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WO2016207782A1 - Oligopeptides synthétiques immunogènes pour un vaccin contre le vih - Google Patents

Oligopeptides synthétiques immunogènes pour un vaccin contre le vih Download PDF

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Publication number
WO2016207782A1
WO2016207782A1 PCT/IB2016/053669 IB2016053669W WO2016207782A1 WO 2016207782 A1 WO2016207782 A1 WO 2016207782A1 IB 2016053669 W IB2016053669 W IB 2016053669W WO 2016207782 A1 WO2016207782 A1 WO 2016207782A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
olpen
pentapeptides
antigen
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2016/053669
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English (en)
Inventor
Jean-Pierre Spinosa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Strelnikov Evgeny
Original Assignee
Strelnikov Evgeny
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Strelnikov Evgeny filed Critical Strelnikov Evgeny
Publication of WO2016207782A1 publication Critical patent/WO2016207782A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • A61K2039/645—Dendrimers; Multiple antigen peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to immunogenic synthetic oligopeptides that are useful for evoking specific and effective immune responses in immunotherapies and immunodiagnostics. It more precisely relates to such oligopeptides for a vaccine against HIV.
  • hydrophobicity hydrophilicity the protrusion index, flexibility, and secondary structure and conformational parameters.
  • the present invention covers a method for constructing immunogenic synthetic oligopeptides, in particular antigen epitopes, to be used in a vaccine against HIV.
  • the invention also concerns all pharmaceutical preparation, in particular a vaccine, which comprises an antigen obtained according to said method.
  • the invention more precisely relates to a method and to products as defined in the claims.
  • the invention applies the concept that peptide uniqueness dictates the self-nonself discrimination, so that only peptide sequences not present in the host may be immunogenic toward the host, and provides a method for constructing immunogenic synthetic oligopeptides that are formed by minimal pentapeptide immune determinants unique to the antigen (or to multiple antigens) of interest and not present in the host proteome.
  • minimal immune determinants refers to pentapeptides.
  • An oligopeptide according to the invention may contain up to n amino acids (with n>5).
  • the method comprise three steps:
  • each linker contains at least one element that is not a human aminoacid.
  • linker Any suitable linker can be used. It may for instance contain one or several of the following elements: amino-3-oxapentanoic acid, PEG1 , PEG2, PEG4, beta amino acid, gamma amino acid, aminohexanoic acid, amino-3,6-dioxaoctanoic acid.
  • linker in the present document has to be indifferently
  • oligopeptide constructs formed by minimal determinants uniquely owned by the antigen of interest, hereafter referred to as "unique oligopeptide constructs", provides the possibility for developing immunogenic, specific and safe immunotherapies and immunodiagnostic tools.
  • oligopeptide constructs are effective immunogens, while cancer entire antigens and entire antigens from infectious agents, are poorly immunogens and need adjuvants to evoke an immune response.
  • Combination(s) of unique oligopeptide constructs offer the concrete possibility of protecting and/or vaccinating against multiple diseases, as for example, against a primary tumor antigen and metastasis associated-antigen(s), against multiple strains of an infectious pathogen, against multiple pathogens, and so forth.
  • the linkers improve aqueous solubility, when applicable, are immunogenically neutral and well tolerated by the organism.
  • Linkers can be of various type, length and composition.
  • Linkers are compatible with general peptide chemistry protocols and reagents such that they can be readily inserted
  • Linkers of any type can be cumulated and can but do not need to be separated by non human amino acids.
  • several types of polymerization processes can be considered such as lactam bridge formation, metathesis, click-chemistry or chemiselective chemistry such as oximes.
  • An advantageous polymerization method involves Cys residues for the preparation of oligopeptides with a mass of 80-100 KDa starting for peptides with a mass of 2,5-4 KDa.
  • Immunogenic pentameric sequences have the possibility but do not need to contain Cys one or more residue, if this is the case one will observe limitation in their immunogenicity due to implication in the polymerization process.
  • Cys residues from the so called active region immunogenic residues belonging to the pentamers
  • orthogonally protected Cys residues in a tandemeric format such as Cys(Trt)/Cys(Acm), Cys(tBu)/Cys(MeBzl), Cys(STmp)/Cys(Mmt), other combinations and other Cys protected residues are not excluded (refer to colored C residues in scheme above).
  • the present invention considerably increases the efficiency of the vaccinating against deadly tumors and threatening infections, even contemporaneously.
  • the method produces unique oligopeptide constructs that may lead to: More efficacious immunotherapies against tumoral diseases,
  • the example uses a hypothetical amino acid sequence X as antigen of interest, and applies the peptide uniqueness principle to identify minimal pentapeptide determinants unique to the antigen of interest and not represented in the human proteome using the above mentioned 3 steps, namely:
  • pentapeptides exclusively present in the antigen of interest X but absent in human proteins are selected.
  • the selected pentapeptides are listed in Table 1 :
  • AHDTC (SEQ ID NO 7); AHEHD (SEQ ID NO 8); AHFDT (SEQ ID NO 9); AHPMM (SEQ ID NO 10); AIEHD (SEQ ID NO 11); AMDHD (SEQ ID NO 12); AMEHD (SEQ ID NO 13); ANEHD (SEQ ID NO 14); APFHD (SEQ ID NO 15); AQFHD (SEQ ID NO 16) CAEHD (SEQ ID NO 17); CAEIC (SEQ ID NO 18); CAHDT (SEQ ID NO 19); CCAFD (SEQ ID NO 20); CCCNI (SEQ ID NO 21); CCDHD (SEQ ID NO 22); CCEDT (SEQ ID NO 23); CEDTC (SEQ ID NO 24) CGFHD (SEQ ID NO 25); CHDPW (SEQ ID NO 26); CMECN (SEQ ID NO 27); CNICC (SEQ ID NO 28); CNIME (SEQ ID NO 29); DAM EH (SEQ ID NO 30); DCNDE (SEQ ID NO 31); DFWF
  • At least one linker is positioned between two adjacent pentapeptides.
  • the linker must contain an element which is not a human amino acid in order to avoid the fortuitous creation (in the area between two "non human” pentapeptides) of a pentapeptide present in human proteins.
  • the linker preferably contains at least one of the following elements : amino-3-oxapentanoic acid, PEG1 , PEG2, PEG4, beta amino acid, gamma amino acid, aminohexanoic acid, amino-3,6-dioxaoctanoic acid.
  • FDTCAHDTCCCNI (SEQ ID NO 117) is a 13-mer peptide formed by 9 consecutively overlapping pentapeptides, all of which are absent in the human proteome.
  • the 13-mer-peptide can be elongated by joining with other unique pentapeptides such as ECNIM (SEQ ID NO 118), thus generating the 18 amino acid long FDTCAHDTCCCNI-ECNIM (SEQ ID NO 119).
  • ECNIM SEQ ID NO 118
  • ECNIM SEQ ID NO 118
  • the junction point (l-E) does not alter the foreignness of the 18-mer to the human proteome.
  • the new generated pentapeptides i.e., CCNIE (SEQ ID NO 120), CNIEC (SEQ ID NO 121), NIECN (SEQ ID NO 122), IECNI (SEQ ID NO 123)
  • CCNIE SEQ ID NO 120
  • CNIEC SEQ ID NO 121
  • NIECN SEQ ID NO 122
  • IECNI SEQ ID NO 123
  • cysteine residues in the oligopeptide FDTCAHDTCCCNI-ECNIM SEQ ID NO 124 sequence provides the possibility of S-S bridges among multiple FDTCAHDTCCCNI-ECNIM (SEQ ID NO 124) units.
  • HDDHD (SEQ ID NO 126), because of biological necessities such as polymorphisms, MHC restriction, tendency of specific sequences to mutate, need of immunologically hitting a specific biologic function, and so forth. This generates the 18 amino acid long oligopeptide FDTCAHDTCCCNI-HDDHD (SEQ ID NO 127), the junction point of which (l-H) alters the foreignness of the
  • CCNIH SEQ ID NO 128)
  • CNIHD SEQ ID NO 129
  • NIHDD SEQ ID NO 130
  • IHDDH SEQ ID NO 131
  • one (NIHDD (SEQ ID NO 130)) is present in the human T-cell receptor-associated transmembrane adapter 1 protein. Hitting this human protein signifies to hit the T-cell defensive function.
  • one or more linkers/spacers are inserted at the juncture point, with these linkers/spacers chosen based on the ability to generate pentapeptide extraneous to the human proteome.
  • FDTCAHDTCCCNI-HDDHD SEQ ID NO 127
  • a PEG4 is inserted in the middle of junction point to give FDTCAHDTCCCNI-PEG4-HDDHD (SEQ ID NO 127)
  • the PEG4 insertion does not generate pentapeptides present in the human proteome.
  • the invention is not limited to the oligopeptide(s) defined in this example above. Any sequence constructed on the basis of the above exposed principles (from a to i) is included.
  • the resulting formulae may therefore be used for a vaccine against HIV : KPCVK -OlPen-C-OlPen- KPCVK -OlPen-C-OlPen- KPCVK -OlPen-C-OlPen- KPCVK -OlPen-C-OlPen- KPCVK -OlPen-C-OlPen- KPCVK (SEQ ID NO 133)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé de production d'oligopeptides synthétiques immunogènes pour un vaccin contre le VIH. Les oligopeptides sont formés par des déterminants d'immunité minimaux exclusivement présents dans des antigènes d'intérêt et qui sont utiles pour susciter des réponses immunitaires spécifiques, efficaces et ne provoquant pas de réaction croisée dans des immunothérapies et des immunodiagnostics. Les déterminants sont connectés les uns aux autres par des lieurs, chaque lieur contenant au moins un élément qui n'est pas un acide aminé humain. L'invention concerne également une préparation pharmaceutique, telle qu'un vaccin, qui comprend lesdits oligopeptides synthétiques immunogènes.
PCT/IB2016/053669 2015-06-22 2016-06-21 Oligopeptides synthétiques immunogènes pour un vaccin contre le vih Ceased WO2016207782A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IB2015054664 2015-06-22
IBPCT/IB2015/054664 2015-06-22

Publications (1)

Publication Number Publication Date
WO2016207782A1 true WO2016207782A1 (fr) 2016-12-29

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998036087A1 (fr) * 1997-02-13 1998-08-20 American National Red Cross Tolerance immunologique aux epitopes du hiv
US20070111261A1 (en) * 2001-11-23 2007-05-17 Applied Immune Technologies, Inc. Antigens
WO2009109428A2 (fr) * 2008-02-01 2009-09-11 Alpha-O Peptides Ag Nanoparticules peptidiques à auto-assemblage utiles comme vaccins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998036087A1 (fr) * 1997-02-13 1998-08-20 American National Red Cross Tolerance immunologique aux epitopes du hiv
US20070111261A1 (en) * 2001-11-23 2007-05-17 Applied Immune Technologies, Inc. Antigens
WO2009109428A2 (fr) * 2008-02-01 2009-09-11 Alpha-O Peptides Ag Nanoparticules peptidiques à auto-assemblage utiles comme vaccins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUGLIELMO LUCCHESE ET AL: "Searching for an effective, safe and universal anti-HIV vaccine: Finding the answer in just one short peptide", SELF NONSELF - IMMUNE RECOGNITION AND SIGNALING, vol. 2, no. 1, 1 January 2011 (2011-01-01), US, pages 49 - 54, XP055308478, ISSN: 1938-2030, DOI: 10.4161/self.2.1.14762 *
KANDUC D: "'Self-nonself' peptides in the design of vaccines", CURRENT PHARMACEUTICAL DESIGN, BENTHAM SCIENCE PUBLISHERS, NL, vol. 15, no. 28, 1 January 2009 (2009-01-01), pages 3283 - 3289, XP009183183, ISSN: 1381-6128 *

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