SART3, STn, PAX5, OY-TES1, sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE 1, B7H3, legumain, TIE2, PAGE4, MAD-CT-1, FAP, MAD-CT-2, and fos related antigen 1.

20. The method of claim 7, wherein each of the first immunogen and the second immunogen is an antigen from an infectious microorganism selected from a virus, a bacterium, a fungus, and a parasite.

21. The method of claim 20, wherein the infectious disease organism is a virus.

22. The method of claim 21, wherein the virus is Herpes Simplex Virus-2 (HSV-2).

23. The method of claim 22, wherein at least one of the first immunogen and the second immunogen is HSV-2 UL19 polypeptide and the other of the first immunogen and the second immunogen is HSV-2 gD polypeptide.

24. The method of claim 1, wherein the lentiviral vector particle delivers the nucleotide sequence to an antigen-presenting cell.

25. The method of claim 24, wherein the antigen-presenting cell is a dendritic cell, preferably a dendritic cell expressing DC-SIGN.

26. The method of claim 1, wherein the vector particle comprises an envelope that delivers the lentiviral vector particle to a dendritic cell expressing DC-SIGN.

27. The method of claim 26, wherein the envelope comprises a Sindbis virus E2 glycoprotein comprising an amino acid sequence having at least one amino acid change compared to SEQ ID NO:

1, wherein residue 160 of SEQ ID NO;

1 is either absent or an amino acid other than glutamic acid, and wherein the E2 glycoprotein is not fused to Sindbis virus E3 protein.

28. The method of claim 27, wherein the E2 glycoprotein binds to dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN).

29. The method of claim 1, wherein R1, R3, R5 and R6 are C11-C20 alkyl, and R2 and R4 are C12-C20 hydrocarbyl.

30. The method of claim 11 wherein the first immunogen is MAGE3 or Lage (NY ESO 1).

31. The method of claim 1, wherein the first immunogenic composition and the second immunogenic composition are administered concurrently and two doses are administered.

32. The method of claim 1 wherein the first composition further comprises (i) at least the first immunogen or an immunogenic fragment thereof and (ii) the TRL4 agonist, and wherein the second composition further comprises a lentiviral vector comprising a nucleotide sequence that encodes the first immunogen or an immunogenic fragment thereof, wherein the lentiviral vector is incorporated into a vector particle, wherein the vector particle comprises a lentiviral vector genome and an alpha virus envelope.

33. A method for priming and boosting a CD8 T cell immune response in a subject, the method comprising (a) administering to the subject at least one dose of a first immunogenic composition comprising (i) a lentiviral vector comprising a nucleotide sequence that encodes a first immunogen or an immunogenic fragment thereof, wherein the lentiviral vector is incorporated into a vector particle, wherein the vector particle comprises a lentiviral vector genome and an alpha virus envelope, and concurrently administering a second immunogenic composition comprising (i) at least the first immunogen or an immunogenic fragment thereof and (ii) a TRL4 agonist;

and (b) subsequently administering the first and second immunogenic compositions of (a), thereby priming and boosting a CD8 T cell immune response specific for the first immunogen, wherein the TRL4 agonist is a compound of the following structure;