EP0371046A1 - Peptides synthetiques apparentes a des proteines hiv-env - Google Patents

Peptides synthetiques apparentes a des proteines hiv-env

Info

Publication number
EP0371046A1
EP0371046A1 EP88905917A EP88905917A EP0371046A1 EP 0371046 A1 EP0371046 A1 EP 0371046A1 EP 88905917 A EP88905917 A EP 88905917A EP 88905917 A EP88905917 A EP 88905917A EP 0371046 A1 EP0371046 A1 EP 0371046A1
Authority
EP
European Patent Office
Prior art keywords
replaced
residues
residue
optionally
polypeptide
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.)
Pending
Application number
EP88905917A
Other languages
German (de)
English (en)
Inventor
Robert V. Fishleigh
Barry Robson
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.)
Protherics Medicines Development Ltd
Original Assignee
Proteus Molecular Design Ltd
Proteus Biotechnology Ltd
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 Proteus Molecular Design Ltd, Proteus Biotechnology Ltd filed Critical Proteus Molecular Design Ltd
Publication of EP0371046A1 publication Critical patent/EP0371046A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing 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
    • 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
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to novel polypeptides. It particularly relates to polypeptides with a three-dimensional structure analogous to the three- dimensional structure of specific sites on the exterior surface of viral envelope proteins. It is of particular interest to the design of vaccines, diagnostics and other medical or scientific agents in relation to the Human Immunodeficiency Virus (HIV) as the causative agent of Acquired Immune Deficiency Syndrome (AIDS) .
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immune Deficiency Syndrome
  • Any one epitopic site may comprise a continuous peptide sequence or may comprise a discontinuous
  • the predicted sequences may be variants of specific sections of the protein sequence or, particularly where they represent a discontinuous determinant, they need not bear a direct resemblance at a primary structural level.
  • the predicted amino acid sequences may be variants of specific sections of the protein sequence or, particularly where they represent a discontinuous determinant, they need not bear a direct resemblance at a primary structural level.
  • amino acid sequences are invariably much shorter than the amino acid sequences of the complete proteins and such polypeptides can be easily synthesised to provide a simple and effective route, using methods already well known in the
  • HIV virus responsible for Acquired Immune Deficiency Syndrome is presently of great medical importance throughout the world and there is an urgent need for agents suitable for the scient- ifi ⁇ study, diagnosis, treatment and/or prevention of infection by the HIV virus.
  • the amino acid sequences of the envelope protein of the HIV I and II viruses are now known (see, for example, Ratner, L. et al. , Nature 313, 277 (1985); Meusing, M.A. et al. , Nature _313_, 450 (1985); Wain-Hobson, S. et al.
  • one aspect of our invention provides a synthetic polypeptide having at least one antigenic property of the envelope protein of at least one strain of Human Immunodeficiency Virus (HIV) .
  • Another aspect of our invention provides a vaccine comprising at least one synthetic antigenic polypeptide effective to promote immunity against at least one strain of HIV.
  • a knowledge of the predicted secondary structure of the protein in question is of benefit in the design of peptide analogues of the continuous antigenic determinants, while a model for the three-dimensional structure of the protein is a prerequisite for the rational design of peptides corresponding to the non-continuous determinants.
  • Some of the predicted polypeptides- are rather short and correspond to predicted continuous antigenic determinants, and are likely to be most effective at raising neutralising antibody when linked to a suitable protein carrier molecule, although they may be effective on their own.
  • Other peptides are rather larger and represent polypeptides designed to be structurally reminiscent of the three-dimensional conformation adopted by - 4 - the equivalent portion of the native protein.
  • non-continuous antigenic determin ⁇ ants present in the native protein.
  • Such non-continuous 5 epitopes are generally thought to comprise around two-thirds of all the antigenic determinants presented by proteins, and so peptide analogues of such predicted sites are likely to have a higher chance of success ⁇ fully raising neutralising antibodies.
  • polypeptides detailed here are very much shorter than the proteins of which they are a part, and in many cases some modification of the basic peptide may be required before it is fit for immunological usage.
  • a suitably antigenic analogue of the protein since not only the relevant region of the amino acid sequence must be selected but also the correct length of peptide chain and its subsequent coupling to a carrier molecule are of vital importance. Only by our complex analyses of the protein sequence, which include secondary and tertiary structure modelling together with considerations of conserved regions of homology and variability between strains and of the sites of most frequent glycosylation, is it possible to design peptide analogues which preserve those features which our analyses have shown to be significant in determining the overall structure and specific surface characteristics of the native protein.
  • amino acid residues defined as follows: G-Glycine, A-Alanine, V-Valine, L-Leucine, I-Isoleucine, S-Serine, T-Threonine, D-Aspartic acid, E-Glutamic acid, N-Asparagine, Q-Glutamine, K- ysine, H-Histidine, R-Arginine, F-Phenylalanine, Y-Tyrosine, W-Tryptophan, C-Cysteine, M-Methionine and P-Proline.
  • the preferred polypeptide sequences were those chosen on the basis of their topographical similarity to at least one other antigenic determinant of the HIV envelope proteins.
  • the antigenic properties of such peptides have been shown to raise antibodies which will interact with more than one antigenic site and hence are more likely to lead to an effective agent and/or vaccine against HIV.
  • the peptides most favoured on this basis were synthesised using either standard 9-fluorenyl- methoxycarbonyl (F-Moc) chemistry (see Kafiffaludy, L. & Schon, I., Synthesis 325 (1973); Atherton, E. & Shepphard, " R.C. , J.C.S. Chem. Com. 165 (1985)) or standard butyloxycarbonate (T-Boc) chemistry. The correctness of the structure and the level of purity was carefully checked, and particular attention was given to the correctness of internal
  • KPCVKLTPLCV were selected because analysis revealed that these resemble a number of other sequence sites in the HIV envelope protein which were promising epitopes on the basis of our computa ⁇ tional analysis. It was found that the envelope proteins can be partitioned into some five or six long segments with weak sequence homology, suggesting duplication of ancestral genes. However, detection of such similarity requires the application of the computer methods developed by us since it is by no means obvious to the eye. Thus, for example, the reader may note the alignment of the first of these two peptides (a) with a sequence of a HIV-1 transmembrane segment (c) and a further sequence (d) defining another predicted antigenic determinant of HIV:
  • the dashes indicate insertions introduced into the alignment in order to optimise sequence homology.
  • the invention further provides the amino acid sequence:
  • sequence (e) YYGVPVWKEATTT FCASDQSLKPCVKLTPLCV.
  • the C-terminal of sequence (a) is linked via a connector peptide to the N-terminal of sequence (b) .
  • the first two cysteine residues are linked to each other via an intramolecular disulphide bridge.
  • the C-terminal dipeptide, CV is not essential and need only be present, for example, if the sequence is to be linked through the cysteine side-chain to another molecule which may serve as a carrier.
  • the invention further provides the amino acid sequence: (e') YYGVPVWKEATTTLFCASDQSLKPCVKLTPL optionally containing an intramolecular disulphide bridge.
  • the peptide (e') was synthesised using T- Boc chemistry and the intramolecular disulphide bridge specifically formed between the two C residues. This peptide was used in an unconjugated form to raise antibodies in laboratory rabbits in conventional manner. The peptide stimulated a very strong antibody response in rabbits. Interaction was also observed between the antibodies raised and HIV protein and between HIV-positive sera and the .synthetic peptide. This peptide is seen as a highly valuable tool for research studies where an agent which recognises a number of different HIV strains rather than one specific strain is highly desirable. However, the topography of the above peptide may be modified to provide particularly preferred variants of peptide (e) or (e') . These include
  • EET peptides wherein one or more C residues are each independently replaced by S residues and/or the DQ peptide is replaced by DGGGDQ or by another related sequence containing a greater or lesser number of G residues between the two D residues.
  • the following points were also considered in the production of preferred sequences: (i) the loop stereochemistry implied by the choice of particular residues for disulphide bonding; (ii) the solubility of the peptide (peptide (e 1 ) is only poorly soluble in aqueous solution) ; (iii) the immunogenicity in the absence of a carrier; and (iv) the ability to interact strongly with HIV- positive sera and to raise anti-HIV antibody.
  • VWK may optionally be replaced by VWGXK, wherein X represents any small hydrophobic residue such as V, L, A or I, preferably A.
  • X represents any small hydrophobic residue such as V, L, A or I, preferably A.
  • the interaction with HIV-positive sera may be further enhanced by replacing the segment KLTCP by KLXCSSXXP, wherein the X residues may each independ ⁇ ently represent any small hydrophobic residues such as V, L, A or I, preferably A, and one or more
  • EET of the S residues may each independently be replaced by T residues.
  • the region around the other C participating in the disulphide bond is preferably changed from KPCV to LGXWGCSG wherein X and S residues may each independently be replaced in the manner described above.
  • the following peptides are predicted to corres ⁇ pond to some of the continuous epitopic sites of the external and transmembrane glycoproteins of HIV and represent very specifically defined lengths and sequences of the native polypeptides:
  • polypeptide IKQIINAW wherein the A is optionally replaced by any residue and one or more I residues may each independently be replaced by F, said polypeptide being optionally preceded by PCR, PCH or PCK or chemically similar sequences, particularly those wherein the C residue is substituted as, for example, in PAR;
  • polypeptide FLGFLAAAGSAMGAASMT wherein the first two A's, the fourth A, and the second M are each optionally replaced by any residue, and in particular wherein the first two A's may each independently be replaced by G or T, the fourth A by T and/or the second M by L or A; - lO - Cl)
  • the polypeptide QARQLLSGIVQQQNNLL which may optionally be preceded by H or a small hydrophobic residue and wherein the first A, the first S, and the second Q may each independently be replaced by any residue, and in particular by S, A, and/or T respectively, and the N residues may each independently be replaced by Q residues;
  • any antigenically significant sub-fragment of the above-identified polypeptide sequences and any variations thereof which maintain the general form and function of the polypeptides, are included within the scope of this invention.
  • substitution of any of the specific residues by residues having comparable physical' properties are collected in the following groups: Group 1 - A, V, L, I, F, Y, W and M; Group 2 - S, T, N and Q; Group 3 - D and E; Group 4 - K, H and R; Group 5 - N and D; Group 6 - E and Q; and Group 7 - G, A, P, S and T, are included.
  • polypeptides are optionally linked to additional amino acids e.g. cysteine residues or to a conventional vaccine carrier, either at their C- or N-terminus or through residue sidechains, to render them optimal for their immunological function.
  • the carrier-polypeptide link may involve the insertion of one or more residues, especially gly ⁇ ine, to form a bridge between the carrier and the polypeptide sequence.
  • Suitable carriers include purified protein derivatives of tuberculin (PPD) and tetanus toxoid although the use of conventional non-protein carrier molecules is not precluded.
  • PPD polypeptide-PPD conjugate
  • a higher titre of antibodies is achieved if the recipient of the polypeptide-PPD conjugate is already tuberculin sensitive, e.g. by virtue of an earlier BCG vaccin ⁇ ation.
  • the population is routinely offered BCG vaccination and is therefore largely PPD-sensitive.
  • PPD is expected to be a preferred carrier for use in such countries.
  • the mode of coupling the polypeptide to the carrier will depend on the nature of the materials to be coupled.
  • a lysine residue in the carrier may be coupled to a C-terminal or other cysteine residue in the polypeptide by treatment with N- - aleimidobutyryloxysuccinimide.
  • Other coupling reactions and reagents have been described in the literature.
  • the HIV envelope protein (as the gene product) is _in vivo proteolytically cleaved into two polypeptide fragments, each of which exists as a separate protein in the virus. The smallest of these two probably corresponds to a transmembrane protein.
  • Synthetic polypeptide sequences corresponding to parts of this transmembrane polypeptide are described in sections (k) - (o) and it is preferred that these polypeptides should be linked to a carrier to enhance their antigenic properties as is also the case for all the preceding peptides. It is particularly preferred for polypeptides (k) - (n) to be linked to a carrier at their C-terminus.
  • (o) corresponds to a site involving the C-terminus end of the native envelope protein and as such it is highly preferred to link a carrier to the N-terminus of this peptide in order to leave the C-terminus-end free.
  • polypeptides of the invention may be synthesised by any conventional method, either directly using manual or automated peptide synthesis techniques, or indirectly by RNA or DNA synthesis and conventional techniques of genetic engineering. Such techniques include the production of hybrid proteins containing one or more of the above peptides inserted into another polypeptide sequence.
  • Another aspect of the present invention therefore provides DNA molecules coding for at least one synthetic antigenic polypeptide as described herein, preferably incorporated into a suitable expression vector replicable in microorganisms or in mammalian cells. The DNA may also appear as part of the
  • DNA sequence for a longer product e.g. the polypeptides may be expressed as parts of other proteins into which they have been inserted by genetic engineering.
  • the antigenic polypeptides are of use, either alone or linked to an appropriate carrier as:
  • the preparation of antibodies, monoclonal or polyclonal, which specifically bind to a synthetic polypeptide according to the present invention may be carried out by conventional means and such antibodies are intended to form part of the invention.
  • the antibodies according to the invention are of use in a method of diagnosing mammalian HIV infection which comprises incubating a sample of tissue or body fluid of a mammal with an effective amount of an antibody as claimed in claim 22 and determining whether, and if desired the extent to which and/or rate at which, cross-reaction between said sample and said antibody occurs.
  • a diagnostic kit which contains at least one of said antibodies is also provided.
  • a further aspect of the invention provides synthetic polypeptides for use in therapy or prophyl ⁇ axis of mammalian HIV infection and/or stimulating the mammalian immune system and/or blocking the cellular receptors for the HIV virus and for the preparation of medicaments suitable for such uses.
  • pharmaceutical compositions containing, as active ingredient, at least one polypeptide or polypeptide-carrier conjugate as described herein in association with one or more pharmaceutically acceptable adjuvants, carriers and/or excipients.
  • the compositions may be formulated for oral, rectal, nasal or especially for parenteral administration.
  • the invention further provides a method of therapy or prophylaxis of mammalian HIV infection and/or of stimulating the mammalian immune system and/or of blocking the cellular receptors for the HIV virus, which comprises administering an effective amount of a polypeptide as hereinbefore defined.
  • Peptide (e') was synthesised using T-Boc chemistry with 10% aqueous acetic acid as solvent.
  • the peptide (6.7 mg per immunisation) was then injected intradermally into rabbits using aluminium hydroxide as the adjuvant. Rabbit sera was taken 7 days after the single immunisation and the cross- reaction between peptide (e') and the rabbit sera was assayed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • AIDS & HIV (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention se rapporte à de nouveaux polypeptides, en particulier à des polypeptides présentant une structure tridimensionnelle analogue à la structure tridimensionnelle de sites spécifiques se trouvant sur la surface extérieure de protéines à enveloppe virale. Lesdits polypeptides trouvent une application particulière dans des vaccins, des diagnostics et comme autres agents médicaux ou scientifiques en rapport avec le virus de l'immunodéficience humaine (HIV), qui est l'agent responsable du syndrome immunodéficitaire acquis (SIDA).
EP88905917A 1987-06-24 1988-06-24 Peptides synthetiques apparentes a des proteines hiv-env Pending EP0371046A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB878714802A GB8714802D0 (en) 1987-06-24 1987-06-24 Synthetic polypeptides
GB8714802 1987-06-24

Publications (1)

Publication Number Publication Date
EP0371046A1 true EP0371046A1 (fr) 1990-06-06

Family

ID=10619478

Family Applications (2)

Application Number Title Priority Date Filing Date
EP88305771A Withdrawn EP0298633A3 (fr) 1987-06-24 1988-06-24 Polypeptides synthétiques
EP88905917A Pending EP0371046A1 (fr) 1987-06-24 1988-06-24 Peptides synthetiques apparentes a des proteines hiv-env

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP88305771A Withdrawn EP0298633A3 (fr) 1987-06-24 1988-06-24 Polypeptides synthétiques

Country Status (7)

Country Link
EP (2) EP0298633A3 (fr)
JP (1) JPH02503916A (fr)
AU (1) AU611457B2 (fr)
FI (1) FI896242A0 (fr)
GB (1) GB8714802D0 (fr)
OA (1) OA09152A (fr)
WO (1) WO1988010267A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU623097B2 (en) * 1987-10-09 1992-05-07 Academisch Ziekenhuis Bij De Universiteit Van Amsterdam Oligopeptides and their use for diagnostic and vaccination purposes for aids and arc
DE3854550T2 (de) * 1987-11-24 1996-04-25 Abbott Lab HIV-Peptide und Methoden für den Nachweis von HIV.
CA1341285C (fr) * 1988-02-12 2001-08-14 Chang Yi Wang Peptides synthetiques servant a la detection d'anticorps de la proteine de surface gp120 du virus hiv, destines au diagnostic du sida, ainsi que d'etats pre-sidatiques, ou aux fins de vaccins
JPH0292298A (ja) * 1988-09-30 1990-04-03 Olympus Optical Co Ltd Ｈｉｖ構成蛋白に対するモノクローナル抗体
GB9005829D0 (en) * 1990-03-15 1990-05-09 Proteus Biotech Ltd Synthetic polypeptides
US5346989A (en) * 1990-08-22 1994-09-13 Syntello Vaccine Development Kb Peptides for use in induction of T cell activation against HIV-1
WO1992021377A1 (fr) * 1991-06-03 1992-12-10 Syntello Inc. Peptides a utiliser pour induire l'activation de lymphocytes t contre le vih-1
GB9208428D0 (en) * 1992-04-16 1992-06-03 Proteus Molecular Design Synthetic polypeptides
GB9215129D0 (en) * 1992-07-16 1992-08-26 Medical Res Council Development relating to human immunodeficiency viruses
DE4228787A1 (de) * 1992-08-29 1994-03-03 Chemotherapeutisches Forschungsinstitut Georg Speyer Haus Neue HIV-1-Virusisolate eines Subtyps, Vakzine gegen HIV-1-Virusinfektionen dieses Subtyps und Verfahren zu ihrer Herstellung, Verwendung der HIV-1-Virusisolate
DE4405810A1 (de) 1994-02-23 1995-08-24 Behringwerke Ag Von einem Retrovirus aus der HIV-Gruppe abgeleitete Peptide und deren Verwendung
EP0923604A1 (fr) * 1996-04-12 1999-06-23 Astra Aktiebolag Peptides contenant de la cysteine ou de la methionine et possedant des effets immunomodulateurs
WO2005097822A1 (fr) * 2004-04-09 2005-10-20 University Of Manitoba Identification de la sequence precise d'acides amines de l'epitope identifie par l'anticorps monoclonal igg1b12 puissant de neutralisation anti-vih 1 humain
GB201612108D0 (en) 2016-07-12 2016-08-24 Univ Strathclyde Preperation of non-ionic surfactant vesicles and variants

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0201540B2 (fr) * 1984-10-18 2001-10-31 Institut Pasteur Antigenes d'enveloppe du virus des lymphadenopathies et leurs applications
US4774175A (en) * 1985-03-01 1988-09-27 Centocor, Inc. Immunochemical methods for the detection of antibody against HTLV-III
GR862412B (en) * 1985-09-25 1987-01-23 Oncogen Vaccines and immuinoassays for acquired immune deficiency syndrome
ZA867281B (en) * 1985-09-25 1987-05-27 Oncogen Vaccines and immunoassays for acquired immune deficiency syndrome
GB8525615D0 (en) * 1985-10-17 1985-11-20 Hoffmann La Roche Polypeptides
ES2054616T3 (es) * 1985-12-17 1994-08-16 Akzo Nv Reactivo inmunoquimico.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8810267A1 *

Also Published As

Publication number Publication date
AU1957288A (en) 1989-01-19
WO1988010267A1 (fr) 1988-12-29
JPH02503916A (ja) 1990-11-15
FI896242A0 (fi) 1989-12-22
EP0298633A2 (fr) 1989-01-11
EP0298633A3 (fr) 1989-04-26
OA09152A (en) 1991-10-31
GB8714802D0 (en) 1987-07-29
AU611457B2 (en) 1991-06-13

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