WO2019075579A1 - Polythérapie de primovaccination-rappel - Google Patents

Polythérapie de primovaccination-rappel Download PDF

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WO2019075579A1
WO2019075579A1 PCT/CA2018/051329 CA2018051329W WO2019075579A1 WO 2019075579 A1 WO2019075579 A1 WO 2019075579A1 CA 2018051329 W CA2018051329 W CA 2018051329W WO 2019075579 A1 WO2019075579 A1 WO 2019075579A1
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seq
sequence
combination
peptide
peptides
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Matthew John ATHERTON
Brian Lichty
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Atherton Matthew John
Brian Lichty
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
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    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/20011—Rhabdoviridae
    • C12N2760/20041—Use of virus, viral particle or viral elements as a vector
    • C12N2760/20043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present disclosure relates to combination prime:boost cancer therapies and compositions for use in the same. Novel prime:boost antigens are also disclosed.
  • Oncolytic viruses specifically infect, replicate in and kill malignant cells, leaving normal tissues unaffected.
  • OVs Oncolytic viruses
  • Several OVs have reached advanced stages of clinical evaluation for the treatment of various neoplasms. Once approved, such viral agents could substitute or be combined with standard cancer therapies, allowing for reduced toxicity and improved therapeutic outcomes.
  • VSV vesicular stomatitis virus
  • other rhabdoviruses displaying oncolytic activity have been described recently.
  • the non-VSV Maraba virus showed the broadest oncotropism in vitro.
  • a mutant Maraba virus with improved tumor selectivity and reduced virulence in normal cells was engineered.
  • the attenuated strain is a double mutant strain containing both G protein (Q242R) and M protein (L123W) mutations.
  • this attenuated strain called MG1 or Maraba MG1 , demonstrated potent anti-tumor activity in xenograft and syngeneic tumor models in mice, with superior therapeutic efficacy than the attenuated VSV, VSVAM51.
  • anti-tumor efficacy of oncolytic viruses includes direct oncolysis stimulating anti-tumor immunity.
  • Tumor-specific adaptive immune cells may patrol the tissues and destroy tumor cells that have been missed by the OV.
  • immune cell memory may also assist in preventing tumor recurrence.
  • Another strategy defined as an oncolytic vaccine, consists of expressing a tumor antigen from the OV.
  • VSV could also be used as a cancer vaccine vector.
  • hDCT VSV-human dopachrome tautomerase
  • the therapies include a lentivirus that encodes as an antigen: a Human Papilloma Virus (HPV) E6/E7 fusion protein, human Six-Transmembrane Epithelial Antigen of the Prostate (huSTEAP) protein, or Cancer Testis Antigen 1 (the "prime”); and a Maraba MG 1 virus (the "boost”) that encodes the same antigen as the prime.
  • HPV Human Papilloma Virus
  • huSTEAP human Six-Transmembrane Epithelial Antigen of the Prostate
  • the primary Cancer Testis Antigen 1
  • a Maraba MG 1 virus Maraba MG 1 virus
  • MAGEA3 as an antigen
  • Maraba MG1 virus that encodes the same antigen
  • Cancer therapies that improve the outcome for cancer patients are desireable.
  • Oncolytic vaccine methods are a field where such improvements are needed.
  • the combination prime:boost therapy uses a peptide or combination of peptides as a priming vaccine.
  • the peptide or combination of peptides includes one or more antigenic epitopes.
  • a recombinant Maraba MG1 virus expressing a protein that includes the antigenic epitope is used as the boosting virus.
  • a method of treating a cancer in a mammal with a combination prime boost vaccine said cancer being a tumor expressing HPV protein comprising first administering a peptide or combination of peptides comprising at least one antigenic peptide of an HPV oncogenic protein said peptide or combination of peptides formulated for use in generating an immune response in said mammal to said HPV oncogenic protein; and second administering an oncolytic virus comprising a nucleic acid that encodes at least one oncogenic peptide present in the sequence of an HPV oncogenic protein, wherein the antigenic protein has an amino acid sequence that includes the amino acid sequences of the antigenic peptide.
  • the second virus is a Maraba MG 1 oncolytic virus.
  • the peptide is not provided by a viral vector encoding the nucleic acid sequence of the peptide.
  • a combination prime:boost therapy for use in inducing an immune response in a mammal.
  • the combination therapy includes: a peptide or combination of peptides formulated to generate an immune response in the mammal, and a Maraba MG1 virus that is capable of expressing an antigenic protein, where the antigenic protein has an amino acid sequence that includes the antigenic amino acid sequences of the peptide or combination of peptides.
  • the peptide or peptides are from 15 to 100 amino acids in length.
  • the peptide or peptides include at least one antigenic amino acid sequence selected from the group consisting of: a sequence that comprises at least 9 sequential amino acids from SEQ ID NO: 1 ; SEQ ID Nos: 2-32, and SEQ ID Nos: 54-61.
  • the antigenic protein is a
  • the antigen protein may have a sequence that includes one or more of SEQ ID Nos: 46-49.
  • the present disclosure provides for uses of the combination of (i) peptide or peptides and (ii) Maraba MG1 virus, and methods of using the combination of (i) peptide or peptides and (ii) Maraba MG1 virus.
  • the uses and methods may relate to: treatment or prevention of an HPV-derived cancer, such as a cancer caused by HPV16 or HPV18; increasing an immune response against E6 and/or
  • FIG. 1 is an illustration of the sequence of an exemplary HPV E6/E7 fusion protein that may be expressed by a Maraba MG1 virus and used in an combination prime:boost therapy according to the present disclosure.
  • Fig. 2 is a graph illustrating the percentage of CD8+ T cells positive for
  • FIG. 3 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 40.
  • Fig. 4 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 53.
  • Fig. 5 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 36.
  • Fig. 6 is a graph illustrating the percentage of CD8+ T cells positive for both IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 38.
  • Fig. 7 is a graph illustrating the percentage of CD8+ T cells positive for both IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 40.
  • Fig. 8 is a graph illustrating the percentage of CD8+ T cells positive for both IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 53.
  • Fig. 9 is a graph illustrating the percentage of CD8+ T cells positive for both IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, or after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, followed by restimulation with a peptide according to SEQ ID NO: 36.
  • Fig. 10 is a graph illustrating the mean tumour volumes over time of mice treated with an exemplary prime:boost therapy according to the present disclosure, or with control treatments.
  • Fig. 1 1 is a graph illustrating the percent survival over time of mice treated with an exemplary prime:boost therapy according to the present disclosure, or with control treatments.
  • Fig. 12 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, or after a prime and a boost with MG1-E6E7, followed by re-stimulation with a peptide according to SEQ ID NO: 2.
  • Fig. 13 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, or after a prime and a boost with MG1-E6E7, followed by re-stimulation with a peptide according to SEQ ID NO: 3.
  • Fig. 14 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, or after a prime and a boost with MG1-E6E7, followed by re-stimulation with a peptide according to SEQ ID NO: 2.
  • Fig. 15 is a graph illustrating the percentage of CD8+ T cells positive for
  • IFN-gamma and TNF-alpha after a single administration of an exemplary peptide vaccine, after a prime and a boost with the exemplary peptide vaccine, after a prime with the exemplary peptide vaccine and a boost with MG1-E6E7, or after a prime and a boost with MG1-E6E7, followed by re-stimulation with a peptide according to SEQ ID NO: 3.
  • Fig. 16 is a graph illustrating the tumour volume over time of untreated mice.
  • Fig. 17 is a graph illustrating the tumour volume over time of mice treated with two doses of an exemplary peptide according to the present disclosure.
  • Fig. 18 is a graph illustrating the tumour volume over time of mice treated with an exemplary prime:boost therapy according to the present disclosure.
  • Fig. 19 is a graph illustrating the tumour volume over time of mice treated with two doses of MG1-E6E7 virus.
  • Fig. 20 is a graph illustrating the survival times of the mice from Figs. 16-
  • Fig. 21 is a graph illustrating the tumour volumes over time of cured mice rechallenged with tumour cells.
  • the present disclosure provides a combination prime:boost therapy for use in inducing an immune response in a mammal.
  • the combination therapy includes a peptide or combination of peptides formulated to generate an immune response in the mammal, where the peptide or peptides are from 15 to 100 amino acids in length.
  • Such peptides may be referred to as "synthetic long peptides" (SLPs), though it should be understood that the term does not necessarily reflect that the peptides were synthesized using chemical techniques.
  • SLPs synthetic long peptides
  • the peptide should be long enough to be taken up and processed by dendridic cells and/or other professional antigen presenting cells for presentation on their cell surface with MHC class I or class II molecules.
  • the peptide or peptides include at least one antigenic amino acid sequence selected from the group consisting of: a sequence that comprises at least 9 sequential amino acids from SEQ. ID. No 1 , and SEQ ID Nos. 2-32, and 54-61.
  • the combination therapy also includes a Maraba MG1 virus that is capable of expressing an antigenic protein.
  • the Maraba MG1 virus is formulated to induce the immune response in the mammal.
  • the antigenic protein capable of being expressed by the Maraba MG1 virus has an amino acid sequence that includes the antigenic amino acid sequences of the peptide or combination of peptides.
  • the authors of the present disclosure have identified, using epitope mapping, the sequence of SEQ ID NO: 1 as encompassing an antigenic epitope.
  • the antigenic epitope of SEQ ID NO: 1 corresponds to a sequence of at least 9 sequential amino acids from SEQ ID NO: 1.
  • peptide or peptides and “peptide or combination of peptides” should be understood to be equivalent.
  • the peptide or combination of peptides may be referred to as the "priming vaccine", the “priming peptide(s)”, the “priming peptide or peptides”, or the “priming peptide or combination of peptides”.
  • the terms “peptide” and “protein” may be used interchangeably.
  • the peptide or peptides may include a combination of different antigenic epitopes, such as the sequences of SEQ ID NOs 12-16 and 25-32.
  • a mixture including these 13 sequences from this group may be used, for example, in a vaccine against vulvar intraepithial neoplasia caused by HPV16.
  • Each of the sequences may be found on separate peptides, or some of the sequences may be combined in a single peptide.
  • having each sequence on separate peptides would correspond to a mixture of at least 13 different peptides being used in the "prime".
  • the combination of peptides may have sequences of SEQ ID NOs 54-61. These 8 sequences correspond to peptides that, in combination, match the sequences of full length HPV18 E6 and E7 proteins. That is, placing SEQ ID Nos: 54-57 together corresponds to 100% sequence identity to the sequence of wild type HPV18 E6; and placing SEQ ID Nos: 58-61 together corresponds to 100% sequence identity to the sequence of wild type HPV18 E7.
  • the peptide or combination of peptides may comprise antigenic epitopes from the HPV18 E6 protein. In various embodiments the peptide or combination of peptides may comprise antigenic epitopes from only the HPV18 E7 protein. In various embodiments, the peptide or combination of peptides may comprise antigenic epitopes from only the HPV16 E6 protein. In various embodiments the peptide or combination of peptides may comprise antigenic epitopes from only the HPV16 E7 protein. In various embodiments the peptide or combination of peptides may comprise antigenic epitopes from only the HPV18 E6 and E7 proteins.
  • the peptide or combination of peptides may comprise antigenic epitopes from only the HPV16 E6 and E7 protein. In various embodiments the peptide or combination of peptides may comprise antigenic epitopes from any combination of the HPV16 E6 and E7; and HPV18 E6 and E7 proteins.
  • a peptide or combination of peptides having some of the sequences combined in a single peptide could result in, for example, a single peptide with a sequence that incorporated a plurality of antigenic epitopes.
  • a peptide having a sequence according to SEQ ID NO: 24 includes the sequenes of SEQ ID Nos: 8 and 9.
  • the peptide or combination of peptides may include a plurality of one or more antigenic epitopes.
  • the peptide or combination of peptides may be from 25 to 100 amino acids, and preferably from 25 to 50 amino acids, in length. In some examples, it is beneficial to use short SLPs since they may be easier to synthesize and purify.
  • a short SLP may be a peptide of less than 50 amino acids.
  • the peptide or combination of peptides has: • a sequence that includes at least 9 sequential amino acids from SEQ ID NO: 1 and that is at least 15 sequential amino acids from the sequence:
  • the peptide or combination of peptides may have the sequence
  • CKCEARIKLWESSADDLRAFQQLFLNTL (SEQ ID NO: 36). This sequence corresponds to a sequence with all 15 amino acids of SEQ ID NO: 1 , and that is 29 sequential amino acids of SEQ ID NO: 33.
  • Sequences SEQ ID NO: 34 and 35 are artificial epitope flanking sequences (Steers NJ, et al. "Designing the epitope flanking regions for optimal generationof CTL epitopes.” Vaccine 32 (2014) 3509-3516). These sequences may be used to promote antigen processing and presentation.
  • the peptide or combination of peptides has:
  • the peptide or combination of peptides may have the sequence
  • YCKQQLLRREVYDFAFRDLCIVYRDGNPY SEQ ID NO: 38. This sequence corresponds to a sequence of SEQ ID NO: 2, and that is 29 sequential amino acids of SEQ ID NO: 37.
  • the peptide or combination of peptides may have:
  • SEQ ID NO: 3 • a sequence that comprises SEQ ID NO: 3, that comprises the sequence MSIQMLAQVIKE (SEQ ID NO: 34) at the N-terminus, and that comprises the sequence KILMFKLNAPA (SEQ ID NO: 35) at the C-terminus.
  • the peptide or combination of peptides may have the sequence
  • DGPAGQAEPDRAHYNIVTFCCKCDSTLRL (SEQ ID NO: 40). This sequence corresponds to a sequence of SEQ ID NO: 3, and that is 29 sequential amino acids of SEQ ID NO: 39.
  • sequences of SEQ ID Nos: 2-9 are minimal antigenic sequences and are less than 15 amino acids in length. Minimal antigenic sequences may be incorporated into the sequence of a longer peptide in order to generate a peptide that is long enough to be taken up and processed by dendridic cells for presentation on their cell surface with MHC class I or class II molecules.
  • the peptide or combination of peptides may have a sequence that includes (i) SEQ ID NO: 4, 5, 6, 7, 8, or 9, (ii) the sequence
  • MSIQMLAQVIKE (SEQ ID NO: 34) at the N-terminus, and (iii) the sequence
  • KILMFKLNAPA (SEQ ID NO: 35) at the C-terminus.
  • the peptide may have an amino acid sequence that includes at least two antigenic sequences selected from the group consisting of: (i) sequences that include at least 9 sequential amino acids from SEQ ID NO: 1 ; and (ii) SEQ ID NOs: 2-9.
  • the combination of peptides may be a mixture of peptides that include the sequences of SEQ ID NOs 12-16 and 25-32.
  • the mixture of peptides may consist of a mixture of 13 different peptides, with each of the 13 different peptides consisting of one of the 13 different sequences.
  • the combination of peptides may be a mixture of peptides that include the sequences of SEQ ID NOs 12-24.
  • the mixture of peptides may consist of a mixture of 13 different peptides, with each of the 13 different peptides consisting of one of the 13 different sequences.
  • the sequences of SEQ ID Nos 12-24 correspond to specific sequences found in a particular example of the peptide expressed by the Maraba MG 1 virus.
  • the combination of peptides may be a mixture of peptides that include the sequences of SEQ ID Nos 12-32 and 54-61.
  • the mixture of peptides may consist of a mixture of 29 different peptides, with each of the 29 different peptides consisting of one of the 29 different sequences.
  • the combination of peptides may be a mixture of peptides that include a subset of the sequences of SEQ ID Nos 12-32 and 54-61.
  • the mixture of peptides may consist of a mixture of different peptides, with each of the different peptides consisting of one of the different sequences.
  • One or more of the sequences discussed herein may be antigenic in more than one species.
  • an immune response may be generated against the sequence of SEQ ID NO: 2 in both a human and in a mouse.
  • the therapy is used to induce an immune response in a human.
  • HLA human leukocyte antigen
  • a peptide with a single antigenic amino acid sequence may induce an immune response in 10% of a population, while a mixture of peptides that includes 10 different antigenic sequences may induce a response in 75% of the same population
  • a peptide with a single antigenic amino acid sequence may induce an immune response in 10% of a population, while a peptide that includes three different different antigenic sequences may induce an immune response in 25% of the same population.
  • a mixture of peptides includes peptides with sequences that, in combination (with optional overlapping of the sequences), substantially match the full length of the antigenic protein.
  • the mixture of peptides may include peptides that, in combination, have at least 80% sequence identity to a full length antigenic protein. The greater the sequence identity, the increased likelihood that the mixture of peptides will induce an immune response in a given individual in a population.
  • the immune response raised by the combination therapy may be a CD8 response, a CD4 response, or both.
  • CD8 + cytotoxic or cytolytic T cells are T cells which, when activated, lyse cells that present the appropriate antigen presented by HLA class I molecules.
  • CD4 + T helper cells are T cells which secrete cytokines to stimulate macrophages and antigen-producing B cells which present the appropriate antigen by HLA class II molecules on their surface. Inducing a CD8 response may be beneficial since CD8 positive cells may kill cancer cells.
  • CD4 + cells may also be directly cytotoxic to cancer cells.
  • the second component of the combination therapy is the Maraba MG1 virus that is capable of expressing an antigenic protein that includes the antigenic amino acid sequences found in the peptide or combination of peptides.
  • the term "boosting maraba virus” should be understood to refer to a Maraba MG1 virus that is capable of expressing the antigenic protein.
  • the antigenic protein is a Human Papilloma Virus E6/E7 fusion protein.
  • the terms "MG1-E6E7”, “Maraba MG1 E6E7”, and “Maraba MG1 virus encoding HPV E6/E7 protein” should all be understood to refer to a Maraba MG1 virus that is capable of expressing a Human Papilloma Virus E6/E7 fusion protein.
  • the Human Papilloma Virus E6/E7 fusion protein includes sequences corresponding to the E6 and E7 transforming proteins of both the HPV16 and HPV18 serotypes, resulting in a fusion protein that includes HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 protein domains.
  • the four protein domains may be linked by proteasomally degradable linkers that result in the separate HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins once the fusion protein is in the proteasome.
  • the proteasomally degradeable linkers in a fusion protein may be the same or different.
  • HPV E6/E7 protein HPV E6/E7 fusion protein
  • therapeutic E6E7 construct should all be understood to be synonymous with "Human Papilloma Virus E6/E7 fusion protein”.
  • the proteasomally degradeable linkers may be amino acid linkers having the sequence GGGGGAAY (SEQ ID NO: 41).
  • HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins are separated from each other in the proteasome (due to the presence of the
  • a Human Papilloma Virus E6/E7 fusion protein may have a sequence where the protein domains are rearranged in any order and still provide the HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins.
  • the protein domains of the protein encoded by the Maraba MG1 virus may be in the order: HPV16 E6, then HPV18 E6, then HPV16 E7, then HPV18 E7. If these sequences corresponded to A, B, C, D, respectively, a Human Papilloma Virus E6/E7 fusion protein according to the present disclosure could have a sequence where the four domains were rearranged in any of the other 23 possibile permutations, for example: ABDC, ACBD, ACDB, ADBC, ADCB, BACD, BACD, BADC, CABD, CADB, DACB, DCAB, DCBA, etc.
  • the protein domains of the protein encoded by the Maraba are identical to the protein domains of the protein encoded by the Maraba
  • MG1 virus may be in an order other than: HPV16 E6, then HPV18 E6, then HPV16 E7, then HPV18 E7.
  • HPV E6/E7 fusion proteins may be formed from wild type sequences of the HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins, it is desirable to modify the wild type sequences to prevent the formation of zinc fingers. If cells transduced with Maraba MG 1 virus HPV E6/E7 were to undergo an integration event with an E6E7 transgene that encoded a fusion protein that produced E6 and E7 proteins that could not form zinc fingers, the proteins produced would be unable to interfere with the functions of p53 or retinoblastoma, thereby reducing the possibility of a de novo neoplasm from forming.
  • sequences of one or more of the wild type are identical to each other.
  • HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins may be modified to abrogate the ability of one or more CXXC motifs to form zinc fingers.
  • the sequences of one or more of the wild type HPV16 E7 and HPV18 E7 proteins may additionally, or alternatively, be modified to abrogate the ability of a LXCXE sequence motif to bind to Retinoblastoma (Rb) protein. Preventing the formation of zinc fingers may be achieved, for example, by deleting one or both of the cysteines in a CXXC motif.
  • Preventing the bind to Rb protein may be achieved, for example, by deleting one or more of the amino acids in a LXCXE sequence motif, such as deleting the CXE amino acids.
  • deleting amino acids replacing one or more of the amino acids in either the CXXC or LXCXE motifs with other amino acids, such as alanine, may prevent binding.
  • all four of the protein sequences are modified to prevent the separated E6 and E7 proteins from forming zinc fingers and/or from binding to p53 (by the E6 protein) and Rb (by the E7 protein).
  • HPV16 E6, HPV18 E6, HPV16 E7 and HPV18 E7 proteins which may be used in a Human Papilloma Virus E6/E7 fusion protein are shown in SEQ ID NOs: 42-45.
  • each Xaa is independently: absent, cysteine, or a non-cystine amino acid.
  • the sequences correspond to the wild type sequences of HPV16 E6 and HPV18 E6, respectively.
  • the Xaa at position 24 is either absent, cysteine, or a non-cysteine amino acid
  • the Xaa at position 25 is either absent, tyrosine, or a non-tyrosine amino acid
  • the Xaa at position 26 is either absent, glutamic acid, or a non-glutamic acid amino acid
  • the Xaa's at positions 91 and 94 are, independently: absent, cysteine, or a non-cysteine amino acid.
  • sequence of SEQ ID NO: 44 corresponds to the wild type sequence of HPV16 E7 when the Xaa's at positions 24-26 are cysteine-tyrosine-glutamic acid and the Xaa's at positions 91 and 94 are cysteines.
  • the Xaa at position 27 is either absent, cysteine, or a non-cysteine amino acid
  • the Xaa at position 28 is either absent, histidine, or a non-histidine amino acid
  • the Xaa at position 29 is either absent, glutamic acid, or a non-glutamic acid amino acid
  • the Xaa's at positions 98 and 101 are, independently: absent, cysteine, or a non-cysteine amino acid.
  • SEQ ID NO: 45 corresponds to the wild type sequence of HPV18 E7 when the Xaa's at positions 27-29 are cysteine-histidine-glutamic acid and the Xaa's at positions 98 and 101 are cysteines.
  • a Human Papilloma Virus E6/E7 fusion protein may be defined as a fusion protein that includes, in any order, four protein domains having sequences according to SEQ ID NOs: 42, 43, 44 and 45, where the protein domains are linked by proteasomally degradable linkers, which may be the same or different.
  • At least one Xaa in each of SEQ ID NOs: 42, 43, 44 and 45 is absent. More preferably, sufficient Xaa's are absent to reduce zinc finger formation in the separated proteins that are generated in the proteasome. In some preferred examples, the Xaa's in the first CXXC motifs of both of SEQ ID NOs: 42 and 43 are absent.
  • the proteasomally degradable linkers are preferably amino acid linkers having the sequence: GGGGGAAY (SEQ ID NO: 41).
  • SEQ ID Nos: 42-45 correspond to, respectively:
  • One example of a Human Papilloma Virus E6/E7 fusion protein according to the present disclosure has an amino acid sequence according to SEQ ID NO: 50.
  • the proteasomally degradable linkers have the sequence GGGGGAAY (SEQ ID NO: 41). This is illustrated in Fig. 1.
  • Other proteasomally degradable linkers could alternatively be used.
  • Nos: 42-45 corresponds to SEQ ID NO: 50 when:
  • the Maraba MG1 virus genome may include a reverse complement and RNA version of a nucleotide sequence of SEQ ID NO: 51.
  • the Maraba MG1 virus genome may include a nucleotide sequence that is the reverse complement and RNA version of SEQ ID NO: 52.
  • a "combination prime:boost therapy” should be understood to refer to therapies where the peptide or combination of peptides and the Maraba MG1 virus discussed herein are to be administered as a prime:boost treatment.
  • the peptide or peptides, and the Maraba MG1 virus need not be physically provided or packaged together since the peptide or peptides is to be administered first and the Maraba MG1 virus is to be administered only after an immune response has been generated in the mammal.
  • the combination is provided to a medical institute, such as a hospital or doctor's office, in the form of a plurality of packages of the priming peptide or peptides, and a separate plurality of packages of the boosting Maraba MG1 virus.
  • the packages of peptide or peptides and the packages of Maraba MG1 virus may be provided at different times.
  • the combination is provided to a medical institute, such as a hospital or doctor's office, in the form of a package that includes both the priming peptide or peptides and the boosting Maraba MG1 virus.
  • the combination prime:boost therapy may additionally include an immune- potentiating compound, such as cyclophosphamide (CPA) or a checkpoint inhibitor (such as anti-PD1 , anti-PDL1 , or anti-CTLA4), that increases the prime immune response to the priming peptide(s).
  • CPA cyclophosphamide
  • a checkpoint inhibitor such as anti-PD1 , anti-PDL1 , or anti-CTLA4
  • Cyclophosphamide is a chemotherapeutic agent that may lead to enhanced immune responses against the antigenic sequence or sequences.
  • CPA administered prior to the priming vaccine significantly increased survival, while CPA administered prior to the boosting vector did not.
  • the therapeutic approach disclosed herein combines: (1) a priming vaccine, and (2) a Maraba MG1 virus as an oncolytic viral vaccine.
  • the MG1 virus expressing an antigenic protein that includes the antigenic amino acid sequences of the peptide or combination of peptides.
  • Boosting with an oncolytic vaccine of the present disclosure may lead to both tumour debulking by the oncolytic virus and a large increase in the number of tumour-specific CTL (cytotoxic T-lymphocytes) in animals primed by the priming vaccine.
  • the expression products of the HPV gene are processed into peptides, which, in turn, are expressed on cell surfaces. This can lead to lysis of the tumour cells by specific CTLs.
  • the T cell response to foreign antigens includes both cytolytic T lymphocytes and helper T lymphocytes.
  • CD8 + cytotoxic or cytolytic T cells are T cells which, when activated, lyse cells that present the appropriate antigen presented by HLA class I molecules.
  • CD4 + T helper cells are T cells which secrete cytokines to stimulate macrophages and antigen-producing B cells which present the appropriate antigen by HLA class II molecules on their surface. CD4 + cells may also be directly cytotoxic to cancer cells.
  • mamal refers to humans as well as non-human mammals.
  • cancer is used herein to encompass any cancer that expresses, as antigenic proteins, the proteins encoded by the priming vaccine and the boost virus, such as E6 and E7 proteins.
  • examples of such a cancer include, but are not limited to: multiple epithelial malignancies such as cervical cancer, anal cancer, oropharyngeal cancer, vaginal cancer, vulvar cancer, or penile cancer.
  • Combination therapies according to the present disclosure may be used to treat a late stage cancer, such as a stage II, III or IV, in the mammal.
  • the priming vaccine, the Maraba MG1 virus, or both may be independently administered to the mammal intravenously, intramuscularly, intraperitoneally, or intranasally.
  • the Maraba MG1 virus may be administered using regional intra-arterial influsion, or intra-tumourally.
  • the priming vaccine may be administered subcutaneously, mucosally, or submucosally.
  • an immune response is generated by the mammal within an immune response interval, e.g. within about 4 days, and extending for months, years, or potentially life.
  • priming vaccine administered using the priming vaccine and the Maraba MG 1 virus may be conducted using well-established techniques.
  • amount of priming vaccine required to generate an immune response will vary with a number of factors, including, for example, the mammal to be treated, e.g. species, age, size, etc.
  • a dose of around 0.3 mg of peptide may be sufficient to generate an immune response in a human.
  • Maraba MG1 virus encoding the antigenic protein is administered in an amount suitable for oncolytic viral therapy within a suitable immune response interval.
  • a suitable immune response interval may be, for example, at least about 24 hours, preferably at least about 2-4 days or longer, e.g. at least about 1 week, or at least about 2 weeks.
  • the amount of Maraba MG 1 virus suitable for oncolytic viral therapy will vary with the mammal to be treated, as will be appreciated by one of skill in the art. For example, 10 9 PFU of Maraba MG1 virus encoding HPV E6/E7 protein administered IV to a mouse is sufficient for oncolytic therapy. A corresponding amount would be sufficient for use in a human. Therapeutic doses of the oncolytic virus may be provided.
  • Maraba MG1 virus encoding HPV E6/E7 protein may be prepared by incorporating a reverse complement of a transgene encoding the HPV E6/E7 protein into the Maraba MG 1 virus using standard recombinant technology.
  • the reverse complement of the transgene may be incorporated into the genome of the Maraba MG1 virus, or alternatively, may be incorporated into the virus using a plasmid incorporating the transgene.
  • the transgene encoding the protein may be a codon optimized transgene.
  • An exemplary combination prime:boost therapy according to the present disclosure is shown in the examples to be capable of curing, in mice, the majority of advanced and bulky subcutaneous tumours with a mean volume of 250-300 mm 3 .
  • Epitope mapping was performed using a library of overlapping 15mer peptides based on wild type E6 and E7 sequences of HPV16 and 18.
  • Intracellular staining of IFN- ⁇ producing CD8+ T cells was performed after ex vivo re-stimulation of splenocytes with individual peptides from the peptide library of overlapping 15mer peptides. The percentage of CD8+ Tcells producing IFN- ⁇ in response to the ex vivo stimulation was used to determine if the peptide included an antigenic sequence.
  • MG1-E6E7 enhances the immunogenicity of SLP vaccination
  • MG1- E6E7 was able to boost immune responses to SLPs having sequences according to SEQ ID NO: 36, 38, and 40. No boosted immune response was found with the SLP having the sequence according to SEQ ID NO: 53.
  • reference to "MG1-E6E7" corresponds to a Maraba MG1 virus that expresses a protein having an amino acid sequence according to SEQ ID NO: 50.
  • SLP vaccine was administered to mice in combination with an agonistic murine anti- CD40 monoclonal antibody and polylC as an adjuvant and given intraperitoneally.
  • mice Groups of five C57BL/6 mice were vaccinated with either a single dose of the mixture of four SLPs, two doses of the mixture of four SLPs administered 8 days apart, or the mixture of four SLPs boosted with intravenous MG1-E6E7 after 8 days.
  • ICS Intracellular cytokine IFN-gamma staining
  • the peptide ⁇ 6 ⁇ 6" of Figs. 2 and 6 corresponds to restimulation with the peptide of SEQ ID NO: 2.
  • the peptide ⁇ 6 ⁇ 7" of Figs. 3 and 7 corresponds to restimulation with the peptide of SEQ ID NO: 3.
  • the peptide ⁇ 8 ⁇ 6" of Figs. 4 and 8 corresponds to restimulation with two overlapping peptides whose sequences in combination correspond to the amino acids from positions 5 to 25 of of SEQ ID NO: 53.
  • the peptide "18E7" of Figs. 5 and 9 corresponds to restimulation with the peptide of SEQ ID NO: 1 .
  • peptide:peptide or the priming SLP vaccine boosted by MG1 -E6E7 (“peptide:MG1 - E6E7”)
  • mice were challenged with 1x10 6 of TC1 cells (murine HPV16 positive cell line) subcutaneously. Both vaccination protocols were completely protective compared to a control group of untreated mice that all succumbed to tumour related end point (Figs 10 and 1 1).
  • Fig. 10 illustrates mean tumour volumes with SEM displayed.
  • Fig. 1 1 illustrates survival time using a Kaplan Meier curve.
  • Both peptide:peptide and peptide:MG1 -E6E7 displayed prophylactic activity in a syngeneic HPV mouse tumour model. SLP vaccination and MG1-E6E7 induce specific immunity in mice with advanced HPV-positive tumours
  • mice bearing advanced subcutaneous TC1 tumours were treated with either two doses of a mixture of two SLPs, where one peptide of the mixture had a sequence according to SEQ ID NO: 38 and the other peptide had a sequence according to SEQ ID NO: 40 ("peptide:peptide”); two doses of MG1-E6E7 ("MG1-E6E7:MG1-E6E7”); or one dose of the mixture of SLPs according to SEQ ID Nos 38 and 40, followed by one dose of MG1-E6E7 ("peptide:MG1-E6E7").
  • the two separate treatments were administered eight days apart.
  • a control group of untreated mice was also included.
  • the mixture of SLPs according to SEQ ID NO: 38 and 40 was used to assess the immune response in the mice with HPV16 postive TC1 tumours.
  • Peripheral blood was collected from the C57BL/6 mice with established HPV16 positive TC1 tumours to assess for the induction of specific immune responses against the HPV16 peptide epitopes used to design the SLPs as indicated by IFN- ⁇ and TNF-a production from CD8+ T cells.
  • PBMCs were isolated from blood that was collected 5 days post boost. Frequencies of single (IFN- ⁇ ) cytokine positive T cells specific for restimulation with a peptide according to SEQ ID NO: 2, and specific for restimulation with a peptide according to SEQ ID NO: 3 are shown in Figs 12 and 13, respectively.
  • peptide:MG1-E6E7 compared to all other groups of mice (Figs 13 and 15).
  • Specific single and double positive CD8+ T cells against the epitope of SEQ ID NO: 2 induced by SLP SEQ ID NO: 38 were detected in both peptide:peptide groups and peptide:MG1-E6E7 mice, however no response was detected in mice treated MG1-E6E7:MG1-E6E7 for 16E6 following restimulation with peptide SEQ ID NO: 2 (Figs 12 and 14).
  • Substantial immune responses were induced by SLP vaccination in tumour bearing mice.
  • SLP vaccination results in complete regression of advanced TC1 tumours in mice.
  • mice were primed 14 days after engraftment when mean tumour volume was approximately 300 mm 3 and were boosted 22 days after engraftment.
  • Individual tumour plots for the 4 different groups are displayed (Figs. 16-19) and survival times are displayed using a Kaplan Meier curve (Fig. 20) (log rank test used to compare survival times, *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001)).
  • mice with large TC1 tumours had prolonged survival when treated with either peptide:peptide, MG1 -E6E7:MG1 -E6E7 or peptide:MG1 -E6E7. Whilst MG1 -E6E7 alone only delayed tumour progression in all but 1 mouse that had a complete response, 80% of peptide:peptide and 80% peptide:MG 1 -E6E7 treated mice had complete tumour regressions (Figs 16-19). Cure rates of 60% and 50% were achieved for mice treated with peptide: MG 1 -E6E7 and peptide: peptide respectively (Fig 20).
  • Two doses of a mixture of peptides according to SEQ ID NO: 38 and 40, or one dose of a mixture of peptides according to SEQ ID NO: 38 and 40 followed by oncolytic MG 1 -E6E7 resulted in frequent, durable and complete responses when administered to mice with bulky neoplastic disease.
  • VYDFAFRDL (SEQ ID NO: 2)
  • KLPQLCTEL (SEQ ID NO: 4)
  • TIHDIILECV SEQ ID NO: 5
  • LLMGTLGIV (SEQ ID NO: 8)
  • TLGIVPI SEQ ID NO: 9
  • RINQKPLCPEEKQRHLDKKQRFHNIRGRWT (SEQ ID NO: 21) MHGDTPTLHEYMLDLQPETTDLYQLNDSSEEE (SEQ ID NO: 22) LYQLNDSSEEEDEIDGPAGQAEPDRAHYNIVT (SEQ ID NO: 23) TLRLCVQSTHVDIRTLEDLLMGTLGIVPICSQKP (SEQ ID NO: 24) RDLCIVYRDGNPYAVCDKCLKFYSKI (SEQ ID NO: 25)
  • YGTTLEQQYNKPLCDLLIRCINCQKPLCPEEK (SEQ ID NO: 28) RCINCQKPLCPEEKQRHLDKKQRFHNIRGRWT (SEQ ID NO: 29) MHGDTPTLHEYMLDLQPETTDLYCYEQLNDSSEEE (SEQ ID NO: 30) LYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVT (SEQ ID NO: 31) TLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP (SEQ ID NO: 32) RHTMLCMCCKCEARIKLWESSADDLRAFQQLFLNTLSFVPWCAS (SEQ ID NO: 33) MSIQMLAQVIKE (SEQ ID NO: 34)
  • VYCKTVLELTEVFEFAFKDLFWYRDSIPHAA (SEQ ID NO: 55)
  • GLYNLLIRCLRCQKPLNPAEKLRHLNEKRRFH (SEQ ID NO: 57)
  • HPV16 E6 (SEQ ID NO: 42):
  • HPV16 E7 (SEQ ID NO: 44):
  • wild type sequence has cysteines at positions 91 and 94 HPV18 E7 (SEQ ID NO: 45):
  • wild type sequence has cysteines at positions 98 and 101
  • HPV16 E6 SEQ ID NO: 46
  • HPV18 E6 SEQ ID NO: 47
  • HPV16 E7 SEQ ID NO: 48
  • HPV18 E7 SEQ ID NO: 49
  • Protein sequence of exemplary HPV E6/E7 fusion protein (SEQ ID NO: 50):

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Abstract

La présente invention concerne une polythérapie de primovaccination-rappel. La polythérapie est destinée à l'utilisation dans l'induction d'une réponse immunitaire chez un mammifère. La polythérapie comprend : un peptide ou une combinaison de peptides formulé-e pour générer une réponse immunitaire chez le mammifère. Le(s) peptide(s) se présentent sous la forme de (15) à (100) acides aminés de longueur. Le(s) peptide(s) compren(d)(nent) au moins une séquence d'acides aminés antigénique sélectionnée parmi : une séquence qui comprend au moins (9) acides aminés séquentiels à partir de SEQ ID no : 1, SEQ ID nos : 2-32, et SEQ ID nos : 54-61. La thérapie comprend également un virus Maraba MG1 qui est susceptible d'exprimer une protéine antigénique qui présente une séquence d'acides aminés qui comprend les séquences d'acides aminés antigéniques du peptide ou la combinaison de peptides. Le virus Maraba MG1 est formulé pour induire la réponse immunitaire chez le mammifère.
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WO2021156404A3 (fr) * 2020-02-07 2021-09-30 Isa Pharmaceuticals Traitement de maladies liées au hpv

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WO2014127478A1 (fr) * 2013-02-21 2014-08-28 Children's Hospital Of Eastern Ontario Research Institute Inc. Composition de vaccin

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WO2014127478A1 (fr) * 2013-02-21 2014-08-28 Children's Hospital Of Eastern Ontario Research Institute Inc. Composition de vaccin

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ZWAVELING S ET AL.: "Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides", J IMMUNOL, vol. 169, no. 1, 1 July 2002 (2002-07-01), pages 350 - 358, XP002515929 *

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WO2021156404A3 (fr) * 2020-02-07 2021-09-30 Isa Pharmaceuticals Traitement de maladies liées au hpv

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