WO2024031045A2 - Approche à antigène négatif dominant pour le traitement prophylactique et post-infection du porc contre le virus de la peste porcine africaine - Google Patents

Approche à antigène négatif dominant pour le traitement prophylactique et post-infection du porc contre le virus de la peste porcine africaine Download PDF

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WO2024031045A2
WO2024031045A2 PCT/US2023/071659 US2023071659W WO2024031045A2 WO 2024031045 A2 WO2024031045 A2 WO 2024031045A2 US 2023071659 W US2023071659 W US 2023071659W WO 2024031045 A2 WO2024031045 A2 WO 2024031045A2
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asfv
antigen
dominant negative
protein
proteins
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PCT/US2023/071659
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WO2024031045A3 (fr
WO2024031045A9 (fr
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Thomas MALCOLM
Dalu CHEN
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Malcolm Thomas
Chen Dalu
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Publication of WO2024031045A3 publication Critical patent/WO2024031045A3/fr
Publication of WO2024031045A9 publication Critical patent/WO2024031045A9/fr

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/12011—Asfarviridae
    • C12N2710/12034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to compositions and methods for treating and preventing African Swine Fever Virus (ASFV).
  • ASFV African Swine Fever Virus
  • African Swine Fever Virus is a large double-stranded DNA virus of the Asfarviridae family that primarily infects domestic pigs, wild boars, warthogs, and bush pigs. It also resides in soft ticks, thereby acting as an infectious vector. ASFV primarily infects the monocytes and macrophages, although, at acute infection many other cell types can be infected. ASFV causes high fever, hemorrhagic lesions, cyanosis, anorexia, and fatalities in these animals. There is no vaccine or treatment for this virus, and the only way to currently prevent its spread is culling animals.
  • ASFV A virion capsid surrounded by an outer lipid bilayer and, 2) a naked virion encompassing a capsid only (FIGURE 1 A).
  • the outer lipid bilayer membrane has been shown to contain human proteins, thereby strongly suggesting that the capsid-based virion buds from the infected cell. This property is mostly associated with the lysogenic replication cycle that is observed in most other viruses.
  • Such a strategy takes into consideration the necessity for an immediate neutralization of early infectious membrane bound virions that are derived from a lysogenic cycle, followed by the rapid neutralization of capsid-based virions that exist in low quantities prior to a lytic cycle switch.
  • outer- membrane-bound proteins include the outer-membrane proteins EP402R (CD2v), and EP153R, the outer-membrane and inner envelope protein 016R (p12), the inner envelope and capsid spanning protein E183L (p54) as well as several main capsid proteins including B646L (p72), E120R (p14.5), B438L (p49) and CP204L (p30), although research is not limited to these proteins (FIGURES 2 and 3).
  • EP402R CD2v
  • EP153R the outer-membrane and inner envelope protein 016R
  • p12 the inner envelope and capsid spanning protein E183L (p54)
  • main capsid proteins including B646L (p72), E120R (p14.5), B438L (p49) and CP204L (p30), although research is not limited to these proteins (FIGURES 2 and 3).
  • capsid-based proteins have thus far not been shown to cause agglutination in RBCs, although the Applicants have observed a mild swine RBC agglutination effect that is species-specific with the DBD containing and capsid interacting subunit of the inner envelope and capsid spanning protein E183L (p54) (FIGURE 5B). As such, E183L mutations may be necessary to block this ability and expose this antigen effectively to the swine immune system to mount a strong neutralizing effect.
  • capsid-based proteins have not been shown to have these agglutination properties, dominant negative mutation to achieve strong neutralizing effects may not be necessary.
  • combinations of capsid antigens with the dominant negative antigens will likely improve immunogenicity against each stage of the ASFV replication cycle, thereby enforcing the Applicants’ thesis that targeting both the lysogenic cycle proteins (mainly outer-membrane proteins) and lytic cycle (mainly capsidbased proteins) will be necessary to effectively protect the swine from ASFV infection.
  • capsid-based antigen protein(s) in combination with dominant negative outermembrane proteins such as EP402R, EP153R, and 016R, as well as inner envelope and capsid spanning proteins like E183L will be used in combination to stimulate and immune response to effectively neutralize AFSV infection in swine.
  • any remaining capsid-based virus is limited to macrophage entry via macropinocytosis and subsequently locked into an early lysogenic phase that are neutralized upon viral budding, as its predecessors (FIGURE 6).
  • remaining capsid-based virions can be neutralized by antibodies derived from capsidbased targets, such as B646L (p72), E120R (p14.5), B438L (p49) and CP204L (p30), thereby eliminating even the smallest threat (FIGURE 6 and 7 - replication cycles and strategy overview).
  • EP402R (termed HA in early publications) and EP153R have been shown to facilitate the binding of virus to RBCs, allowing the virus to tunnel/burrow into the RBC membranes. This allows the virus to hide by preventing the exposure of critical surface epitopes from a strong and sustained antibody mediated immune response (Qunitero, et al., Ruiz-Gonzalvo et al.). Noting as well, that several of the outer-membrane proteins also have immune suppressive properties against T-cell responses (Teklue, et al., Petrovan, et al.).
  • EP153R has been shown to sequester MHC class I complexes from being expressed on the surface of T-cells.
  • the amino acid at position Arg133 is critical for the sequestering of MHC Class I complexes after macrophage infection.
  • the present invention provides for a composition including engineered ASFV outer-membrane protein antigen mutants (dominant negatives) that do not bind to RBCs yet elicit an antibody response that neutralizes wild type proteins present on infectious outer-membrane containing ASFV virions.
  • the present invention provides for a method of treating and/or preventing ASFV by administering a composition of a dominant negative antigen to an animal, preventing RBC aggregation from the antigen, and treating and/or preventing ASFV.
  • the present invention provides for a composition of a vaccine for ASFV, including a dominant negative antigen in a vaccine.
  • the present invention provides for a composition to use these dominant negative antigens in combination with antigens derived from capsid-based proteins, to address both the lysogenic and lytic viral replication cycles to achieve maximum immune stimulatory protection.
  • FIGURE 1 A shows the structure of ASFV derived from the lysogenic replication cycle (left) and the subsequent lytic replication cycle(right),
  • FIGURE 1 B shows why current neutralizing strategies do not work for both replication cycles, and
  • FIGURE 1 C shows the major defined proteins that exist in the membrane of ASFV virions derived from the lysogenic replication cycle (top) vs. the major defined capsid proteins from virions derived from the lytic replications cycle (bottom);
  • FIGURE 2 shows the legend of polyclonal antibodies that have been raised against the parallel ASFV proteins for pre-clinical studies
  • FIGURE 3 shows the overall strategy for neutralizing each type of ASFV (with or without membrane) by neutralizing antibodies produced after antigen injection;
  • FIGURE 4 is a representation showing why the dominant negative effect will work far more effectively than using wild type protein or subunit antigens. Immune system exposure;
  • FIGURE 5A shows how ASFV protein EP402R specifically causes porcine RBC aggregation
  • FIGURE 5B shows how ASFV protein E183L causes porcine RBC aggregation
  • FIGURE 6 is a detailed representation of the ASFV infection and replication cycle via RBC-mediated macrophage entry
  • FIGURE 7 is a detailed representation of strategy to block the cycle(s) shown in FIGURE 6;
  • FIGURE 8A and FIGURE 8B shows how polyclonal antibodies raised against EP402R and E183L (p54) block these proteins from causing RBC aggregation;
  • FIGURE 9A are graphs showing the effect of the deglycosylation of EP402R by PNGase F on porcine RBC aggregation and FIGURE 9B shows the deglycosylation of EP402R and by PNGase F on a Coomassie stained gel;
  • FIGURE 10A are sequence and structure diagrams showing the proposed regions and amino acid sequences of EP402R where dominant negative mutations will be made and screened to prevent RBC burrowing/binding resulting in exposure to the immune system. Each is derived from reference sequence China_AnhuiXCGQ_2018;
  • FIGURE 10B is a representation of the orientation of folded full length EP402R in the outermembrane of ASFV;
  • FIGURE 11 A are sequence and structure diagrams showing the proposed regions and amino acid sequences of EP153R where dominant negative mutations will be made and screened to prevent RBC burrowing/binding resulting in exposure to the immune system. Each is derived from reference sequence China_AnhuiXCGQ_2018;
  • FIGURE 1 1 B is a representation of the orientation of folded full length EP153R in the outermembrane of ASFV;
  • FIGURE 12A are sequence and structure diagrams showing the proposed regions and amino acid sequences of E183L where dominant negative mutations will be made and screened to prevent RBC burrowing/binding resulting in exposure to the immune system. Each is derived from reference sequence China_AnhuiXCGQ_2018;
  • FIGURE 12B is a representation of the orientation of folded full length E183L in the capsid and viral envelope of ASFV.
  • the present invention provides generally for compositions and methods of treating and/or preventing ASFV.
  • the compositions include engineered ASFV outermembrane protein antigen mutants (dominant negatives) that do not bind to RBCs yet elicit an antibody response that neutralizes wild type proteins present on infectious outermembrane containing ASFV virions.
  • Pig or “swine” as used herein, can be a domestic pig, wild boar, warthog, or bush pig.
  • vector includes cloning and expression vectors, as well as viral vectors and integrating vectors.
  • An “expression vector” is a vector that includes a regulatory region. Vectors are also further described below.
  • antibody refers to a blood protein produced in response to and counteracting a specific antigen. Antibodies combine chemically with substances which the body recognizes as alien, such as bacteria, viruses, and foreign substances in the blood.
  • mRNA refers to a type of RNA in cells that carries genetic information required to make proteins.
  • the term “dominant negative” antigen for ASFV is used to describe a change to the native ASFV protein, so that the protein becomes exposed to the swine’s immune system resulting in a strong immune response that can effectively inactivate the natural proteins on the virus. [00047] Dominant negative antigens can be engineered several ways:
  • the dominant negative antigens can be screened using peptide libraries that define the epitope regions responsible for the RBC interaction.
  • the epitopes responsible for binding can then be mutated to prevent binding.
  • the mutations can be silent mutations to structure.
  • the dominant negative antigens can be screened using any type of applicable yeast two hybrid screening platform.
  • the two-hybrid library can constitute a reticulocyte to protein antigen bait prey system.
  • RBC receptor resolution can be defined using multiple methods including two hybrid systems, crystallography, ligand linking systems, peptide interaction screening methods to name a few.
  • the dominant negative antigen can include a modification to the protein that prevents binding, such as; i) a structural component that sterically hinders the RBC interaction yet leaves critical amino residues exposed for immune recognition, ii) an alternate glycosylation (branched carbohydrate) that prevents binding, iii) a pegylated residue, iv) and other type of conjugated ligand that interferes with RBC binding without disrupting the structure of the protein so it maintains relevant immunoreactive epitopes that cross react with wild type virus.
  • a modification to the protein that prevents binding such as; i) a structural component that sterically hinders the RBC interaction yet leaves critical amino residues exposed for immune recognition, ii) an alternate glycosylation (branched carbohydrate) that prevents binding, iii) a pegylated residue, iv) and other type of conjugated ligand that interferes with RBC binding without disrupting the structure of the protein so it maintains relevant immunoreactive epitopes that cross
  • composition can include any degree of modification such as, but not limited to, 1 %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.
  • a dominant negative antigen is necessary for a robust and efficacious antigen vaccine approach since the wild type antigens cause/lead to RBC aggregation and ‘hide’ from the immune response. Since capsid-based ASFV does not cause aggregation of RBCs, the use of dominant negative antigens is not necessary at this stage.
  • the present invention provides for a method of treating and/or preventing ASFV infection by administering a composition of a dominant negative antigen to an animal, preventing RBC aggregation from the antigen, and treating and/or preventing ASFV.
  • the present invention provides for a method of treating and/or preventing ASFV infection by administering a composition of a dominant negative antigen in combination with a wild type capsid protein or capsid subunit/domain/peptide to address both the lysogenic and lytic viral replication cycles, respectively.
  • the composition can be provided in a vaccine such as by 1 ) an mRNA vaccine for delivery to APCs and B-cells so that the mRNA expresses the antigen internally to create an immune response, 2) a direct antigen injection, or 3) a DNA vaccine (which sends instructions for making the antigen as DNA). Therefore, the present invention provides for a composition of a vaccine for ASFV, including a dominant negative antigen in a vaccine.
  • reticulocytes or RBCs There can be additional applications for dominant negative proteins for viruses, bacteria, fungus, or parasites binding to reticulocytes or RBCs, which can be masked in other tissues. Hemagglutination is a tactic used by a handful of viruses to enhance their infectivity into target cells. For example, HIV-1 and HIV-2 bind to Duffy Antigen Receptor for Chemokines (DARC), a receptor on RBCs.
  • DARC Duffy Antigen Receptor for Chemokines
  • the binding causes hemagglutination that in turn increases viral infectivity up to approximately 100-fold higher than unbound and circulating virus (Lachgar, et al., He and Neil, et al., Beck, et al.), the degree of which depends on the blood type of the infected individual (Abdulazeez, et al.).
  • HIV-1 has also been shown to bind to P k receptor of PBMCs to block competing viruses (Lund, et al.).
  • Noroviruses also cause hemagglutination by selectively binding to group A, H, and/or difucosylated Lewis blood groups via Receptor / Le b ligand interactions (Nillson, et al., Shirato-Horikoshi, et al.).
  • Other examples of viruses that bind to RBCs and cause hemagglutination include Bovine Corona Virus (BCV), Porcine Hemagglutinating Encephalomyelitis Virus (PHEV), Influenza C, and Toroviruses (Zeng, et al.). Each of these RNA viruses cause hemagglutination by the binding of their Hemagglutinin Esterase (HE) protein to sialic acid containing receptors on RBCs.
  • HE Hemagglutinin Esterase
  • the HE protein has two functions: 1 ) binding to sialic acid containing receptors to cause agglutination.
  • the aggregated RBCs then transport the virus to the target cells more efficiently than unbound and circulating virus.
  • Once in contact with the target cell the HE protein 2) undergoes conformational change to activate its target cell receptor destroying properties, allowing the RBC to release its viral payload for cellular entry.
  • these RNA viruses do not contain an outer-membrane or outer coat like ASFV. There is no outer-membrane to protect the inner core of the virus from an immune response.
  • PHEV is dominated by spike proteins that protrude from a single membrane that also contains the HE and other membrane proteins.
  • PHEV does not differentiate between species. It causes hemagglutination in mice, rats, chickens, and several other animals. Therefore, even though the agglutination of RBCs is a common tactic by some viruses to increase their infectivity to targeted cells, the modes of action are considerably different.
  • ASFV is a DNA virus with much slower mutation rates caused by genetic drift or environmental mutagens, as opposed to many RNA viruses with higher mutations rates caused by lack of replicative proofreading.
  • RNA viruses may not be masked as well by agglutinated RBCs due to their lack of a protective outer coat, but they make up for the difference by rapidly mutating to allow immune evasion. Taking into account these differences (especially the lack of species specificity in HE-containing RNA viruses), it is highly likely that ASFV binds specifically to swine RBCs by a different receptor, sialic acid motif, or carbohydrate than HE-containing RNA viruses.
  • compositions described herein can be dosed in animals according to knowledge of those skilled in the art.
  • the compositions can be in a concentration of 1 - 100% and include any suitable excipients such as further described below.
  • Delivery routes can include, but are not limited to, epicutaneous, intradermal, subcutaneous, transdermal, intramuscular, intravenous, oral, transcorneal, intraocular, intracerebral, epidural, intrathecal, intraperitoneal, intraosseous, intranasal (such as into a snout of a pig), intratracheal, as well as other routes described further below.
  • the composition can be stored in various states that allow for shelf stability (one month to years) of proteins at various temperatures (4 degrees C, -20 degrees C, - 20 to -80 degrees C), such as a lyophilized dry powder, aqueous solution, tris or phosphate buffers, or a solution including 25-50% glycerol or ethylene glycol that act as cryoprotectants.
  • the compound of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual animal, the site and method of administration, scheduling of administration, animal age, sex, body weight and other factors known to medical practitioners.
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
  • the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles.
  • the compounds can be administered orally, subcutaneously, or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, intratonsillar, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful.
  • the patient being treated is a warm-blooded animal and, in particular, mammals including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the doses can be single doses or multiple doses over a period of several days.
  • the treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
  • Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
  • a pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow- release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • any compatible carrier such as various vehicle, adjuvants, additives, and diluents
  • the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow- release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • Nilsson etal. Norwalk virus-like particles bind specifically to A, H and difucosylated Lewis but not to B histo-blood group active glycosphingolipids. Glycoconj J. 2009 Dec;26(9):1171 -80.

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Abstract

L'invention divulguée concerne et englobe une composition comprenant des mutants d'antigène de protéine de membrane externe ASFV modifiés (appelés négatifs dominants) qui présentent une affinité de non liaison aux RBC, tout en induisant une réponse à médiation par anticorps pouvant neutraliser des protéines non modifiées découvertes sur des virions ASFV comportant une membrane externe infectieuse. De plus, l'invention concerne une méthode de traitement et/ou de prévention d'ASFV, impliquant l'administration d'une composition antigénique négative dominante à des animaux, ce qui permet d'éviter l'agrégation de RBC provoquée par ledit antigène et de traiter et/ou de prévenir simultanément l'ASFV. En outre, l'invention concerne une composition de vaccin ASFV contenant l'antigène négatif dominant en tant que constituant. De plus, l'invention concerne une formulation incorporant lesdits antigènes négatifs dominants conjointement avec des antigènes dérivés de protéines à base de capside, qui ciblent collectivement à la fois des cycles de réplication virale lysogène et lytique, ce qui permet d'obtenir une protection de stimulation immunitaire optimale.
PCT/US2023/071659 2022-08-04 2023-08-04 Approche à antigène négatif dominant pour le traitement prophylactique et post-infection du porc contre le virus de la peste porcine africaine WO2024031045A2 (fr)

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