EP3370765A1 - Nouvelle plateforme de vaccins à adn - Google Patents

Nouvelle plateforme de vaccins à adn

Info

Publication number
EP3370765A1
EP3370765A1 EP16863078.8A EP16863078A EP3370765A1 EP 3370765 A1 EP3370765 A1 EP 3370765A1 EP 16863078 A EP16863078 A EP 16863078A EP 3370765 A1 EP3370765 A1 EP 3370765A1
Authority
EP
European Patent Office
Prior art keywords
antigen
fusion protein
protein
immune response
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16863078.8A
Other languages
German (de)
English (en)
Other versions
EP3370765A4 (fr
Inventor
Victor G. SOLODUSHKO
Brian Fouty
Vira BITKO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of South Alabama
Original Assignee
University of South Alabama
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of South Alabama filed Critical University of South Alabama
Priority claimed from PCT/US2016/060631 external-priority patent/WO2017079625A1/fr
Publication of EP3370765A1 publication Critical patent/EP3370765A1/fr
Publication of EP3370765A4 publication Critical patent/EP3370765A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K39/002—Protozoa antigens
    • A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6075—Viral proteins
    • 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
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
    • C12N2760/18534—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • Communicable diseases and cancer represent a worldwide health problem making their prevention and treatment a public health priority.
  • Vaccines have eliminated naturally occurring cases of smallpox, have nearly eliminated polio, and have reduced the incidence and severity of numerous diseases, such as typhus, rotavirus, hepatitis A, and hepatitis B.
  • diseases and conditions such as cancer, AIDS, hepatitis C, malaria, and tuberculosis, which collectively kill millions of people worldwide each year.
  • DNA vaccination utilizes genetically engineered DNA that encodes for specific antigens, such as pathogen-specific antigens, to produce an immunologic response to such antigens in a recipient.
  • Introduction of a DNA vaccine into a cell induces the cell to transcribe and translate the proteins encoded by the vaccine. These translated proteins are then processed and presented on the surface of these cells on a major histocompatibility complex (MHC) class I molecule.
  • MHC major histocompatibility complex
  • vaccination by an antigen-encoding DNA plasmid can induce humoral and cellular immune responses against cancer, pathogenic parasites, bacteria, and viruses that express the selected antigen.
  • DNA vaccines Unfortunately, the efficacy of DNA vaccines in clinical trials has been disappointing. Indeed, only four DNA vaccines are currently approved for use in animals, and none are approved for use in humans.
  • the major limitation of DNA vaccines has been their inability to generate a strong humoral (antibody) and/or T cell-mediated (CD4+ helper T cell and/or CD 8+ cytotoxic T cell) immune response and the inability of transcribed product to be secreted from antigen-producing transfected cells.
  • the Applicants describe novel compositions and methods of use that induce a more robust immune response by increasing the duration and the level of antigen expression, which cannot be efficiently accomplished by current DNA vaccines.
  • the present disclosure pertains to a DNA vaccine composition
  • a DNA vaccine composition comprising: a DNA vector containing at least one isolated nucleotide sequence; wherein each nucleotide sequence encodes a multi-domain protein conjugate comprising at least one extracellular domain of a fusion protein from an enveloped virus and at least one additional domain.
  • the DNA vector is configured to integrate stably into the genome of a target cell.
  • the DNA vector is configured to transiently express the at least one antigen in a target cell.
  • the fusion protein is modified.
  • the fusion protein is truncated.
  • the fusion protein is a protein expressed by the Paramyxoviridae family.
  • the fusion protein is Respiratory Syncytial Virus F protein (RSV-F).
  • the at least one additional domain comprises an antigen.
  • the antigen is selected from the group consisting of parasite, viral, bacterial, fungal, and cancer cell antigens.
  • the antigen is fused directly to the enveloped fusion protein.
  • the antigen is fused directly to another protein that interacts with the enveloped fusion protein.
  • the antigen is not directly fused to the enveloped fusion protein.
  • the antigen interacts with the enveloped fusion protein via a polypeptide connected by a covalent or non-covalent bond.
  • the at least one additional domain comprises an antigen-binding polypeptide configured to interact with a previously-delivered or naturally occurring antigen.
  • the present disclosure pertains to a method of eliciting an immune response against an antigen in a subject, comprising the steps of: administering a DNA vaccine to a subject; wherein the DNA vaccine comprises a DNA vector containing at least one isolated nucleotide sequence; wherein each nucleotide sequence encodes a multi-domain protein conjugate comprising at least one fusion protein from an enveloped virus and at least one additional domain.
  • the DNA vector is configured to integrate stably into the genome of a target cell in the subject.
  • the DNA vector is configured to transiently express antigen in a target cell in the subject.
  • the fusion protein is from the Paramyxoviridae family.
  • the fusion protein is RSV-F protein.
  • the at least one additional domain comprises an antigen.
  • the antigen is selected from the group consisting of parasite, viral, bacterial, fungal, and cancer cell antigens.
  • the at least one additional domain comprises an antigen-binding polypeptide configured to interact with a previously-delivered or naturally occurring antigen.
  • the DNA vaccine is administered in an amount sufficient to elicit an immune response in the subject.
  • the immune response is a cytotoxic immune response.
  • the immune response is a humoral immune response.
  • the immune response includes protective immunity against the antigen.
  • the present disclosure pertains to a method of manufacturing a medicament for use in eliciting an immune response against an antigen in a subject, comprising the step of forming a medicament comprising a DNA vaccine comprising a DNA vector containing at least one isolated nucleotide sequence, wherein each nucleotide sequence encodes a multi-domain protein conjugate comprising at least one fusion protein from an enveloped virus and at least one additional domain.
  • the DNA vector is configured to integrate stably into the genome of a target cell.
  • the DNA vector is configured to transiently express antigen in a target cell.
  • the fusion protein is from the Paramyxoviridae family.
  • the fusion protein is an RSV-F protein.
  • the at least one additional domain comprises an antigen.
  • the antigen is selected from the group consisting of parasite, virus, bacteria, fungi, or cancer cell antigens.
  • the antigen is fused directly to the fusion protein.
  • the antigen interacts indirectly with the fusion protein through another protein.
  • the at least one additional domain comprises an antigen-binding polypeptide configured to interact with a previously-delivered or naturally occurring antigen.
  • Figure 1 illustrates evidence that RSV-F covalently linked to mCherry can transfer the fluorescent protein between cells.
  • the Applicants constructed an RSV-F-mCherry fusion protein and stably integrated it into CT26.WT cells.
  • Cells stably expressing mCherry without RSV-F were used for the signal comparison and cells not expressing mCherry were used as a background control.
  • Each cell population was then co-cultured with CT26.WT cells expressing eGFP for easy identification of the acceptor cells. Forty-eight hours later, cells were analyzed by flow cytometry.
  • Figure 1C shows a background signal of eGFP-expressing cells on the mCherry panel. (Only populations of eGFP expressing cells are gated, enlarged and presented in the figure.) The data indicate that RSV-F can shepherd mCherry between cells.
  • Figure 2 provides an example of a three-domain coding sequence for a DNA vaccine that will lead to the expression of a fusion protein (collectively, SEQ ID NO: 1).
  • the RSV-F protein (plain text; SEQ ID NO: 2) is linked to two antigens normally expressed on the surface of Plasmodium falciparum, Thrombospondin-Related Anonymous Protein, also known as Thrombospondin-Related Adhesive Protein (TRAP, underlined; SEQ ID NO: 3) and circumsporozoite (CS, bold and italicized; SEQ ID NO: 4) protein.
  • the RSV-F protein will allow entry of the fusion protein (RSVF-TRAP-CS) into neighboring cells.
  • FIG 3 shows an example of the humoral immune response induced by the proposed DNA fusion vaccine.
  • the Applicants generated different DNA vaccine constructs that expressed two surface antigens of P. falciparum (TRAP and CS) fused together.
  • One construct expressed a fully secretable TRAP-CS (i.e., the antigen can be both expressed and secreted by the cell); one construct expressed a TRAP-CS variation that remained attached to the extracellular surface of the membrane after secretion; and one construct (the experimental vaccine) expressed a secretable TRAP-CS that was also fused to RSV-F (RSVF-TRAP-CS; the full sequence of this vaccine is shown in Figure 2).
  • mice were immunized with one of these vaccines; non-immunized age- matched animals were also included for study.
  • seram samples were collected three months after vaccination and incubated with CT26.WT cells that expressed the membrane-associated TRAP-CS (without RSV-F) and intracellular mCherry. Cells were then probed with FITC-labeled anti-mouse IgG.
  • mice immunized with the experimental (RSVF-TRAP-SC) vaccine demonstrated significantly higher FITC intensity than serum from mice immunized with vaccines lacking the RSV-F domain, a result that suggested the presence of a significantly higher level of circulating specific antibodies against cells expressing TRAP and CS in RSVF- TRAP-CS-immunized mice.
  • FIG. 4 shows an example of a T cell immune response to the proposed DNA fusion vaccination.
  • the Applicants generated different DNA vaccine constructs that expressed two surface antigens of P. falciparum (TRAP and CS) fused together.
  • One construct expressed a fully secretable TRAP-CS (i.e., the antigen can be both expressed and secreted by the cell); one construct expressed a TRAP-CS variation that remained attached to the extracellular surface of the membrane after secretion; and one construct (the experimental vaccine) expressed a secretable TRAP-CS also fused to RSV-F (RSVF- TRAP-CS).
  • RSVF- TRAP-CS secretable TRAP-CS also fused to RSV-F
  • a vaccine composed of RSV-F alone i.e., without TRAP or CS was used as a control for this experiment.
  • mice were immunized with one of these vaccines.
  • Four months after vaccination animals were stimulated by CT26.WT cells stably expressing TRAP and CS (i.e. a model of malaria-infected cells) intraperitoneally.
  • CT26.WT cells stably expressing TRAP and CS (i.e. a model of malaria-infected cells) intraperitoneally.
  • TRAP and CS i.e. a model of malaria-infected cells
  • the DNA vaccine comprises the extracellular domain of a fusion protein from an enveloped virus cloned into a DNA vector and at least one additional domain.
  • the additional domain may comprise an antigen from a virus, bacteria, parasite, fungi, or cancer cell or polypeptide binding the antigen indirectly.
  • the additional domain may also comprise an antigen-binding polypeptide configured to interact with a previously-delivered or naturally occurring antigen.
  • the method comprises the step of delivering a DNA vaccine to cells in a subject via intramuscular, intraperitoneal, intravenous, or subcutaneous injection, or via inhalation or ingestion.
  • antigen means a peptide, polypeptide or protein expressed by a virus, bacteria, parasite, fungi, or cancer cell.
  • enveloped fusion protein means a fusion protein from an enveloped virus.
  • immune response means a change in the phenotype of a subject's immune system.
  • an immune response may be an increase in the absolute or relative number of a particular lymphocyte subset, such as an increase in the percentage of circulating CD8+ T cells.
  • An immune response can be measured using methods known in the art, such as flow cytometry to assess changes in the surface markers of lymphocytes from a subject.
  • modified fusion protein means a fusion protein modified from its native state.
  • a modified fusion protein may include, but is not limited to, a protein in which one or more peptides have been altered from their native state and a native protein to which one or more additional molecules (e.g., glycosylation) or peptides have been added.
  • “native fusion protein” means a fusion protein that has not been modified or truncated.
  • protective immunity means an immune response that prevents, retards the development of, or reduces the severity of a disease, symptoms thereof, or other deleterious condition that is associated, directly or indirectly, with an antigen.
  • subject means a vertebrate, preferably a mammal, including, but not limited to, a human.
  • target cell means a cell to which a DNA vaccine is delivered, either in vitro or in vivo, for example within a subject.
  • truncated fusion protein means a fusion protein in which a portion of the native fusion protein has been removed.
  • a native fusion protein may be enzymatically cleaved to remove a portion of the protein.
  • the present disclosure pertains to a DNA vaccine composition
  • a DNA vaccine composition comprising a DNA vector containing at least one isolated nucleotide sequence encoding a multi-domain protein conjugate comprising at least one fusion protein from an enveloped virus and at least one additional domain.
  • the additional domain may comprise at least one antigen and/or antigen-binding polypeptide.
  • the antigen-binding polypeptide may be configured to bind to antigen that is naturally- occurring in a target cell or that was delivered to the target cell.
  • the DNA vector may be configured: to integrate stably into the genome of the target cell; to stably express protein conjugate without integration into the target cell genome (for example via Adeno-Associated Virus (AAV) delivery); or to transiently express protein conjugate in a target cell.
  • AAV Adeno-Associated Virus
  • the fusion protein in the DNA vaccine composition can be selected from different families of enveloped viruses, including, but not limited to, the RSV-F protein of the Paramyxoviridae family, HA protein of the Orthomyxoviridae family, Env protein of the Retroviridae family, S protein of the Coronaviridae family, GP protein of the Filoviridae family, GP, SSP proteins of the Arenaviridae, the E1/E2 of the Togaviridae family, E(TBEV), (E1/E2 (HPV) proteins of the Flaviviridae family, GN GC proteins of the Bunyaviridae family, of the G protein of the Rhabdoviridae family, gB, gD, gH/L proteins of the Herpesviridae family, eight proteins of the Poxviridae family, and S, L proteins of the Hepadnaviridae family.
  • the fusion protein can be a native fusion protein, a modified fusion protein, or
  • Antigens may be selected from a variety of sources.
  • Viruses that contain antigens suitable for use in the present invention include, but are not limited to Human Immunodeficiency Virus (HIV) and Respiratory Syncytial Virus (RSV).
  • HIV Human Immunodeficiency Virus
  • RSV Respiratory Syncytial Virus
  • Bacteria that contain antigens suitable for use in the present invention include, but are not limited to, organisms causing the Mycobacterium tuberculosis complex in humans (M tuberculosis, M. bovis, M. africonum, M. microti, M. canetti, and M. pinnipedii).
  • Fungi that contain antigens suitable for use in the present invention include, but are not limited to, Cryptococcus neoformans, Coccidioidomycosis, Blastomycosis, and Histoplasmosis.
  • Cancer cells that contain antigens suitable for use in the present invention include, but are not limited to, adenocarcinoma, small cell, and squamous cell cancer.
  • the present disclosure pertains to method of administering a DNA vaccine to a subject to induce an immune response to an antigen.
  • the DNA vaccine comprises a DNA vector containing at least one isolated nucleotide sequence encoding a multi-domain protein conjugate comprising at least one fusion protein from an enveloped virus and at least one antigen or antigen-binding polypeptide.
  • the vector can be configured either to integrate stably in the genome of a target cell to express antigen or, alternatively, to transiently express protein conjugate. Suitable vectors are described below.
  • the fusion protein can be from any of the aforementioned proteins. Examples of suitable parasites, viruses, bacteria, fungi or cancer cells as sources of antigens are described hereinabove.
  • the DNA vaccine can be administered to a subject in an amount sufficient to elicit an immune response.
  • the immune response may be cytotoxic and/or humoral.
  • the immune response may also induce protective immunity to one or more antigens in a subject.
  • the DNA vaccine can be administered to a subject in an amount sufficient to induce an immune response.
  • the immune response may be humoral and/or cellular and may induce protective immunity.
  • Suitable routes of administering the DNA vaccine include, but are not limited to, inhalation, ingestion and intravenous, intramuscular, intraperitoneal, intradermal, and subcutaneous injection.
  • the DNA vaccine can be delivered using a vector that has the ability to stably integrate into the genome of target cells.
  • Suitable vectors include, but are not limited to, lentiviruses, gamma-retroviruses, and transposons.
  • the present disclosure also pertains to a method of manufacturing a medicament configured to induce an immune response against an antigen in a subject, the method comprising the step of forming a medicament comprising a DNA vaccine.
  • the DNA vaccines described herein are suitable for use in this manufacturing method.
  • the target cells After delivery of DNA vector to target cells, the target cells express and secrete the protein conjugate.
  • the natural ability of the viral fusion proteins to fuse with cell membranes and actively enter cells allows for delivery of the antigens into neighboring cells. This leads to the presentation of the delivered antigens on a major histocompatibility complex (MHC) class I molecule in a much larger population of cells than is possible with the initial DNA vector, thus inducing a more robust (e.g., cytotoxic) response.
  • MHC major histocompatibility complex
  • the fusion of antigen to the extracellular domain of a viral envelope protein also allows for antigen secretion and induction of a humoral immune response to the antigen. This innovative approach can be used to target infections in both humans and animals that are otherwise difficult or impossible to vaccinate using conventional methods.
  • this DNA vaccine can significantly increase the number of antigen-presenting cells.
  • clone the coding region for the RSV-F protein along with the extracellular domains of two target antigens on the surface of Plasmodium falciparum - Circumsporozoite and Thromobospondin Related Adhesive Protein - and use this DNA vaccine for immunization.
  • the initially transfected cells express and secrete the RSV-F fusion protein, the natural ability of RSV-F to enter cells allows for delivery of the target antigens into neighboring, non-transfected cells.
  • the innovative strategy of fusing the extracellular domain of a viral envelope protein to target antigens, and to deliver them using a DNA vector forms the basis for a platform DNA vaccine in which antigens of interest can be easily modified or replaced to induce the immune response of a subject to target different diseases.
  • cloning specific antigen coding regions into the platform DNA vaccine different cancers and diseases, such as malaria, tuberculosis, melioidosis, and Dengue fever can be targeted.
  • compositions and methods disclosed herein for DNA vaccines provide significant benefits compared with conventional vaccination methods.
  • the compositions and methods enable significant increases in the presentation of antigen; further, the DNA vaccination described herein was shown to significantly increase CD8+ lymphocytes and decrease CD62L+ cells relative to control (indicative of an augmented cytotoxic response).
  • the presently disclosed compositions and methods may result in significant clinical benefits to subjects with a variety of diseases.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne de nouveaux vaccins à ADN, conçus pour induire une réponse immunitaire robuste et durable, et les méthodes d'utilisation de ces derniers. Les vaccins à ADN de l'invention sont conçus pour obtenir cette réponse immunitaire en réalisant la fusion du domaine extracellulaire d'une protéine de fusion virale à des antigènes ou polypeptides de liaison à l'antigène sélectionnés. Après expression et sécrétion par les cellules transfectées initialement du complexe protéine de fusion virale-antigène, la capacité naturelle de la protéine de fusion virale à fusionner avec des membranes cellulaires et à pénétrer de façon active dans des cellules permettra l'administration passive des épitopes cibles fusionnés aux cellules avoisinantes, induisant ainsi une réponse immune plus robuste. La méthode de l'invention permet l'utilisation de ce vaccin à ADN contre des antigènes connus présents dans des protéines produites par des agents infectieux ou des cellules cancéreuses chez le patient, contre des antigènes inconnus produits par des agents infectieux ou des cellules cancéreuses chez le patient, ou contre des antigènes naturels ou d'origine synthétique administrés par d'autres voies, telles que l'injection.
EP16863078.8A 2015-11-06 2016-11-04 Nouvelle plateforme de vaccins à adn Withdrawn EP3370765A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562285732P 2015-11-06 2015-11-06
PCT/US2016/060631 WO2017079625A1 (fr) 2015-11-06 2016-11-04 Nouvelle plateforme de vaccins à adn

Publications (2)

Publication Number Publication Date
EP3370765A1 true EP3370765A1 (fr) 2018-09-12
EP3370765A4 EP3370765A4 (fr) 2019-06-12

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EP16863078.8A Withdrawn EP3370765A4 (fr) 2015-11-06 2016-11-04 Nouvelle plateforme de vaccins à adn

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