WO2018175633A1 - Methods of inducing anti-malarial immune responses and compositions related thereto - Google Patents
Methods of inducing anti-malarial immune responses and compositions related thereto Download PDFInfo
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- WO2018175633A1 WO2018175633A1 PCT/US2018/023628 US2018023628W WO2018175633A1 WO 2018175633 A1 WO2018175633 A1 WO 2018175633A1 US 2018023628 W US2018023628 W US 2018023628W WO 2018175633 A1 WO2018175633 A1 WO 2018175633A1
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/47—Quinolines; Isoquinolines
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- A61K31/33—Heterocyclic compounds
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Definitions
- the malaria vaccine is administered to the subject and, after a period of time, the chemoprophylaxis is administered to the subject.
- the chemoprophylaxis is administered to a subject who develops malaria after treatment with the vaccine (e.g., to avoid treating subjects who successfully develop an immune response and/or eradicate the administered Plasmodium falciparum).
- the hepcidin or mini-hepcidin and the malaria vaccine are in the same composition.
- the hepcidin or mini-hepcidin and the malaria vaccine are in separate compositions and may be administered at the same time or sequentially.
- A10 is L-Cys, L-Ser, L-Ala, D-Cys, D-Ser, or D-Ala;
- the malaria vaccine further comprises an adjuvant and a pharmaceutically acceptable carrier.
- adjuvant refers to an agent that stimulates the immune system and increases the response to a vaccine.
- Vaccine adjuvants are well-known to those of skill in the art.
- carrier refers to an ingredient other than the active component(s) in a formulation. The choice of carrier will to a large extent depend on factors such as the particular mode of administration or application, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutically acceptable carriers for polypeptide antigens are well known in the art.
- the subject is further administered a malarial chemoprophylaxis (e.g., chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin).
- the malaria vaccine may comprise a radiation attenuated PfSPZ.
- the composition disclosed herein may be administered at the same time or sequentially.
- the malaria vaccine may comprise a chemoattenuated PfSPZ vaccine.
- materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
- Treating" a disease in a subject or “treating” a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.
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Abstract
Provided herein are methods and compositions for vaccinating subjects against malaria, or otherwise promoting the development of an immune response against Plasmodium falciparum. In some aspects, provided here are compositions comprising a malaria vaccine and hepcidin or mini-hepcidin.
Description
METHODS OF INDUCING ANTI-MALARIAL IMMUNE RESPONSES AND
COMPOSITIONS RELATED THERETO
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application serial number 62/474,894, filed March 22, 2017, which is herein incorporated by reference in its entirety.
BACKGROUND
A global public health goal is the control and eventual eradication of human malaria. It is estimated that over 500 million people in tropical regions are exposed to malaria annually, and 1.5 to 2 million people die from this disease (Sturchler, D., 1984, Experientia 40: 1357). Efforts to control malaria have historically focused on control of the mosquito vector and the development of antimalarial drugs. These efforts have met with only limited success. New prophylactic and therapeutic drugs are of limited effectiveness because drug- resistant strains can appear rapidly in endemic areas. Control of the mosquito vector depends largely upon implementation of insecticide-based control programs which, due to cost and other factors, are difficult to maintain in developing nations. Vector resistance to modern insecticides has compounded the problem, and resulted once again in the resurgence of malaria. Thus, there is a need to develop new and improved malaria therapies.
SUMMARY
Generally, the present disclosure relates to treating and/or preventing malaria. In some aspects, provided here are methods and compositions for treating or preventing malaria by administering to a subject a composition comprising hepcidin or mini-hepcidin and a malaria vaccine (e.g., an inactivated or live vaccine). The present disclosure also provides methods for promoting the development of an immune response to Plasmodium falciparum in a subject by conjointly administering a composition comprising hepcidin or mini-hepcidin and a malaria vaccine to the subject. In some embodiments, the malaria vaccine comprises Plasmodium falciparum sporozoites (PfSPZ) (e.g., attenuated PfSPZ), such as radiation attenuated PfSPZ. Most preferably, the malaria vaccine comprises an infectious Plasmodium falciparum strain that is sensitive to a predetermined anti-malarial drug, such as chloroquine. In some embodiments, a chemoprophylaxis (e.g., chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin) is also administered to the subject. The chemoprophylaxis may be
administered to the subject prior to malaria vaccine administration. In some embodiments, the chemoprophylaxis is administered to the subject at about the same time as the malaria vaccine. In some embodiments, the malaria vaccine is administered to the subject and, after a period of time, the chemoprophylaxis is administered to the subject. In certain preferred embodiments, the chemoprophylaxis is administered to a subject who develops malaria after treatment with the vaccine (e.g., to avoid treating subjects who successfully develop an immune response and/or eradicate the administered Plasmodium falciparum). In some embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in the same composition. In other embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in separate compositions and may be administered at the same time or sequentially.
DETAILED DESCRIPTION
In some aspects, provided here are methods and compositions for preventing malaria and/or promoting the development of an immune response to Plasmodium falciparum by conjointly administering to a subject (e.g., a subject in need thereof) a composition comprising hepcidin or mini-hepcidin and a malaria vaccine. In certain aspects, provided herein are methods and compositions for inhibiting the development of erythrocytic (blood- stage) malaria in a subject by administering a composition comprising hepcidin or mini- hepcidin and a malaria vaccine to the subject. In some aspects, provided herein are methods and compositions for inhibiting the infection of hepatocytes in a subject by Plasmodium falciparum by conjointly administering a composition comprising hepcidin or mini-hepcidin and a malaria vaccine to the subject. In some embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in the same composition. In other embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in separate compositions. The malaria vaccine is preferably a live vaccine, e.g., capable of infecting a human host. A live malaria vaccine may comprise a malarial sporozoites, and may be infectious, chemoattenuated, or radiation attenuated. For example, a live malaria vaccine may comprise chemoattenuated or radiation attenuated PfSPZ sporozoites. Preferably, the live malaria vaccine comprises a strain of Plasmodium falciparum that is sensitive to a predetermined anti-malarial drug, such as chloroquine. Combinations of malaria vaccines may also be employed. For example, the vaccine may further comprise an inactivated (e.g., protein-based) vaccine, such as a
Plasmodium epitope or any immunogenic peptide of the species Plasmodium. For example, an inactivated or protein-based vaccine may comprise at least one antigen expressed by
Plasmodium falciparum at any stage of its life cycle. An inactivated vaccine may comprise a malarial peptide capable of inducing an immune response against a malarial parasite in a subject.
In some aspects, provided herein are methods for prophylactic treatment of a subject at risk of malaria infection by administering a composition comprising hepcidin or mini- hepcidin as described herein prior to exposure to malarial parasites, e.g., within about a month of exposure, within about two weeks of exposure, or preferably within one week of exposure to the malarial parasites.
In some embodiments, the methods disclosed herein further comprise administering to the subject an anti-malarial drug (e.g., chloroquine, tetracycline, proguanil,
chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin). The compositions provided herein may comprise adjuvants and/or carriers. The compositions of the present invention (e.g., compositions comprising hepcidin, mini- hepcidin and/or a malaria vaccine) may be administered by any suitable means.
HEPCIDIN AND MINI-HEPCIDIN
Provided herein are compositions comprising hepcidin or mini-hepcidin. The hepcidin peptide is a 25-amino acid peptide with the amino acid sequence set forth in SEQ ID NO: 1. The hepcidin peptide may be a cleavage product of a larger pre-propeptide, which is further processed into a prohepcidin precursor, which the cell membrane protein furin can convert into the hepcidin peptide. The term "hepcidin" as used herein may therefore refer to a peptide comprising the sequence set forth in SEQ ID NO: 1, including peptides that are longer than 25 amino acids, such as peptides consisting of 26 to 100 amino acids, or precursor peptides such as pre-prohepcidin or prohepcidin that can be converted to hepcidin or an analog having hepcidin activity.
Conservative amino acid substitutions, additions, and deletions may be made to SEQ ID NO: 1 without significantly affecting the function of hepcidin. Thus, the term "hepcidin" may refer to a peptide comprising an amino acid sequence having at least 90%, 91%, 92%, 93%), 94%), 95%), or 96%> sequence homology with the amino acid sequence set forth in SEQ ID NO: 1. Sequence homology may be determined using any suitable sequence alignment program, such as Protein Blast (blastp) or Clustal {e.g., Clustal V, ClustalW, ClustalX, or Clustal Omega), e.g., using default parameters, such as default weights for gap openings and gap extensions. Sequence homology may refer to sequence identity. The term "hepcidin"
may refer to a peptide comprising an amino acid sequence that is identical to the sequence set forth in SEQ ID NO: l except that 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids of SEQ ID NO: 1 are substituted with different amino acids. In preferred embodiments, hepcidin comprises a cysteine at each of the positions in which a cysteine occurs in SEQ ID NO: l .
"Hepcidins" according to the invention can also include mini-hepcidins and hepcidin mimetic peptides, for example as disclosed in US. Patent No. 8,435,941, hereby incorporated by reference herein, in particular for its disclosure of compounds that share one or more activities with hepcidin.
Further, the compositions and formulations contemplated herein are suitable for formulating modified and/or derivatized forms of hepcidin, such as, and without limitation, hepcidins bearing those modifications that may affect bio-availability, concentration, duration of action, and/or membrane permeability, such as pegylated hepcidins and other covalently-modified hepcidins.
SEQ ID NO: 1
DTHFPICIFCCGCCHRSKCGMCCKT
In some embodiments, the hepcidin is a hepcidin disclosed herein, such as human hepcidin. In some embodiments, the hepcidin may comprise the amino acid sequence of any one of SEQ ID NOs: 1-10 or analogs and/or mimetics thereof.
N-terminal and C-terminal residues may be deleted from the hepcidin peptide without significantly affecting its function. Thus, in some embodiments, hepcidin refers to a peptide comprising the sequence set forth in SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4, or a peptide comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%), or 96%) sequence homology with the amino acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. The term hepcidin may refer to a peptide comprising an amino acid sequence that is identical to the sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 except that 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 are substituted with different amino acids. In preferred embodiments, hepcidin comprises a cysteine at each of the positions in which a cysteine occurs in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
SEQ ID NO:2
PICIFCCGCCHRSKCGMCCKT
SEQ ID NO: 3
PICIFCCGCCHRSKCGMCC
SEQ ID NO:4
ICIFCCGCCHRSKCGMCCKT SEQ ID NO:5
CIFCCGCCHRSKCGMCC
In some embodiments, the term "hepcidin" refers to a peptide comprising an amino acid sequence that is identical to the sequence set forth in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10. In SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10, the amino acids labeled "X" may be any amino acid, including naturally occurring and non-naturally occurring amino acids. In some embodiments, each of the amino acids labeled "X" is a naturally occurring amino acid. SEQ ID NO: 6
XXHXPXCXXCCGCCHRSKCGMCCXX
SEQ ID NO: 7
PXCXXCCGCCHRSKCGMCCKX
SEQ ID NO: 8
PXCXXCCGCCHRSKCGMCC SEQ ID NO: 9
XCXXCCGCCHRXXCGXCCKX
SEQ ID NO: 10
CXXCCGCCHRXXCGXCC
In preferred embodiments, hepcidin is a molecule that specifically binds to ferroportin and/or iron (e.g., an iron cation). Hepcidin may comprise 1, 2, 3, or 4 disulfide bonds. In preferred embodiments, hepcidin comprises four disulfide bonds, e.g.,
intramolecular disulfide bonds. In preferred embodiments, each of the eight cysteines of SEQ ID NO: l, 2, 3, 4, 5, 6, 7, 8, 9, or 10 participates in one of four intramolecular disulfide bonds with another one of the eight cysteines.
In preferred embodiments, hepcidin has about 10% to 1000%) of the activity of a 25 amino acid long peptide comprising the amino acid sequence set forth in SEQ ID NO: l, i.e., wherein the 25 amino acid long peptide comprises the four intramolecular disulfide bonds found in native human hepcidin. For example, hepcidin may have about 50% to about 200% of the activity of a 25 amino acid long peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 (i.e., wherein the 25 amino acid long peptide comprises the four intramolecular disulfide bonds found in native human hepcidin), such as about 75% to about 150% of the activity, about 80% to about 120% of the activity, about 90% to about 110% of the activity, or about 95% to about 105% of the activity. The term "activity" may refer to the ability of hepcidin to specifically bind to ferroportin, e.g., thereby inhibiting the transport of intracellular iron into the extracellular space, inhibiting the absorption of dietary iron, and/or reducing serum iron concentration. Activity may refer to the ability of hepcidin to inhibit the transport of intracellular iron into the extracellular space. Activity may refer to the ability of hepcidin to inhibit the absorption of dietary iron. Activity may refer to the ability of hepcidin to reduce serum iron concentration in vivo. Such molecules preferably retain at least 10% of one characteristic hepcidin activity, such as iron-lowering activity (hepcidin mimetic).
In some embodiments, mini-hepcidin may refer to a mini-hepcidin, modified hepcidin or a hepcidin mimetic peptide, any of which can be used in the compositions and methods disclosed herein. For the purposes of this application, the terms mini-hepcidin, a modified hepcidin, or a hepcidin mimetic peptide may be used interchangeably. Mini- hepcidins, modified hepcidins, and hepcidin mimetic peptides are disclosed in U.S. Patent No. 9,315,545, 9,328,140, and 8,435,941, each of which are hereby incorporated herein by reference, in particular for their disclosure of compounds that share one or more activities with hepcidin.
(XV)
A mini-hepcidin may have the structure of formula A1-A2-A3-A4-A5-A6-A7-A8- A9-A10, A10-A9-A8-A7-A6-A5-A4-A3-A2-A1, or a pharmaceutically acceptable salt thereof, wherein:
Al is L-Asp, L-Glu, pyroglutamate, L-Gln, L-Asn, D-Asp, D-Glu, D-pyroglutamate, D-Gln, D-Asn, 3-aminopentanedioic acid, 2,2'-azanediyldiacetic acid,
(methylamino)pentanedioic acid, L-Ala, D-Ala, L-Cys, D-Cys, L-Phe, D-Phe, L-Asp, D-Asp, 3,3-diphenyl-L-alanine, 3,3-diphenyl-D-alanine; and if Al is L-Asp or D- Asp, then A2 is L-Cys or D-Cys; if Al is L-Phe or D-Phe, then the N-terminus is optionally attached to a PEG molecule linked to chenodeoxvcholate,
ursodeoxvcholate, or palmitoyl; or if Al is 3,3-diphenyl-L-alanine or 3,3-diphenyl- D-alanine, then the N-terminus is attached to palmitoyl;
A2 is L-Thr, L-Ser, L-Val, L-Ala, D-Thr, D-Ser, D-Val, L-tert-leucine, isonipecotic acid, L- a-cyclohexylglycine, bhThr, (2S)-3-hydroxy-2-(methylamino)butanoic acid, D-Ala, L-Cys, D-Cys, L-Pro, D-Pro, or Gly;
A3 is L-His, D-His, 3,3-diphenyl-L-alanine, 3,3-diphenyl-D-alanine, or 2-aminoindane;
A4 is L-Phe, D-Phe, (S)-2-amino-4-phenylbutanoic acid, 3,3-diphenyl-L-alanine, L- biphenylalanine, (l-naphthyl)-L-alanine, (S)-3-Amino-4,4-diphenylbutanoic acid, 4- (aminomethyl)cyclohexane carboxylic acid, (S)-2-amino-3-
(perfluorophenyl)propanoic acid, (S)-2-amino-4-phenylbutanoic acid, (S)-2-amino-2-
(2,3-dihydro-lH-inden-2-yl)acetic acid, or cyclohexylalanine;
A5 is L-Pro, D-Pro, octahydroindole-2-carboxylic acid, L-P-homoproline, (2S,4S)-4- phenylpyrrolidine-2-carboxylic acid, (2S,5R)-5-phenylpyrrolidine-2-carboxylic acid, or (R)-2-methylindoline;
A6 is L-Ile, D-Ile, L-phenylglycine, L-a-cyclohexylglycine, 4-(aminomethyl)cyclohexane carboxylic acid, (3R)-3-amino-4-methylhexanoic acid, 1-aminocyclohexane-l- carboxylic acid, or (3R)-4-methyl-3-(methylamino)hexanoic acid;
A7 is L-Cys, D-Cys, S-t-Butylthio-L-cysteine, L-homocysteine, L-penicillamine, or D- penicillamine;
A8 is L-Ile, D-Ile, L-a-cyclohexylglycine, 3,3-diphenyl-L-alanine, (3R)-3-amino-4- methylhexanoic acid, 1-aminocyclohexane-l -carboxylic acid, or (3R)-4-methyl-3- (methylamino)hexanoic acid;
A9 is L-Phe, L-Leu, L-Ile, L-Tyr, D-Phe, D-Leu, D-Ile, (S)-2-amino-3-
(perfluorophenyl)propanoic acid, N-methyl-phenylalainine, benzylamide, (S)-2- amino-4-phenylbutanoic acid, 3,3-diphenyl-L-alanine, L-biphenylalanine, (1- naphthyl)-L-alanine, (S)-3-amino-4,4-diphenylbutanoic acid, cyclohexylalanine, L- Asp, D-Asp, or cysteamide, wherein L-Phe or D-Phe are optionally linked at the N- terminus to RA, wherein RA is -CONH-CH2-CH2-S-, or D-Pro linked to Pro-Lys or Pro-Arg, or L-P-homoproline linked to L-Pro linked to Pro-Lys or Pro-Arg, or D-Pro linked to L-P-homoproline-Lys or L-P-homoproline-Arg; L-Asp or D-Asp are optionally linked at the n-terminus to RB, wherein RB is -(PEG 11)- GYIPEAPRDGQAYVRKDGEWVLLSTFL, or -(PEG 1 l)-(Gly-Pro-HydroxyPro)io, (S)-2-amino-4-phenylbutanoic acid is linked to RC, wherein RC is D-Pro linked to ProLys or ProArg, or D-Pro linked to L-P-homoproline-Lys or L-P-homoproline- L- Arg;
A10 is L-Cys, L-Ser, L-Ala, D-Cys, D-Ser, or D-Ala;
the carboxy-terminal amino acid is in amide or carboxy- form;
at least one sulfhydryl amino acid is present as one of the amino acids in the sequence; and AI, A2, A9, A10, or a combination thereof are optionally absent.
A mini-hepcidin of formula A1-A2-A3-A4-A5-A6-A7-A8-A9-A10 or A10-A9-A8- A7-A6-A5-A4-A3-A2-A1 may be a cyclic peptide or a linear peptide.
For example, AI may be L-Asp; A2, may be L-Th; A3 may be L-His; A4 may be L- Phe; A5 may be L-Pro; A6 may be L-Ile; A7 may be L-Cys, D-Cys, S-t-butylthio-L-cysteine, L-homocysteine, L-penicillamine, or D-penicillamine; A8 may be L-Ile; A9 may be L-Phe; A10 may be absent; and the C-terminus may be amidated. Alternatively, A3 may be L-His; A4 may be L-Phe; A5 may be L-Pro; A6 may be L-Ile; A7 may be L-Cys, D-Cys, S-t- butylthio-L-cysteine, L-homocysteine, L-penicillamine, or D-penicillamine; A8 may be L- Ile; AI, A2, A9, and A10 may be absent, and the C-terminus may be amidated.
Alternatively, A3 may be L-His; A4 may be L-Phe; A5 may be L-Pro; A6 may be L-Ile; A7 may be L-Cys, D-Cys, S-t-butylthio-L-cysteine, L-homocysteine, L-penicillamine, or D- penicillamine; AI, A2, A8, A9, and A10 may be absent; and the C-terminus may be amidated.
A mini-hepcidin may comprise the amino acid sequence HFPICI (SEQ ID NO: 11), HFPICIF (SEQ ID NO: 12), DTHFPICIDTHFPICIF (SEQ ID NO: 13), DTHFPIAIFC (SEQ ID NO: 14), DTHAPICIF (SEQ ID NO: 15), DTHFPICIF (SEQ ID NO: 16), or CDTHFPICIF
(SEQ ID NO: 17). The mini-hepcidin may comprise the sequence set forth in SEQ ID NO: 15, for example, wherein the cysteine forms a disulfide bond with S-tertbutyl.
A mini-hepcidin may comprise the amino acid sequence D-T-H-F-P-I-(L- homocysteine)-I-F; D-T-H-F-P-I-(L-penicillamine)-I-F; D-T-H-F-P-I-(D-penicillamine)-I-F; D-(L-tert-leucine)-H-(L-phenylglycine)-(octahydroindole-2-carboxylic acid)-(L-a- cyclohexylglycine)-C-(L-a-cyclohexylglycine)-F; or D-(L-tert-leucine)-H-P- (octahydroindole-2-carboxylic acid)-(L-a-cyclohexylglycine)-C-(L-a-cyclohexylglycine)-F.
A mini-hepcidin may comprise the amino acid sequence FICIPFHTD (SEQ ID NO: 18), FICIPFH (SEQ ID NO: 19), R2-FICIPFHTD (SEQ ID NO:20), R3 -FICIPFHTD (SEQ ID NO:21), FICIPFHTD-R6 (SEQ ID NO:22), R4-FICIPFHTD (SEQ ID NO:23), or R5 -FICIPFHTD (SEQ ID NO:24), wherein each amino acid is a D amino acid; Rl is - CONH2-CH2-CH2-S; R2 is chenodeoxycholate-(PEG 11)-; R3 is ursodeoxycholate-(PEGl l)- ; R4 is palmitoyl-(PEGl 1)-; R5 is 2(palmitoyl)-diaminopropionic acid-(PEG 11)-; and R6 is (PEG 11)-GYIPEAPRDGQAYVRKDGEWVLLSTFL, wherein each amino acid of R6 is an L amino acid.
A mini-hepcidin may comprise the amino acid sequence D-T-H-((S)-2-amino-4- phenylbutanoic acid)-P-I-C-I-F; D-T-H-(3,3-diphenyl-L-alanine)-P-I-C-I-F; D-T-H-(L- biphenylalanine)-P-I-C-I-F; D-T-H-((l-naphthyl)-L-alanine)-P-I-C-I-F; D-T-H-((S)-3- amino-4,4-diphenylbutanoic acid)-P-I-C-I-F; D-T-H-F-P-I-C-I-((S)-2-amino-4- phenylbutanoic acid); D-T-H-F-P-I-C-I-(3,3-diphenyl-L-alanine); D-T-H-F-P-I-C-I-(L- biphenylalanine); D-T-H-F-P-I-C-I-((l-naphthyl)-L-alanine); D-T-H-F-P-I-C-I-((S)-3- amino-4,4-diphenylbutanoic acid); D-T-H-(3,3-diphenyl-L-alanine)-P-I-C-I-(3,3-diphenyl-L- alanine); D-(3 ,3 -diphenyl-L-alanine)-P-I-C-I-F; D-(3 ,3 -diphenyl-L-alanine)-P-I-C-I-(3 ,3 - diphenyl-L-alanine); D-T-H-(3,3-diphenyl-L-alanine)-P-R-C-R-(3,3-diphenyl-L-alanine); D- T-H-(3,3-diphenyl-L-alanine)-(octahydroindole-2-carboxylic acid)-I-C-I-F; D-T-H-(3,3- diphenyl-L-alanine)-(octahydroindole-2-carboxylic acid)-I-C-I-(3,3-diphenyl-L-alanine); or D-T-H-(3,3-diphenyl-L-alanine)-P-C-C-C-(3,3-diphenyl-L-alanine).
A mini-hepcidin may comprise the amino acid sequence D-T-H-F-P-I-C-I-F-R8; D- T-H-F-P-I-C-I-F-R9; D-T-H-F-P-I-C-I-F-RIO; D-T-H-F-P-I-C-I-F-Rl 1; D-T-H-F-P-I-C-I-F- R12; D-T-H-F-P-I-C-I-F-Rl 3; D-T-H-F-P-I-C-I-((S)-2-amino-4-phenylbutanoic acid)-R8; D-T-H-F-P-I-C-I-((S)-2-amino-4-phenylbutanoic acid)-R9; D-T-H-F-P-I-C-I-((S)-2-amino- 4-phenylbutanoic acid)-R12; or D-T-H-F-P-I-C-I-((S)-2-amino-4-phenylbutanoic acid)-R13, wherein R8 is D-Pro-L-Pro-L-Lys; R9 is D-Pro-L-Pro-L-Arg; RIO is (L-P-homoproline)-L-
Pro-L-Lys; Rl l is (L-P-homoproline)-L-Pro-L-Arg; R12 is D-Pro-(L-P-homoproline)-L-Lys; and R13 is D-Pro-(L-P-homoproline)-L-Arg.
A mini-hepcidin may comprise the amino acid sequence D-T-H-(3,3-diphenyl-L- alanine)-P-(D)R-C-(D)R-(3,3-diphenyl-L-alanine).
A mini-hepcidin may comprise the amino acid sequence C-(isonipecotic acid)-(3,3- diphenyl-D-alanine)-(4-(aminomethyl)cyclohexane carboxylic acid)-R-(4- (aminomethyl)cyclohexane carboxylic acid)-(isonipecotic acid)-(3,3-diphenyl-L-alanine)- cysteamide. A mini-hepcidin may comprise the amino acid sequence C-P-(3,3-diphenyl-D- alanine)-(4-(aminomethyl)cyclohexane carboxylic acid)-R-(4-(aminomethyl)cyclohexane carboxylic acid)-(isonipecotic acid)-(3,3-diphenyl-L-alanine)-cysteamide. A mini-hepcidin may comprise the amino acid sequence C-(D)P-(3,3-diphenyl-D-alanine)-(4- (aminomethyl)cyclohexane carboxylic acid)-R-(4-(aminomethyl)cyclohexane carboxylic acid)-(isonipecotic acid)-(3,3-diphenyl-L-alanine)-cysteamide. A mini-hepcidin may comprise the amino acid sequence C-G-(3,3-diphenyl-D-alanine)-(4- (aminomethyl)cyclohexane carboxylic acid)-R-(4-(aminomethyl)cyclohexane carboxylic acid)-(isonipecotic acid)-(3,3-diphenyl-L-alanine)-cysteamide.
A mini-hepcidin may comprise the amino acid sequence (2,2'-azanediyldiacetic acid)-Thr-His-(3,3-diphenyl-L-alanine)-(L-P-homoproline)-Arg-Cys-Arg-((S)-2-amino-4- phenylbutanoic acid)-(aminohexanoic acid)-(2,2'-azanediyldiacetic acid having a
palmitylamine amide on the side chain), which is described in U.S. Patent No. 9,328, 140 (e.g., SEQ ID NO:94 of the Ί40 patent; hereby incorporated herein by reference).
In some embodiments, a mini-hepcidin has about 10% to 1000%) of the activity of a 25 amino acid long peptide comprising the amino acid sequence set forth in SEQ ID NO: l . For example, a mini-hepcidin may have about 50% to about 200%> of the activity of a 25 amino acid long peptide comprising the amino acid sequence set forth in SEQ ID NO: 1, such as about 75% to about 150% of the activity, about 80%> to about 120%> of the activity, about 90%) to about 110%) of the activity, or about 95% to about 105% of the activity. The term "activity" may refer to the ability of a mini-hepcidin to specifically bind to ferroportin, e.g., thereby inhibiting the transport of intracellular iron into the extracellular space, inhibiting the absorption of dietary iron, and/or reducing serum iron concentration. Activity may refer to the ability of a mini-hepcidin to inhibit the transport of intracellular iron into the
extracellular space. Activity may refer to the ability of a mini-hepcidin to inhibit the
absorption of dietary iron. Activity may refer to the ability of a mini-hepcidin to reduce serum iron concentration in vivo.
MALARIA VACCINES
Provided herein are methods and compositions for treating and/or preventing malaria by administering to a subject a composition comprising hepcidin or mini-hepcidin (e.g., a hepcidin or a mini-hepcidin disclosed herein) and a malaria vaccine. The malaria vaccine may be any malaria vaccine known in the art. The malaria vaccine may be an inactivated vaccine (e.g., a protein-based vaccine comprising a malarial antigen). In some embodiments, the malaria vaccine is an immunogenic composition comprising an immunogenic polypeptide (e.g., a peptide produced by the malarial parasite or sporozoites). In some embodiments, the malarial vector comprises a nucleotide vector (e.g., a recombinant nucleotide vector) encoding for the immunogenic malarial peptide. The malaria vaccine may be a live vaccine. The malaria vaccine may be an attenuated vaccine, such as
chemoattentuated or radiation-attenuated vaccine. The vaccine may be genetically attenuated. In some embodiments, the vaccine is administered prophylactically to prevent malaria.
In some embodiments, the malaria vaccine further comprises an adjuvant and a pharmaceutically acceptable carrier. As used herein, the term "adjuvant" refers to an agent that stimulates the immune system and increases the response to a vaccine. Vaccine adjuvants are well-known to those of skill in the art. As used herein, the term "carrier" refers to an ingredient other than the active component(s) in a formulation. The choice of carrier will to a large extent depend on factors such as the particular mode of administration or application, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutically acceptable carriers for polypeptide antigens are well known in the art.
Malaria is transmitted to humans by the females of the Anopheles species of mosquito. Prior to transmission, the malarial parasite resides within the salivary gland of the mosquito. The parasite is in its sporozoite stage at this point. Typically, each infected bite contains 5-200 sporozoites which proceed to infect the human. Once in the human bloodstream, the sporozoites circulate throughout the blood stream and infect liver cells (hepatocytes). Once in the hepatocyte, the parasite loses its apical complex and surface coat, and transforms into a trophozoite, and continues its reproductive cycle to ultimately produce
infectious merozoites and establish the erythrocytic stage of the life cycle. The malaria vaccine may be genetically attenuated. In some embodiments, the vaccine is genetically engineered to interrupt the malarial reproductive cycle or to inhibit the molecular mechanisms underlying infection. For example, the vaccine may comprise a Plasmodium organism that is genetically engineered to disrupt gene function of the parasite during its liver infectious stage (infection of heptatocytes). In some embodiments, t e Plasmodium parasite is genetically engineered to disrupt a liver-stage-specific gene function. The term "disrupt liver-stage-specific gene function" means interfering with a liver-stage-specific gene function such as to completely or partially inhibit, inactivate, attenuate, or block the liver- stage-specific gene function, for example, by gene disruption or influencing transcription, translation, protein folding, and/or protein activity. The term "liver-stage-specific gene function" or refers to a function that is required in liver stage parasites to ultimately produce infectious merozoites and establish the erythrocytic stage of the life cycle, but that is not required for entry into host hepatocytes or, preferably, maintenance of the parasite in asexual blood cell stages and production of infective sporozoites in mosquitoes. More details on genetically attenuated malaria vaccines may be found in U.S. Patent No. 7,122, 179, hereby incorporated in its entirety.
In some embodiments, the malaria vaccine is a live vaccine (e.g., a live attenuated vaccine) In some embodiments, the malaria vaccine comprises a radiation attenuated vaccine. In some embodiments, the malaria vaccine comprises malarial sporozoites (e.g., P. falciparum, P. vivax, P. ovale, or P. malariae sporozoites). In some embodiments, the malaria vaccine comprises Plasmodium falciparum sporozoites (PfSPZ) (e.g., attenuated PfSPZ or infectious PfSPZ). In some embodiments, the subject is further administered a malarial chemoprophylaxis (e.g., chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin). The malaria vaccine may comprise a radiation attenuated PfSPZ. The composition disclosed herein may be administered at the same time or sequentially. The malaria vaccine may comprise a chemoattenuated PfSPZ vaccine. For example, a chemoattenuated PfSPZ vaccine approach may comprise administering Plasmodium falciparum sporozoites in combination with a malaria chemoprophylaxis. Exemplary malaria chemoprophylaxis drugs include chloroquine, tetracyclines (e.g., tetracycline or tetracycline derivatives), proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, and/or artesunate. The method may comprise the conjoint administration of artemisinin or an
artemisinin derivative to the subject. The method may comprise the conjoint administration of artesunate, artemisinin, dihydro-artemisinin, artelinate, arteether, and/or artemether to the subject. More information on chemoattentuated malaria vaccines may be found in
Mordmuller et al., 2017, Nature, 542, pp.445-447.
The vaccine may be an inactivated vaccine. In some embodiments, the vaccine comprises a malarial peptide (e.g., a peptide capable of producing an immunogenic response in a subject) or a nucleotide vector encoding for said malarial peptide. In some embodiments, the vaccine comprises a Plasmodium epitope or a nucleotide vector that expresses a
Plasmodium epitope. Any DNA sequence which encodes a Plasmodium epitope, which when expressed as a fusion or non-fusion protein, produces protective immunity against malaria, can be isolated for use in the malaria vaccines disclosed herein. The species of Plasmodium which can serve as DNA sources include but are not limited to the human malaria parasites P. falciparum, P. vivax, P. ovale, P. malariae, and the animal malaria parasites P. berghei, P. yoelii, P. knowlesi, and P. cynomolgi. The malarial peptides or antigens, or fragments thereof, which can be expressed by, for example, recombinant bacteria in the vaccines disclosed herein are antigens which are expressed by the malaria parasite at any of the various stages in its life cycle, such as the sporozoite, exoerythrocytic (development in hepatic parenchymal cells), asexual erythrocytic, or sexual (e.g., gametes, zygotes, ookinetes) stages. The antigen can be expressed by the malaria parasite itself or by an infected cell. The Plasmodium antigens which may be used include but are not limited to those described in the following publications, incorporated by reference herein: Vaccines85, 1985, Lerner, R. A., et al., eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., pp. 1-57; Vaccines86, 1986, Brown, F., et al., eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., pp. 135-179; Vaccines87, 1987, Channock et al., eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, pp. 81-106, 117-124; Kemp, D. J., et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:3787; Anders, R. F., et al., 1984, Mol. Biol. Med. 2(3): 177-191; Miller, L. H., et al., 1984, J. Immunol. 132(l):438-442; Carter, R., et al., Nov. 13, 1984, Philos. Trans. R. Soc. Lond. (Biol.) 307(1131):201-213; Holder, A. A. and
Freeman, R. R., 1981, Nature 294:361; Leech, J. H., et al., 1984, J. Exp. Med. 159: 1567; Rener, J., et al., 1983, J. Exp. Med. 158:971; Dame, J. B., et al., 1984, Science 225:593; Arnot, D. E., et al., 1985, Science 230:815; Coppel, R. L., et al., 1983, Nature 306:751;
Coppel, R. L., et al., 1984, Nature 310:789; Holder, A. A., et al., 1985, Nature 317:270; Ardeshir, F., et al., 1987, EMBO J. 6:493; Ravetch, J. V., et al., 1985, Science 227: 1593;
Stahl, H.-D., et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:543; Langsley, G., et al., 1985, Nucl. Acids Res. 11 :4191; Coppel, R. L., et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:5121; Howard, R. J., et al., 1987, J. Cell Biol. 104: 1269; Buranakitjaroen, P. and Newbold, C. L, 1987, Mol. Biochem. Parasitol. 22:65; Schofield, L., et al., 1986, Mol. Biochem. Parasitol. 18: 183; Knowles, G. and Davidson, W. L., 1984, Am. J. Trop. Med. Hyg. 33 :789; Kilejian, A., 1979, Proc. Natl. Acad. Sci. U.S.A. 76:4650; Leech, J. H., et al., 1984, J. Cell. Biol. 98: 1256; Hadley, T. J., et al., 1986, Ann. Rev. Microbiol. 40:451; Camus, D. and Hadley, T. J., 1985, Science 230:553; Vermeulen, A. M., et al., 1985, J. Exp. Med. 162: 1460.;
Vermeulen, A. M., et al., 1986, Mol. Biochem. Parasitol. 20: 155; Kumar, N. and Carter, R., 1984, Mol. Biochem. Parasitol. 13 :333; Patarroyo, M. E., et al., 1987, Nature 328:629-632; and Miller, L. H., et al., 1984, Phil. Trans. R. Soc. Lond. B307:99-115.
Exemplary malarial antigens include the circumsporozoite antigen, the P. falciparum blood-stage ring-infected erythrocyte surface antigen (RESA), S antigen, Falciparum interspersed repeat antigen (FIRA), glycophorin binding protein (GBP), Pf 195 kD antigen, circumsporozoite protein-related antigen (CRA), Pf 155 antigen, Pf 75 kD antigen, Pf EMP 2 antigen, and Pf knob-associated antigens; P. falciparum sexual stage antigens of 260,000, 59,000 and 53,000 molecular weight, antigens of 230,000, 48,000, and 45,000 molecular weight, etc. In some embodiments, the malarial antigen may be expressed in bacteria. In some embodiments, the malarial antigen may be expressed in an attenuated enteroinvasive bacteria.
In some embodiments, the malaria peptide (e.g., malaria epitope) to be expressed is an epitope of the circumsporozoite (CS) protein of a species of Plasmodium. Analogous CS proteins have been identified on the surfaces of sporozoites of all serotypes of Plasmodium. Circumsporozoite protein antigens expressed in bacteria (e.g., attenuated enteroinvasive bacteria, such as salmonella) can be used as live vaccines directed against sporozoites. The genes which encode a CS epitope and which those Plasmodium species disclosed herein. In some embodiments, genes encoding the CS proteins of the human malaria parasites P.
falciparum, P. vivax, the simian parasites P. cynomolgi and P. knowlesi, and the rodent parasite P. berghei can be used; these genes have been cloned and sequenced, as reported in the following publications, which are incorporated by reference herein: Dame, J. B., et al., 1984, Science 225:593; Arnot, D. D., et al., 1985, Science 230:815; Weber et al., 1987, Exp. Parasitol. 63 :295; Enea, V., et al., 1984, Science 225:628; Enea, V., et al., 1984, Proc. Natl. Acad. Sci. U.S.A. 81 :7520; Godson, G. N., et al., 1983, Nature 305:29; and McCutchan, T.
F., et al., 1985, Science 230: 1381. A characteristic feature of the CS genes of each of the parasites is a central region which comprises over one third of the protein and contains a large series of repeated peptide sequences (Dame, J. B., et al., 1984, Science 225:593; Ozaki, L. S., et al., 1983, Cell 34:815). The primary amino acid sequence, the length of the repeating sequence, and the number of repeats varies with each species of parasite. As examples, the gene encoding the CS protein of P. falciparum specifies a central repeat region of a tetrapeptide (asn-ala-asn-pro) repeated thirty-seven times, interrupted in four locations by a variant tetrapeptide (asn-val-asp-pro). The central repeat region of P. vivax contains nineteen nonapeptides; the central sequence of P. knowlesi contains eight dodecapeptides, and the repeat region of P. berghei contains twelve octapeptides. Comparison of sequences from P. knowlesi (H strain) and P. falciparum and P. vivax revealed no sequence homology, except for two short amino acid sequences flanking the repeat region, termed Region I and Region II. The repeat regions appear to be highly conserved within the human malaria parasites P. falciparum and P. vivax (Weber, J. L. and Hockmeyer, W. T., 1984, Mol.
Biochem. Parasitol. 15:305; Zavala, F., et al., 1985, J. Immunol. 135:2750), though intra- species variation has been observed in P. knowlesi and P. cynomolgi. The repeat region also appears to be immunodominant (Dame, J. B., et al., 1984, Science 225:593; Hockmeyer, W. T. and Dame, J. B., 1985, in Immunobiology of Proteins and Peptides III, Atassi, M. Z., ed., Plenum Press, New York, pp. 233-246; Zavala, F., et al., 1983, J. Exp. Med. 157: 1947;
Zavala, F., et al., 1985, Science 228: 1436). In some embodiments, DNA sequences containing the repeat region, Region I, or Region II, can be isolated for use in the vaccine formulations of the present invention. For example, the peptide asn-ala-asn-pro, related to the P. falciparum CS repeat region, may be expressed by the recombinant bacteria of the invention. In some embodiments, the peptide asp-pro-ala-pro-pro-asn-ala-asn, representing the P. berghei CS protein repeat region, is expressed.
The Plasmodium CS peptides to be expressed, whether produced by recombinant DNA methods, chemical synthesis, or purification techniques, include but are not limited to all or part of the amino acid sequences of Plasmodium-speciiic antigens, including altered sequences in which functionally equivalent amino acid residues are substituted for residues within the sequence resulting in a silent change. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity which acts as a functional equivalent, resulting in a silent alteration. Substitutes for an amino
acid within the sequence may be selected from other members of the class to which the amino acid belongs.
The transformation of bacteria with the recombinant DNA molecules that incorporate the Plasmodium DNA enables generation of multiple copies of the Plasmodium sequence. A variety of vector systems may be utilized for expression within the bacterial host, including but not limited to plasmids such as pUC plasmids and derivatives, PBR322 plasmid and derivatives, bacteriophage such as lambda and its derivatives, and cosmids. Further details concerning the transformation and expression of recombinant DNA molecules that incorporate the Plasmodium DNA may be found in U.S. Patent No. 5,112,749, hereby incorporated in its entirety.
The malaria vaccine may be a RTS or S/AS01 malaria vaccine. The RTS vaccine is engineered using genes from the repeat and T-cell epitope in the pre-erythrocytic
circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite. In some embodiments, the malaria parasite comprises a viral envelope protein (e.g., a viral envelope protein of the hepatitis B virus (HBsAg)). In some embodiments, the malaria parasite comprises a chemical adjuvant (AS01) to increase the immune system response.
The vaccine may be a liposome-based vaccine. In some embodiments, the liposome may contain a malarial antigen (e.g., a malarial peptide disclosed herein). Liposomes and liposome-derived nanovesicles, such as archaeosomes and virosomes, have become important carrier systems in vaccine development. As used herein, a "malarial antigen" is an antigen that is capable of inducing an immune response against a malarial parasite in humans and/or in animals. Malarial antigens suitable for the compositions and methods disclosed herein may include (1) a natural antigen of a malarial parasite or a malarial parasite-infected cell or a portion of such conjugated to a carrier or, (2) a synthetic protein or peptide that has the entire amino acid sequence of a natural malarial antigen or a portion thereof conjugated to a carrier. Examples of malaria liposome based vaccine may be found in U.S. Patent No. 6,093,406, which is hereby incorporated in its entirety.
DOSING
The method may comprise administering about 10 μg to about 1 gram of hepcidin or mini-hepcidin to the subject, such as about 100 μg to about 100 mg, about 200 μg to about 50 mg, or about 500 μg to about 10 mg, about 500 μg to about 5 mg, or about 500 μg to about 2 mg of hepcidin or mini-hepcidin. The method may comprise administering about
100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 333 μg, about 400 μg, about 500 μg, about 600 μg, about 667 μg, about 700 μ , about 750 μg, about 800 μg, about 850 μ , about 900 μg, about 950 μ , about 1000 μg, about 1200 μg, about 1250 μ , about 1300 μg, about 1333 μ , about 1350 μg, about 1400 μg, about 1500 μ , about 1667 μg, about 1750 μg, about 1800 μ§, about 2000 μg, about 2200 μ§, about 2250 μg, about 2300 μg, about 2333 μ§, about 2350 μg, about 2400 μ§, about 2500 μg, about 2667 μg, about 2750 μ§, about 2800 μg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.7 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of hepcidin or mini-hepcidin.
Administering a composition disclosed herein to the subject comprises administering a bolus of the composition.
The method may comprise administering a composition disclosed herein to the subject at least once per month, such as at least once per week. The method may comprise administering the composition to the subject 1, 2, 3, 4, 5, 6, or 7 times per week. In preferred embodiments, the method comprises administering the composition to the subject 1, 2, or 3 times per week.
The method may comprise administering about 10 μg to about 1 gram of hepcidin or mini-hepcidin to the subject each time the composition is administered, such as about 100 μg to about 100 mg, about 200 μg to about 50 mg, about 500 μg to about 10 mg, about 500 μg to about 5 mg, or about 500 μg to about 2 mg of hepcidin or mini-hepcidin. The method may comprise administering about 100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 333 μg, about 400 μg, about 500 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 1200 μg, about 1250 μg, about 1300 μg, about 1333 μg, about 1350 μg, about 1400 μg, about 1500 μg, about 1667 μg, about 1750 μg, about 1800 μg, about 2000 μg, about 2200 μg, about 2250 μg, about 2300 μg, about 2333 μg, about 2350 μg, about 2400 μg, about 2500 μg, about 2667 μg, about 2750 μg, about 2800 μg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.7 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of hepcidin or mini-hepcidin to the subject each time the composition is administered.
In some embodiments, less than about 200 mg hepcidin or mini-hepcidin is administered to a human subject each time the composition is administered. In some embodiments, less than about 150 mg hepcidin or mini-hepcidin is administered to a human
subject each time the composition is administered, such as less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 70 mg, less than about 60 mg, or less than about 50 mg.
In some embodiments, less than 10 mg of hepcidin or mini-hepcidin is administered to a human subject each time the composition is administered, such as less than about 9 mg, less than about 8 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2 mg, or less than about 1 mg. In some embodiments, about 100 μg to about 10 mg of hepcidin or mini-hepcidin is
administered to a human subject each time the composition is administered, such as about 100 μg to about 9 mg, about 100 μg to about 8 mg, about 100 μg to about 7 mg, about 100 μg to about 6 mg, about 100 μg to about 5 mg, about 100 μg to about 4 mg, about 100 μg to about 3 mg, about 100 μg to about 2 mg, or about 100 μg to about 1 mg.
Malaria vaccine dosing may comprise any suitable dosing regimen and will depend, among other factors, the type of malaria vaccine being administered. A malaria vaccine may comprise a single dose or multiple doses. For example, the RTS vaccine disclosed herein may be given in four doses, with each dose about 25 to 50 μg of CPS protein. Malaria vaccines comprising malarial antigens may comprise at least 1, at least 2, at least 3, at least 4, or at least 5 malarial antigens. Malaria vaccines given in multiple doses may be given in doses of equal amounts or different amounts (e.g., doses may be escalating in concentration of active ingredient). The time period between malaria vaccine doses may be about one day to about one week, about one week to two weeks, about three weeks to about one month, about one month to six months, or about six months to one year. Time periods in between doses and concentrations of active ingredient will depend on a variety of features including but not limited to, the type of malaria vaccine, medical history of the patient, and the reaction of the patient to a previous malaria vaccine dose. For example, a patient may receive an initial dose of malaria vaccine, monitored for adverse effects, and, assuming no adverse effects, is administered at least one additional malaria vaccine dose. Malaria vaccines comprising sporozoites may be administered in single or multiple doses, and may comprise about l x lO3 sporozoites, about l x lO4 sporozoites, about l x lO5 sporozoites, about l x lO6 sporozoites, about l x lO7 sporozoites, about l x lO8 sporozoites, about l x lO9 sporozoites, or about 1 x 1010 sporozoites.
In some embodiments, the subject's parasitic load is measured prior to the vaccine administration, during vaccine administration and/or after vaccine administration. In some
embodiments, parasitic load is measured in peripheral blood. For example, to assess disease severity or malaria vaccine efficacy, parasitic load in peripheral blood may be measured. Parasitic load may be measured by obtaining a blood sample from an infected subject, and counting malaria parasites under a microscope. In some embodiments, the concentration of a Plasmodium secreted protein in the subject's peripheral blood may be used as a measure of disease severity and/or vaccine efficacy. The secreted protein may be Histidine-rich protein 2 (PfHRP2).
In some embodiments, a chemoprophylaxis (e.g., chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin) is also administered to the subject. The chemoprophylaxis may be administered to the subject and, after a period of time, the malaria vaccine is
administered. In some embodiments, the chemoprophylaxis is administered to the subject at about the same time as the malaria vaccine. In some embodiments, the malaria vaccine is administered to the subject and, after a period of time, the chemoprophylaxis is administered to the subject. The period of time may be at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 2 days, at least 3 days, at least 1 week, at least 2 weeks, or at least 1 month.
ROUTES OF ADMINISTRATION
Provided here are methods and compositions for treating or preventing malaria by administering to a subject (e.g., a subject in need thereof) a composition comprising hepcidin or mini-hepcidin and a malaria vaccine. In some embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in different compositions. In some embodiments, the hepcidin or mini-hepcidin and the malaria vaccine are in the same composition. The compositions and/or vaccines disclosed herein can be administered in a variety of conventional ways. In some aspects, the compositions and/or vaccines of the invention are suitable for parenteral administration. The compositions and/or vaccines disclosed herein may be administered subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, orally, enterally, sublingually, by buccal administration, topically, transdermally, intrarenally, intrathecally, or transmucosally. The composition and/or vaccine may be administered by injection. In certain embodiments, the composition and/or vaccine is administered by subcutaneous injection.
One of skill in the art would appreciate that a method of administering a therapeutically effective substance formulation or composition of the invention would depend on factors such as the age, weight, and physical condition of the patient being treated, and the disease or condition being treated. The skilled worker would, thus, be able to select a method of administration suitable for a patient on a case-by-case basis.
SUBJECTS
The subject may be a mammal. The subject may be a rodent, lagomorph, feline, canine, porcine, ovine, bovine, equine, or primate. In preferred embodiments, the subject is a human. The subject may be a female or male. The subject may be an infant, child, or adult. The subject may or may not have malaria, although is preferably a subject not already infected with malaria.
Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or
components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components). The singular forms "a," "an," and "the" include the plurals unless the context clearly dictates otherwise. The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably. The terms "patient" and "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines, equines), companion animals (e.g., canines, felines) and rodents (e.g., mice, rabbits and rats).
"About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typically, exemplary degrees of error are within 20%, preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" may mean values that are within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" or "approximately" can be inferred when not expressly stated.
As used herein, the term "administering" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical
professional and self-administering. Such an agent, for example, may be hepcidin or a hepcidin analogue.
As used herein, the phrase "pharmaceutically acceptable" refers to those agents, compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
As used herein, "polypeptide" and "peptide" may be used interchangeably. In some embodiments, the polypeptides can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, polypeptides are produced by recombinant DNA techniques. Alternatively, polypeptides can be chemically synthesized using standard peptide synthesis techniques. In some
embodiments, polypeptide is a chimeric or fusion polypeptide. A fusion or chimeric polypeptide can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, for example by employing blunt-ended or stagger- ended termini for ligation, restriction enzyme digestion to provide for appropriate termini,
filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.
Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons: 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety.
The polypeptides described herein can be produced in prokaryotic or eukaryotic host cells by expression of polynucleotides encoding a polypeptide(s). Alternatively, such peptides can be synthesized by chemical methods. Methods for expression of heterologous polypeptides in recombinant hosts, chemical synthesis of polypeptides, and in vitro translation are well known in the art and are described further in Maniatis et al., Molecular Cloning: A Laboratory Manual (1989), 2nd Ed., Cold Spring Harbor, N. Y.; Berger and Kimmel, Methods in Enzymology, Volume 152, Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, Calif ; Merrifield, J. (1969) J. Am. Chem. Soc. 91 :501; Chaiken I. M. (1981) CRC Crit. Rev. Biochem. 11 :255; Kaiser et al. (1989) Science 243 : 187; Merrifield, B. (1986) Science 232:342; Kent, S. B. H. (1988) Annu. Rev. Biochem. 57:957; and Offord, R. E. (1980) Semisynthetic Proteins, Wiley Publishing, which are incorporated herein by reference.
As used herein, a therapeutic that "prevents" a condition (e.g., malaria) refers to a compound that, when administered to a statistical sample prior to the onset of the disorder or condition, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
In certain embodiments, agents of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic agents (e.g., a composition comprising hepcidin or mini-hepcidin and a malaria vaccine) such that the second agent is administered while the previously administered therapeutic agent is still effective in the body {e.g., the two agents are simultaneously effective in the subject, which may include synergistic effects of the two agents). For example, the different
therapeutic agents can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. In certain embodiments, the different therapeutic agents can be administered within about one hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic agents.
In some embodiments, the agents of the invention are administered prior to exposure to malarial parasites, e.g., within about a month of exposure, within about two weeks of exposure, or preferably within one week of exposure to the malarial parasites. In certain embodiments, the agents of the invention are administered after infection or risk of infection (e.g., after being bitten by a mosquito, e.g., bitten by a mosquito bearing malarial parasites) before malarial symptoms appear, e.g. within about two weeks of infection, within one week of infection, within 3 days of infection, or more preferably within 1 day of infection by malarial parasites.
"Treating" a disease in a subject or "treating" a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.
As used herein, a "malaria vaccine" is a composition that promotes the development of an immune response against Plasmodium falciparum, e.g., by presenting an antigen that will stimulate a host's immune response against Plasmodium falciparum. The resulting protection against a malarial infection will either completely prevent infection or will reduce the severity or duration of infection. For purposes herein, a malaria vaccine may comprise a live, live attenuated, or an inactivated vaccine. A malaria vaccine may comprise, for example, malarial sporozoites (e.g., attenuated or infectious) or a malarial peptide (e.g., a malaria antigen) from human malaria parasites P. falciparum, P. vivax, P. ovale, P.
malariae, or animal malaria parasites P. berghei, P. yoelii, P. knowlesi, and P. cynomolgi. In some embodiments, the malaria vaccine induces an immune response against a malarial parasite in the subject. As used herein, amelioration of the symptoms of a malarial infection by administration of a particular composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
EXEMPLIFICATION
Example 1: Treating and/or Preventing Malaria with Hepcidin and a Malaria Vaccine
Patients at risk or infected with malaria are administered a composition comprising hepcidin and/or mini-hepcidin. Patients may also be administered an attenuated malaria vaccine or an inactivated malaria vaccine, either concurrently with the hepcidin and/or mini- hepcidin, or after a period of time while the hepcidin is still effective in inhibiting infection of the subject's liver by Plasmodium falciparum. The vaccine may be an attenuated malaria vaccine comprising PfSPZ. Preferably, the vaccine comprises a strain of Plasmodium falciparum that is sensitive to a pre-determined anti-malarial drug, so that if infection results, it can be readily treated with the drug (e.g., chloroquine). Thus, the method may also comprise administering to the patient an anti-malarial drug (e.g., chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate and artemisinin) if the patient subsequently develops a malarial infection.
The patient may be dosed with the vaccine and/or hepcidin or mini-hepcidin over several days and the method may comprise administering escalating doses of hepcidin or mini-hepcidin and/or a malaria vaccine. After the initial dose of hepcidin drug composition, a feature may be measured in the patient. The feature may be, for example, serum iron. The feature may also be, for example, malarial parasitic load. Adverse effects may also be measured in the patient.
INCORPORATION BY REFERENCE
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present specification, including its specific definitions, will control. While specific aspects of the patient matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to
the claims, along with their full scope of equivalents, and the specification, along with such variations.
Claims
1. A method for promoting the development of an immune response to Plasmodium falciparum in a subject, comprising conjointly administering a composition comprising hepcidin or mini-hepcidin and a malaria vaccine to the subject.
2. A method for inhibiting the development of erythrocytic (blood-stage) malaria in a subject, comprising conjointly administering a composition comprising hepcidin or mini- hepcidin and a malaria vaccine to the subject.
3. A method for inhibiting the infection of hepatocytes by Plasmodium falciparum in a subject, comprising conjointly administering a composition comprising hepcidin or mini- hepcidin and a malaria vaccine to the subject.
4. The method of any one of claims 1 to 3, wherein the malaria vaccine is a live vaccine.
5. The method of claim 4, wherein the malaria vaccine comprises infectious
Plasmodium falciparum.
6. The method of claim 5, wherein the Plasmodium falciparum is a strain sensitive to a pre-determined anti-malarial drug.
7. The method of claim 6, further comprising administering an anti-malarial drug to the subject if the subject develops malaria after administration of the malaria vaccine.
8. The method of claim 7, wherein the anti-malarial drug is the pre-determined antimalarial drug.
9. The method of claim 7 or 8, wherein the anti-malarial drug is chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate, or artemisinin.
10. The method of claim 9, wherein the anti-malarial drug is chloroquine.
11. The method of any one of claims 1 to 3, wherein the malaria vaccine is an attenuated vaccine.
12. The method of claim 11, wherein the attenuated vaccine is a chemoattenuated vaccine.
13. The method of claim 11, wherein the malaria vaccine is a radiation-attenuated vaccine.
14. The method of claim 11, 12, or 13, wherein the malaria vaccine comprises attenuated sporozoites.
15. The method of claim 10, wherein the attenuated sporozoites are Plasmodium falciparum sporozoites (PfSPZ).
16. The method of any one of claims 11 to 15, further comprising administering an antimalarial drug.
17. The method of claim 16, wherein the anti-malarial drug is chloroquine, tetracycline, proguanil, chlorproguanil, pyronaridine, lumefantrinel, mefloquine, dapsone, atovaquone, artesunate, or artemisinin.
18. The method of claim 17, wherein the anti-malarial drug is chloroquine.
19. The method of any one of claims 1 to 18 wherein the composition comprising hepcidin or mini-hepcidin and a malaria vaccine are administered in the same composition.
20. The method of any one of claims 1 to 18, wherein the composition comprising hepcidin or mini-hepcidin and a malaria vaccine are administered in different compositions.
21. The method of claim 20, wherein the composition comprising hepcidin or mini- hepcidin and the malaria vaccine are administered at the same time.
22. The method of claim 20, wherein the composition comprising hepcidin or mini- hepcidin and the malaria vaccine are administered sequentially.
23. A method of promoting the development of an immune response to Plasmodium falciparum in a subject, comprising conjointly administering to the subject a composition comprising hepcidin or mini-hepcidin and a malaria vaccine comprising attenuated Plasmodium falciparum sporozoites (PfSPZ).
24. A method for inhibiting the development of erythrocytic (blood-stage) malaria in a subject, comprising conjointly administering to the subject a composition comprising hepcidin or mini-hepcidin and a malaria vaccine comprising attenuated Plasmodium falciparum sporozoites (PfSPZ).
25. A method for inhibiting erythrocytic (blood-stage) malaria in a subject at risk of being infected by Plasmodium falciparum, comprising conjointly administering to the subject a composition comprising hepcidin or mini-hepcidin and a malaria vaccine comprising attenuated Plasmodium falciparum sporozoites (PfSPZ).
26. A method for inhibiting the infection of hepatocytes by Plasmodium falciparum, comprising conjointly administering to the subject a composition comprising hepcidin or mini-hepcidin and a malaria vaccine comprising attenuated Plasmodium falciparum sporozoites (PfSPZ).
27. The method of any one of claims 23 to 26, further comprising administering to the subject an anti-malarial drug with PfSPZ.
28. The method of any one of claims 23 to 26, wherein the malaria vaccine comprises radiation-attenuated PfSPZ.
29. The method of any one of claims 23 to 28, wherein the composition comprising hepcidin or mini-hepcidin and the malaria vaccine are administered at the same time.
30. The method of any one of claims 23 to 28, wherein the composition comprising hepcidin or mini-hepcidin and the malaria vaccine are administered sequentially.
31. The method of any one of claims 1 to 30, wherein administering the composition to the subject comprises administering about 10 μg to about 1 gram of hepcidin or mini- hepcidin.
32. The method of claim 31, wherein administering the composition to the subject comprises administering about 100 μg to about 100 mg of hepcidin or mini-hepcidin.
33. The method of claim 32, wherein administering the composition to the subject comprises administering about 200 μg to about 50 mg of hepcidin or mini-hepcidin.
34. The method of claim 33, wherein administering the composition to the subject comprises administering about 500 μg to about 10 mg of hepcidin or mini-hepcidin.
35. The method of claim 34, wherein administering the composition comprising hepcidin or mini-hepcidin to the subject comprises administering about 500 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 1200 μg, about 1250 μg, about 1300 μg, about 1333 μg, about 1350 μg, about 1400 μg, about 1500 μg, about 1667 μg, about 1750 μg, about 1800 μg, about 2000 μg, about 2200 μg, about 2250 μg, about 2300 μg, about 2333 μg, about 2350 μg, about 2400 μg, about 2500 μg, about 2667 μg, about 2750 μg, about 2800 μg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.7 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of hepcidin or mini-hepcidin.
36. The method of any one of the preceding claims, wherein administering the composition to the subject comprises administering a bolus of the composition.
37. The method of any one of the preceding claims, wherein administering the composition comprises administering the composition at least once per month.
38. The method of claim 37, wherein administering the composition comprises administering the composition at least once per week.
39. The method of claim 38, wherein administering the composition comprises administering the composition 1, 2, 3, 4, 5, 6, or 7 times per week.
40. The method of claim 39, wherein administering the composition comprises administering the composition 1, 2, or 3 times per week.
41. The method of any one of claims 37 to 40, wherein about 10 μg to about 1 gram of hepcidin or mini-hepcidin is administered each time the composition is administered.
42. The method of claim 41, wherein about 100 μg to about 100 mg of hepcidin or mini- hepcidin is administered each time the composition is administered.
43. The method of claim 42, wherein about 200 μg to about 50 mg of hepcidin or mini- hepcidin is administered each time the composition is administered.
44. The method of claim 43, wherein about 500 μg to about 10 mg of hepcidin or mini- hepcidin is administered each time the composition is administered.
45. The method of claim 44, wherein about 500 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 1200 μg, about 1250 μg, about 1300 μg, about 1333 μg, about 1350 μg, about 1400 μg, about 1500 μg, about 1667 μg, about 1750 μg, about 1800 μg, about 2000 μg, about 2200 μg, about 2250 μg, about 2300 μg, about 2333 μg, about 2350 μg, about 2400 μg, about 2500 μg, about 2667 μg, about 2750 μg, about 2800 μg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.7 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of hepcidin or mini-hepcidin is administered each time the composition is administered.
46. The method of any one of claims 1 to 45, wherein the composition is administered subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, orally, sublingually, by buccal administration, topically, transdermally, or transmucosally.
47. The method of any one of claims 1 to 46, wherein the composition is administered by injection.
48. The method of claim 47, wherein the composition is administered intravenously.
49. The method of any one of claims 1 to 48, wherein the composition comprises hepcidin and the hepcidin comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
50. The method of any one of claims 1 to 48, wherein the composition comprises hepcidin and the hepcidin comprises an amino acid sequence having at least 90% sequence homology with the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
51. The method of claim 50, wherein the hepcidin comprises each of the 8 cysteines in SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
52. The method of claim 50 or 51, wherein the 8 cysteines in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 form 4 disulfide bonds in the hepcidin.
53. The method of any one of claims 49 to 51, wherein the hepcidin comprises the amino acid sequence set forth in SEQ ID NO: 1.
54. The method of any one of claims 1 to 48, wherein the composition comprises hepcidin and the hepcidin comprises the sequence set forth in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10.
55. The method of claim 54, wherein the 8 cysteines of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10 form 4 disulfide bonds in the hepcidin.
56. The method of any one of claims 1 to 48, wherein the composition comprises a mini- hepcidin.
57. A composition comprising a hepcidin or mini-hepcidin and a malaria vaccine.
58. The composition of claim 57, wherein the malaria vaccine is a live vaccine.
59. The composition of claim 57 or 58, wherein the malaria vaccine comprises infectious Plasmodium falciparum.
60. The composition of claim 59, wherein the Plasmodium falciparum is a strain sensitive to a pre-determined anti-malarial drug.
61. The composition of claim 57, wherein the malaria vaccine is an attenuated vaccine.
62. The composition of claim 61, wherein the malaria vaccine is a radiation-attenuated vaccine.
63. The composition of claim 61, wherein the attenuated vaccine is a chemoattenuated vaccine.
64. The composition of any one of claims 61 to 63, wherein the malaria vaccine comprises attenuated sporozoites.
65. The composition of claim 64, wherein the attenuated sporozites are Plasmodium falciparum sporozoites (PfSPZ).
66. The composition of any one of claims 57 to 65, wherein the composition further comprises an anti-malarial drug.
67. The composition of claim 66, wherein the anti-malarial drug is chloroquine, tetracycline, proguanil, chlorproguanil, pyronandine, lumefantnnel, mefloquine, dapsone, atovaquone, artesunate, or artemisinin.
68. The composition of claim 67, wherein the anti-malarial drug is chloroquine.
69. The method of claim 62, wherein the malaria vaccine comprises radiation attenuated PfSPZ.
70. The composition of any one of claims 57 to 69, wherein the composition comprises about 10 μg to about 1 gram of hepcidin or mini-hepcidin.
71. The composition of claim 70, wherein the composition comprises about 100 μg to about 100 mg of hepcidin or mini-hepcidin.
72. The composition of claim 71, wherein the composition comprises about 200 μg to about 50 mg of hepcidin or mini-hepcidin.
73. The composition of claim 72, wherein the composition comprises about 500 μg to about 10 mg of hepcidin or mini-hepcidin.
74. The composition of claim 73, wherein the composition comprises about 500 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1000 μg, about 1200 μg, about 1250 μg, about 1300 μg, about 1333 μg, about 1350 μg, about 1400 μg, about 1500 μg, about 1667 μg, about 1750 μg, about 1800 μg, about 2000 μg, about 2200 μg, about 2250 μg, about 2300 μg, about 2333 μg, about 2350 μg, about 2400 μg, about 2500 μg, about 2667 μg, about 2750 μg, about 2800 μg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.7 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of hepcidin or mini- hepcidin.
75. The composition of any one of claims 57 to 74, wherein the composition comprises hepcidin and the hepcidin comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
76. The composition of any one of claims 57 to 74, wherein the composition comprises hepcidin and the hepcidin comprises an amino acid sequence having at least 90% sequence homology with the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
77. The composition of claim 76, wherein the hepcidin comprises each of the 8 cysteines in SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
78. The composition of claim 76 or 77, wherein the 8 cysteines in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5 form 4 disulfide bonds in the hepcidin.
79. The composition of any one of claims 75 to 78, wherein the hepcidin comprises the amino acid sequence set forth in SEQ ID NO: 1.
80. The composition of any one of claims 57 to 74, wherein the composition comprises hepcidin and the hepcidin comprises the sequence set forth in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10.
81. The composition of claim 80, wherein the 8 cysteines of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10 form 4 disulfide bonds in the hepcidin.
82. The composition of any one of claims 57 to 81, wherein the composition comprises a mini-hepcidin.
83. A method for prophylactic treatment of a subject at risk of infection by malarial parasites, comprising administering to the subject a composition comprising hepcidin or
mini-hepcidin, wherein the composition is administered prior to exposure to the malarial parasites.
84. The method of claim 83, wherein the composition is administered prior to exposure to mosquitoes bearing malarial parasites.
85. A method for treatment of a subject exposed or possibly exposed to malarial parasites, comprising administering to the subject a composition comprising hepcidin or mini-hepcidin, wherein the composition is administered after exposure (e.g., within two weeks of exposure, within one week of exposure, within four days of exposure, within three days of exposure, within two days of exposure, or within one day of exposure) to the malarial parasites.
86. The method of claim 83, wherein the composition is administered after exposure (e.g., within two weeks of exposure, within one week of exposure, within four days of exposure, within three days of exposure, within two days of exposure, or within one day of exposure) to mosquitoes bearing malarial parasites.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US201762474894P | 2017-03-22 | 2017-03-22 | |
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---|---|---|---|---|
EP4288055A4 (en) * | 2021-02-05 | 2024-12-18 | Merck Sharp & Dohme LLC | <SMALLCAPS/>?LASMODIUM ?CHEMOVACCINES AGAINST INFECTION WITH SELECTIVE PLASMEPSIN-X INHIBITORS |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010065815A2 (en) * | 2008-12-05 | 2010-06-10 | The Regents Of The University Of California | Mini-hepcidin peptides and methods of using thereof |
WO2010083111A1 (en) * | 2009-01-16 | 2010-07-22 | Sanaria Inc. | Purified plasmodium and vaccine compositions |
WO2015157283A1 (en) * | 2014-04-07 | 2015-10-15 | Merganser Biotech Llc | Hepdicin mimetic peptides and uses thereof |
WO2017120419A1 (en) * | 2016-01-08 | 2017-07-13 | La Jolla Pharmaceutial Company | Methods of administering hepcidin |
WO2018048944A1 (en) * | 2016-09-06 | 2018-03-15 | La Jolla Pharmceutical Company | Methods of treating iron overload |
-
2018
- 2018-03-21 WO PCT/US2018/023628 patent/WO2018175633A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010065815A2 (en) * | 2008-12-05 | 2010-06-10 | The Regents Of The University Of California | Mini-hepcidin peptides and methods of using thereof |
WO2010083111A1 (en) * | 2009-01-16 | 2010-07-22 | Sanaria Inc. | Purified plasmodium and vaccine compositions |
WO2015157283A1 (en) * | 2014-04-07 | 2015-10-15 | Merganser Biotech Llc | Hepdicin mimetic peptides and uses thereof |
WO2017120419A1 (en) * | 2016-01-08 | 2017-07-13 | La Jolla Pharmaceutial Company | Methods of administering hepcidin |
WO2018048944A1 (en) * | 2016-09-06 | 2018-03-15 | La Jolla Pharmceutical Company | Methods of treating iron overload |
Non-Patent Citations (4)
Title |
---|
PORTUGAL , S. ET AL.: "Host-mediated regulation of superinfection in malaria", NATURE MEDICINE, vol. 17, no. 6, 15 May 2011 (2011-05-15), pages 732 - 737, XP055544040, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200394/pdf/nihms330622.pdf> [retrieved on 20180517] * |
PRENTICE, ANDREW M. ET AL.: "Iron and malaria interactions: research needs from basic science to global policy", ADVANCES IN NUTRITION, vol. 3.4, 6 July 2012 (2012-07-06), pages 583 - 591, XP055544038, Retrieved from the Internet <URL:https://academic.oup.com/advances/article/3/4/583/4591520><doi:10.3945/an.111.001230> [retrieved on 20180517] * |
WANG, HAI-ZHEN ET AL.: "Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection", JOURNAL OF IMMUNOLOGY, 14 November 2011 (2011-11-14), pages 6410 - 6416, XP055494691, Retrieved from the Internet <URL:https://pdfs.semanticscholar.org/1362/3fb3771277e05fb649155cfcab4af6fdlc81.pdf> [retrieved on 20180517] * |
YA-QUN, F. A. N. G. ET AL.: "In vivo antimalarial activity of synthetic hepcidin against Plasmodium berghei in mice", CHINESE JOURNAL OF NATURAL MEDICINES, vol. 15.3, 20 March 2017 (2017-03-20), pages 161 - 167, XP029978743, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S1875536417300328> [retrieved on 20180521] * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4288055A4 (en) * | 2021-02-05 | 2024-12-18 | Merck Sharp & Dohme LLC | <SMALLCAPS/>?LASMODIUM ?CHEMOVACCINES AGAINST INFECTION WITH SELECTIVE PLASMEPSIN-X INHIBITORS |
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