WO2023056527A1 - Molécules protéiques et leurs utilisations - Google Patents

Molécules protéiques et leurs utilisations Download PDF

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WO2023056527A1
WO2023056527A1 PCT/AU2022/051209 AU2022051209W WO2023056527A1 WO 2023056527 A1 WO2023056527 A1 WO 2023056527A1 AU 2022051209 W AU2022051209 W AU 2022051209W WO 2023056527 A1 WO2023056527 A1 WO 2023056527A1
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proteinaceous molecule
proteinaceous
seq
receptor
subject
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PCT/AU2022/051209
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English (en)
Inventor
Richard James Clark
Declan Malcolm GORMAN
Trent Martin Woodruff
Xiang Li
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The University Of Queensland
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Priority claimed from AU2021903225A external-priority patent/AU2021903225A0/en
Application filed by The University Of Queensland filed Critical The University Of Queensland
Publication of WO2023056527A1 publication Critical patent/WO2023056527A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates generally to proteinaceous complement factor C5a receptor agonists, and their use for treating or inhibiting the development of a condition in which enhancing C5a receptor activity stimulates or effects treatment or inhibition of the development of the condition, such as a cancer, an infection, an inflammatory disorder or a central nervous system trauma (such as a spinal cord injury), as well as for eliciting or enhancing an immune response, regenerating tissue and mobilising cells.
  • a condition in which enhancing C5a receptor activity stimulates or effects treatment or inhibition of the development of the condition, such as a cancer, an infection, an inflammatory disorder or a central nervous system trauma (such as a spinal cord injury), as well as for eliciting or enhancing an immune response, regenerating tissue and mobilising cells.
  • the complement system is an important part of the immune system which assists antibodies and phagocytes to remove pathogens and damaged cells, promotes inflammation and triggers pathogen cell lysis.
  • the complement system comprises a series of soluble and cell surface proteins, including plasma components, receptors and diverse regulators (Zheng et al. (2019) Front Immunol, 10: 1866).
  • Complement component 5a (C5a) is a fragment of complement component 5, which exhibits a number of immunoregulatory and pro-inflammatory biological activities through interaction with two receptors: C5a receptor 1 (C5aRl) and C5a receptor-like 2 (C5aR2) (Kumar et al. (2020) ACS Omega, 5: 2345-2354).
  • C5aRl is known to be expressed on a number of cell types, including granulocytes, monocytes, mast cells, dendritic cells, astrocytes, T cells, microglia and cancer cells.
  • C5a and the C5a receptors are involved in the pathology of a number of diseases and conditions, including inflammatory, autoimmune and neurological diseases and conditions as well as cancers.
  • C5a and the C5a receptors have been targets of drug development for several years. While antibodies which inhibit the proteolysis of C5 to C5a and C5b have reached the market (e.g. eculizumab) and a small molecule C5aRl antagonist, avacopan, has completed Phase III trials in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, little attention has been directed to development of C5a receptor agonist compounds. Such compounds have significant therapeutic potential.
  • ANCA antineutrophil cytoplasmic antibody
  • C5a The C-terminus of C5a (residues 64-74) has been shown to be important for both binding and activation of C5aRl.
  • C5aRl The C-terminus of C5a (residues 64-74) has been shown to be important for both binding and activation of C5aRl.
  • the development of truncated hexa/deca-peptide agonists and antagonists for C5aRl have focused on this portion of the sequence (Higginbottom et al. (2005) J Biol Chem, 280: 17831-17840; Konteatis et al. (1994) J Immunol , 153: 4200-4205; Sanderson etal. (1994) J Med Chem, 37: 3171-3180; and Vogen et al. (2001) Int Immunopharmacol, 1: 2151-2162).
  • EP54 was one of the first truncated C5a full agonists developed with nanomolar potency. However, this peptide is not selective for C5aRl, and in fact, more potently induces C3a receptor activation (Sanderson et al. (1994) J Med Chem , 37: 3171-3180; and Sanderson et al. (1995) J Med Chem, 38: 3669-3675).
  • Agonists of the C5a receptor are desired, particularly agonists with selectivity for the C5a receptor over other complement receptors.
  • the present invention is predicated in part on the discovery of proteinaceous molecules that are selective agonists of the C5a receptor, particularly C5aRl. Accordingly, the inventors have conceived that proteinaceous molecules represented by Formula I may be useful as C5a receptor agonists for treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development or progression of the condition (conditions such as cancers, infections, inflammatory disorders or central nervous system trauma, e.g. spinal cord injuries), as well as for eliciting or enhancing an immune response, regenerating tissue and mobilising cells. [0009] Accordingly, in one aspect of the invention, there is provided a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula I:
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety;
  • Xi is selected from amide-containing amino acids including Q, N and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W and modified forms thereof;
  • X2 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof;
  • X3 is selected from any amino acid residue
  • X4 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and the corresponding D amino acids.
  • Xi is Q or L. In particular embodiments, Xi is L.
  • X2 is P or A.
  • X3 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W, Nva, Nle, Abu and modified forms thereof.
  • X3 is selected from L, A, T, F, V, I, Nva and Abu, especially A, T or Abu.
  • X4 is selected from A and D-Ala.
  • the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 12:
  • FKPLAFaR [SEQ ID NO: 6]; FKPLAVaR [SEQ ID NO: 7];
  • FKPQPLaR [SEQ ID NO: 12].
  • the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 4 or
  • the N-terminus is an amine
  • the C-terminus is an acid
  • Zi is a protecting moiety, particularly an acetyl group. In alternative embodiments, Zi is absent.
  • Z2 is absent.
  • composition comprising a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.
  • the composition further comprises an anti-inflammatory agent, cancer therapy, antibiotic, anti-viral, anti-protozoal, anti-fungal, anthelmintic or therapy for a central nervious system trauma.
  • the composition further comprises one or more immune modulating agents or antigen-encoding nucleic acid molecules, such as DNA or RNA (e.g. mRNA).
  • a method of treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition comprising administering the proteinaceous molecule of the invention.
  • the C5a receptor is C5aRl.
  • the condition is selected from the group consisting of a cancer, an infection, an inflammatory disorder and a central nervous system trauma.
  • the central nervous system trauma is a spinal cord injury.
  • the spinal cord injury is a chronic phase spinal cord injury.
  • the invention further provides a method of eliciting an immune response in a subject, comprising administering the proteinaceous molecule of the invention to the subject.
  • the invention provides a method of enhancing an immune response in a subject to a target antigen by an immune modulating agent, comprising administering the proteinaceous molecule of the invention to the subject.
  • the immune modulating agent is selected from an antigen that corresponds to at least a portion of the target antigen, an antigen-binding molecule that is immuno-interactive with the target antigen and an immune modulating cell that modulates an immune response to the target antigen.
  • a method of treating a cancer in a subject comprising administering the proteinaceous molecule of the invention to the subject.
  • the cancer is breast cancer.
  • a method of treating an infection in a subject comprising administering the proteinaceous molecule of the invention to the subject.
  • the infection is a bacterial, viral, protozoan, fungal or helminth infection.
  • a method of agonising a C5a receptor comprising contacting a cell expressing a C5a receptor with a proteinaceous molecule of the invention.
  • the C5a receptor is C5aRl.
  • a method of agonising a C5a receptor in a subject comprising administering to the subject a proteinaceous molecule of the invention, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor.
  • the C5a receptor is C5aRl.
  • the subject has a condition selected from the group consisting of a cancer, an infection, an inflammatory disorder and a central nervous system trauma (such as a spinal cord injury).
  • a condition selected from the group consisting of a cancer, an infection, an inflammatory disorder and a central nervous system trauma (such as a spinal cord injury).
  • Figure 1 is a graph showing the relative potencies for C5aRl over C3aR (ECso for C5aRl/ECso for C3aR) for each peptide analogue.
  • Figure 2 is a graphical illustration of the dose-response curves of peptides at C5aRl and C3aR measured by ERK1/2 phosphorylation in CHO cells.
  • Figure 2A is a graph showing dose-response curves for C5a, BM1, BM210, BM213 and BM221 in CHO cells stably transfected with C5aRl
  • Figure 2B is a graph showing dose-response curves for C3a, BM1, BM210, BM213 and BM221 in CHO cells stably transfected with C3aR.
  • Figure 3 is a graphical illustration of the ligand induced beta-arrestin 2 recruitment for C5a, BM1, BM210, BM221, BM205 and BM206 measured by bioluminescence resonance energy transfer (BRET) in HEK293 cells.
  • BRET bioluminescence resonance energy transfer
  • Figure 3A is a graph showing the BRET ratio at C5aRl in HEK293 cells transiently transfected with C5aRl-Renilla luciferase 8 and 0-arrestin 2-Rluc8 for C5a, BM1, BM210 and BM221;
  • Figure 3B is a graph showing the BRET ratio at C5aR2 in HEK293 cells transiently transfected with C5aR2-Venus and p-arrestin 2-Rluc8 for C5a, BM1, BM210 and BM221;
  • Figure 4 is a graphical illustration of calcium mobilisation and ERK1/2 phosphorylation in HMDM upon C5aRl agonist stimulation.
  • Figure 5 is a graphical illustration of the stability and cytotoxicity of the peptides.
  • Figure 6 is a graphical illustration showing the effect of C5a, BM210, BM213 and BM221 on cytokine release in HMDMs.
  • Figure 6C is a graph showing the effect of C5a, BM210, BM213 and BM221 on TNFo release in HMDMs [Data were
  • Figure 7 is a graph showing the effect of C5a, BM201, BM203, BM204, BM205 and BM206 on p-arrestin recruitment measured by BRET in HEK293 cells transiently transfected with C5aRl-Renilla luciferase 8 and 0-arrestin 2-Rluc8.
  • Figure 7A shows the effect of 100 pM BM201, BM203, BM204, BM205 and BM206
  • Figure 7B shows the effect of 10 pM BM201, BM203, BM204, BM205 and BM206.
  • Figure 9 is a graph showing the ERK1/2 phosphorylation in RAW 264.7 mouse macrophages upon administration of ⁇ ECioo-so concentrations of C5a, BM213 and BM221 either with or without 100 pM JPE1375.
  • administering concurrently or “co-administering” and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and/or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition.
  • simultaneous is meant that the agents are administered at substantially the same time, and desirably together in the same composition.
  • temporary it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful.
  • the agents when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours.
  • the agents are suitably administered at the same site on the subject.
  • the term "same site” includes the exact location, but can be within about 0.5 to about 15 centimeters, preferably from within about 0.5 to about 5 centimeters.
  • the term "separately” as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order.
  • the term “sequentially” as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.
  • agent includes a compound that induces a desired pharmacological and/or physiological effect.
  • the term also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those compounds specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like.
  • pharmaceutically acceptable and pharmacologically active ingredients include but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like.
  • agent is not to be construed narrowly but extends to small molecules, proteinaceous molecules such as peptides, polypeptides and proteins as well as compositions comprising them and genetic molecules such as RNA, DNA and mimetics and chemical analogs thereof as well as cellular agents.
  • agonist and grammatical equivalents thereof as used herein refers to a molecule that activates, either partially or completely, by any mechanism, an effect of another molecule such as a receptor or intracellular mediator.
  • agonist refers to a molecule that is a direct agonist that activates a C5a receptor, especially C5aRl.
  • Agonism or “activation” (and equivalents thereof) of a C5a receptor may increase C5a receptor activity and/or function, including any one or more of G protein activation; activation of signaling pathways including phosphatidylinositol 3-kinase/protein kinase B (Akt), phospholipase D, protein kinase C and MAP kinase pathways; recruitment and signaling through p-arrestins; activation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IKBO); inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) in neutrophils; activation of NF-KB in macrophages; sphingosine-l-phosphate (SIP) generation; myeloid-derived suppressor cell recruitment; and neovascularisation.
  • Akt phosphatidylinositol 3-kinase/protein kinase B
  • Amino acid residues are referred to herein interchangeably using their full name or the one or three letter codes standard in the art. Abbreviations used for unnatural or modified amino acid residues or derivatives thereof are defined herein where appropriate.
  • the term "antigen" and grammatical variants thereof refer to a compound, composition or substance that may be specifically bound by the products of specific humoral or cellular immunity, such as an antibody molecule or T-cell receptor.
  • Antigens can be any type of molecule including, for example, haptens, simple intermediary metabolites, sugars (e.g. oligosaccharides), lipids, and hormones as well as macromolecules such as complex carbohydrates (e.g. polysaccharides), phospholipids, and proteins.
  • antigens include, but are not limited to, viral antigens, bacterial antigens, fungal antigens, protozoa and other parasitic antigens, tumour/cancer antigens, antigens involved in autoimmune disease, allergy and graft rejection, toxins and other miscellaneous antigens.
  • antigen also encompasses antigens produced by an antigen-encoding nucleic acid molecule introduced into the subject, such as DNA or RNA (e.g. mRNA).
  • antigen-binding molecule a molecule that has binding affinity for a target antigen. It will be understood that this term extends to immunoglobulins, immunoglobulin fragments and non-immunoglobulin derived protein frameworks that exhibit antigen-binding activity.
  • any amino acid residue is used herein to refer to any of the 20 naturally occurring amino acid residues and modified versions thereof, including residues with modified side chains, N-methyl amino acids, o-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.
  • C5a receptor activity refers to the biological activity and/or function of the C5a receptor and includes C5a receptor activation, G protein activation and/or C5a receptor signaling and downstream effects, including activation of signaling pathways such as, but not limited to, phosphatidylinositol 3-kinase/protein kinase B (Akt), phospholipase D, protein kinase C and MAP kinase pathways; recruitment and signaling through p-arrestins; activation of IKBO; inhibition of NF-KB in neutrophils; activation of NF-KB in macrophages; SIP generation; myeloid-derived suppressor cell recruitment; and neovascularisation.
  • the receptor is C5aRl.
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, which can be generally sub-classified as follows: TABLE 1
  • Conservative amino acid substitution also includes groupings based on side chains.
  • a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine.
  • Amino acid substitutions falling within the scope of the present invention are, in general, accomplished by selecting substitutions that do not differ significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. After the substitutions are introduced, the variants are screened for biological activity. TABLE 2
  • derivative is meant a molecule, such as a polypeptide, that has been derived from the basic molecule by modification, for example by conjugation or complexing with other chemical moieties or by post-translational modification techniques as would be understood in the art.
  • derivative also includes within its scope alterations that have been made to a parent molecule including additions or deletions that provide for functionally equivalent molecules.
  • drug unit form refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.
  • an effective amount in the context of treating or inhibiting the development of a condition is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and/or treating existing symptoms, of that condition.
  • the effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • the term "enhance" and variants thereof mean to increase a phenomenon.
  • to enhance an immune response means to increase the animal's capacity to respond to foreign or disease-specific antigens (e.g. cancer antigens or antigens of infectious agents) i.e. those cells primed to attack such antigens are increased in number, activity, and ability to detect and destroy the those antigens.
  • Strength of an immune response is measured by standard tests including: direct measurement of peripheral blood lymphocytes by means known to the art; natural killer cell cytotoxicity assays (refer to Provinciali et al. (1992) J. Immunol.
  • an enhanced immune response is also indicated by physical manifestations such as fever and inflammation, as well as healing of systemic and local infections, and reduction of symptoms of a disease, such as decrease in tumour size or alleviation of symptoms of a disease or condition such as an infection. Such physical manifestations also define an "enhanced immune response" and variants thereof as used herein.
  • the phrase "eliciting an immune response” as used herein means to bring about an animal's response to a foreign or disease-specific antigen (e.g. cancer antigens or antigens of infectious agents).
  • a foreign or disease-specific antigen e.g. cancer antigens or antigens of infectious agents.
  • an immune response refers to a response by the immune system of a subject.
  • an immune response may be to an antigen/immunogen that the subject's immune system recognises as foreign (e.g. nonself-antigens) or self (e.g. self-antigens recognised as foreign).
  • Immune responses may be humoral, involving production of immunoglobulins or antibodies, or cellular, involving various types of B and T lymphocytes, dendritic cells, macrophages, antigen presenting cells and the like, or both. Immune responses may also involve the production or elaboration of various effector molecules such as cytokines.
  • immuno response encompasses immunogenic responses that cause, activate, elicit, stimulate, or induce an immune response against a particular antigen (e.g. a pathogenic antigen or a cancer antigen) or organism (e.g. a pathogenic microorganism) in a subject, as well as immunosuppressive or tolerogenic immune responses that inhibit, suppress, diminish or eliminate an immune response, or render the immune system unresponsive, or delay the occurrence or onset of an immune response, to an allergen, or to a self-antigen or a cell, tissue or organ that expresses such an antigen.
  • an immune response is one that includes immunogenic responses that cause, activate, elicit, stimulate, or induce an immune response against a particular antigen or organism in a subject.
  • immuno-interactive includes reference to any interaction, reaction, or other form of association between molecules and in particular where one of the molecules is, or mimics, a component of the immune system.
  • the phrase "inhibit the development of” refers to a prophylactic treatment which increases the resistance of a subject to developing the disease or condition or, in other words, decreases the likelihood that the subject will develop the disease or condition as well as a treatment after the disease or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse.
  • This phrase also includes within its scope preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it.
  • isolated refers to material that is substantially or essentially free from components that normally accompany it in its native state.
  • an "isolated proteinaceous molecule” refers to in vitro isolation and/or purification of a proteinaceous molecule from its natural cellular environment and from association with other components of the cell. "Substantially free” means that a preparation of proteinaceous molecule is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% pure.
  • the preparation of proteinaceous molecule has less than about 30, 25, 20, 15, 10, 9, 8, 7 , 6, 5, 4, 3, 2 or 1% (by dry weight), of molecules that are not the subject of this invention (also referred to herein as "contaminating molecules").
  • the proteinaceous molecule is recombinantly produced, it is also desirably substantially free of culture medium, i.e., culture medium represents less than about 20, 15, 10, 5, 4, 3, 2 or 1% of the volume of the preparation.
  • the invention includes isolated or purified preparations of at least 0.01, 0.1, 1.0, and 10 milligrams in dry weight.
  • modulating is meant increasing or decreasing, either directly or indirectly, the level or functional activity of a target molecule or response.
  • an agent may indirectly modulate the level/activity by interacting with a molecule other than the target molecule.
  • pharmaceutically acceptable carrier is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction.
  • Carriers may include excipients and other additives such as diluents, fillers, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives and the like.
  • a "pharmacologically acceptable" salt, ester, amide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.
  • polypeptide As used herein, the terms “polypeptide”, “proteinaceous molecule”, “peptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. Thus, these terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non-naturally- occurring amino acid, such as a chemical analogue of a corresponding naturally-occurring amino acid, as well as to naturally-occurring amino acid polymers. These terms do not exclude modifications, for example, glycosylations, acetylations, phosphorylations, attachment of lipid or protecting moieties and the like. Soluble forms of the subject proteinaceous molecules are particularly useful. Included within the definition are, for example, polypeptides containing one or more analogues of an amino acid including, for example, unnatural amino acids, polypeptides with substituted linkages and polypeptides with PEG groups and lipophilic moieties.
  • the first sample may be a sample in the presence of the molecule or agent and the second sample may be a comparative sample without the molecule or agent.
  • the reduction may be determined subjectively, for example when a patient refers to their subjective perception of disease symptoms, such as pain, fatigue, motor symptoms, etc.
  • the reduction may be determined objectively, for example when the number of cancer cells in a sample from a patient is lower than in an earlier sample from the patient.
  • the quantity of substance and/or phenomenon in the first sample is at least 10% lower than the quantity of the same substance and/or phenomenon in a second sample.
  • the quantity of the substance and/or phenomenon in the first sample is at least 25% lower than the quantity of the same substance and/or phenomenon in a second sample.
  • the quantity of the substance and/or phenomenon in the first sample is at least 50% lower than the quantity of the same substance and/or phenomenon in a second sample.
  • the quantity of the substance and/or phenomenon in the first sample is at least 75% lower than the quantity of the same substance and/or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and/or phenomenon in the first sample is at least 90% lower than the quantity of the same substance and/or phenomenon in a second sample.
  • a difference may be expressed as an "n-fold" difference.
  • salts and “prodrugs” include any pharmaceutically acceptable salt, ester, hydrate or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a proteinaceous molecule of the invention, or an active metabolite or residue thereof.
  • pharmaceutically acceptable salts refers without limitation to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g. by reacting the free base group with a suitable organic acid).
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in, for example, Remington (1985) Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 17th edition; Stahl and Wermuth (2002) Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; and Berge et al. (1977) Journal of Pharmaceutical Science, 66: 1-19, each of which is incorporated herein by reference in its entirety.
  • sequence identity refers to the extent that sequences are identical on an amino acid-by-amino acid basis over a window of comparison.
  • a “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical amino acid residue (e.g. Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e. the window size), and multiplying the result by 100 to yield the percentage of sequence identity.
  • the identical amino acid residue e.g. Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met
  • Similarity refers to the percentage number of amino acids that are identical or constitute conservative substitutions as defined in Tables 1 and 2 supra. Similarity may be determined using sequence comparison programs such as GAP (Deveraux et al. 1984, Nucleic Acids Research 12: 387-395). In this way, sequences of a similar or substantially different length to those cited herein might be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.
  • references to describe sequence relationships between two or more polypeptides include “reference sequence,” “comparison window”, “sequence identity,” “percentage of sequence identity” and “substantial identity”.
  • a “reference sequence” is at least 8 but frequently 8 to 15 amino acid residues in length.
  • two amino acid sequences may each comprise (1) a sequence (i.e. only a portion of the complete proteinaceous molecule) that is similar between the two proteinaceous molecules, and (2) a sequence that is divergent between the two proteinaceous molecules, sequence comparisons between two (or more) proteinaceous molecules are typically performed by comparing sequences of the two proteinaceous molecules over a "comparison window” to identify and compare local regions of sequence similarity.
  • a “comparison window” refers to a conceptual segment of at least 6 contiguous positions in which a sequence is compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • the comparison window may comprise additions or deletions (i.e. gaps) of about 20% or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • Optimal alignment of sequences for aligning a comparison window may be conducted by computerised implementations of algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, WI, USA) or by inspection and the best alignment (/.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected.
  • GAP Garnier et al.
  • subject refers to a vertebrate subject, particularly a mammalian or avian (bird) subject, for whom therapy or prophylaxis is desired. Suitable subjects include, but are not limited to, primates; avians (birds); livestock animals such as sheep, cows, horses, deer, donkeys and pigs; laboratory test animals such as rabbits, mice, rats, guinea pigs and hamsters; companion animals such as cats and dogs; and captive wild animals such as foxes, deer and dingoes. In particular, the subject is a human. However, it will be understood that the aforementioned terms do not imply that symptoms are present.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be therapeutic in terms of a partial or complete cure for a disease or condition and/or adverse effect attributable to the disease or condition.
  • These terms also cover any treatment of a condition or disease in a subject, particularly in a human, and include: (a) inhibiting the disease or condition, i.e. arresting its development; or (b) relieving the disease or condition, i.e. causing regression of the disease or condition.
  • tumor refers to any neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterised in part by unregulated cell growth.
  • cancer refers to non-metastatic and metastatic cancers, including early stage and late stage cancers.
  • non-metastatic refers to a cancer that is benign or that remains at the primary site and has not penetrated into the lymphatic or blood vessel system or to tissues other than the primary site.
  • a non-metastatic cancer is any cancer that is a Stage 0, I or II cancer.
  • stage cancer is meant a cancer that is not invasive or metastatic or is classified as a Stage 0, I or II cancer.
  • late stage cancer generally refers to a Stage III or IV cancer, but can also refer to a Stage II cancer or a substage of a Stage II cancer.
  • Stage II cancer is classified as either an early stage cancer or a late stage cancer depends on the particular type of cancer.
  • the term "vaccine” is used herein to refer to a composition comprising at least one antigen or antigen-encoding nucleic acid molecule (e.g. DNA or RNA) which, upon inoculation into a subject, induces an immune response specific for that antigen or a cell or organism expressing the antigen and thereby confers protective immunity to the vaccinated subject against the antigen or a cell or organism expressing the antigen.
  • the antigen may be derived for example from a pathogen, such as from bacteria, viruses, fungi, helminths, protozoans etc., or from a tumour or cancerous tissue.
  • Vaccines may induce a complete or partial immunity to the pathogen or tumour, and/or alleviates the symptoms of disease caused by pathogen or tumour.
  • the protective effects of a vaccine against a pathogen or tumour are normally achieved by inducing in the subject an immune response, either a cell-mediated or a humoral immune response, or a combination of both.
  • an immune response either a cell-mediated or a humoral immune response, or a combination of both.
  • abolished or reduced incidence of infection or tumour, amelioration of symptoms, or accelerated elimination of the pathogen or tumour in subjects are indicative of the protective effects of the vaccine.
  • the present invention is predicated in part on the discovery that proteinaceous molecules comprising a sequence represented by Formula I are agonists of the C5a receptor, and in particular embodiments, have selectivity for the C5a receptor over similar receptors, such as the C3a receptor. Accordingly, the inventors have conceived that proteinaceous molecules comprising, consisting or consisting essentially of a sequence represented by Formula I may be useful as C5a receptor agonists and, therefore, for treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition.
  • a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula I:
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety;
  • Xi is selected from amide-containing amino acids including Q, N and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W and modified forms thereof;
  • X2 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof;
  • X3 is selected from any amino acid residue
  • X4 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and the corresponding D amino acids (i.e. D-Ala (a), D-Ser (s), D-Thr (t), D-Pro (p) and modified forms thereof).
  • Xi is selected from Q, N, M, I, L, V, F, Y and W; especially Q, N, I, L and V.
  • Xi is Q or L.
  • Xi is L.
  • Xi is selected from hydrophobic amino acid residues including M, I, L, V, F, Y, W and modified forms thereof; especially M, I, L, V, F, Y or W.
  • Xi is selected from I, L, V and modified forms thereof; especially I, L or V.
  • X2 is selected from A, G, S, T and P. In some embodiments, X2 is P or A.
  • X3 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W, Nva, Nle, Abu and modified forms thereof. In some embodiments, X3 is selected from A, G, S, T, P, M, I, L, V, F, Y, W, Nva, Nle and Abu. [0088] In particular embodiments, X3 is selected from L, A, T, F, V, I, Nva and Abu; especially A, T or Abu. In some embodiments, X3 is A or Abu, especially Abu.
  • X4 is selected from A, G, S, T, P, D-Ala, D-Ser, D-
  • X4 is selected from A and D-Ala; especially D-
  • Xi is selected from Q, N, M, I, L, V, F, Y and W;
  • X2 is selected from A, G, S, T and P;
  • X3 is selected from A, G, S, T, P, M, I, L, V, F, Y, W, Nva, Nle and Abu;
  • X4 is selected from A, G, S, T, P, D-Ala, D-Ser, D-Thr and D-Pro.
  • Xi is selected from Q, N, I, L and V;
  • X2 is selected from A, G, S, T and P;
  • X3 is selected from L, A, T, F, V, I, Nva and Abu;
  • X4 is selected from A, G, S, T, P, D-Ala, D-Ser, D-Thr and D-Pro.
  • Xi is Q or L
  • X2 is A or P
  • X3 is selected from L, A, T, F, V, I, Nva and Abu;
  • X4 is A or D-Ala.
  • the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 12:
  • FKPLAVaR [SEQ ID NO: 7]; FKPLAIaR [SEQ ID NO: 8];
  • FKPQPLaR [SEQ ID NO: 12].
  • the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 4 or
  • the proteinaceous molecule is a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula II:
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety;
  • X2 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof;
  • X3 is selected from any amino acid residue
  • X4 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and the corresponding D amino acids.
  • Suitable embodiments of Zi, Z2, X2 X3 and X4 are as described above for Formula I.
  • the proteinaceous molecule is a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula III:
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety;
  • X2 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof;
  • X3 is selected from any amino acid residue.
  • Suitable embodiments of Zi, Z2, X2 and X3 are as described above for Formula I.
  • the N-terminus is an amine. In some embodiments, the C-terminus is an acid.
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising or consisting of from about 1 to about 40, 30, 20, 10 or 5 amino acid residues (and all integer residues in between), and a protecting moiety.
  • Zi is a protecting moiety, particularly an acetyl group. In alternative embodiments, Zi is absent.
  • Z2 is absent.
  • Suitable protecting moieties include any moiety which delays or prevents substantial degradation of the proteinaceous molecule.
  • a skilled person will be well aware of suitable protecting moieties.
  • Exemplary protecting moieties include, but are not limited to, a peptide or protein such as an albumin, a polymer such as a polyethylene glycol (PEG), a glycan or polysaccharide, a lipid moiety or a capping moiety, including an acetyl group, pyroglutamate or an amino group.
  • the protecting moiety is an acetyl group.
  • Exemplary lipid moieties include a C10-C20 fatty acyl group, such as hexadecanoyl (palmitoyl; Cie) or tetradecanoyl (myristoyl; C ) ; most especially tetradecanoyl.
  • the acetyl group and/or pyroglutamate are coupled to the N-terminal amino acid residue of the proteinaceous molecule.
  • the N-terminus of the proteinaceous molecule is an acetamide (i.e. the proteinaceous molecule has an acetylated N-terminus).
  • the amino group is coupled to the C-terminal amino acid residue of the proteinaceous molecule.
  • the proteinaceous molecule of the invention has a primary amide or a free carboxyl group (acid) at the C-terminus and a primary amine or acetamide at the N-terminus; especially a C-terminal acid, and an N-terminal amine or acetamide.
  • the protecting moiety may be attached to the N- and/or C-terminus of the proteinaceous molecule, e.g. when Zi or Z2 is a protecting moiety, a protecting moiety may also be attached to the proteinaceous molecule through a side-chain of an amino acid residue, such as through the amino group in the side chain of an amine- containing amino acid residue, such as lysine, arginine, glutamine and asparagine or other suitably modified side chain, especially through a lysine side chain.
  • an amino acid residue such as through the amino group in the side chain of an amine- containing amino acid residue, such as lysine, arginine, glutamine and asparagine or other suitably modified side chain, especially through a lysine side chain.
  • the proteinaceous molecule is a selective agonist of the C5a receptor, especially C5aRl, over at least one other complement receptor, such as the C3a receptor (C3aR).
  • C3aR C3a receptor
  • the proteinaceous molecule exhibits C5aRl selectivity of greater than about 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or greater than about 100-fold with respect to agonism of another complement receptor, especially C3aR.
  • the proteinaceous molecule displays at least 50-fold greater agonism of C5aRl than another complement receptor, especially C3aR.
  • the proteinaceous molecule displays at least 100-fold greater agonism of C5aRl than another complement receptor, especially C3aR. In still further embodiments, the proteinaceous molecule displays at least 500-fold greater agonism of C5aRl than another complement receptor, especially C3aR. In yet further embodiments, the proteinaceous molecule displays at least 1000-fold greater agonism of C5aRl than another complement receptor, especially C3aR.
  • the proteinaceous molecule of the invention is a cyclic molecule.
  • the proteinaceous molecule is cyclized through N-to-C cyclization (head to tail cyclization), preferably through an amide bond (i.e. an amide bond between the N- and C-termini of the linear peptide).
  • Such peptides do not possess N- or C-terminal amino acid residues.
  • the proteinaceous molecules of the invention have an amide-cyclized peptide backbone.
  • the proteinaceous molecules of the invention are cyclized using sidechain to side-chain cyclization, such as through a disulfide bond or a lactam bridge.
  • the N- and C-termini are linked using a linking moiety.
  • the linking moiety may be a peptide linker such that cyclization produces an amide-cyclized peptide backbone. Variation within the peptide sequence of the linking moiety is possible, such that the linking moiety may be modified to alter the physicochemical properties of the proteinaceous molecules and potentially reduce side effects of the proteinaceous molecules of the invention or otherwise improve the therapeutic use of the proteinaceous molecules, for example, by improving stability.
  • the linking moiety will be of suitable length to span the distance between the N- and C-termini of the peptide without substantially altering the structural conformation of the proteinaceous molecule, for example, a peptidic linking moiety may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues in length. In some embodiments, longer or shorter peptidic linking moieties may be required. In alternative embodiments, the proteinaceous molecule is a linear molecule.
  • the proteinaceous molecule of the invention has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence similarity to the amino acid sequence of any one of SEQ ID NOs: 1-12; especially SEQ ID NO: 4 or 11.
  • the proteinaceous molecule of the invention has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-12; especially SEQ ID NO: 4 or 11.
  • the present invention also contemplates compounds comprising proteinaceous molecules that are variants of any one of SEQ ID NOs: 1-12.
  • variant proteinaceous molecules include proteinaceous molecules derived from any one of SEQ ID NOs: 1-12 by deletion or addition of one or more amino acids to the N-terminal and/or C- terminal end of the proteinaceous molecule, deletion or addition of one or more amino acids at one or more sites in the proteinaceous molecule, or substitution of one or more amino acids at one or more sites in the proteinaceous molecule.
  • Variant proteinaceous molecules encompassed by the present invention are biologically active, that is, they continue to possess the desired biological activity of the parent proteinaceous molecule, for example, C5a receptor agonism (especially C5aRl agonism) and, in some embodiments, selectivity for C5aRl over other complement receptors, such as C3aR.
  • C5a receptor agonism especially C5aRl agonism
  • selectivity for C5aRl over other complement receptors such as C3aR.
  • amino acid sequence variants of any one of SEQ ID NOs: 1-12 may be prepared by mutagenesis of nucleic acids encoding the amino acid sequence of any one of SEQ ID NOs: 1-12. Methods for mutagenesis and nucleotide sequence alterations are well known in the art. Refer to, for example, Kunkel (1985, Proc. Natl. Acad. Sci. USA.
  • REM Recursive ensemble mutagenesis
  • Variant proteinaceous molecules of the invention may contain conservative amino acid substitutions (e.g. 1, 2 or 3 substitutions) at various locations along their sequence, as compared to a parent or reference amino acid sequence, such as any one of SEQ ID NOs: 1-12.
  • modified amino acid residues may include residues with modified side chains, N-methyl amino acids, o-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.
  • side chain modifications include modifications of amino groups, such as by acetylation with acetic anhydride; acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; amidination with methylacetimidate; carbamoylation of amino groups with cyanate; pyridoxylation of lysine with pyridoxal-5- phosphate followed by reduction with sodium borohydride; reductive alkylation by reaction with an aldehyde followed by reduction with sodium borohydride; and trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulfonic acid (TNBS).
  • modifications of amino groups such as by acetylation with acetic anhydride; acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; amidination with methylacetimidate; carbamoylation of amino groups with cyanate; pyridoxylation of lysine with pyridoxal-5- phosphat
  • the carboxyl group may be modified by carbodiimide activation through O-acylisourea formation followed by subsequent derivatization, for example, to a corresponding amide.
  • the guanidine group of arginine residues may be modified by formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal. Tryptophan residues may be modified, for example, by alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfonyl halides, or by oxidation with /V-bromosuccinimide.
  • Tyrosine residues may be modified by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.
  • Suitable modified arginine residues include, but are not limited to, N m - carboxymethyl-L-arginine, No-carboxyethyl-L-arginine, N a -acetyl-L-arginine, di(phenylglyoxal)-L-arginine, N-methylarginine, o-methylarginine, 0-arginine, N'-nitro-L- arginine, N',N"-dimethyl-L-arginine, N',N"-diethyl-L-arginine and L-homoarginine.
  • Suitable modified lysine residues include, but are not limited to, Ne- carboxycarbonyl-L-lysine, Ne-succinimidyl-L-lysine, 2-amino-6-(2- hydroxyacetamido)hexanoic acid, Ne-3-hydroxypropyl-L-lysine, ornithine, Ne- allyloxycarbonyl-L-lysine, N-methyllysine, o-methyllysine, 0-lysine, N a -acetyl-L-lysine, Ne- acetyl-L-lysine, Ne-methyl-L-lysine, Ne-dimethyl-L-lysine and Ne-formyl-L-lysine.
  • Suitable modified alanine residues include, but are not limited to, N- methylalanine, o-methylalanine (2-aminoisobutyric acid), p-alanine, N a -acetyl-L-alanine, o-aminobutyric acid (or 2-aminobutyric acid, Abu), homoalanine and p-homoalanine.
  • Suitable modified leucine residues include, but are not limited to, o- methylleucine, N-methylleucine, p-leucine, t-butylglycine, homoleucine, N a -acetyl-L- leucine and p-homoleucine.
  • Suitable modified glutamine residues include, but are not limited to, o- methylglutamine, Na-methylglutamine, N Y -methylglutamine, p-glutamine, homoglutamine, Na-acetyl-L-glutamine and p-homoglutamine.
  • Exemplary modified asparagine residues include Np-methyl-Np-methoxy- asparagine, o-methylasparagine, N a -methylasparagine, Np-methylasparagine, p- asparagine, homoasparagine, N a -acetyl-L-asparagine and p-homoasparagine.
  • Modified glycine residues include, but are not limited to, N-methylglycine, P-homoglycine and N a -acetyl-L-glycine.
  • Modified serine residues may include N-methylserine, o-methylserine, p- serine, N a -acetyl-L-serine, isoserine, O-methylserine, homoserine and p-homoserine.
  • Exemplary modified threonine residues include N-methylthreonine, o- methylthreonine, p-threonine, N a -acetyl-L-threonine, O-methylthreonine, homothreonine and p-homothreonine.
  • Suitable modified methionine residues include, but are not limited to, norleucine, N-methylmethionine, o-methylmethionine, p-methionine, N a -acetyl-L- methionine, methionine sulfoxide, methionine sulfone, selenomethionine, homomethionine and p-homomethionine.
  • Exemplary modified proline residues include o-methylproline, p-proline, Na-acetyl-L-proline, 4-phenoxy-pyrrolidine-2-carboxylic acid, 5,5-dimethylpyrrolidine-2- carboxylic acid, 5-methylpyrrolidine-2-carboxylic acid, homoproline and p-homoproline.
  • Suitable modified isoleucine residues include, but are not limited to, o- methylisoleucine, N-methylisoleucine, p-isoleucine, homoisoleucine, N a -acetyl-L- isoleucine, p-methylisoleucine and p-homoisoleucine.
  • Modified valine residues may include, but are not limited to, norvaline, o- methylvaline, N-methylvaline, p-valine, p-homovaline and N a -acetyl-L-valine.
  • Suitable modified phenylalanine residues include, but are not limited to, o-methylphenylalanine, N-methylphenylalanine, p-phenylalanine, p-methylphenylalanine, P,P-dimethylphenylalanine, p-hydroxyphenylalanine, homophenylalanine, N a -acetyl-L- phenylalanine and p-homophenylalanine.
  • Exemplary modified tyrosine residues include o-methyltyrosine, N- methyltyrosine, p-tyrosine, p-methyltyrosine, p,p-dimethyltyrosine, p-hydroxytyrosine, homotyrosine, O-methylhomotyrosine, N a -acetyl-L-tyrosine, O-methyltyrosine, O- ethyltyrosine, m-tyrosine and p-homotyrosine.
  • Suitable modified tryptophan residues include, but are not limited to, o- methyltryptophan, N-methyltryptophan, p-tryptophan, p-methyltryptophan, homotryptophan, N-formyl-tryptophan, 2-methyltryptophan, N a -acetyl-L-tryptophan and P-homotryptophan.
  • the proteinaceous molecules of the invention also encompass a proteinaceous molecule comprising unnatural amino acid residues and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods which impose conformational constraints on the proteinaceous molecules.
  • Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of 4-amino butyric acid, 6- aminohexanoic acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 4-amino-3-hydroxy-6- methylheptanoic acid, t-butylglycine, norleucine, norvaline, phenylglycine, 2-aminobutyric acid, ornithine, /Vs-acetyl-L-ornithine, sarcosine, 2-thienyl alanine and/or D-isomers of amino acids.
  • a list of unnatural amino acids contemplated by the present invention is shown in Table 3, in addition to the modified resides discussed supra.
  • Additional amino acids or other substituents may be added to the N- termini of the proteinaceous molecules of the invention.
  • the proteinaceous molecules of the invention may form part of a longer sequence with additional amino acids added to the N-termini.
  • the proteinaceous molecules may be isolated or purified.
  • the proteinaceous molecules of the invention may also be in the form of salts or prodrugs.
  • the salts of the proteinaceous molecules of the present invention are preferably pharmaceutically acceptable, but it will be appreciated that non- pharmaceutically acceptable salts also fall within the scope of the present invention.
  • the proteinaceous molecules may be in crystalline form and/or in the form of solvates, for example, hydrates. Solvation may be performed using methods known in the art.
  • the present invention also contemplates nucleic acid molecules which encode a proteinaceous molecule of the invention.
  • an isolated nucleic acid molecule comprising a polynucleotide sequence that encodes a proteinaceous molecule of the invention or is complementary to a polynucleotide sequence that encodes a proteinaceous molecule of the invention, such as the proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula I, II or III or any one of SEQ ID NOs: 1-12 as described herein.
  • the isolated nucleic acid molecules of the present invention may be DNA or RNA.
  • the nucleic acid When the nucleic acid is in DNA form, it may be genomic DNA or cDNA.
  • RNA forms of the nucleic acid molecules of the present invention are generally mRNA.
  • nucleic acid molecules are typically isolated, in some embodiments the nucleic acid molecules may be integrated into, ligated to, or otherwise fused or associated with other genetic molecules, such as an expression vector.
  • an expression vector includes transcriptional and translational regulatory nucleic acid operably linked to the polynucleotide sequence.
  • an expression vector comprising a polynucleotide sequence that encodes a proteinaceous molecule of the invention, such as a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula I, II or III or any one of SEQ ID NOs: 1-12 as described herein.
  • the proteinaceous molecules of the invention may be produced inside a cell by introduction of one or more expression constructs, such as an expression vector, that comprise a polynucleotide sequence that encodes a proteinaceous molecule of the invention.
  • the invention contemplates recombinantly producing the proteinaceous molecules of the invention inside a host cell, such as a mammalian cell (e.g. Chinese hamster ovary (CHO) cell, mouse myeloma (NSO) cell, baby hamster kidney (BHK) cell or human embryonic kidney (HEK293) cell), yeast cell (e.g.
  • Pichia pastoris cell Saccharomyces cerevisiae cell, Schizosaccharomyces pombe cell, Hansenula polymorpha cell, Kluyveromyces lactis cell, Yarrowia lipolytica cell or Arxula adeninivorans cell
  • insect cell e.g. Spodoptera frugiperda cell, such as an Sf9 cell
  • bacterial cell e.g. Escherichia coli cell, Corynebacterium glutamicum or Pseudomonas fluorescens cell.
  • the invention also contemplates producing the proteinaceous molecules of the invention in vivo inside a C5a receptor expressing cell, especially a C5aRl expressing cell, such as a vertebrate cell, particularly a mammalian cell.
  • the expression of natural or synthetic nucleic acids is typically achieved by operably linking a polynucleotide sequence encoding a proteinaceous molecule of the invention to a regulatory element (e.g. a promoter, which may be either constitutive or inducible), suitably incorporating the construct into an expression vector and introducing the vector into a suitable host cell.
  • a regulatory element e.g. a promoter, which may be either constitutive or inducible
  • Typical vectors contain transcription and translation terminators, transcription and translation initiation sequences and promoters useful for regulation of the expression of the nucleic acid.
  • the vectors optionally comprise generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in eukaryotes, prokaryotes or both (e.g.
  • Vectors may be suitable for replication and integration in prokaryotes, eukaryotes, or both. See, Giliman and Smith (1979), Gene, 8: 81-97; Roberts etal. (1987) Nature, 328: 731-734; Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology, volume 152, Academic Press, Inc., San Diego, Calif. (Berger); Sambrook et al. (1989), Molecular Cloning - a Laboratory Manual (2nd ed.) Vol.
  • Expression vectors containing regulatory elements from eukaryotic viruses are typically used for expression of nucleic acid sequences in eukaryotic cells.
  • exemplary vectors include SV40 vectors such as pSVT7 and pMT2, vectors derived from bovine papilloma virus such as pBV-lMTHA, and vectors derived from Epstein Bar virus such as pHEBO, and p2O5.
  • exemplary vectors include pMSG, pAV009/A+, pMTO10/A+, pMAMneo-5, baculovirus pDSVE, and any other vector allowing expression of proteins under the direction of the SV-40 early promoter, SV-40 later promoter, metallothionein promoter, murine mammary tumour virus promoter, Rous sarcoma virus promoter, polyhedrin promoter, or other promoters shown to be effective for expression in eukaryotic cells.
  • viral expression vectors are useful for modifying eukaryotic cells because of the high efficiency with which the viral vectors transfect target cells and integrate into the target cell genome.
  • Illustrative expression vectors of this type can be derived from viral DNA sequences including, but not limited to, adenovirus, adeno-associated viruses, herpes-simplex viruses and retroviruses such as B, C, and D retroviruses as well as spumaviruses and modified lentiviruses.
  • Suitable expression vectors for transfection of animal cells are described, for example, by Wu and Ataai (2000) Curr. Opin.
  • the polypeptide or peptide-encoding portion of the expression vector may comprise a naturally-occurring sequence or a variant thereof, which has been engineered using recombinant techniques.
  • the codon composition of a polynucleotide encoding a proteinaceous molecule of the invention is modified to permit enhanced expression of the proteinaceous molecule of the invention in a mammalian host using methods that take advantage of codon usage bias, or codon translational efficiency in specific mammalian cell or tissue types as set forth, for example, in International Publications WO 99/02694 and WO 00/42215.
  • codon-optimized polynucleotides at least one existing codon of a parent polynucleotide is replaced with a synonymous codon that has a higher translational efficiency in a target cell or tissue than the existing codon it replaces.
  • the replacement step affects 5%, 10%, 15%, 20%, 25%, 30%, more preferably 35%, 40%, 50%, 60%, 70% or more of the existing codons of a parent polynucleotide.
  • the expression vector is compatible with the cell in which it is introduced such that the proteinaceous molecule of the invention is expressible by the cell.
  • the expression vector is introduced into the cell by any suitable means which will be dependent on the particular choice of expression vector and cell employed. Such means of introduction are well-known to those skilled in the art. For example, introduction can be effected by use of contacting (e.g. in the case of viral vectors), electroporation, transformation, transduction, conjugation or triparental mating, transfection, infection membrane fusion with cationic lipids, high-velocity bombardment with DNA-coated micro projectiles, incubation with calcium phosphate-DNA precipitate, direct microinjection into single cells, and the like.
  • the vectors are introduced by means of cationic lipids, e.g., liposomes.
  • liposomes are commercially available (e.g. Lipofectin®, LipofectamineTM, and the like, supplied by Invitrogen Waltham MA, USA).
  • the proteinaceous molecules may be prepared using any suitable method, such as chemical synthesis or recombinant DNA techniques.
  • the proteinaceous molecules are prepared using standard peptide synthesis methods, such as solution synthesis or solid phase synthesis.
  • the chemical synthesis of the proteinaceous molecules may be performed manually or using an automated synthesizer.
  • the linear peptides may be synthesized using solid phase peptide synthesis using either Boc or Fmoc chemistry, as described in Merrifield (1963) J Am Chem Soc, 85(14): 2149- 2154; Schnolzer, et al. (1992) Int J Pept Protein Res, 40: 180-193; Cardoso, et al.
  • the proteinaceous molecules of the invention may be cyclized. Cyclization may be performed using several techniques, for example, as described in Davies (2003) J Pept Sci, 9: 471-501. For example, N-to-C cyclization may be conducted in the solution phase, using a dilute solution of the linear peptide in the presence of a coupling agent such as BOP (1-benzotriazole-tris-dimethyl aminophosphonium hexafluorophosphate), PyBOP (1-benzotriazolyloxy-tris-pyrrolidino phosphonium hexafluorophosphate), PyAOP (7-azabenzotriazol-l-yloxy tris pyrrolidino phosphonium hexafluorophosphate), AOP (7-azabenzotriazol-l-yloxy-tris-dimethyl aminophosphonium hexafluorophosphate), HBTU (O-(benzotriazol-l-yl)
  • the cyclized peptide may then be deprotected (i.e. the side chain protecting groups may then be removed) using standard techniques, followed by purification using suitable methods, such as preparative chromatography.
  • suitable methods such as preparative chromatography.
  • N-to-C cyclization may be achieved on resin using a suitable coupling agent, such as those described above, and a suitable resin, such as a Kaiser oxime resin, and/or linker (e.g. a safety catch linker).
  • the proteinaceous molecules of the invention are prepared using recombinant DNA techniques.
  • the proteinaceous molecules of the invention may be prepared by a procedure including the steps of: (a) preparing a construct comprising a polynucleotide sequence that encodes the proteinaceous molecule of the invention and that is operably linked to a regulatory element; (b) introducing the construct into a host cell; (c) culturing the host cell to express the polynucleotide sequence to thereby produce the encoded proteinaceous molecule of the invention; and (d) isolating the proteinaceous molecule of the invention from the host cell.
  • the proteinaceous molecule of the present invention may be prepared recombinantly using standard protocols, for example, as described in Klint, et al. (2013) PLOS One, 8(5): e63865; Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual (Cold Spring Harbour Press), in particular Sections 16 and 17; Ausubel, et al. (1998) Current Protocols in Molecular Biology (John Wiley and Sons, Inc.), in particular Chapters 10 and 16; and Coligan, et al. (1997) Current Protocols in Protein Science (John Wiley and Sons, Inc.), in particular Chapters 1, 5 and 6.
  • the proteinaceous molecules are also useful in compositions and methods for treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition.
  • the proteinaceous molecules may be in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.
  • the proteinaceous molecule may be formulated into the pharmaceutical composition as a neutral or salt form.
  • the choice of pharmaceutically acceptable carrier or diluent will be dependent on the route of administration and on the nature of the condition and subject to be treated.
  • the particular carrier or delivery system and route of administration may be readily determined by a person skilled in the art.
  • the carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the proteinaceous molecule is not depleted during preparation of the formulation and the proteinaceous molecule is able to reach the site of action intact.
  • compositions of the invention may be administered through a variety of routes including, but not limited to, oral, rectal, topical, intranasal, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration; especially oral, intravenous, intramuscular, subcutaneous, intrathecal, or intraperitoneal administration.
  • the pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and may be preserved against reduction, oxidation and microbial contamination.
  • Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane (Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers.
  • carboxylic acid buffers such as acetate, citrate, lactate, tartrate and succinate
  • Tris tris(hydroxymethyl)aminomethane
  • arginine sodium hydroxide
  • glutamate and carbonate buffers.
  • Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulphite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.
  • BHT butylated hydroxytoluene
  • reducing agents such as methionine or sulphite
  • metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride
  • sodium bisulfite sodium metabisulfite
  • sodium sulfite ascorbyl palmitate
  • lecithin propyl gallate
  • alpha-tocopherol al
  • the proteinaceous molecule may be formulated in an aqueous solution, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, dextrose solution or physiological saline buffer, such as phosphate buffered saline (PBS).
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, dextrose solution or physiological saline buffer, such as phosphate buffered saline (PBS).
  • PBS physiological saline buffer
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present invention may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline and sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance.
  • acceptable diluents such as saline and sterile water
  • Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as non-ionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives and hydrophilic beeswax derivatives.
  • ethoxylated and nonethoxylated surfactants include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils
  • the proteinaceous molecule can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration, which is also contemplated for the practice of the present invention.
  • pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration, which is also contemplated for the practice of the present invention.
  • Such carriers enable the proteinaceous molecules of the invention to be formulated in dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • These carriers may be selected from sugars, chitosan, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water.
  • compositions for parenteral administration include aqueous solutions of the composition in water-soluble form.
  • suspensions of the proteinaceous molecule may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the proteinaceous molecules to allow for the preparation of highly concentrated solutions.
  • Sterile solutions may be prepared by combining the proteinaceous molecule in the required amount in the appropriate solvent with other excipients as described above as required, followed by sterilization, such as filtration.
  • dispersions are prepared by incorporating the various sterilized active agents into a sterile vehicle which contains the basic dispersion medium and the required excipients as described above.
  • Sterile dry powders may be prepared by vacuum- or freeze-drying a sterile solution comprising the active agents and other required excipients as described above.
  • compositions for oral use can be obtained by combining the proteinaceous molecules with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatine, gum tragacanth, methyl cellulose, hydroxypropyl methyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents as described above with the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of particle doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the proteinaceous molecules may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations.
  • the proteinaceous molecules may be administered in a local rather than systemic manner, such as by injection directly into a tissue, which is preferably subcutaneous or omental tissue, often in a depot or sustained release formulation. In other embodiments, the proteinaceous molecule is systemically administered.
  • the proteinaceous molecule may be administered in a targeted drug delivery system, such as in a particle which is suitable targeted to and taken up selectively by a cell or tissue.
  • the proteinaceous molecule is contained or otherwise associated with a vehicle selected from liposomes, micelles, dendrimers, biodegradable particles, artificial DNA nanostructure, lipid-based nanoparticles and carbon or old nanoparticles.
  • the vehicle is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), PLA-PEG copolymers and combinations thereof.
  • PDA poly(lactic acid)
  • PGA poly(glycolic acid)
  • PLGA poly(lactic-co-glycolic acid)
  • PEG poly(ethylene glycol)
  • PLA-PEG copolymers PLA-PEG copolymers and combinations thereof.
  • compositions in dosage unit form for ease of administration and uniformity of dosage.
  • determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the proteinaceous molecule of the invention may be the sole active ingredient administered to the subject, the administration of other active ingredients concurrently with said proteinaceous molecule is within the scope of the invention.
  • the proteinaceous molecule may be administered concurrently with one or more anti-inflammatory agents, cancer therapies, antibiotics, anti-virals, anti-protozoals, anti-fungals, anthelmintics or therapies for a central nervous system trauma.
  • the proteinaceous molecule may be therapeutically used after the other active ingredient or may be therapeutically used together with the other active ingredient.
  • the proteinaceous molecule may be administered separately, simultaneously or sequentially with the other active ingredient.
  • composition comprising a proteinaceous molecule of the invention and an antiinflammatory agent, cancer therapy, antibiotic, anti-viral, anti-protozoal, anti-fungal, anthelmintic or therapy for a central nervous system trauma.
  • Suitable cancer therapies include, but are not limited to, radiotherapy, surgery, chemotherapy, hormone ablation therapy, pro-apoptosis therapy, oncolytic viral therapy and immunotherapy.
  • the cancer therapy is radiotherapy.
  • Suitable radiotherapies include radiation and waves that induce DNA damage, for example, y- irradiation, X-rays, UV irradiation, microwaves, electronic emissions and radioisotopes.
  • therapy may be achieved by irradiating the localized tumour site with the above described forms of radiations. It is most likely that all of these factors cause a broad range of damage to DNA, on the precursors of DNA, on the replication and repair of DNA and on the assembly and maintenance of chromosomes.
  • the dosage range for X-rays ranges from daily doses of 50-200 roentgens for prolonged periods of time such as 3-4 weeks, to single doses of 2000-6000 roentgens.
  • Dosage ranges for radioisotopes vary widely and depend on the half-life of the isotope, the strength and type of radiation emitted and the uptake by the neoplastic cells.
  • Suitable radiotherapies may include, but are not limited to, conformal external beam radiotherapy (50-100 Gray given as fractions over 4-8 weeks), either single shot or fractionated high dose brachytherapy, permanent interstitial brachytherapy and systemic radioisotopes such as Strontium 89.
  • the radioisotope may be administered alone, or as part of a conjugate, such as an antibody-radioisotope conjugate (e.g. 131I-M195, 213Bi-HuM195, actinium- 225 labelled daratumumab, BAY2287411, BAY2315497, BAY 1862864, ibritumomab tiuxetan, iodine-131 tositumomab and HER2-TTC).
  • the radiotherapy may be administered with a radiosensitising agent.
  • Suitable radiosensitising agents may include, but are not limited to, efaproxiral, etanidazole, fluosol, misonidazole, nimorazole, temoporfin and tirapazamine.
  • Suitable chemotherapeutic agents contemplated herein include any agent that can be used to treat a disease or disorder in a subject, and in preferred embodiments encompasses agents that are used to treat a tumour or cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxa
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
  • Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumours such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMA
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugates, gemtuzumab ozogamicin (MYLOTARG®, Wyeth), trastuzumab deruxtecan (ENHERTU®, AstraZeneca/Daiichi Sankyo Company, Ltd) and trastuzumab emtansine (KADCYCLA®, Genentech).
  • antibodies such as alemtuzumab (Campath
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab
  • Chemotherapeutic agent also includes "EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro- 4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl- amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl- piperidin
  • Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-
  • Suitable chemotherapeutic agents also include cyclin-dependent kinase (CDK) inhibitors, representative examples of which include, but are not limited to, CDK4/6 inhibitors such as palbociclib, ribociclib, abemaciclib and trilaciclib; zotiraciclib; alvocidib; atuveciclib; voruciclib; olomoucine; and seleciclib.
  • CDK cyclin-dependent kinase
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, opre
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17- propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone farnesyltransferase inhibitors
  • SCH 6636 farnesyltransferase inhibitors
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non- selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, pare
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • Suitable oncolytic viral therapies include, but are not limited to, talimogene laherparepvec (OncoVEX-GM-CSF, T-VEC, Imlygic), HSV1716 (Seprehvir), G207, NV1020, ONCOS-102, PVS-RIPO, pexastimogene devacirepvec (JX-594), CG0070, pelareorep (Reolysin), G47A, H101 (Oncorine) and ONYX-015 (dll520, CI-1042).
  • Suitable immunotherapy approaches may include, but are not limited to ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines including interleukin 2, interleukin 4 or granulocytemacrophage colony stimulating factor; approaches to decrease T-cell anergy; approaches using transfected immune cells such as cytokine-transfected dendritic cells; approaches using cytokine-transfected tumor cell lines; and approaches using anti-idiotypic antibodies.
  • cytokines including interleukin 2, interleukin 4 or granulocytemacrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune cells such as cytokine-transfected dendritic cells
  • approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
  • the immune effector may be, for example, an antibody specific for some marker on the surface of a malignant cell.
  • the antibody alone may serve as an effector of therapy or it may recruit other cells to actually facilitate cell killing.
  • the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
  • the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a malignant cell target.
  • Various effector cells include cytotoxic T cells and NK cells. Immunotherapy approaches may also include administration of checkpoint inhibitors.
  • such approaches may include administering inhibitors of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, B7-H3, B7-H4, B7-H5, B7-H6 and/or B7-H7.
  • Suitable checkpoint inhibitors include, but are not limited to, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, spartalizumab, JTX-4014, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), KN035, CK-301 (cosebelimab), AUNP-12, CA- 170 and BMS-986189.
  • Examples of other cancer therapies include phytotherapy, cryotherapy, toxin therapy or pro-apoptosis therapy.
  • phytotherapy phytotherapy
  • cryotherapy toxin therapy
  • pro-apoptosis therapy pro-apoptosis therapy
  • NSAIDs e.g. acetylsalicylic acid (aspirin), diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, zomepirac, celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib), disease-modifying antirheumatic drugs (DMARDs) (e.g. acetylsal
  • methotrexate leflunomide, sulfasalazine, hydroxychloroquinone, penicillamine, anatacept, baricitinib, cetolizumab, sarilumab, tocilizumab or tofacitinib), prednisone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, prednisolone, etanercept, golimumab, infliximab, adalimumab, anakinra, rituximab, natalizumab and abatacept.
  • antibiotics include, but are not limited to, quinolones (e.g. amifloxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, levofloxacin, lomefloxacin, oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin, gatifloxacin, moxifloxacin, gemifloxacin, or garenoxacin), tetracyclines, glycylcyclines or oxazolidinones (e.g.
  • chlortetracycline demeclocycline, doxycycline, lymecycline, methacycline, minocycline, oxytetracycline, tetracycline, tigecycline, linezolide or eperezolid
  • aminoglycosides e.g. amikacin, arbekacin, butirosin, dibekacin, fortimicins, gentamicin, kanamycin, menomycin, netilmicin, ribostamycin, sisomicin, spectinomycin, streptomycin or tobramycin
  • p-lactams e.g.
  • ketolides e.g. telithromycin or cethromycin
  • coumermycins e.g. clindamycin or lincomycin
  • chloramphenicol e.g. clindamycin or lincomycin
  • Suitable anti-virals include, but are not limited to, abacavir sulfate, acyclovir sodium, amantadine hydrochloride, amprenavir, cidofovir, delavirdine mesylate, didanosine, efavirenz, famciclovir, fomivirsen sodium, foscarnet sodium, ganciclovir, indinavir sulfate, lamivudine, lamivudine/zidovudine, nelfinavir mesylate, nevirapine, oseltamivir phosphate, ribavirin, rimantadine hydrochloride, ritonavir, saquinavir, saquinavir mesylate, stavudine, valacyclovir hydrochloride, zalcitabine, zanamivir or zidovudine.
  • anti-protozoals include atovaquone, chloroquine hydrochloride, chloroquine phosphate, doxycycline, hydroxychloroquine sulfate, mefloquine hydrochloride, primaquine phosphate, pyrimethamine, metronidazole, metronidazole hydrochloride and pentamidine isethionate.
  • Anthelmintics can be at least one selected from mebendazole, albendazole, fenbendazole, triclabendazole, flubendazole, abamectin, diethylcarbamazine, pyrantel pamoate, levamisole, niclosamide, oxyclozanide, nitazoxanide, praziquantel, emodepside, monepantel, derquantel, artemisinin, albendazole, ivermectin and thiabendazole.
  • Illustrative anti-fungals include, but are not limited to, amphotericin B, amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposomal, anidulafungin, caspofungin, clotrimazole, fluconazole, flucytosine, griseofulvin, griseofulvin microsize, griseofulvin ultramicrosize, isavuconazonium, itraconazole, ketoconazole, micafungin, miconazole, nystatin, posaconazole, terbinafine, voriconazole, fosflu con azole, isavuconazole, candicidin, hamycin, natamycin, bifonazole, butoconazole, econazole, fenticonazole, isoconazole, luliconazole, omoconazole, oxiconazole,
  • Examplary therapies for a central nervous system trauma include, but are not limited to, a steroid, such as methylprednisolone, levetiracetam and rapamycin.
  • the proteinaceous molecule of the invention is used for enhancing an immune response in a subject to a target antigen by an immune modulating agent.
  • the proteinaceous molecule may be administered concurrently with one or more immune modulating agents.
  • the proteinaceous molecule may be therapeutically used after the one or more immune modulating agents or may be therapeutically used together with the one or more immune modulating agents.
  • the proteinaceous molecule may be administered separately, simultaneously or sequentially with the one or more immune modulating agents.
  • compositions comprising a proteinaceous molecule of the invention and an immune modulating agent.
  • Such compositions may be, for example, a vaccine composition, which may also comprise a pharmaceutically acceptable carrier or diluent as discussed supra.
  • Suitable immune modulating agents are as described in further detail herein.
  • the invention also provides a composition comprising a proteinacecous molecule of the invention and an antigen-encoding nucleic acid molecule (e.g. DNA or RNA, especially mRNA).
  • an antigen-encoding nucleic acid molecule e.g. DNA or RNA, especially mRNA.
  • These vaccine compositions may also comprise a pharmaceutically acceptable carrier or diluent as discussed supra. Suitable antigens are described in further detail herein.
  • the proteinaceous molecule may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form.
  • a unit dosage form may comprise the proteinaceous molecule in an amount in the range of from about 0.25 pg to about 2000 mg.
  • the proteinaceous molecule may be present in an amount of from about 0.25 pg to about 2000 mg/mL of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • proteinaceous molecules of the invention are agonists of the C5a receptor.
  • the inventors have determined that such proteinaceous molecules may have selectivity for agonism of the C5a receptor, especially C5aRl, over other complement factor receptors, such as the C3a receptor.
  • the inventors have conceived that the proteinaceous molecules of the invention may be useful as C5a receptor agonists and, therefore for treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition.
  • Such conditions include, for example, a cancer, an infection, an inflammatory disorder or a central nervous system trauma, such as a spinal cord injury.
  • the proteinaceous molecules may also be used for eliciting or enhancing an immune response, regenerating tissue and mobilising cells. Accordingly, a proteinaceous molecule of the invention for use in therapy is contemplated.
  • a method of treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition comprising administering a proteinaceous molecule of the invention.
  • the invention also provides a proteinaceous molecule of the invention for use in treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition, the use of a proteinaceous molecule of the invention for in treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition, and the use of a proteinaceous molecule of the invention in the manufacture of a medicament for this purpose.
  • the condition is selected from the group consisting of a cancer, an infection, an inflammatory disorder and a central nervous system trauma (e.g. a spinal cord injury).
  • a central nervous system trauma e.g. a spinal cord injury
  • Suitable cancers include, but are not limited to breast (including invasive breast carcinoma), gastric (including stomach adenocarcinoma), prostate, lung (including non-small cell lung cancer, lung squamous carcinoma and lung adenocarcinoma), bladder, pancreatic, colon, liver (including hepatocellular carcinoma), ovarian (including ovarian serous cystadenocarcinoma), kidney (including kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma), brain (e.g.
  • glioma or glioblastoma urothelial, renal, bone, bowel, cervical, thyroid, testis, endometrial, skin and head and neck cancer (including head and neck squamous cell carcinoma), and lymphoma (e.g. diffuse large B cell lymphoma), melanoma, mesothelioma and sarcoma, such as a bone or soft tissue sarcoma.
  • lymphoma e.g. diffuse large B cell lymphoma
  • melanoma mesothelioma
  • sarcoma such as a bone or soft tissue sarcoma.
  • the cancer is breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney or gastric cancer or mesothelioma, lymphoma, melanoma or sarcoma; especially breast, colon or lung cancer or melanoma; most especially breast cancer.
  • the cancer comprises at least one C5a receptor (e.g. C5aRl) expressing cell, such as a cell with aberrant expression of the C5a receptor.
  • the proteinaceous molecules as described herein are suitable for treating an individual who has been diagnosed with a cancer, who is suspected of having a cancer, who is known to be susceptible and who is considered likely to develop a cancer, or who is considered to develop a recurrence of a previously treated cancer.
  • the condition is an infection.
  • Suitable infections include, but are not limited to, a bacterial, viral, protozoan, fungal or helminth infection.
  • Exemplary bacterial infections include those caused by Neisseria species (e.g. N. meningitidis and N. gonorrhoeae), Haemophilus species (e.g. H. influenzae), Salmonella species (e.g. S. enterica and S. bongori), Streptococcus species (e.g. S. pyogenes, S. pneumoniae, S. mitis, S. agalactiae, S. dysgalactiae, S. gallolyticus, S. anginosus, S. sanguinis and S. /nutans), Legionella species (e.g. L. pneumophila), Mycoplasma species (e.g. M. pneumoniae, M.
  • Neisseria species e.g. N. meningitidis and N. gonorrhoeae
  • Haemophilus species e.g. H. influenzae
  • Salmonella species e.g. S. enterica and S. bongori
  • Bacillus species e.g. B. anthracis and B. cereus
  • Staphylococcus species e.g. S. aureus and S. epidermis
  • Chlamydia species e.g. C. trachomatis, C. pneumoniae and C. psittacci
  • Acinetobacter species e.g. A. baumannii
  • Actinomadura species Actinomyces species (e.g. A. israelii)
  • Anabaena species Anaplasma species, Acanobacterium species (e.g. A. haemolyticum), Bacteroides species (e.g. B. fragilis), Bdellovibrio species (e.g.
  • B. bacteriovorus Bordetella species (e.g. B. pertussis), Borrelia species (e.g. B. burgdorferi), Brucella species (e.g. B. melitensis), Burkholderia species (e.g. B. cepacia, B. pseudomallei, B. xenovorans and B. mallei), Campylobacter species (e.g. C. jejuni and C. coli), Caulobacter species (e.g. C. crescentus), Chlrorbium species, Chromatium species, Clostridium species (e.g. C. difficile, C. botulinum, C. perfringens, C. tetani and C.
  • Bordetella species e.g. B. pertussis
  • Borrelia species e.g. B. burgdorferi
  • Brucella species e.g. B. melitensis
  • Burkholderia species e.g.
  • sordellii Corynebacterium species (e.g. C. diptheriae and C. pseudotuberculosis), Coxiella species (e.g. C. burnetti), Cytophaga species, Deinococcus species, Ehrlichia species (e.g. E. chaffeensis and E. ewingii), Enterococcus species (e.g. E. faecal is and E. faecium), Escherichia species (e.g. E. coli), Francisella species (e.g. F. tularensis, F. novi ci da and F. philomiragia), Fusobacterium species, Helicobacter species (e.g. H.
  • Haemophilus species e.g. H. influenzae and H. ducreyi
  • Hyphomicrobium species Kingella species (e.g. K. kingae), Klebsiella species (e.g. K. pneumoniae), Leptospira species (e.g. L. interrogans), Listeria species (e.g. L. monocytogenes), Micrococcus species (e.g. M. luteus), Myxococcus species, Nitrobacter species, Nocardia species (e.g. N. asteroids, N. brasiliensis and N. caviae), Oscillatoria species, Pasteurella species (e.g. P.
  • Prochloron species Prevotella species (e.g. P. intermedia, P. nigrescens and P. copri), Proteus species (e.g. P. mirabilis), Pseudomonas species (e.g. P. aeruginosa, P. oryzihabitans and P. plecoglossicida), Rhodospirillum species, Rickettsia species (e.g. R. typhi, R. rickettsia, R. akari, R. conorii, R. sibirica, R. australis, R. felis, R. japonica, R. africae and R.
  • Prevotella species e.g. P. intermedia, P. nigrescens and P. copri
  • Proteus species e.g. P. mirabilis
  • Pseudomonas species e.g. P. aeruginosa, P. oryzihabitans and
  • Shigella species e.g. S. dysenteriaw, S. flexneri, S. boydii and S. sonnet
  • Spirillum species Spirochaeta species
  • Streptobacillus species e.g. S. moniliformis and S. minus
  • Streptomyces species e.g. Thiobacillus species
  • Treponema species e.g. T. pallidum
  • Ureaplasma species e.g. U. urealyticum
  • Vibrio species e.g. V. cholera, V. parahaemolyticus and V. vulnificus
  • Yersinia species e.g. Y. pestis and Y. enterocolitica
  • Mycobacterium species e.g. M. tuberculosis and M. leprae.
  • Suitable viral infections include, but are not limited to, infections caused by Picornaviruses (e.g. hepatitis A virus, enteroviruses such as poliovirus, enterovirus 71, 70, 69, and 68, Coxsackieviruses, echoviruses, foot and mouth disease virus, and rhinoviruses), Caliciviruses (e.g. hepatitis E virus, noroviruses such as Norwalk virus, feline calicivirus), Arteriviruses (e.g. equine arteritis virus), Togaviruses (e.g.
  • Picornaviruses e.g. hepatitis A virus, enteroviruses such as poliovirus, enterovirus 71, 70, 69, and 68, Coxsackieviruses, echoviruses, foot and mouth disease virus, and rhinoviruses
  • Caliciviruses e.g. hepatitis E virus, noroviruses such
  • Sindbis virus the equine encephalitis viruses, chikungunya virus, rubella virus, Ross River virus, bovine diarrhea virus, hog cholera virus, Semliki forest virus), Flaviviruses (e.g. dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, St. Louis encephalitis virus, tick-borne encephalitis virus, bovine viral diarrhea virus, classical swine fever virus), Coronaviruses (e.g.
  • human coronaviruses including betacoronaviruses such OC43 and HKU1 of the A lineage, SARS-CoV and SARS-CoV-2 of the B lineage and MERS-CoV of the C lineage, swine gastroenteritis virus), Rhabdoviruses (e.g. rabies virus, Australian bat lyssavirus, vesicular stomatitis viruses), Filoviruses (e.g. Marburg virus, Ebola virus), Paramyxoviruses (e.g.
  • measles virus canine distemper virus, mumps virus, parainfluenza viruses, respiratory syncytial virus, Newcastle disease virus, rinderpest virus, Nipah virus, Hendra virus), Orthomyxoviruses (e.g. human influenza viruses, including human influenza virus types A, B and C, avian influenza viruses, equine influenza viruses), Bunyaviruses (e.g. hantavirus, LaCrosse virus, Rift Valley fever virus), Arenaviruses (e.g. Lassa virus, Machupo virus), Reoviruses (e.g. human and animal reoviruses, such as rotaviruses, bluetongue virus), Birnaviruses (e.g.
  • Retroviruses e.g. HIV 1, HIV 2, HTLV-1, HTLV-2, bovine leukemia virus, feline immunodeficiency virus, feline sarcoma virus, mouse mammary tumor virus
  • Hepadnaviruses e.g. hepatitis B virus
  • Parvoviruses e.g. B19 virus, canine parvovirus, feline panleukopenia virus
  • Papovaviruses e.g. human papillomaviruses, SV40, bovine papillomaviruses
  • Adenoviruses e.g.
  • Herpesviruses e.g. herpes simplex viruses, varicella-zoster virus, infectious bovine rhinotracheitis virus, cytomegalovirus, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8, Epstein-Barr virus
  • Poxviruses e.g.
  • vaccinia fowl poxviruses, raccoon poxvirus, skunkpox virus, monkeypoxvirus, cowpox virus, buffalopox virus, musculum contagiosum virus), human T-cell lymphotropic virus, small pox virus, polyoma virus, junin virus, an astrovirus, BK virus, machupo virus, sabia virus, sapovirus, a coltivirus, bocavirus, human metapneumovirus, lymphocytic choriomeningitis mammarenavirus, guanarito mammarenavirus, molluscum contagiosum virus and JC virus; especially infections caused by a coronavirus, such as SARS-CoV-2.
  • a coronavirus such as SARS-CoV-2.
  • Suitable helminth infections include, but are not limited to, infections caused by Ascaris species, Baylisascaris species, Clonorchis species, Taenia species, Diphyllobothrium species, Dracunculus species, Echinococcus species, Enterobius species, Fasciolopsiasis species, Fasciola species, Wuchereria species, Brugia species, Gnathostoma species, Ancylostoma species, Hymenolepis species, Metagonimiasis species, Onchocerciasis species, Paragonimus species, Schistosoma species, Strongyloides species, Toxocara apecies, Trichinella species and Trichuris species.
  • the protozoan infection may include, but is not limited to, malaria (e.g. an infection caused by Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax or Plasmodium knowlesi), or an infection caused by Entamoeba histolytica, Balantidium coli, Blastocystis species, Cyclospora cayetanensis, Acanthamoeba species, Balamuthia species, Naegleria species, Leishmania species, Sappinia species, Giardia species, Isospora species, Rhinosporidium species, Toxoplasma species, Trichomonas species, Trypanosoma species (e.g. T. brucei or T. cruzi), Babesia species, Cryptosporidium species or Theileria species.
  • malaria e.g. an infection caused by Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale,
  • Exemplary fungal infections include, but are not limited to, infections caused by Candida species (e.g. C. parapsilosis, C. famata, C. krusei, C. albicans, C. glabrata and C. tropicalis), Aspergillus species, Blastomyces species, Coccidioides species, Cryptococcus species, Trichophyton species, Microsporum species, Geotrichum species, Histoplasma species, Madurella species, Paracoccidioides species, Pneumocystis species, Sporothrix species, Nannizzia species, Rhizopus species, Mucor species, Rhizomucor species and Syncephalastrum species.
  • Candida species e.g. C. parapsilosis, C. famata, C. krusei, C. albicans, C. glabrata and C. tropicalis
  • Aspergillus species Blastomyces species, Coccidioides species, Cryptococcus species, T
  • Suitable inflammatory disorders include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), systemic lupus erythematosus, sepsis, septic shock, chronic obstructive pulmonary disorder, lung injury, osteoarthritis, ischaemia-reperfusion injury, asthma, fibrosis, vasculitis and multiple organ dysfunction syndrome (e.g. sepsis-induced multiple organ dysfunction syndrome).
  • the inflammatory disorder is sepsis, fibrosis or asthma.
  • the central nervous system trauma is a traumatic brain injury or a spinal cord injury, particularly a spinal cord injury.
  • the spinal cord injury may be a post-acute or chronic phase spinal cord injury, particularly a chronic phase spinal cord injury.
  • the invention further provides a method of eliciting an immune response in a subject, comprising administering the proteinaceous molecule of the invention to the subject.
  • a proteinaceous molecule of the invention for use in eliciting an immune response in a subject the use of a proteinaceous molecule of the invention for eliciting an immune response in a subject, and the use of a proteinaceous molecule of the invention in the manufacture of a medicament for eliciting an immune response in a subject.
  • the subject is suffering from an infection or a cancer, suitable examples of which are discussed supra.
  • the method may comprise promoting or enhancing the subject's immune response to the infection or cancer.
  • the subject is immunocompromised, has an impaired immune response, and/or is immunosenescent.
  • a method of enhancing an immune response in a subject to a target antigen by an immune modulating agent comprising administering the proteinaceous molecule of the invention to the subject.
  • a proteinaceous molecule of the invention for use in enhancing an immune response in a subject to a target antigen by an immune modulating agent use of a proteinaceous molecule of the invention for enhancing an immune response in a subject to a target antigen by an immune modulating agent, and use of a proteinaceous molecule of the invention in the manufacture of a medicament or preparation for enhancing an immune response in a subject to a target antigen by an immune modulating agent.
  • the immune modulating agent is selected from an antigen that corresponds to at least a portion of the target antigen, an antigen-binding molecule that is immuno-interactive with the target antigen and an immune modulating cell that modulates an immune response to the target antigen.
  • the proteinaceous molecule of the invention is conjugated or otherwise attached, directly or indirectly, to the immune modulating agent, such as via a covalent bond.
  • the proteinaceous molecule is conjugated to the immune modulating agent through the N- terminus.
  • the immune modulating agent is an antigen that corresponds to at least a portion of the target antigen, which is produced following administration of an antigen-encoding nucleic acid molecule, such as DNA or RNA, especially mRNA.
  • the target antigen may be any substance that will elicit a desired immune response, which is typically associated with a disease or condition of interest, such as an infection or a cancer.
  • the target antigen may be any substance, such as a peptide or protein, that reacts with antibodies or T-cells.
  • Target antigens may be selected from endogenous antigens produced by a host or exogenous antigens that are foreign to the host, preferably exogenous antigens.
  • the target antigen may be a component of an infectious agent, such as a bacterium, virus, protozoan, fungi or helminth (e.g. the infectious agent produces the target antigen). Suitable examples of such infectious agents are described supra.
  • Exemplary bacterial antigens include, but are not limited to, pertussis bacterial antigens such as pertussis toxin, filamentous hemagglutinin, pertactin, F M2, FIM3, adenylate cyclase and other pertussis bacterial antigen components; diphtheria bacterial antigens such as diphtheria toxin or toxoid and other diphtheria bacterial antigen components; tetanus bacterial antigens such as tetanus toxin or toxoid and other tetanus bacterial antigen components; streptococcal bacterial antigens such as M proteins and other streptococcal bacterial antigen components; gram-negative bacilli bacterial antigens such as lipopolysaccharides and other gram-negative bacterial antigen components; Mycobacterium tuberculosis bacterial antigens such as mycolic acid, heat shock protein 65 (HSP65), the
  • influenzae bacterial antigen components anthrax bacterial antigens such as anthrax protective antigen and other anthrax bacterial antigen components
  • rickettsiae bacterial antigens such as rompA and other rickettsiae bacterial antigen component.
  • bacterial antigens described herein are any other bacterial, mycobacterial, mycoplasmal, rickettsial, or chlamydial antigens.
  • Exemplary viral antigens include, but are not limited to, retroviral antigens derived from HIV such as gene products of the gag, pol and env genes, the Nef protein, reverse transcriptase, and other HIV components; hepatitis viral antigens such as the S, M, and L proteins of hepatitis B virus, the pre-S antigen of hepatitis B virus, and other hepatitis, e.g., hepatitis A, B, and C, viral components such as hepatitis C viral RNA; influenza viral antigens such as hemagglutinin and neuraminidase and other influenza viral components; measles viral antigens such as the measles virus fusion protein and other measles virus components; rubella viral antigens such as proteins El and E2 and other rubella virus components; rotaviral antigens such as VP7sc and other rotaviral components; cytomegaloviral antigens such as envelope glycoprotein
  • Non-limiting exemplary fungal antigens include Candida fungal antigen components; histoplasma fungal antigens such as heat shock protein 60 (HSP60) and other histoplasma fungal antigen components; cryptococcal fungal antigens such as capsular polysaccharides and other cryptococcal fungal antigen components; coccidiodes fungal antigens such as spherule antigens and other coccidiodes fungal antigen components; and tinea fungal antigens such as trichophytin and other coccidiodes fungal antigen components.
  • HSP60 heat shock protein 60
  • cryptococcal fungal antigens such as capsular polysaccharides and other cryptococcal fungal antigen components
  • coccidiodes fungal antigens such as spherule antigens and other coccidiodes fungal antigen components
  • tinea fungal antigens such as trichophytin and other coccidiodes fungal antigen components.
  • Exemplary protozoal and helminth antigens include, but are not limited to, Plasmodium falciparum antigens such as merozoite surface antigens, sporozoite surface antigens, circumsporozoite antigens, gametocyte/gamete surface antigens, blood-stage antigen pf 155/RESA and other plasmodial antigen components; toxoplasma antigens such as SAG-1, p30 and other toxoplasmal antigen components; schistosomae antigens such as glutathione-S-transferase, paramyosin, and other schistosomal antigen components; leishmania major and other leishmaniae antigens such as gp63, lipophosphoglycan and its associated protein and other leishmanial antigen components; and Trypanosoma cruzi antigens such as the 75-77kDa antigen, the 56kDa antigen and other trypanosomal antigen components.
  • the present invention also contemplates toxin components as antigens.
  • toxins include, but are not limited to, staphylococcal enterotoxins, toxic shock syndrome toxin, retroviral antigens (e.g., antigens derived from HIV), streptococcal antigens, staphylococcal enterotoxin-A (SEA), staphylococcal enterotoxin-B (SEB), staphylococcal enterotoxin 1-3 (SE1-3), staphylococcal enterotoxin-D (SED), staphylococcal enterotoxin-E (SEE) as well as toxins derived from mycoplasma, mycobacterium and herpes viruses.
  • SEA staphylococcal enterotoxin-A
  • SEB staphylococcal enterotoxin-B
  • SE1-3 staphylococcal enterotoxin 1-3
  • SED staphylococcal enterotoxin-D
  • SEE staphylococcal enterotoxin
  • the target antigen may also be a component of a cancer cell (e.g. the cancer cell produces the target antigen). Suitable cancers are discussed supra.
  • the target antigen is a carbonic anhydrase IX, alphafetoprotein (AFP), o-actinin-4, PIGF, ILGF, ILGF-1R, IL-6, IL-25, RS5, RANTES, T101, SAGE, S100, survivin, survivin-2B, A3, antigen specific for A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, CASP-8/m, CCL19, CCL21, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38,
  • AFP alphafeto
  • the target antigen is associated with an unwanted immune response including, for example, transplant rejection, graft versus host disease, allergies, parasitic diseases, inflammatory diseases and autoimmune diseases.
  • the methods may involve inducing a tolerogenic response including the induction of an anergic response, and the suppression of a future or existing immune response, to the target antigen.
  • the antigen that corresponds to at least a portion of a target antigen may be in soluble form (e.g. peptide, polypeptide or an antigen-encoding nucleic acid molecule from which a peptide or polypeptide is expressible) or in the form of whole cells or attenuated pathogen preparations (e.g. attenuated virus or bacteria) or it may be presented by antigen-presenting cells as described in more detail below.
  • soluble form e.g. peptide, polypeptide or an antigen-encoding nucleic acid molecule from which a peptide or polypeptide is expressible
  • attenuated pathogen preparations e.g. attenuated virus or bacteria
  • the present invention also contemplates the use of antigen-presenting cells as the immune modulating cells, which present an antigen corresponding to at least a portion of the target antigen.
  • antigen-presenting cells include professional or facultative antigen-presenting cells.
  • Professional antigen-presenting cells function physiologically to present antigen in a form that is recognised by specific T cell receptors so as to stimulate or anergise a T lymphocyte or B lymphocyte mediated immune response.
  • Professional antigen-presenting cells not only process and present antigens in the context of the major histocompatability complex (MHO), but also possess the additional immunoregulatory molecules required to complete T cell activation or induce a tolerogenic response.
  • MHO major histocompatability complex
  • Professional antigen-presenting cells include, but are not limited to, macrophages, monocytes, B lymphocytes, cells of myeloid lineage, including monocytic- or granulocytic-DC precursors, marginal zone Kupffer cells, microglia, T cells, Langerhans cells and dendritic cells including interdigitating dendritic cells and follicular dendritic cells.
  • Non-professional or facultative antigen-presenting cells typically lack one or more of the immunoregulatory molecules required to complete T lymphocyte activation or anergy.
  • non-professional or facultative antigen-presenting cells include, but are not limited to, activated T lymphocytes, eosinophils, keratinocytes, astrocytes, follicular cells, microglial cells, thymic cortical cells, endothelial cells, Schwann cells, retinal pigment epithelial cells, myoblasts, vascular smooth muscle cells, chondrocytes, enterocytes, thymocytes, kidney tubule cells and fibroblasts.
  • the antigen-presenting cells described above are useful for producing primed T lymphocytes to an antigen or group of antigens.
  • the antigen-specific antigen-presenting cells are useful for producing T lymphocytes that exhibit tolerance/anergy to an antigen or group of antigens.
  • the immune modulating cells may also be antigen-specific B or T lymphocytes, which respond in an antigen-specific fashion to representation of the antigen.
  • Antigen-specific T lymphocytes may be produced by contacting an antigen- presenting cell as defined above with a population of T lymphocytes, which may be obtained from any suitable source such as spleen or tonsil/lymph nodes but is preferably obtained from peripheral blood.
  • the T lymphocytes can be used as crude preparations or as partially purified or substantially purified preparations.
  • the invention also contemplates the use of antigen-binding molecules that are specifically immuno-interactive with a selected target antigen as immune modulating agents.
  • the antigen-binding molecule is suitably interactive with a target antigen as described supra.
  • Numerous antigen-binding molecules useful as immune modulating agents are known in the art.
  • the antigen-binding molecule is a whole polyclonal antibody.
  • Such antibodies may be prepared, for example, by injecting an antigen that corresponds to at least a portion of the target antigen into a production species, which may include mice or rabbits, to obtain polyclonal antisera. Methods of producing polyclonal antibodies are well known to those skilled in the art.
  • monoclonal antibodies may be produced using the standard method, for example, by immortalising spleen or other antibody producing cells derived from a production species which has been inoculated with one or more antigens as described above.
  • the invention also contemplates as antigen-binding molecules Fv, Fab, Fab' and F(ab')2 immunoglobulin fragments.
  • the antigen-binding molecule may comprise a synthetic stabilised Fv fragment.
  • Exemplary fragments of this type include single chain Fv fragments (sFv, frequently termed scFv) in which a peptide linker is used to bridge the N-terminus or C-terminus of a VH domain with the C-terminus or N-terminus, respectively, of a VL domain.
  • sFv single chain Fv fragments
  • scFv single chain Fv fragments
  • ScFv lack all constant parts of whole antibodies and are not able to activate complement.
  • the synthetic stabilised Fv fragment comprises a disulfide stabilised Fv (dsFv) in which cysteine residues are introduced into the VH and VL domains such that in the fully folded Fv molecule the two residues will form a disulfide bond between them.
  • dsFv disulfide stabilised Fv
  • the proteinaceous molecule of the invention may be useful as a component of a vaccine, such as an adjuvant.
  • the invention contemplates co-administration of antigenic compositions, including immunogenic compositions and vaccines, with a proteinaceous molecule of the invention to a subject.
  • Representative antigenic compositions include but are not limited to killed or attenuated live viral vaccines, live-vectored vaccines, subunit vaccines, virus-like particle vaccines, and DNA or RNA vaccines (refer to Roth et al. (2011) Veterinary Clinics North America: Food Animal Practice, 17: 585-597).
  • the antigenic compositions may comprise one or more immune modulating agents as discussed herein, or a nucleic acid molecule which encodes one or more immune modulating agents, such as an antigenencoding nucleic acid molecule (e.g. DNA or RNA).
  • nucleic acid encoding a proteinaceous molecule of the invention especially when the immune modulating agent is an antigen that corresponds to at least a portion of the target antigen, which is produced following administration of an antigen-encoding nucleic acid molecule, such as DNA or RNA, especially mRNA.
  • an antigen-encoding nucleic acid molecule such as DNA or RNA, especially mRNA.
  • nucleic acid encoding the proteinaceous molecule of the invention for use in enhancing an immune response in a subject to a target antigen by an antigen that corresponds to at least a portion of the target antigen, use of a nucleic acid encoding the proteinaceous molecule of the invention for enhancing an immune response in a subject to a target antigen by an antigen that corresponds to at least a portion of the target antigen, and use of a nucleic acid encoding the proteinaceous molecule of the invention in the manufacture of a medicament for enhancing an immune response in a subject to a target antigen by an antigen that corresponds to at least a portion of the target antigen.
  • the nucleic acid encoding the proteinaceous molecule of the invention is administered concurrently with a nucleic acid molecule encoding the antigen, or is conjugated, directly or indirectly, to a nucleic acid molecule encoding the antigen.
  • nucleic acid encoding the proteinaceous molecule of the invention is conjugated to a nucleic acid molecule encoding the antigen
  • translation of the conjugated nucleic acid molecule will produce a proteinaceous molecule of the invention conjugated to the antigen, such as through the N-terminus of the proteinaceous molecule.
  • the nucleic acid molecule encoding the antigen is DNA or RNA, especially mRNA.
  • Suitable target antigens are as discussed supra.
  • a related aspect provides a conjugate comprising a nucleic acid encoding a proteinaceous molecule of the invention conjugated to a nucleic acid molecule encoding an antigen that corresponds to at least a portion of a target antigen.
  • Compositions comprising such conjugate and a pharmaceutically acceptable carrier or diluent are also contemplated.
  • the conjugate nucleic acid is DNA or RNA, especially mRNA.
  • Suitable target antigens and pharmaceutically acceptable carriers and diluents are as discussed supra.
  • a method of treating a cancer in a subject comprising administering the proteinaceous molecule of the invention to the subject.
  • a proteinaceous molecule of the invention for use in treating a cancer in a subject the use of a proteinaceous molecule of the invention for treating a cancer in a subject, and the use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating a cancer in a subject.
  • the cancer is suitably one in which agonising a C5a receptor, e.g. C5aRl, stimulates or effects treatment or inhibition of the development of the cancer.
  • a C5a receptor e.g. C5aRl
  • Suitable cancers are as discussed supra.
  • the cancer is breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney or gastric cancer or mesothelioma, lymphoma, melanoma or sarcoma; especially breast, colon or lung cancer or melanoma; most especially breast cancer.
  • the invention further provides a method of treating an infection in a subject, comprising administering the proteinaceous molecule of the invention to the subject.
  • Further aspects include a proteinaceous molecule of the invention for use in treating an infection in a subject, the use of a proteinaceous molecule of the invention for treating an infection in a subject, and the use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating an infection in a subject.
  • Suitable infections are as described supra.
  • the infection is a bacterial, viral, protozoan, fungal or helminth infection.
  • a method of treating or inhibiting the development of an inflammatory disorder in a subject comprising administering the proteinaceous molecule of the invention to the subject; the proteinaceous molecule of the invention for use in treating or inhibiting the development of an inflammatory disorder in a subject; use of the proteinaceous molecule of the invention for treating or inhibiting the development of an inflammatory disorder in a subject; and use of the proteinaceous molecule of the invention in the manufacture of a medicament for treating or inhibiting the development of an inflammatory disorder in a subject.
  • the proteinaceous molecule of the invention may be used as an anti-inflammatory agent.
  • the invention further provides a method of treating or inhibiting the development of a central nervous system trauma in a subject, comprising administering the proteinaceous molecule of the invention to the subject; the proteinaceous molecule of the invention for use in treating or inhibiting the development of a central nervous system trauma in a subject; use of the proteinaceous molecule of the invention for treating or inhibiting the development of a central nervous system trauma in a subject; and use of the proteinaceous molecule of the invention in the manufacture of a medicament for treating or inhibiting the development of a central nervous system trauma in a subject.
  • central nervous system trauma Suitable examples of central nervous system trauma are discussed supra.
  • the central nervous system trauma is a spinal cord injury.
  • a method of treating or inhibiting the development of a spinal cord injury in a subject comprising administering the proteinaceous molecule of the invention to the subject; the proteinaceous molecule of the invention for use in treating or inhibiting the development of a spinal cord injury in a subject; use of the proteinaceous molecule of the invention for treating or inhibiting the development of a spinal cord injury in a subject; and use of the proteinaceous molecule of the invention in the manufacture of a medicament for treating or inhibiting the development of a spinal cord injury in a subject.
  • the spinal cord injury is a post-acute or chronic phase spinal cord injury, particularly a chronic phase spinal cord injury.
  • C5a receptor signalling has previously been shown to play a role in tissue regeneration, such as liver and bone tissue regeneration.
  • a method of stimulating tissue regeneration in a subject comprising administering a proteinaceous molecule of the invention to the subject; a proteinaceous molecule of the invention for use in stimulating tissue regeneration in a subject; use of a proteinaceous molecule of the invention for stimulating tissue regeneration in a subject; and use of a proteinaceous molecule of the invention in the manufacture of a medicament for stimulating tissue regeneration in a subject.
  • exemplary tissues include, but are not limited to, liver and bone tissue.
  • the tissue is liver tissue.
  • the subject may have undergone liver surgery, such as a liver transplant, partial hepatectomy or liver resection, or has a toxic or viral injury to the liver in such embodiments.
  • the tissue is bone tissue.
  • the subject may have a bone injury, such as a fracture, a defect caused by an infection or surgery, a skeletal abnormality, or a disorder such as avascular necrosis or osteoporosis.
  • the proteinaceous molecules of the invention will also be useful for mobilising cells in a subject and, accordingly, for treating or inhibiting the development of a condition in a subject where cellular mobilisation effects treatment or inhibition of the development of the condition.
  • the cell is a stem cell (e.g. a hematopoietic stem cell), progenitor cell (e.g. a hematopoietic progenitor cell), or a neutrophil, especially a bone marrow stem cell or progenitor cell.
  • the subject has impaired cellular mobilisation, such as a subject who is undergoing or has previously undergone chemotherapy or radiotherapy, or a subject with multiple myeloma or lymphoma.
  • the further use of the mobilised cells for stem cell transplantation Accordingly, following cellular mobilisation from the bone marrow to the bloodstream, for example, the cells may be collected and stored for future transplantation.
  • Exemplary conditions where cellular mobilisation effects treatment or inhibition of the development of the condition include an ischaemic disease (e.g. myocardial infarction, limb ischaemia, ischaemic stroke and acute kidney injury), multiple myeloma, lymphoma, infection or tissue injury; especially multiple myeloma or lymphoma.
  • an ischaemic disease e.g. myocardial infarction, limb ischaemia, ischaemic stroke and acute kidney injury
  • multiple myeloma, lymphoma, infection or tissue injury especially multiple myeloma or lymphoma.
  • a method of agonising a C5a receptor comprising contacting a cell expressing a C5a receptor with a proteinaceous molecule of the invention.
  • the invention further provides a proteinaceous molecule of the invention for use in agonising a C5a receptor in a cell expressing a C5a receptor and the use of a proteinaceous molecule of the invention for agonising a C5a receptor in a cell expressing a C5a receptor.
  • Also provided herein is a method of agonising a C5a receptor in a subject, comprising administering to the subject a proteinaceous molecule of the invention, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor.
  • a proteinaceous molecule of the invention for use in agonising a C5a receptor in a subject, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor; the use of a proteinaceous molecule of the invention for agonising a C5a receptor in a subject, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor; and the use of a proteinaceous molecule of the invention in the manufacture of a medicament for agonising a C5a receptor in a subject, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor.
  • the subject has a condition selected from the group consisting of a cancer, an infection, an inflammatory disorder and a central nervous system trauma (e.g. a spinal cord injury). Suitable further embodiments of each of these conditions are as discussed supra.
  • a method of enhancing or increasing C5a receptor activity or function comprising contacting a cell expressing a C5a receptor with a proteinaceous molecule of the invention.
  • a proteinaceous molecule of the invention for use in enhancing or increasing C5a receptor activity or function in a cell expressing a C5a receptor and the use of a proteinaceous molecule for enhancing or increasing C5a receptor activity or function in a cell expressing a C5a receptor are also provided.
  • C5a receptors Numerous cells are known to express C5a receptors, including granulocytes (such as mast cells, neutrophils, basophils and eosinophils), monocytes, dendritic cells, astrocytes, T cells (e.g. CD4 + T cells, CD8 + T cells, memory T cells and regulatory T cells), microglia, macrophages, oligodendrocytes, endothelial cells, fibroblasts, smooth muscle cells, neurons and cancer cells. As such, in some embodiments, the cell expressing a C5a receptor is one of these cell types.
  • granulocytes such as mast cells, neutrophils, basophils and eosinophils
  • monocytes e.g. CD4 + T cells, CD8 + T cells, memory T cells and regulatory T cells
  • microglia e.g. CD4 + T cells, CD8 + T cells, memory T cells and regulatory T cells
  • macrophages oligodendrocytes
  • C5a receptor activity or function is one or more of G protein activation; activation of signalling pathways such as phosphatidylinositol 3-kinase/protein kinase B (Akt), phospholipase D, protein kinase C and MAP kinase pathways; recruitment and signalling through p-arrestins; activation of IKBO; inhibition of NF-KB in neutrophils; activation of NF-KB in macrophages; SIP generation; myeloid- derived suppressor cell recruitment; and neovascularisation.
  • signalling pathways such as phosphatidylinositol 3-kinase/protein kinase B (Akt), phospholipase D, protein kinase C and MAP kinase pathways
  • Akt phosphatidylinositol 3-kinase/protein kinase B
  • phospholipase D protein kinase C
  • the C5a receptor is C5aRl.
  • any one of the aspects described above may involve administration of an effective amount of the proteinaceous molecule of the invention as described in Section 4 supra.
  • the proteinaceous molecule of the invention may be administered via any suitable route of administration, such as oral, rectal, topical, intranasal, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration.
  • the proteinaceous molecule is administered via oral administration.
  • the dosage and frequency will depend on the subject, the condition, disease or disorder to be treated and the route of administration. A skilled person will readily be able to determine suitable dosages and frequency of such dosages.
  • the proteinaceous molecule may be administered in an amount in the range of from about 0.25 pg to about 2000 mg, and may be administered at a frequency of, for example, once daily, or twice or three times daily. The treatment may be continued for multiple days, weeks, months or years.
  • the dosages and frequency of administration are determined by reference to the usual dose and manner of administration of the said ingredients.
  • Any one of the methods described above may, in some embodiments, involve the administration of one or more further active agents as described in Section 4 supra, such as an anti-inflammatory agent, cancer therapy, antibiotic, anti-viral, antiprotozoal, anti-fungal, anthelmintic or therapy for a central nervous system trauma.
  • further active agents such as an anti-inflammatory agent, cancer therapy, antibiotic, anti-viral, antiprotozoal, anti-fungal, anthelmintic or therapy for a central nervous system trauma.
  • binding may be assessed by contacting a cell expressing a C5a receptor with a compound and screening for the inhibition of binding of a ligand of a C5a receptor, such as C5a (e.g. a ligand binding assay).
  • Agonist activity may be assessed by screening for the activity, presence or expression of a downstream cellular target or product (e.g. ERK 1/2 phosphorylation, calcium influx and/or p-arrestin 2 recruitment).
  • Detecting such activity, presence or expression may be achieved utilising techniques including, but not limited to, surface plasmon resonance, bioluminescence resonance energy transfer, chemiluminescence, luminescent proximity assays, immunofluorescence, Western blots, immunoprecipitation, immunostaining, scintillation proximity assays or cell proliferation assays such as a WST-1 proliferation assay.
  • kits and/or products may also be used, such as PathHunter CHO-K1 C5AR1 Bioassay Kit (Catalogue No.
  • a polynucleotide from which the C5a receptor is regulated or expressed may be naturally occurring in the cell which is the subject of testing or it may have been introduced into the host cell for the purposes of testing.
  • Peptides of Table 4 were synthesised using Fmoc (9- fluorenylmethyloxycarbonyl)-based solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride resin (or Rink Amide MBHA for BM212) on a 0.25 mmole scale.
  • SPPS solid phase peptide synthesis
  • 2-chlorotrityl chloride resin or Rink Amide MBHA for BM212
  • a ratio of 4:4:8 equivalents of amino acid : 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU): diisopropylethylamine (DIPEA) were used for each coupling.
  • BM213 The N-terminus of BM213 was acetylated on-resin with a solution of acetic anhydride (5%) (Sigma-Aldrich, Inc.) and DIPEA (3%) (Sigma-Aldrich, Inc.) in N,N'-dimethylformamide (DMF) at 25°C for 2 x 10 minutes.
  • BM214 was cyclised overnight with 4 eq. benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 15 eq. DIPEA at a peptide concentration of 10 mM in DMF.
  • peptides were cleaved off resin and side chain protecting groups were removed by treatment with trifluoroacetic acid (TFA)/triisopropylsilane (TIPS)/H2O at a ratio of 95:2.5:2.5 for 2 hours at room temperature.
  • TFA trifluoroacetic acid
  • TIPS triisopropylsilane
  • H2O hydrogen trifluoropropylsilane
  • Peptides were then purified using reverse phase high performance liquid chromatography (RP-HPLC) with an increasing gradient of 1%/min buffer B (90% acetonitrile, 0.05% TFA) in buffer A (0.05% TFA) over 80 minutes (Phenomenex Jupiter 300A, 10 pm, 250 x 21.2 mm; Phenomenex, Torrance, USA).
  • HPLC fractions were analysed by electrospray mass spectrometry (ESI-MS) (AB SCIEX API 2000; AB Sciex LLC, Framingham, USA) and fractions containing the desired product were combined. Each peptide was purified until >95% purity. Purity was assessed using analytical RP-HPLC (Agilent, 300A, 5 pm, 150 x 2.1 mm; Agilent Technologies, Inc., Santa Clara, USA). All experimentation was performed using peptides produced according to this example unless otherwise indicated.
  • ESI-MS electrospray mass spectrometry
  • CH0-C5aRl or human C3aR (CHO-C3aR) were maintained in Ham's F12 medium containing 10% foetal bovine serum (FBS), 100 U/mL penicillin, 100 pg/mL streptomycin (ThermoFisher Scientific Inc., Waltham, Massachusetts, USA) and 400 pg/ml G418 (InvivoGen, San Diego, California, USA).
  • Human embryonic kidney-293 (HEK293) and RAW 267.4 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% foetal bovine serum (FBS), 100 U/mL penicillin and 100 pg/mL streptomycin (Thermo Fisher Scientific, Melbourne, Australia).
  • DMEM Dulbecco's Modified Eagle Medium
  • the level of recombinant protein expression for the CHO cells lines are 27 ⁇ 7.6 pmol/mg protein for CHO-C3aR and 7.0 pmol/mg for CHO-C5aRl respectively based on the manufacturer's certificate (PerkinElmer, Melbourne, Australia).
  • HMDM Human monocyte-derived macrophages
  • the isolated monocytes were differentiated for 7 days in Iscove's Modified Dulbecco's Medium (IMDM; ThermoFisher Scientific Inc., Waltham, Massachusetts, USA) supplemented with 10% FBS, 100 U/mL penicillin, 100 pg/mL streptomycin and 15 ng/mL recombinant human macrophage colony stimulating factor (hM-CSF) (Lonza, Melbourne, Australia) on 10 mm square dishes (Bio-strategy, Brisbane, Australia).
  • IMDM Iscove's Modified Dulbecco's Medium
  • ligand-induced phospho-ERK (pERK) 1/2 signalling was assessed using the AlphaLISA Surefire Ultra p-ERKl/2 (Thr202/Tyr204) kit (PerkinElmer, Melbourne, Australia) according to the manufacturer's instructions. Briefly, CHO-C5aRl, CHO-C3aR or HMDMs were seeded (50,000/well) in tissue culture-treated 96-well plates (Corning Inc., Corning, New York, USA) for 24 hours and serum-starved overnight. RAW264.7 cells were seeded at 100,000 cells/well and also serum-starved overnight.
  • HMDMs were seeded (50,000/well) in black clear-bottom 96-well tissue culture plates (Corning Inc., Corning, New York, USA) overnight. Cells were firstly loaded with the Fluo-4 dye in assay buffer [IX Hank's Balanced Salt Solution (HBSS), 20 mM HEPES] for 45 min (37°C, 5% CO2). Respective ligands were prepared in assay buffer containing 0.1% BSA.
  • MTT assays were conducted in SH-SY5Y cells. Twenty-four hours prior to treatment, cells were differentiated with 10 pM retinoic acid in media and seeded (10,000/well) overnight (37°C, 5% CO2). All ligand dilutions were prepared in serum-free RPMI 1640, alongside PBS and 1% Triton-XlOO controls. Treatments were then applied to the cells and incubated for 2.5 hours.
  • HMDMs lipopolysaccharide (LPS)-induced cytokine release were assessed in HMDMs.
  • HMDMs were seeded in 96-well tissue culture plates (100,000/well) for 24 hours before treatment. All ligands were prepared in serum-free medium containing 0.1% BSA.
  • LPS InvivoGen, San Diego, USA
  • C5aR ligands for 24 hours (37°C, 5% CO2).
  • the supernatant was collected and stored at -20°C until use.
  • the TNF-o and IL-6 levels in the supernatant were quantified using respective human enzyme- linked immunosorbent assay (ELISA) kits (BD Biosciences, Sydney, Australia) as per the manufacturer's protocol.
  • ELISA human enzyme- linked immunosorbent assay
  • BM01 exhibited an EC50 of 121 nM for C3aR and an ECso of 39 nM for C5aRl, resulting in a 3 fold selectivity for C5aRl over C3aR (Table 5 and Figure 1).
  • BM210 is still a full agonist of C5aRl as it exhibits an efficacy of 100% relative to C5a ( Figure 2).
  • BM210 was counterscreened for C5aR2 activity but did not activate C5aR2-mediated p-arrestin 2 recruitment at 100 pM (Figure 3B).
  • BM210 was found to induce calcium mobilisation in primary human monocyte-derived macrophages (HMDMs) with an EC50 of 590 nM and full agonist efficacy (Figure 4A).
  • HMDMs primary human monocyte-derived macrophages
  • Figure 4A full agonist efficacy
  • selectivity of BM1 and BM210 was assessed by measuring the induced ERK1/2 activity in the absence and presence of a C5aRl selective antagonist PMX53. Under control conditions, both BM01 and BM210 exhibited a dose-responsive induction of ERK1/2 signalling, with an efficacy of 82% that of C5a.
  • BM210 In contrast to the full agonist profiles displayed for ERK1/2 signalling and calcium mobilisation, BM210 exhibited only partial activity at recruiting p-arrestin 2 to C5aRl (66.7% of that of C5a at 100 pM) (Figure 3A), making BM210 a biased agonist compared to native C5a. BM206 also exhibited reduced recruitment p-arrestin 2 to C5aRl, unlike BM205 ( Figure 3C).
  • BM210 Functional similarity between BM210 and C5a was assessed by examining the effects of BM210 on LPS-induced release of the acute response cytokines IL-6 and TNFo and the anti-inflammatory IL-10 from HMDMs (Figure 6).
  • BM210 suppressed IL-6 and TNFo release, and induced IL-10 release at comparable levels to C5a.
  • the down- regulatory effect of C5a on LPS-induced TNFo release was attenuated when used at its highest dose of 100 nM. In contrast, no such reversal was observed for BM210 even at 10 pM.
  • a third generation of analogues was designed and synthesised based on BM210, and included peptide modifications such as an amidated C-terminus (BM212), acetylated N-terminus (BM213), and cyclisation of the lysine sidechain to the C-terminus (BM214), with a view to increasing peptide stability.
  • BM212 amidated C-terminus
  • BM213 acetylated N-terminus
  • BM214 cyclisation of the lysine sidechain to the C-terminus
  • the 900-fold selectivity, and increased potency of BM213 promoted further exploration of its pharmacological properties.
  • Peptide stability was determined by incubating each peptide in serum free RPMI 1640 media (Gibco®; ThermoFisher Scientific Inc., Waltham, Massachusetts, USA) (40 pM) with SH-SY5Y cells. Each peptide was run in triplicate with one sample without cells. Samples were collected at 0, 5, 10, 15, 30, 60, 120 and 240 mins. Urea (6 M, 40 pL) was used to quench protease activity immediately following sample collection (40 pL) (10 mins, on ice).
  • Trichloroacetic acid (20%, 40 pL) (Sigma Aldrich, Inc.; Merck KGaA, Darmstadt, Germany) was used to precipitate large proteins before returning samples (10 mins, on ice). Samples were centrifuged at 10,000 g for 10 minutes then supernatants were collected and stored at 4°C. Samples were analysed using LC-MS to determine the percentage of intact peptide remaining.
  • BM210, BM213 and BM215 were assessed in 20% human serum (Figure 5A).
  • BM210 and BM215 displayed half-lives of less than 10 minutes, but there was >75% of BM213 remaining after four hours, indicating that N-terminal acetylation resulted in substantial improvements in stability.
  • the improvement of stability was emphasised by assessing the stability of BM213 in 100% human serum, finding that under these conditions, the peptide displayed a half-life of two hours (Figure 5B).
  • BM221 was more stable than BM210 in human serum, with a half-life of around 60 minutes in 100% human serum (Figure 5B). Both BM210 and BM215 were undetectable in 100% human serum at five minutes (data not shown).
  • RAW 267.4 cells were maintained in DMEM medium containing 10% FBS, 100 U/mL penicillin and 100 pg/mL streptomycin (Thermo Fisher Scientific, Melbourne, Australia).
  • the pERK 1/2 signalling assay was performed in accordance with the protocol of Example 2.
  • C5a, BM213 and BM221 injection one drop of blood was collected from the tail tip to make a blood smear on a slide at 0, 15, 30 and 60 minutes.
  • Blood smears were stained using Microscopy Hemacolor® Rapid Staining of Blood Smear Kit (Merck KGaA, Darmstadt, Germany). Briefly, blood smears were fixed in Hemacolor® Solution 1 (methanol).
  • the slides were then stained with Hemacolor® Solution 2 (Eosin Y), followed by Hemacolor® Solution 3 (Azur B).
  • the slides were washed with 1 x PBS (pH 7.2) and mounted with dibutyphthalate polystyrene xylene. Using 20x/0.4 NA objective on an Olympus CX21 microscope, first 400 white blood cells were counted, and the proportion of neutrophil (granules that are light violet) was calculated.
  • Tumour volume was measured every two days by the same individual using a digital vernier caliper (Mitutoyo Corporation, Kawasaki, Kanagawa, Japan). The tumour volume was calculated using the formula (length x (width) 2 )/2 and expressed as mm 3 (refer to Fung, et al. (2013) American Journal of Physiology-Endocrinology and Metabolism, 305: E305- E313).
  • mice in all groups were euthanised by CO2 inhalation and the tumours were removed and weighed. The drug injections, tumour volume and weight measurements were performed in a blinded fashion in this study.
  • BM210, BM213 and BM221 were first tested on the murine macrophage cell line RAW 264.7 cells to ensure the compounds are active at murine C5aRl (mC5aRl). All compounds demonstrated some level of activity at mC5aRl, but potencies were ⁇ 1000 times lower than that on human C5aRl. BM210 did not reach 100% activation at doses up to 100 pM, while BM213 exhibited an ECso of 22.9 pM and BM221 displayed an ECso of 2.3 pM (Figure 8).
  • BM213 and BM221 The ability of BM213 and BM221 to induce neutrophil mobilisation in mice was assessed via a polymorphonuclear leucocytes (PMN) mobilisation assay.
  • PMN polymorphonuclear leucocytes
  • treatment with BM213 resulted in significantly higher levels of neutrophil mobilisation compared to both mC5a and BM221 treatments 30 minutes post administration (60% vs 43% for C5a and 41% for BM221).
  • BM213 The activity of BM213 in the EMT6 tumour model was assessed.
  • EMT6 tumour injected mice were treated with BM213 or vehicle (saline) from 7 days after the tumour inoculation (Figure 11).
  • BM213 treatment showed significant reduction in tumour volume at 14 days when compared with vehicle treatment (vehicle: 753.0 ⁇ 91.8 mm 3 vs BM213: 465.0 ⁇ 38.6 mm 3 ; Figure 11).
  • Excised tumour weights were also reduced with BM213 treatment (vehicle: 539.5 ⁇ 75.4 mg vs BM213: 439.1 ⁇ 70.4 mg; Figure 11).
  • Exemplary embodiments include, but are not limited to:
  • a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by Formula I:
  • Zi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety comprising from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety;
  • Xi is selected from amide-containing amino acids including Q, N and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W and modified forms thereof;
  • X2 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof;
  • X3 is selected from any amino acid residue
  • X4 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and the corresponding D amino acids.
  • X3 is selected from small amino acid residues including A, G, S, T, P and modified forms thereof, and hydrophobic amino acid residues including M, I, L, V, F, Y, W, Nva, Nle, Abu and modified forms thereof.
  • FKPQPLaR [SEQ ID NO: 12].
  • proteinaceous molecule according to embodiment 9, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 4 or 11.
  • composition comprising the proteinaceous molecule according to any one of embodiments 1-16 and a pharmaceutically acceptable carrier or diluent. 18.
  • composition according to embodiment 17, further comprising one or more immune modulating agents.
  • a method of treating or inhibiting the development of a condition in which agonising a C5a receptor stimulates or effects treatment or inhibition of the development of the condition comprising administering the proteinaceous molecule according to any one of embodiments 1-16.
  • cancer selected from the group consisting of breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney and gastric cancer, and mesothelioma, lymphoma, melanoma and sarcoma.
  • a method of eliciting an immune response in a subject comprising administering the proteinaceous molecule according to any one of embodiments 1-16 to the subject.
  • a method of enhancing an immune response in a subject to a target antigen by an immune modulating agent comprising administering the proteinaceous molecule according to any one of embodiments 1-16 to the subject.
  • the immune modulating agent is selected from an antigen that corresponds to at least a portion of the target antigen, an antigen-binding molecule that is immuno-interactive with the target antigen and an immune modulating cell that modulates an immune response to the target antigen.
  • a method of treating a cancer in a subject comprising administering the proteinaceous molecule according to any one of embodiments 1-16 to the subject.
  • cancer selected from the group consisting of breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney and gastric cancer, and mesothelioma, lymphoma, melanoma and sarcoma.
  • a method of treating an infection in a subject comprising administering the proteinaceous molecule according to any one of embodiments 1-16 to the subject.
  • a method of agonising a C5a receptor comprising contacting a cell expressing a C5a receptor with a proteinaceous molecule according to any one of embodiments 1-16.
  • a method of agonising a C5a receptor in a subject comprising administering to the subject a proteinaceous molecule according to any one of embodiments 1-16, wherein the proteinaceous molecule contacts a cell expressing a C5a receptor in the subject and agonises the C5a receptor.
  • the cancer is selected from the group consisting of breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney and gastric cancer, and mesothelioma, lymphoma, melanoma and sarcoma.
  • the cancer is selected from the group consisting of breast, colon and lung cancer, and melanoma.
  • the proteinaceous molecule for use according to embodiment 50 wherein the cancer is selected from the group consisting of breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney and gastric cancer, and mesothelioma, lymphoma, melanoma and sarcoma.
  • the immune modulating agent is selected from an antigen that corresponds to at least a portion of the target antigen, an antigen-binding molecule that is immuno-interactive with the target antigen and an immune modulating cell that modulates an immune response to the target antigen.
  • the proteinaceous molecule for use according to embodiment 62, wherein the cancer is selected from the group consisting of breast, colon and lung cancer, and melanoma.
  • the cancer is selected from the group consisting of breast, bladder, colon, lung, pancreatic, ovarian, liver, head and neck, brain, kidney and gastric cancer, and mesothelioma, lymphoma, melanoma and sarcoma.
  • the cancer is selected from the group consisting of breast, colon and lung cancer, and melanoma.

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  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des agonistes du récepteur C5a du facteur de complément protéique, et leur utilisation pour traiter ou inhiber le développement d'un état dans lequel l'amélioration de l'activité du récepteur C5a stimule ou permet le traitement ou l'inhibition du développement de l'état, tel qu'un cancer, une infection, un trouble inflammatoire ou un traumatisme du système nerveux central (tel qu'une lésion de la moelle épinière), ainsi que pour déclencher ou améliorer une réponse immunitaire, régénérer un tissu et mobiliser des cellules.
PCT/AU2022/051209 2021-10-07 2022-10-07 Molécules protéiques et leurs utilisations WO2023056527A1 (fr)

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AU2021903225A AU2021903225A0 (en) 2021-10-07 Proteinaceous molecules and uses therefor
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044848A1 (fr) * 2003-11-11 2005-05-19 National Cancer Center Epitope de hgf pouvant etre neutralise et anticorps neutralisant lie a celui-ci
WO2012006149A2 (fr) * 2010-06-29 2012-01-12 Board Of Regents Of The University Of Nebraska Analogues de c5a et procédés d'utilisation associés
WO2018231838A1 (fr) * 2017-06-12 2018-12-20 Board Of Regents Of The University Of Nebraska Sels de chlorhydrate de peptides agonistes de récepteur c5a
CN105753941B (zh) * 2016-04-26 2019-04-09 中国石油大学(华东) 一种自组装抗菌肽
WO2019154515A1 (fr) * 2018-02-09 2019-08-15 The Cyprus Foundation For Muscular Dystrophy Research Procédés et compositions pour le traitement de maladies amyloïdes
WO2020056229A1 (fr) * 2018-09-14 2020-03-19 Prommune, Inc. Compositions immunologiques antiparasitaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044848A1 (fr) * 2003-11-11 2005-05-19 National Cancer Center Epitope de hgf pouvant etre neutralise et anticorps neutralisant lie a celui-ci
WO2012006149A2 (fr) * 2010-06-29 2012-01-12 Board Of Regents Of The University Of Nebraska Analogues de c5a et procédés d'utilisation associés
CN105753941B (zh) * 2016-04-26 2019-04-09 中国石油大学(华东) 一种自组装抗菌肽
WO2018231838A1 (fr) * 2017-06-12 2018-12-20 Board Of Regents Of The University Of Nebraska Sels de chlorhydrate de peptides agonistes de récepteur c5a
WO2019154515A1 (fr) * 2018-02-09 2019-08-15 The Cyprus Foundation For Muscular Dystrophy Research Procédés et compositions pour le traitement de maladies amyloïdes
WO2020056229A1 (fr) * 2018-09-14 2020-03-19 Prommune, Inc. Compositions immunologiques antiparasitaires

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