IP Library › Granted Patent US 12,390,525
Granted Patent B2
US 12,390,525 · App. 17/529,665 · Granted Aug 19, 2025

Constructs for enhancing immune responses

Inventors: Hildegund C. J. Ertl (Villanova, PA); Marcio O. Lasaro (Maple Shade, NJ); Luis C. S. Ferreira (Sao Paulo, BR)
Assignee: THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY
A61K39/245A61K39/12C07K14/005C12N7/00A61K2039/53A61K2039/57C07K2319/00C07K2319/10C12N2710/10043C12N2710/16622C12N2710/16634Y02A50/30
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Quick Facts
Patent No.
US 12,390,525
App. No.
17/529,665
Granted
Aug 19, 2025
Kind
B2
Abstract

Chimeric protein constructs including a herpesvirus glycoprotein D (gD) and a heterologous polypeptide that interact with herpes virus entry mediator (HVEM) and enhance and enhance an immune response against the heterologous polypeptide and methods for their use are provided.

Claims (30)

1. A method of inducing an immune response comprising providing to a subject in need thereof a vaccine comprising a nucleic acid molecule which encodes a fusion protein, wherein the fusion protein comprises:

a. a first polypeptide segment comprising at least amino acids 1-240 of a mature Herpes simplex virus (HSV) glycoprotein D, wherein the first polypeptide segment does not comprise a full length mature glycoprotein D;

b. a second polypeptide segment comprising at least one antigen, wherein the at least one antigen is not an HSV glycoprotein D antigen, wherein the N terminus of the second polypeptide segment is linked to the C terminus of the first polypeptide segment; and

c. a third polypeptide segment comprising a C terminal portion of the HSV glycoprotein D, wherein the N terminus of the third polypeptide segment is linked to the C terminus of the second polypeptide segment,

wherein the at least one antigen is selected from the group consisting of: an influenza virus antigen; a nucleoprotein P influenza virus antigen, a Plasmodium antigen, a human papilloma virus (HPV) antigen, a human papilloma virus HPV16 antigen, an HPV E5 protein, an HPV E6 protein, an HPV E7 protein, a human immunodeficiency virus (HIV) antigen, and an HIV gag antigen.

2. The method of claim 1 , wherein the HSV is selected from the group consisting of HSV-1 and HSV-2.

3. The method of claim 2 , wherein the first polypeptide segment comprises an amino acid sequence selected from the group consisting of: amino acids 26-265 of SEQ ID NO: 27; amino acids 26-265 of SEQ ID NO: 29; amino acids 26-269 of SEQ ID NO: 27; amino acids 26-269 of SEQ ID NO: 29; amino acids 26-313 of SEQ ID NO: 27; amino acids 26-313 of SEQ ID NO: 29; amino acids 26-319 of SEQ ID NO: 27 with the exception that amino acid 319 is alanine instead of tryptophan; and amino acids 26-319 of SEQ ID NO: 29 with the exception that amino acid 319 is alanine instead of tryptophan.

4. The method of claim 3 , wherein the first polypeptide segment is encoded by a nucleic acid sequence comprising nucleotides 76-795 of SEQ ID NO:26; or nucleotides 350-1069 of SEQ ID NO:28.

5. The method of claim 1 , wherein the nucleic acid molecule encodes the amino acid sequence encoded SEQ ID NO:35.

6. The method of claim 1 , wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO: 34; SEQ ID NO:35; SEQ ID NO:36; and SEQ ID NO:37.

7. The method of claim 1 , wherein the fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:33.

8. The method of claim 1 , wherein the nucleic acid molecule is in a viral vector.

9. The method of claim 1 , wherein the nucleic acid molecule is naked DNA.

10. The method of claim 1 , wherein the nucleic acid molecule is in a bacterial vector.

11. The method of claim 1 , wherein the second polypeptide segment comprises the HPV E5 protein, the HPV E6 protein, and the HPV E7 protein.

12. The method of claim 1 , wherein the third polypeptide segment comprises the transmembrane domain of the HSV glycoprotein D.

13. A method of inducing an immune response comprising providing to a subject in need thereof a vaccine comprising a fusion protein, wherein the fusion protein comprises:

a. a first polypeptide segment comprising at least amino acids 1-240 of a mature Herpes simplex virus (HSV) glycoprotein D, wherein the first polypeptide segment does not comprise a full length glycoprotein D;

b. a second polypeptide segment comprising at least one antigen, wherein the at least one antigen is not an HSV glycoprotein D antigen, wherein the N terminus of the second polypeptide segment is linked to the C terminus of the first polypeptide segment; and

c. a third polypeptide segment comprising a C terminal portion of the HSV glycoprotein D, wherein the N terminus of the third polypeptide segment is linked to the C terminus of the second polypeptide segment.

14. The method of claim 13 , wherein the HSV is selected from the group consisting of HSV-1 and HSV-2.

15. The method of claim 14 , wherein the first polypeptide segment comprises an amino acid sequence selected from the group consisting of amino acids 26-265 of SEQ ID NO: 27, amino acids 26-265 of SEQ ID NO: 29; amino acids 26-269 of SEQ ID NO: 27; amino acids 26-269 of SEQ ID NO: 29; amino acids 26-313 of SEQ ID NO: 27; amino acids 26-313 of SEQ ID NO: 29; amino acids 26-319 of SEQ ID NO: 27 with the exception that amino acid 319 is alanine instead of tryptophan; and amino acids 26-319 of SEQ ID NO: 29 with the exception that amino acid 319 is alanine instead of tryptophan.

16. The method of claim 15 , wherein the first polypeptide segment is encoded by a nucleic acid sequence comprising nucleotides 76-795 of SEQ ID NO:26; or nucleotides 350-1069 of SEQ ID NO:28.

17. The method of claim 13 , wherein the at least one antigen is selected from the group consisting of an influenza virus antigen, a nucleoprotein P influenza virus antigen, a Plasmodium antigen, a human papilloma virus (HPV) antigen, human papilloma virus HPV16 antigen, HPV E5 protein, HPV E6 protein, HPV E7 protein, a human immunodeficiency virus (HIV) antigen, and an HIV gag antigen.

18. The method of claim 13 , wherein the fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:33.

19. The method of claim 13 , wherein the fusion protein is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO: 34; SEQ ID NO:35; SEQ ID NO:36; and SEQ ID NO:37.

20. The method of claim 17 , wherein the second polypeptide segment comprises the HPV E5 protein, the HPV E6 protein, and the HPV E7 protein.

21. The method of claim 13 , wherein the third polypeptide segment comprises the transmembrane domain of the HSV glycoprotein D.

22. The method of claim 1 , wherein the Plasmodium antigen selected from the group consisting of thrombospondin-related anonymous protein (TRAP), ring-infected erythrocyte surface antigen (RESA), merozoite surface protein 1 (MSP1), merozoite surface protein 2 (MSP2), merozoite surface protein 3 (MSP3), and glutamate-rich antigen (GLURP).

23. The method of claim 17 , wherein a Plasmodium antigen selected from the group consisting of thrombospondin-related anonymous protein (TRAP), ring-infected erythrocyte surface antigen (RESA), merozoite surface protein 1 (MSP1), merozoite surface protein 2 (MSP2), merozoite surface protein 3 (MSP3), and glutamate-rich antigen (GLURP).

Assignments (1)
CONFIRMATORY LICENSE Recorded Jan 3, 2024
From: WISTAR INSTITUTE
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066001/0823 →
Continuity (7)
Continuation 16408730 · May 10, 2019
Continuation 15639296 · Jun 30, 2017
Continuation 14628784 · Feb 23, 2015
Continuation 13239771 · Sep 22, 2011
Continuation 12438889
Provisional Application 60840526 · Aug 28, 2006
Related Publication 20220331423A1 · Oct 20, 2022
References Cited (58)
US 5814486A · Cohen et al. · 1998 [cited by applicant]
US 6936255B1 · Wettendorff et al. · 2005 [cited by applicant]
US 8962816B2 · Ertl et al. · 2015 [cited by applicant]
US 9624510B2 · Ertl et al. · 2017 [cited by applicant]
US 9724406B2 · Ertl · 2017 [cited by examiner]
US 10328146B2 · Ertl et al. · 2019 [cited by applicant]
US 11207402B2 · Ertl · 2021 [cited by examiner]
US 20040253210A1 · Robert-Guroff et al. · 2004 [cited by applicant]
US 20050095270A1 · Staecker et al. · 2005 [cited by applicant]
US 20130315871A1 · Roy et al. · 2013 [cited by applicant]
US 20140065105A1 · Wilson et al. · 2014 [cited by applicant]
US 20140248305A1 · Ertl et al. · 2014 [cited by applicant]
US 20190167813A1 · Ertl et al. · 2019 [cited by applicant]
EP 1336619A2 · 2003 [cited by applicant]
WO 2006120034A1 · 2006 [cited by applicant]
WO 2007071997A2 · 2007 [cited by applicant]
European Search Report, EP17837398, date of mailing Apr. 20, 2020. [cited by applicant]
International Search Report and Written Opinion, PCT/US17/43315, date of mailing Nov. 30, 2017. [cited by applicant]
International Search Report, PCT/US2007/018939, date of mailing May 16, 2008. [cited by applicant]
Singapore Search Report, SG Application No. 11201900808S, mailing date Apr. 29, 2020. [cited by applicant]
Altstein , et al., “Immunization with influenza A NP-Expressing Vaccinia Virus Recombinant Protects Mice Against Experimental Infection with Hyuman and Avian Influenza Viruses”, Archives of Virology, vol. 151, No. 5, Ma… [cited by applicant]
Alves , et al., “Antibody Response in Mice Immunized with a Plasmid DNA Encoding the Colonization Factor Antigen I of Enterotoxigenic [cited by applicant]
Bayer , et al., “Improved vaccine protection against retrovirus infection after co-administration of adenoviral vectors encoding viral antigens and type I interferon subtypes.”, 2011 Retrovirology 8:75 (15 pages). [cited by applicant]
Casimiro , et al., “Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with DNA and recombinant adenoviral vaccine vectors expressing Gag.”, 2005, J Virol 79(24):15547-15555. [cited by applicant]
Casimiro , et al., “Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene”, 2003,… [cited by applicant]
Cervasi , et al., “Immunological and Virological Analyses of Rhesus Macaques Immunized with Chimpanzee Adenoviruses Expressing the Simian Immunodeficiency Virus Gag/Tat Fusion Protein and Challenged Intrarectally with R… [cited by applicant]
Chawla , et al., “Adenovirus-vectored vaccines”, Dev Biol Stand, Mar. 16, 2008, vol. 18, No. 3, pp. 293-307, Table 1. [cited by applicant]
Chen , et al., “Adenovirus-Based Vaccines: Comparison of Vectors from Three Species of Adenoviridae.”, 2010, Journal of Virology 84(20):10522-32. [cited by applicant]
Chen , et al., “Direct Observation of Xe and Kr Adsorption in a Xe-Selective Microporous Metal-Organic Framework.”, J. Am. Chem. Soc., May 2015, 137, 7007-7010. [cited by applicant]
Engram , et al., “Vaccine-induced, simian immunodeficiency virus-specific CD8+ T cells reduce virus replication but do not protect from simian immunodeficiency virus disease progression.”, 2009, J Immunol 183:706-717. [cited by applicant]
Hazama , et al., “Adjuvant-independent enhanced immune responses to recombinant Herpes Simplex Virust Type 1 Glycoprotein D by fusion biologically active interlukin-2”, Vaccine, vol. 11, No. 6, 1993, pp. 629-636. (Abstr… [cited by applicant]
He , et al., “A simplified system for generating recombinant adenoviruses.”, 1998, PNAS 95:2509-14. [cited by applicant]
Hinuma , et al., “A novel strategy for converting recombinant viral protein into high immunogeic antigen”, FEBS Letters, vol. 288, No. 1/2, Aug. 1991, pp. 138-142 (Abstract Only). [cited by applicant]
Horwitz , “Function of adenovirus E3 proteins and their interactions with immunoregulatory cell proteins.”, 2004, J Gene Med 6:S172-S183 (Abstract only). [cited by applicant]
Lasaro , et al., “Antibody-inducing properties of a prototype bivalent Herpes Simplex virus/Enterotoxigenic [cited by applicant]
Lasaro , et al., “Anti-Tumor DNA Vaccines based on the Expression of Human Papillomavirus-16 E6/E7 Oncoproteins Genetically Fused With The Glycoprotein D from Herpes Simplex Virus-1”, Microbes and Infection, vol. 7, No.… [cited by applicant]
Lasaro , et al., “Human papillomavirus-associated cervical cancer: Prophylactic and therapeutic vaccines.”, Gene Therapy Molecular Biology, 2004, vol. 8, pp. 291-306. [cited by applicant]
Lasaro , et al., “New insights on adenovirus as vaccine vectors”, Molecular Therapy, vol. 17, No. 8, Aug. 1, 2009, pp. 1333-1339. [cited by applicant]
Lasaro , et al., “Vaccine-induced T cells Provide Partial Protection Against High-dose Rectal SIVmac239 Challenge of Rhesus Macaques”, Molecular Therapy, 19(2), Feb. 2011, 417-426. [cited by applicant]
Lewis , et al., “Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treament for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy”,… [cited by applicant]
Lichtenstein , et al., “Functions and mechanisms of action of the adenovirus E3 proteins.”, 2004, International Reviews of Immunology 23: 75-111. [cited by applicant]
McCoy , et al., “Effect of Preexisting Immunity to Adenovirus Human Serotype 5 Antigens on the Immune Responses of Nonhuman Primates to Vaccine Regimens Based on Human- or Chimpanzee-Derived Adenovirus Vectors”, Journal… [cited by applicant]
Michel , et al., “Enhanced Immunogenicity of HPV 16 E7 Fusion Proteins in DNA Vaccination”, Virology, 2002, vol. 294, pp. 47-59. [cited by applicant]
Patel , et al., “DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge”, PNAS, 110(8), Feb. 2013, 2975-2980. [cited by applicant]
Plonka , et al., “Light Hydrocarbon Adsorption Mechanisms in Two Calcium-Based Microporous Metal Organic Frameworks.”, Chem. Mater. 2016, 28, 1636-1646 (Abstract Only). [cited by applicant]
Saha , et al., “A Fused Gene of Nucleoprotein (NP) and Herpes Simplex Virus Genes (VP22) Induces Highly Protective Immunity Against Different Subtypes of Influenza Virus”, Virology, vol. 354, No. 1, Oct. 10, 2006, pp. 4… [cited by applicant]
Santra , et al., “Heterologous Prime/Boost Immunizations of Rhesus Monkeys Using Chimpanzee Adenovirus Vectors”, Vaccine, 27(42), Sep. 2009, 5837-5845. [cited by applicant]
Shiver , et al., “Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.”, 2002, Nature 415:331-335. [cited by applicant]
Small , et al., “Viruses—From Pathogens to Vaccine Carriers”, Curr. Opin. Virol., 1(4), Oct. 2011, 241-245. [cited by applicant]
Tatsis , et al., “Adenovirus Vector-Induced Immune Responses in Nonhuman Primates: Responses to Prime Boost Regimens”, Journal of Immunology, 182, 2009, 6587-6599. [cited by applicant]
Tatsis , et al., “Chimpanzee-origin adenovirus vectors as vaccine”, 2006, Gene Therapy 13:421-429. [cited by applicant]
Tatsis , et al., “Multiple Immunizations with Adenovirus and MVA vectors improve CD8+ T cell functionality and mucosal homing”, Virology, 367(1), Oct. 2007, 156-167. [cited by applicant]
Watson , et al., “Herpes Simplex Virus Type=1 Glycoprotein D Gene: Nucleotide Sequence and Expression in [cited by applicant]
Xiang , “Chimpanzee Adenovirus Antibodies in Humans, Sub-Saharan Africa”, 2006, Emerging Infectious Diseases 12(10):1596-1599. [cited by applicant]
Zago , et al., “Use of herpes simplex virus and pseudorabies virus chimeric glycoprotein D molecules to identify regions critical for membrane fusion.”, PNAS, 2004, vol. 101, No. 50, pp. 17498-17503. [cited by applicant]
Zhou , et al., “A Universal Influenza A Vaccine Based on Adenovirus Expressing Matrix-2 Ectodomain and Nucleoprotein Protects Mice from Lethal Challenge”, Molecular Therapy, 18(12), Dec. 2010, 2182-2189. [cited by applicant]
Zhou , et al., “An efficient method of directly cloning chimpanzee adenovirus as a vaccine vector”, Natl. Protoc., 5(11), Nov. 2010, 1775-1785. [cited by applicant]
Zolla-Pazner , et al., “Analysis of V2 Antibody Responses Induced in Vaccinees in the ALVAC/AIDSVAX HIV-1 Vaccine Efficacy Trial”, PLOS ONE, 8(1), Jan. 2013, 1-11. [cited by applicant]