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EP0269712A1 - Peptides impliques dans la pathogenese d'une infection du type hiv - Google Patents

Peptides impliques dans la pathogenese d'une infection du type hiv

Info

Publication number
EP0269712A1
EP0269712A1 EP87903968A EP87903968A EP0269712A1 EP 0269712 A1 EP0269712 A1 EP 0269712A1 EP 87903968 A EP87903968 A EP 87903968A EP 87903968 A EP87903968 A EP 87903968A EP 0269712 A1 EP0269712 A1 EP 0269712A1
Authority
EP
European Patent Office
Prior art keywords
hiv
peptides
peptide
amino acid
virus
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.)
Withdrawn
Application number
EP87903968A
Other languages
German (de)
English (en)
Other versions
EP0269712A4 (fr
Inventor
Richard A. Fisher
Vicki L. Sato
Kuzhalmannam L. Ramachandran
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.)
Gilbert Walter
Biogen Inc
Original Assignee
Biogen NV
GILBERT Walter
Biogen Inc
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 Biogen NV, GILBERT Walter, Biogen Inc filed Critical Biogen NV
Publication of EP0269712A1 publication Critical patent/EP0269712A1/fr
Publication of EP0269712A4 publication Critical patent/EP0269712A4/fr
Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

  • This invention relates to peptides involved in the pathogenesis of human immunodeficiency virus ("HIV”). More particularly, this invention relates to peptides from the env region of the HIV genome and the use of such peptides in methods and composi ⁇ tions for preventing, treating, or detecting acquired immune deficiency syndrome (“AIDS”) infection.
  • HIV human immunodeficiency virus
  • AIDS Acquired immune deficiency syndrome
  • AIDS is a disease characterized by severe or, typically, complete immunosuppression and attendant host sus- ceptibility to a wide range of opportunistic infec ⁇ tions and malignancies. AIDS' complete clinical manifestation is usually preceded by AIDS related complex ("ARCS”), a syndrome accompanied by symptoms such as lymphadenopathy, fever and weight loss.
  • the human immunodeficiency virus (“HIV”) retrovirus is thought to be the etiological agent -2- responsible for AIDS infection and the ARCS syndrome [M. G.
  • T-4 lymphocytes Upon infection of a host, the primary tar ⁇ gets of the HIV virus are T-4 lymphocytes, also known as helper or inducer cells.
  • T-4 lymphocytes interact with other specialized cell types of the immune system to confer immunity to or defense against infection. More specifically, T-4 lymphocytes stimu ⁇ late production of growth factors which are critical to the functioning of the immune system. For example, they act to stimulate B cells, the descendants of hemopoietic stem cells, which promote the production of defensive antibodies. They also activate macro- phages (“killer cells”) to attack infected or other ⁇ wise abnormal host cells, and induce monocytes (“scavenger cells”) to encompass and destroy invading microbes.
  • killer cells macro- phages
  • scavenger cells induce monocytes
  • T-4 lymphocytes are rendered non-functional by HIV infection, this com ⁇ plex immune defense system is destroyed and the host becomes susceptible to a wide range of opportunistic infections.
  • the HIV virus has also been shown to infect central nervous system
  • HIV human immunodeficiency virus
  • HTLV-III human T-cell lymphotropic virus type III
  • LAV lymphadenopathy-associated virus
  • ARV AIDS-associated retrovirus
  • the genome of retroviruses such as HIV contains three regions encoding structural proteins.
  • the gag region encodes the core proteins of the virion.
  • the pol region encodes the virion RNA-depen- dent DNA polymerase (reverse transcriptase).
  • the env region encodes the major glycoprotein found in the membrane envelope of the virus and in the. cyto- plasmic membrane of infected cells.
  • the capacity of the virus to attach to target cell receptors and to cause fusion of cell membranes are two HIV virus properties controlled by the env gene. These pro- perties are believed to play a fundamental role in the pathogenesis of the virus.
  • HIV env proteins arise from a precursor polypeptide that, in mature form, is cleaved into a large heavily glycosylated exterior membrane protein of about 481 amino acids — gpl20 — and a smaller transmembrane protein of about 345 amino acids which may be glycosylated — gp41 [L. Ratner et al., "Com ⁇ plete Nucleotide Sequence Of The Aids Virus, HTLV-III", Nature, 313, pp. 277-84 (1985)].
  • preventative measures include HIV antibody screening of all blood, organ and semen donors and education of AIDS high-risk groups regarding transmission of the disease.
  • HIV is experiencing genetic drift in humans. At least two classes of the virus have now been identi ⁇ fied in AIDS patients in the United States. Further ⁇ more, patients having high levels of HIV neutralizing antibodies suffer more serious forms of the disease than those patients with poor neutralizing capabi ⁇ lities [Dr. William Haseltine, speech at Memorial Sloan-Kettering Cancer Center, October 9, 1985]. These recent observations suggest serious obstacles to the development of an effective vaccine or mono ⁇ clonal antibody-directed therapeutic method against HIV AIDS infections.
  • the present invention solves the problems referred to above by providing peptides involved in the pathogenesis of the HIV virus.
  • the peptides of this invention are selected from the group consisting of peptides characterized by an amino acid sequence derived sub ⁇ stantially from the region between about amino acid 600 and amino acid 750 of the HIV env gene. This region is believed to have an important role in -5- virus-mediated pathogenic events.
  • the peptides of this invention consist substantially of the following amino acid sequences of the HIV env gene — peptide 1: amino acids 616-632; peptide 2: amino acids 667-680; peptide 3: amino acids 627-639*; peptide 4: amino acids 728-751 and peptide 64: amino acids 627-639.
  • This invention also includes the D-retro form of each of the above-identified pep ⁇ tides — those produced by synthesis with D amino acids in the opposite orientation, beginning with the carboxy terminal amino acid of the L form.
  • peptide 5 which consists substantially of amino acids 426-450 of the HIV env gene
  • peptide 6 which consists substantially of amino acids 496-519 of the HIV env gene
  • peptide 31 which consists sub ⁇ stantially of amino acids 148-165 of the HIV env gene
  • peptide 78 which consists substantially of peptides 298-314 of the HIV env gene.
  • This invention also includes the D-retro form of each the above-identified peptides.
  • These peptides produce antisera which, in conventional assays, bind to the HIV virus, inhibit syncytium formation or neutralize the virus.
  • the peptides themselves may be capable of inhibiting HIV-directed syncytium formation or neutralizing HIV in conventional assays. Such peptides, therefore, are useful in compositions
  • peptide 3 refers to a peptide having the sequence of amino acids 627-639 of the HIV env gene. This is the same sequence as peptide 64. Thus, peptides 3 and 64 are identical. The two num- bers are used to distinguish the preparations of the two peptides. and methods for preventing, treating and detecting AIDS infection.
  • the peptides of this invention comprise functional regions of the HIV env protein involved in virus-mediated events, such as adsorption to normal cells and syncytium formation, which con ⁇ tribute to the pathogenesis of the disease.
  • the functional regions encompassed by these peptides also correspond to immunogenic determinants of the HIV env gene which are highly conserved.
  • these peptides comprise segments of HIV env protein which are highly immunogenic and are in ⁇ volved in virus pathogenesis over the range of genetic variants of the HIV virus.
  • the peptides of this invention may be advantageously used in vaccines or therapeutic com ⁇ positions which elicit antibodies reactive with the native env protein of the HIV virus or which inter ⁇ fere with the virus by neutralization or inhibition of syncytium formation. Furthermore, these peptides are easily modified in composition and conformation to improve the specific activity of those peptides against the HIV virus. In addition, these peptides may be used as diagnostic agents for detecting HIV infections.
  • Figure 1 depicts the amino acid sequences of each of peptides 1-6, 31, 64 and 78 of this inven ⁇ tion, as- well as that of the region between amino acid 600 and amino acid 750 of the HIV env gene.
  • the amino acids are represented by single letter codes as follows:
  • a peptide falling within the scope of this invention may extend outside of or comprise less than the region between amino acid 600 and amino acid 750 of the HIV env gene, as long as a substantial part of that pep- tide is characterized by an amino acid sequence from that region, or segments or combinations thereof, and that peptide demonstrates the desired immuno- logical or biological activity against HIV.
  • peptides according to this invention include those having amino acid sequences which are longer or shorter in length than those of peptides 1-4 and 64 or which comprise segments or combinations thereof, as long as such peptides consist substan ⁇ tially of the region between amino acids 600-750 of the HIV env gene and demonstrate the desired immuno- logical or biological activity.
  • pep ⁇ tides according to this invention include those characterized by a sequence of amino acids which is longer or shorter than that of any one of peptide 5, peptide 6, peptide 31 or peptide 78, or which comprise segments of each of those peptides and which display immunological or biological activity against HIV.
  • any one peptide within the peptides of this invention is not critical. Such a selection may be carried out by taking a number of peptides and testing them for their immunological and biological activity against HIV as described herein.
  • the peptides according to this invention may be prepared by conventional synthesis using any of the known peptide synthesis methods, including synthesis on a solid support.
  • the peptides of the invention may also be prepared in appropriate hosts transformed with DNA sequences that code for the desired peptide.
  • a peptide of this invention may be prepared by the fermentation of appropriate hosts that have been transformed with and which express a DNA sequence encoding that pep ⁇ tide.
  • DNA sequences coding for several of the peptides of this invention may be linked together and those sequences may then be used to transform appropriate hosts to permit the expres ⁇ sion of peptides involved in the pathogenesis of HIV infection.
  • a combination of such methods may also be employed.
  • chemical synthesis alone is employed. By means of that method, the peptides of this invention are additionally advantaged because they are easily purified and are non-biological in origin.
  • the peptides of this invention are prefer- ably coupled to one or more carrier proteins, such as keyhole limpet hemocyanin ("KLH") before use in the compositions and methods described herein.
  • KLH keyhole limpet hemocyanin
  • the peptides are coupled to the carrier protein in various conventional ways, such as those described by M. Reichlin, "Use Of Glutaraldehyde As A Coupling
  • the antigen is employed in the methods and compositions of this invention in a conventional manner.
  • the. peptide or coupled peptide alone or in combi- -9- nation with other peptides of this invention, is usually mixed with one or a combination of well- recognized adjuvants and additives, preferably by first dissolving the peptide, for example, in PBS with 0.1% SDS.
  • the peptides may be linked to hydrophobic groups to build the adjuvant into the composition.
  • other well- known methods of preparing therapeutic compositions may be employed using the peptides of this invention.
  • compositions are then employed in a conventional manner for the treatment of HIV infections.
  • Such methods of treatment and their dosage levels and requirements are well- recognized in the art and may be chosen by those of skill in the art from available methods and tech ⁇ niques.
  • the peptides of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to an HIV-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the HIV infection.
  • the dosage and treatment regimens will depend upon factors such as the patient's health status, the severity and course of infection and the judgment of the treating physician.
  • the peptides of this inven ⁇ tion are useful in vaccines and methods for protec ⁇ ting humans against HIV infection for at least some period of time.
  • the peptides may be employed in these vaccines and methods either alone or together with other peptides of this invention in a manner consistent with the conventional utilization of anti ⁇ gens in vaccines.
  • the peptides of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in immunologically effec- tive amounts to protect patients for some time against HIV infection.
  • compositions and vaccines of this invention may be administered to patients via con- ventional modes of administration.
  • the frequency of administration will depend upon factors such as the particular composition or vaccine employed and the condition of the patient.
  • the need for subsequent treatments with these compositions or boosters of these vaccines will depend upon the results of the initial treatment or vaccination.
  • peptides of this invention and the antibodies raised to them may be employed in presently available methods and kits designed to detect the presence of HIV and antibodies to HIV in blood, organ or semen samples.
  • pep ⁇ tides 1-6,* 31, 64 and 78 were preferably coupled to one or more carrier proteins before use. Accordingly, we coupled each of those peptides prepared as described above to the carrier protein keyhole limpet haemo- cyanin (KLH, Sigma) by mixing 2 mg of peptide in
  • the pep ⁇ tides of this invention may be coupled with tetanus toxoid antigen, diphteria toxoid antigen or another natural or synthetic carrier suitable for use in humans using conventional techniques.
  • the peptides may be coupled with a suitable adjuvant to enhance the immune response in the patient.
  • the peptides may also be used in combination with any suitable synthetic low molecular weight carrier before use.
  • an additional cysteine residue may be added to the C or N terminus of the peptide for coupl ⁇ ing to a suitable carrier by disulfide linkage.
  • each mouse received a booster injection of 100 ⁇ g/250 ⁇ l of the same coupled peptide emulsified 1:1 in Freund's incomplete adjuvant. Tail bleeds were taken on days 21 and 42, ' with serum samples being stored at -20°C until the time of assay. -13-
  • the third and fourth plates which served as controls for, respectively, the first and second plates, were treated identically to those plates but were not pre-coated with peptide.
  • FCS/PBS 5% fetal calf serum/PBS
  • HRP horseradish peroxidase
  • the 873,621 appli- cation referred to the preparation of HIV virus-coated plates.
  • the virus-coated plates as employed in the examples of both the '621 application and the present application were a gift of Dr. Robert Gallo. It is our understanding that the plates used were in fact made, or at. least could have been made, by coating
  • titer plates are also available from Electronucleonics, Fairfield, New Jersey. Subsequently, we rinsed the plates 3 times with deionized water.
  • Each plate had a series of "blank" control wells containing no human serum or anti-human IgG-HRF conjugate and to which one of the following had been added:
  • H,0 Sorenson's phosphate-citrate buffer
  • each plate had a series of
  • PBS-Tween-20 0.05%) containing 1% normal goat serum and goat - anti-human-IgG HRP at a dilution of 1:4000
  • test plate also had a negative and positive control serum.
  • peptides of this invention inhibit virus-mediated events, such as virus adsorption to cells and syncytium formation.
  • virus-mediated events such as virus adsorption to cells and syncytium formation.
  • peptides 1-6, 31 and 64 and antiserum raised against each of peptides 1-6, 31, 64 and 78 were tested. Only peptide 3 inhibited syncytium formation.* Additionally, antiserum raised against each of peptides 1, 2, 4, 5, 31 and 78 inhibited syncytium formation.
  • this assay indicates the utility of the peptides of this invention and the antisera raised thereto as therapeutic agents.
  • administration of such peptides to an infected host may inhibit cell-to-cell transmission of the virus and virus-induced cell fusion suffi ⁇ ciently to prevent spread of the infection and ultimate destruction of the immune system.
  • these peptides may be usefully administered in a priming dose which would permit a subsequently infected host to raise neutralizing antibodies effective against the virus.
  • Virus Neutralization Assay a HIV Neutralization Based On Lysis Of Cells
  • peptide 64 did not inhibit syncytium formation in this assay and because peptide 64 is identical to peptide 3, the inhibitory activity previously reported for peptide 3 may have been attributable to impurities present with peptide 3 in the sample assayed. antisera, incubated them for several days and then observed the cells microscopically for lysis.
  • Such neutralizing activities indicate that the peptides of this invention and antisera thereto are useful in vaccines for preventing HIV infection. Alternatively, these peptides and antisera are useful in therapeutic compositions for inhibiting virus replication in an infected host.
  • kits are presently available which are designed to detect the presence of HIV and antibodies to HIV.
  • Peptides involved in the pathogenicity of HIV infection prepared by the processes of this invention and antibodies raised with them can also be employed in these methods and kits to detect the presence of HIV and antibodies to HIV.
  • These peptides and their antibodies may be packaged in diagnostic kits which allow the rapid and conven ⁇ ient identification of AIDS carriers.
  • the peptides of this invention or antibodies raised using them can be employed in the immunological diagnostic tests currently available for HIV antigen or antibody detection, e.g., radio- immunoassay or ELISA techniques.
  • both the peptides of this invention and antibodies to these peptides are used.
  • the antibodies are produced by injecting laboratory animals with the peptides of this invention in a suitable solution, such as Freund's adjuvant, followed by bleeding the animal some six weeks later, removing the red blood cells by centrifugation, and using the resulting serum.
  • a suitable solution such as Freund's adjuvant
  • monoclonal antibodies to the peptides of this invention may be produced using standard hybridoma techniques.
  • antibodies to an HIV peptide produced as above are attached to a solid phase, for example, the inside of a test tube.
  • a sample of the patient's serum is added to the tube, together with a known amount of a peptide of this invention, produced as above, and labelled with a radioactive isotope such as radioactive iodine.
  • a radioactive isotope such as radioactive iodine.
  • Any HIV antigen in the patient's serum will compete with the labelled peptide for binding with the HIV antibodies.
  • the excess liquid is removed, the test tube washed, and the amount of radioactivity measured.
  • a positive result i.e., that the patient's serum contains HIV antigen, is indicated by a low radio ⁇ activity count left in the tube, as compared with a control.
  • a microtiter plate is coated with a peptide prepared in accordance with this invention, and to this is added a sample of patient's serum. After a period of incubation permitting interaction of any HIV antibody present in the serum with the HIV antigen, the plate is washed. A preparation of anti-human antibodies, raised in a laboratory animal by injection of semi- purified human immunoglobulin, and then linked to an enzyme, is added. Incubation allows an antibody- antigen reaction to take place, and the plate is then rewashed. Thereafter, enzyme substrate is added to the microtiter plate and incubated for a period of time to allow the enzyme to react with the sub- strate. The absorbance of the final preparation is then measured. A large change in absorbance indicates a positive result, i.e., that the patient's serum contains antibodies to HIV.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • AIDS & HIV (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Peptides impliqués dans la pathogenèse du virus immunodéficitaire humain ("HIV"), et plus particulièrement peptides de la région env du génome HIV, et utilisation de tels peptides dans des procédés et des compositions pour la prévention, le traitement ou la détection d'une infection du syndrome immunodéficitaire acquis ("SIDA").
EP19870903968 1986-06-12 1987-06-09 Peptides impliques dans la pathogenese d'une infection du type hiv. Withdrawn EP0269712A4 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US87362186A 1986-06-12 1986-06-12
US873621 1986-06-12
US4193687A 1987-04-24 1987-04-24
US41936 1987-04-24

Publications (2)

Publication Number Publication Date
EP0269712A1 true EP0269712A1 (fr) 1988-06-08
EP0269712A4 EP0269712A4 (fr) 1990-06-26

Family

ID=26718709

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870903968 Withdrawn EP0269712A4 (fr) 1986-06-12 1987-06-09 Peptides impliques dans la pathogenese d'une infection du type hiv.

Country Status (5)

Country Link
EP (1) EP0269712A4 (fr)
JP (1) JPH01501547A (fr)
AU (1) AU617088B2 (fr)
NZ (1) NZ220653A (fr)
WO (1) WO1987007616A1 (fr)

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JPH01501547A (ja) 1989-06-01
EP0269712A4 (fr) 1990-06-26
AU617088B2 (en) 1991-11-21
AU7540487A (en) 1988-01-11
WO1987007616A1 (fr) 1987-12-17
NZ220653A (en) 1990-06-26

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