WO1984000687A1 - Antiserums de la grippe a large spectre - Google Patents

Antiserums de la grippe a large spectre Download PDF

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WO1984000687A1
WO1984000687A1 PCT/US1983/001291 US8301291W WO8400687A1 WO 1984000687 A1 WO1984000687 A1 WO 1984000687A1 US 8301291 W US8301291 W US 8301291W WO 8400687 A1 WO8400687 A1 WO 8400687A1
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terminus
peptide
amino acid
amino
acid residue
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PCT/US1983/001291
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English (en)
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Nicola Green
Stephen Alexander
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Scripps Clinic Res
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Publication of WO1984000687A1 publication Critical patent/WO1984000687A1/fr
Priority to NO841540A priority Critical patent/NO161002C/no
Priority to DK203684A priority patent/DK203684A/da
Priority to FI841583A priority patent/FI841583A/fi

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    • 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
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16211—Influenzavirus B, i.e. influenza B virus
    • C12N2760/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to immunochemistry, and, more specifically, to immunological reagents and reactions involving influenza viruses.
  • Influenza remains a major epidemic disease worldwide despite intensive vaccination programs. Webster et al. , Nature, 296, 115-121 (1982) and Palese et al. , Science, 215, 1469-1474 (1982). To date, vaccines for these efforts have utilized whole virus as antigen to elicit antibody responses against the particular influenza strain in circulation. Tyrrel et al., Br. Med. Bull., 3_5, 77-83 (1979). These conventional vaccines suffer from several standpoints including poor characterization and non-uniformity due to production of virus in embryonated eggs, and can cause serious adverse side reactions. Most importantly, they suffer from a lack of generality required to be effective against the broad spectrum of influenza strains which can arise by genetic recombination. A well-defined vaccine which eliminates these problems is needed.
  • the primary target of the neutralizaing response of vaccination is the hemagglutinin molecule which is the major surface glycoprotein of the virus.
  • Dowdle et al. J.Virol. , 13, 269-275 (1974).
  • This hemagglutinin is synthesized ⁇ n vivo as a precursor molecule (HA) , and is subsequently cleaved proteolytically to two subunits, HA. and HA-. Cleavage is necessary for the virus to be infective.
  • Klenk et al. J. Virol. , 69, 426-439 (1975) and Lazarowitz et al. , Virology, 68, 440-454 (1975).
  • HA genes of several epidemic strains of influenza have been described and indicate that there is rapid genetic variation occurring within these genes.
  • Laver et al. Nature, 283, 454-457 (1980) ; Webster et al. Virology, 104, 139-148 (1980); Wiley et al. , Nature, 289, 373-378 (1981); and Gething et al. , Nature, 187, 373-378 (1981) .
  • mutational changes are reflected as alterations of the antigenic structure of HA allowing escape of the virus from the protection of the previous immunization, and the subsequent rise of a new epidemic strain.
  • serologically distinct viruses from previous epidemics occasionally reenter the population, possibly from non-human hosts, where they may have undergone genetic recombination.
  • Antibodies made against synthetic peptides representing virtually all regions of the X-47 (H3N2) influenza virus hemagglutinin were [Min-Jou, Cell, 19, 683-696 (1980)] tested for their ability to neutralize virus infection in vitro.
  • peptides particularly synthetic peptides (built-up -5- ⁇ from component amino acid residues) as compared to those materials cleaved from the hemagglutinin molecule or those prepared by recombinant DNA technology, are capable of eliciting the production of antibodies that neutralize more than one strain of influenza virus, and consider that neutralization a useful step in the prevention and treatment of influenza.
  • Each of the peptides of this invention ⁇ has a molecular weight less than that of the intact hemagglutinin molecule, and typically has a length of about 8 to about 40 amino acid residues.
  • the specific synthetic peptides which have been found to be most effective have amino acid residue sequences that correspond to portions of the influenza hemagglutinin molecule amino acid residue sequence. Those peptides are defined by the following amino residue acid sequence formulas, from left to right and in the direction of amino-terminus to carboxy-terminus: (a) SIMRSDAPIGTCSSECITPNGSIPNDKPFQNVNKITY;
  • One additional synthetic peptide whose amino acid residue sequence corresponds to positions 306-330, the carboxy-terminus, of the H 1 molecule has also been found to (a) stimulate T-cell proliferation, (b) induce production of antibodies that cross-react with influenza strains other than X-47, as well as (c) protect animals from challenge with live virus when used in a vaccine.
  • the amino acid residue sequence of that peptide, from left to right and in the direction from amino-terminus to carboxy-terminus, is shown in the formula below: (d) CPKYVKQNTLKLATGMRNVPEKQTR.
  • Another peptide also induces the production of neutralizing antibodies to strain X-47 as well as antibodies that cross-react and neutralize, to some extent, other influenza strains.
  • the amino acid residue sequence of this peptide, from left to right and in the direction of amino-terminus to carboxy-terminus is shown in formula (e) below: (e) CNNPHRIL.
  • CKRGPDSGFFSRLNWLYKSGSC comprises, as compositions of matter, amino acid residue sequences containing the above defined peptides, or portions thereof, produced synthetically or isolated from proteins, and may be used either alone or together. Synthetic peptides are preferred. This invention also comprises the antisera resulting from the challenge of an organism by one or more peptides containing the above defined peptides, and compositions in which antibodies to the
  • OMPI above peptides alone or combined, are an immunologically active agent.
  • This invention further contemplates the processes of preparation of these compositions and the use of these compositions in immunological diagnosis or treatment.
  • this invention in one facet comprises vaccines for use in conventional innoculation or ingestion or inhalation vaccination in which an immunologically active agent induced in the immunized host is one or more antibodies to the above defined peptides.
  • Figure 1 depicts the amino acid residue sequence of the X-47 HA molecule derived from the neucleotide sequence [Min-Jou .et al. , Cell, 19, 683-696 (1980)];
  • Figure 2 depicts. the results of the micro-titratio of X-47 influenza virus on Madin-Darby canine kidney (MDCK) epithelial cells;
  • Figure 3 depicts the neutralization of X-47 virus by combinations of anti-peptide antisera. Description of the Best Mode The full names for individual amino acid residues are sometimes used herein as are the well-known three-letter abbreviations. The one-letter symbols for amino acid residues are used most often.
  • the Table of Correspondence, below, provides the full name as well as the abbreviation and symbols for each amino acid residue named herein.
  • FIG. 1 the amino acid residue sequence of the X-47 HA molecule [Min Jou et al.. Cell, 19, 683-696 (1980)] is depicted. The entire HA. and the amino-terminus of HA ⁇ are shown. The lines under the sequence represent the peptides which were synthesized and used for immunization. C or Y at ends of those lines represent additions of cysteine or tyrosine not found in the primary sequence. Disulfide bonds are
  • OMP / -10- cells/milliliter in growth medium 50 Microliters of the suspension were added to each well of a 96 well flat-bottomed icrotiter plate (Falcon) containing an additional 50 microliters medium. The plates were incubated overnight at 37° C. allowing cell attachment for either virus or serum titrations on the following day.
  • Virus was titrated by making 50 microliter two-fold serial dilutions in a 96 well microtiter plate in MEM containing antibiotics (dilution medium) . An additional 50 microliters of dilution medium were added to each well and the plate was incubated for 60 minutes at 37°C. (mock neutralization) . The medium covering the MDCK cell monolayers in the 96 well plate was aspirated and the cells were washed with 100 microliters of dilution medium.
  • the titrated virus was then transferred to the corresponding wells of the plate containing the washed MDCK cells.
  • the virus was allowed to absorb for 60 minutes at 37°C. , whereupon it was removed, and the cells were washed with 100 microliters of diultion medium.
  • the cells were then overlayed with 100 microliters of overlay meidum consisting of Basal Medium (Eagle) containing antibiotics, 0.005%
  • DEAE-dextran Pulacia
  • 2 millimolar L-glutamine 2 millimolar L-glutamine, 0.05% fetal calf serum and 2 micrograms per milliliter trypsin (type III, 2x crystalized, Sigma) .
  • the cells were incubated for 48 hours, at which time they were observed microscopically for cytopathic effect (CPE) , and were subsequently stained with 0.1% crystal violet in 20% ethanol, followed by rinsing in tap water. Each virus was screened for the last dilution which gave complete • lysis of the MDCK monolayer in 48 hours and this
  • Figure 2A shows one and two day (24 and 48 hour) end points for a titration of X-47 virus.
  • the end points of the CPE are quite easy to score visually.
  • the plates can be mechanically read in a microtiter plate reader and the results plotted graphically as shown in Figure 2B.
  • a two-day assay was chosen because it was found that the virus inoculum needed from a complete CPE in 48 hours allowed the best overall sensitivity in testing the neutralizing strenghts of the anti-peptide antisera.
  • Figure 2B shows graphical displays of the stained plates in Figure 2A after reading in a Titertek Multiskan apparatus with a 492 nanometer filter.
  • the extent of CPE was expressed as percent of the control well (C) which received no virus.
  • Open and closed circles are the 24 and 48 hour end points, respectively.
  • the CPE end point dilutions for X-47 virus are 1:5 and 1:300 for 24 and 48 hours respectively.
  • the assay is based on the cytopathic effect (CPE) of influenza virus on monolayers of Madin-Darby canine kidney epithelial (MDCK) cells. Gaush et al. , Applied Microbiology, 16, 588-594 (1968) .
  • the neutralization assay is accomplished by making serial dilutions of the sera in microtiter plates and then adding to each well an aliquot of virus at the dilution previously shown by titration to give a complete CPE in 48 hours. Thus for X-47 virus this was a 1:300 dilution of allantoic fluid. We have determined that this is approximately 10,000 plaque-forming units per well.
  • Figure 3 depicts results of neutralization of X-47 virus by combinations of anti-peptide antisera.
  • NRS Normal rabbit serum
  • the antisera are, ( • ) anti-X47 virus; ( D ) normal rabbit serum; (O) anti-peptide 23; ( ⁇ ) anti-peptide-24; and ( - ⁇ ) anti-peptide-23 and -24.
  • Regions of the molecule containing disulfide bridges including: a. The proposed antigenic site "C" of Wiley et al. [Wiley et al. , Nature, 289, 373-378 (1981)], which is a protruding bulge in the molecule formed by a disulfide bond between cysteine 53 and cysteine 278. Peptides in the regions of cysteine 53 (peptides 5, 6, and 7) and cysteine 278 (peptides 21 and 23) elicited neutralizing antibodies. b. The disulfide bridge between cysteine 282 and cysteine 306. Antisera against peptides 22 and 20 which encompass these cysteines were neutralizing. c.
  • HA 2 is the most highly conserved sequence in HA. Waterfield et al. , Br.Med.Bull. , 35, 47-63 (1979). It is similar to the amino-terminus of the F. component of the Sendai virus fusion glycoprotein [Gething et al. , Proc.Natl.Acad.Sci. USA, 75,
  • the amino acid sequences of a number of influenza virus HA molecules have been derived from the nucleotide sequences of their HA genes. Considerable conservation exists among the sequences despite variation in HA subtype. Webster et al. , Nature, 296, 115-121 (1982) ; Laver et al. , Nature, 283, 454-457 (1980) ; Webster et al. Virology, 104, 139-148 (1980); Wiley et al. , Nature, 289, 373-378 (1981); and Gething et al. , Nature, 187, 373-378 (1981) . These regions include those for which we have demonstrated neutralizing activity with our antipeptide antisera. Table 2 presents data demonstrating that antipeptide antisera containing antibodies of this invention are able to cross-neutralize heterologous virus.
  • H3 strains show patterns of neutralization similar to those of X-47.
  • the HI strains were not neutralized by the very high titered anti-X-47 virus serum, but they were neutralized by at least some of the antipeptide sera.
  • Antipeptide sera to synthetic peptides 23, 24 and 26 were particularly effective.
  • the degree to which A/WSN/33 (Virus B; H1N1) was neutralized by anti-X-47 antiserum was insignificant compared to the performance of the antivirus antiserum towards H3 subtype viruses. For those viruses for which HA sequences are available, the results appear to be in accord with the degree of amino acid sequence homology between the HI and H3 subtypes.
  • the data imply that it is necessary to bind antibody to a site functional in the infection and replication process or to a structurally distinct site such as that formed by a disulfide bridge.
  • the relatively low titers of the antipeptide sera relative to the anti-X-47 virus antiserum was probably a function of the limited proportion of antibodies in the antipeptide antiserum recognizing the conformation that the corresponding amino acid sequence attains in the infectious virus.
  • the anti-X-47 virus antiserum contains antibodies to other viral components, e.g., neuramidase, which may enhance the neutralizing activity of the HA antibodies in this serum.
  • the reason for this discrepancy may be due to the limited immunogenicity of the intact virus, or the effect of carbohydrate on the immune response to the intact virus.
  • Peptide 20 CPKYVKQNTLKLATGMRNVPEKQTR; Peptide 23 SIMRSDAPIGTCSSECITPNGSIPNDKPFQNVNKITY; Peptide 24 RGIFGAIAGFIENGWEGMIDGWYGFRHQN; Peptide 26 EKQTRGIFGA.
  • peptide 5 corresponds in amino acid residue sequence to positions 53-60 from the amino-terminus of the HA.
  • molecule of the X-47 influenza virus corresponds in amino acid residue sequence to positions 306-330, from the amino-terminus and includes the carboxy-terminus of the HA.
  • peptide of X-47 corresponds in amino acid residue sequence to positions 267-300 from the amino-terminus of the HA.
  • peptide of X-47; peptide 24 corresponds in amino acid residue sequence to position 330, the carboxy-terminus, of the HA.
  • peptide 26 corresponds to position 326 from the amino-terminus of the HA. molecule through the carboxy-terminus (position 330) and to position 6 of the HA 2 molecule of X-47.
  • synthetic peptides whose amino acid residue sequences correspond to the above amino acid residue positions in hemagglutinin molecules of strains of influenza virus other than X-47 and listed in Table 2 also induce production of antibodies that cross-react and neutralize at least some of the influenza strains or subtypes of Table 2, above, in addition to neutralizing the strain or subtype to a portion of whose hemagglutinin molecule amino acid residue sequence such peptides correspond. While not wishing to be bound by theory, it is thus believed that production of cross-reactive, neutralizing antibodies induced by immunization with synthetic peptides is a function of the positional sequence of the immunizing synthetic peptide.
  • OMFI -21- one of the above peptides corresponds to amino acid residue sequences.
  • the word "corresponds" when used in conjunction with amino acid residue sequences means that the sequences of two peptides or of a peptide and protein are so similar that antibodies raised to a peptide of this invention cross-react and bind to both that peptide and to a second corresponding peptide or to a corresponding protein.
  • the amino acid residue sequences are identical, although strict identity of sequences is not required. For example, conservative changes between amino acid residues such as lysine and arginine, or glutamic acid and aspartic acid, or leucine and isoleucine may be made. In additions and deletions of residues in the sequences may be made without destroying the cross-reactive antibody binding.
  • Peptide 20 corresponds in amino acid residue sequence to positions 306 through 330, the carboxy-terminus of the HA., molecule. Stated differently, this peptide extends from the carboxy-terminus of the HA., toward the amino-terminus of the HA. to the residue adjacent the carboxy-terminal-most cysteine (cysteine 306) in the HA.. In the intact HA. molecule, cysteine 306 exists as a portion of a cystine residue forming a disulfide bond with the residue at position 282. Thus, cysteine 306 is more accurately referred to as half-cystine 306, as is known in the art. It is believed that this region of the HA., molecule is a region (position 306-330, or the position of the carboxy-terminus to the first half-cystine on the HA. molecule) that stimulates T-cell proliferation in influenza viruses generally.
  • Another embodiment of this invention utilizes a peptide whose amino acid sequence corresponds to the amino acid residue sequence of synthetic peptide 20 alone or as a conjugate to stimulate T-cell proliferation and/or to also induce antibody production by B-cells. That peptide can be used for those purposes or it can be used in conjunction with one or more additional peptides or their conjugates to stimulate both T-cells and B-cells to provide both cellular as well as humoral responses.
  • mice were immunized with a mixture of six synthetic peptide conjugates whose sequences
  • M corresponded to amino acid residue sequences throughout the HA., molecule.
  • Each mouse was given three injections containing 20 micrograms of mixed peptide each in complete Fruend's adjuvant. Serum titers after five weeks ranged from zero through 320 using the ELISA assay discussed by Green et al. , above. Analogous rabbit titers would have been about 5120.
  • the peptide mixture utilized in the above protection determination contained peptides 2, 4, 7, 11, 19 and 20 (Table 1) in approximately equal amounts. Each peptide was conjugated to KLH.
  • the vaccination protocol for the above determinations was as follows. Groups of 4-week old CAF. male mice were vaccinated with the peptide-containing vaccine or saline-containing vaccine in complete Freund's adjuvant on days 0, 14 and 28. Animals were bled to obtain serum titer data on day 35, and then challenged on day 38 with an intranasal inoculation of mouse-adapted X-47 influenza virus at a concentration designed to deliver an LD 5Q -LD 80 ; i.e., to kill 50% to 80% of the population.
  • the challenged animals were then housed in an isolation facility and examined daily for signs of disease. After three weeks of isolation, the perecent mortality was calculated and compared to the control group.
  • peptides were used alone or as a conjugates with KLH. Depending on their solubilites, peptides containing fewer than about 34 residues were typically used as conjugates while peptides longer than 35 residues were typically used alone.
  • the peptides of this invention may be used alone or linked (coupled) to a carrier as a conjugate.
  • KLH Keyhole limpet hemocyanin
  • Additional carriers useful in preparing conjugates includes, but are not limited to, agarose, cross-linked agarose, edestin, curcubin, bovine serum albumin, human serum albumin, red blood cells such as sheep erythrocytes, and polyamino acids such as poly (D-lysine: D-glutamic acid) .
  • Immunizations utilizing conjugates have been found to be more effective, than similar immunizations using the peptide alone, and not coupled to a carrier. A study was therefore carried out to examine the effects of the carrier on the B-cell, neutralizing antibody-producing (humoral) response in mice.
  • the peptide used in these studies was synthetic peptide 20 which contains a Cys residue at its amino-terminus.
  • the carriers in these studies were thiopropyl-Sepharose 6B and thiopropyl-Sepharose 4B available from Pharmacia Fine Chemicals, Piscataway, New Jersey.
  • Mouse Number X-47 Titer Group 1 3 ip/sq injections of Sepharose 6B - Peptide 20 (at 50 micrograms of peptide (conjugate)/mouse with 4 milligrams of alum)
  • ip/sq One intraperitioneal injection, and four subcutaneous injections (one subcutaneous injection in each hip and in each shoulder) .
  • 2 sq Four subcutaneous injections as described above. 3
  • the Sepharose carriers have several advantages over KLH as a carrier. These materials have a solid phase composed of cross-linked polysaccharide chains (agarose) , a spacer moiety and a protected thiol group (prior to the linking reaction with the peptide) .
  • Thiopropyl Sepharose 6B has a higher binding capacity, a greater binding efficiency, e.g. yield of 60-65% vs. 40%, and shows apparently more immunogenicity as compared to thiopropyl Sepharose 4B.
  • the immunogenicity of the thiopropyl Sepharose 6B - peptide 20 conjugate was greater in the presence of alum which can be used in humans than in the presence of compute Freund's adjuvant (CFA) which is not used for human vaccines.
  • CFA compute Freund's adjuvant
  • Peptides were coupled to Sepharose carriers in de-aerated 0.01 molar phosphate buffer solution additionally containing 0.5 molar NaCl, 0.001 molar ethylene diaminethetracetic acid and 0.2 percent NaN., at a pH value of 7.
  • 0.01 molar phosphate buffer solution additionally containing 0.5 molar NaCl, 0.001 molar ethylene diaminethetracetic acid and 0.2 percent NaN., at a pH value of 7.
  • For couplings to Sepharose 4B 1 milliliter of packed, swollen Sepharose 4B was added to 2 milliliters of the phosphate buffer further containing 5 milligrams per milliliter of peptide.
  • For couplings to Sepharose 6B 0.5 milliliters of packed, swollen Sepharose 6B was added to 5 milliliters of the phosphate buffer further containing 5 milligrams per milliliter of peptide.
  • the reaction solutions were gently agitated at a temperature
  • Conjugates were prepared from about 40-50 micrograms of peptide and about 25-32 micrograms of KLH as desscribed in Green et al. , Cell, 28, 477-487 (1982). 100 Percent reaction was presumed. The immunization was carried out in complete Freunds* adjuvant that contained 0.6 milligrams of Mycobacterium Tuberculosis per mouse in a total volume of 0.2 milliliters per mouse.
  • mice having antibody titers in the above, six-month, ranges were protected against infection by the virus.
  • Cyclic peptides whose amino acid residue sequences correspond to HA., positions 306 to 330
  • the first synthesized, straight chain cyclic peptide-precursors contained cysteine residues at the amino- and carboxy-terminii which were subsequently oxidized to form cyclic and/or oligomeric materials that are also referred to herein as cyclic peptides in as much as oxidations were continued until no free mercaptan could be detected by the Ellman test [Ellman, Arch. Bioche . Biophys.
  • the cyclic peptides were prepared by dissolving the peptides in a 0.1 molar bicarbonate solution. Cyclic, monomeric or substantially monomeric peptides were prepared by dissolution of the peptide at a concentration of 0.1 milligrams per milliliter, while the oligomeric material was prepared at a concentration of 10 milligrams per milliliter. The peptide solutions so prepared were stirred overnight while being exposed to atmospheric oxygen to effect the cyclizing oxidations. The oxidized solutions were thereafter tested for completeness of reaction and then lyophylized. The -31- dried materials so prepared were thereafter used for immunizations.
  • this invention comprises specifically defined peptides. It will be understood by those in the art that minor deviations from the exact sequences of the above-disclosed peptides may be made without substantially impairing the immunological characteristics of the peptides.
  • neutralizing and protective antibody-producing peptides of this invention contain the following amino residue. acid sequences, from left to right and in the direction of amino-terminus to carboxy terminus,
  • Biologically active receptor molecules constitute another embodiment of this invention. These molecules are antibodies, or idiotype-containing polyamide portions of antibodies,
  • OMPI s WIPO -32- induced or raised to a synthetic peptide of this invention or to its conjugate with a carrier.
  • the receptors are raised to the preferred synthetic peptides of this invention.
  • the receptors are biologically active in that they bind at least with the synthetic peptide when admixed therewith in aqueous solution, at least at physiological pH values and ionic strengths.
  • the receptors also bind with the naturally occurring virus or the hemaglutinin molecule under the same conditions. It is more preferred that the receptors bind to the synthetic peptide, hemagglutinin and virus within a pH value range of about 5 to about 9, and at ionic strengths such as that of distilled water to that of about one molar sodium chloride.
  • Idiotype-containing polyamide portions of antibodies are the portions of antibodies that bind to an antigen. Such portions include the Fab, Fab' , and F(ab*) 2 fragments prepared from antibodies by well-known enzymatic cleavage techniques. Inasmuch as antibodies are discussed in the art as being “raised” or “induced”, idiotype-containing polyamide portions of antibodies will also be discussed herein as being “raised” or “induced” with the understanding that a subsequent cleavage step is normally required to prepare such materials from antibodies.
  • the receptor molecules may be polyclonal as is the case for the ⁇ antibodies in antisera discussed hereinbefore, or the receptors may be monoclonal. Techniques for preparing monoclonal antibodies are well known, and monoclonal receptors of this invention may be prepared by using the synthetic peptides of this invention, preferably coupled to a carrier, as the immunogen as was done by Arnheiter et al.. Nature, 294, 278-280 (1981).
  • OMP -33- Monoclonal antibodies are typically obtained from hybridoma tissue cultures or from ascites fluid obtained from animals into which the hybridoma -tissue was introduced. Nevertheless, monoclonal antibodies may be described as being “raised to” or “induced by” the synthetic peptides of this invention or their conjugates with a carrier.
  • Receptors are utilized along with an "indicating group", also sometimes referred to as a "label".
  • the indicating group or label is utilized in conjunction with the receptor as a means for determining whether an immune reaction has taken place, and in some instances for determining the extent of such a reaction.
  • the indicating group may be a single atom as in the case of radioactive elements such as iodine 125 or 131, hydrogen 3 or sulfur 35, or elements active in nuclear magnetic resonance (NMR) spectroscopy such as fluorine 19 or nitrogen 15.
  • the indicating group may also be a molecule such as a fluorescent dye like fluoresein, or an enzyme, such as horseradish peroxidase (HRP) , or the like.
  • the indicating group may also constitute all or a portion of a separate molecule or atom that reacts with the receptor molecule such as HRP-linked to goat anti-rabbit antibodies where the antibody receptor was raised in a rabbit, or where a radioactive element such as 125I is bonded to protein A obtained from Staphylococcus Aureus.
  • additional reagents are required to visualize the fact that an immune reaction has occurred.
  • additional reagents for HRP include
  • OMP -34- hydrogen peroxide and an oxidation dye precursor such as diaminobenzidine or 2,2'-azino-di-(3- athylbenzthiazolin sulfonat) from whom? + Where city, state or country, used herein.
  • indicating group or “label” are used herein to include single atoms and molecules that are linked to the receptor or used separately, and whether those atoms or molecules are used alone or in conjunction with additional reagents. Such indicating groups or labels are themselves well-known in immunochemistry and constitute a part of this invention only insofar as they are utilized with otherwise novel receptors, methods and/or systems.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Antisérums contre peptides synthétiques qui neutralisent les virus de la grippe de sous-types divergeants d'hémagglutinine, protègent contre une infection par le virus de la grippe, ainsi que leurs procédés de préparation.
PCT/US1983/001291 1982-08-23 1983-08-23 Antiserums de la grippe a large spectre WO1984000687A1 (fr)

Priority Applications (3)

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NO841540A NO161002C (no) 1982-08-23 1984-04-17 Analogifremgangsmaate for fremstilling av terapeutisk aktive polypeptider.
DK203684A DK203684A (da) 1982-08-23 1984-04-18 Bredspektrede influenza-antisera
FI841583A FI841583A (fi) 1982-08-23 1984-04-19 Influensaantisera med brett spektrum.

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JP (1) JPS59501714A (fr)
KR (1) KR840006198A (fr)
AU (1) AU570929B2 (fr)
DK (1) DK203684A (fr)
ES (1) ES525088A0 (fr)
FI (1) FI841583A (fr)
GR (1) GR78931B (fr)
IL (1) IL69556A (fr)
IT (1) IT1168636B (fr)
NO (1) NO161002C (fr)
NZ (2) NZ205341A (fr)
PH (1) PH18872A (fr)
PT (1) PT77230B (fr)
WO (1) WO1984000687A1 (fr)
ZA (1) ZA836080B (fr)

Cited By (30)

* Cited by examiner, † Cited by third party
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EP0176493A1 (fr) * 1984-08-30 1986-04-02 Smithkline Beecham Corporation Polypeptides vaccinaux
WO1990008161A1 (fr) * 1989-01-12 1990-07-26 The Blood Center Of Southeastern Wisconsin Modulation par peptides mediateurs de la reconnaissance d'antigenes par les lymphocytes t, utilises comme moyens d'affectation de reactions immunitaires
EP0621339A2 (fr) * 1992-09-17 1994-10-26 Takara Shuzo Co. Ltd. Polypeptides immunogès dérivées du haemagglutinen de virus de la influenza type A humain
US6605448B1 (en) 1985-08-28 2003-08-12 George Pieczenik Method and means for sorting and identifying biological information
WO2007134327A2 (fr) * 2006-05-15 2007-11-22 Sea Lane Biotechnologies, Llc. Anticorps neutralisants dirigés contre les virus de la grippe
ITTO20090414A1 (it) * 2009-06-01 2010-12-02 Pomona Biotechnologies Llc Anticorpi monoclonali come medicamento per il trattamento terapeutico e/o profilattico delle infezioni da virus influenzale a (h1n1) di origine suina (s-oiv)
WO2010132604A3 (fr) * 2009-05-13 2011-03-24 Sea Lane Biotechnologies, Llc Molécules neutralisantes dirigées contre les virus de la grippe
US8148085B2 (en) 2006-05-15 2012-04-03 Sea Lane Biotechnologies, Llc Donor specific antibody libraries
US8367061B2 (en) 2007-01-30 2013-02-05 Pomona Ricera S.R.L. Anti-idiotype monoclonal antibodies mimicking the HIV gp120 CD4-binding (CD4bs)
US20130209499A1 (en) * 2010-02-18 2013-08-15 Mount Sinai School Of Medicine Vaccines for use in the prophylaxis and treatment of influenza virus disease
US8623363B2 (en) 2008-12-22 2014-01-07 Pomona Ricerca S.R.L. Anti-HCV monoclonal antibody as a medicament for the therapeutic treatment and prevention of HCV infections
US8877200B2 (en) 2012-05-10 2014-11-04 Visterra, Inc. HA binding agents
US8975378B2 (en) 2008-12-25 2015-03-10 Osaka University Human anti-human influenza virus antibody
US9169318B2 (en) 2008-03-28 2015-10-27 Sea Lane Biotechnologies, Inc. Neutralizing molecules to viral antigens
US9175069B2 (en) 2009-05-26 2015-11-03 Icahn School Of Medicine At Mount Sinai Monoclonal antibodies against influenza virus generated by cyclical administration and uses thereof
US9200063B2 (en) 2008-03-17 2015-12-01 Pomona Ricerca S.R.L. Monoclonal antibodies capable of reacting with a plurality of influenza virus A subtypes
US9243054B2 (en) 2008-05-27 2016-01-26 Pomona Ricerca S.R.L. Monoclonal antibodies having homosubtype cross-neutralization properties against influenza A viruses subtype H1
US9371366B2 (en) 2012-12-18 2016-06-21 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9708373B2 (en) 2010-03-30 2017-07-18 Icahn School Of Medicine At Mount Sinai Influenza virus vaccine and uses thereof
US9849172B2 (en) 2009-03-30 2017-12-26 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9908930B2 (en) 2013-03-14 2018-03-06 Icahn School Of Medicine At Mount Sinai Antibodies against influenza virus hemagglutinin and uses thereof
US9975956B2 (en) 2011-12-22 2018-05-22 I2 Pharmaceuticals, Inc. Surrogate binding proteins which bind DR4 and/or DR5
US10131695B2 (en) 2011-09-20 2018-11-20 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US10214580B2 (en) 2007-03-27 2019-02-26 I2 Pharmaceuticals, Inc. Constructs and libraries comprising antibody surrogate light chain sequences
US10300140B2 (en) 2011-07-28 2019-05-28 I2 Pharmaceuticals, Inc. Sur-binding proteins against ERBB3
US10513553B2 (en) 2015-11-13 2019-12-24 Visterra, Inc. Compositions and methods for treating and preventing influenza
US10736956B2 (en) 2015-01-23 2020-08-11 Icahn School Of Medicine At Mount Sinai Influenza virus vaccination regimens
US11230593B2 (en) 2019-03-25 2022-01-25 Visterra, Inc. Compositions and methods for treating and preventing influenza
US11254733B2 (en) 2017-04-07 2022-02-22 Icahn School Of Medicine At Mount Sinai Anti-influenza B virus neuraminidase antibodies and uses thereof
US11266734B2 (en) 2016-06-15 2022-03-08 Icahn School Of Medicine At Mount Sinai Influenza virus hemagglutinin proteins and uses thereof

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PL2059532T3 (pl) * 2006-09-07 2013-05-31 Crucell Holland Bv Ludzkie cząsteczki wiążące zdolne do neutralizowania wirusa grypy H5N1 i ich zastosowania

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CHEMICAL ABSTRACTS, Volume 95, No. 21, issued 1981, (Columbus, Ohio, USA), ASCUM et al., "Antigenic Peptides of Influenza Virus Hemagglutinin: Reactivity with Virus-Neutralizing Antibodies". See page 493, Column 1, Abstract No. 1854225, Intervirology 1981, 15(3), 145-63 (Eng.) *
CHEMICAL ABSTRACTS, Volume 98, No. 23. issued 1983 (Columbus, Ohio, USA), WABUKE-BUNOTI, et al., "Isolation and Characteriztion of a Cyanogen Bromide Cleavage Peptide of Influenza Viral Hemagglutinin Stimulatory for Mouse Cytolytic Lymphocytes". see page 471, Abstract No. 196118k, J. IMMUNOL. 1983, 130(5), 2386-91 (Eng.) *
CHEMICAL ABSTRACTS, Volume 99. No. 1 issued 1983 (Columbus, Ohio, USA), LAMB et al., "Human T-Cell Clones Recognize Chemically Synthesized Peptides of Influenza Hemagglutinin". see pages 375, column 1, Abstract No. 3891w, Nature, 1982, 300(5887) 66-69 (Eng.) *
Proc. Natl. Acad. Sci, Volume 79, issued 1982 (United States), MULLER et al., "Anti-Influenza Response Achieved by Immunization with a Synthetic Conjugate". seepages 569-573. *

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176493A1 (fr) * 1984-08-30 1986-04-02 Smithkline Beecham Corporation Polypeptides vaccinaux
US6605448B1 (en) 1985-08-28 2003-08-12 George Pieczenik Method and means for sorting and identifying biological information
WO1990008161A1 (fr) * 1989-01-12 1990-07-26 The Blood Center Of Southeastern Wisconsin Modulation par peptides mediateurs de la reconnaissance d'antigenes par les lymphocytes t, utilises comme moyens d'affectation de reactions immunitaires
EP0621339A2 (fr) * 1992-09-17 1994-10-26 Takara Shuzo Co. Ltd. Polypeptides immunogès dérivées du haemagglutinen de virus de la influenza type A humain
EP0621339A3 (en) * 1992-09-17 1995-11-29 Takara Shuzo Co Immunogenic human influenza a virus haemagglutinin polypeptides.
EP2522678A1 (fr) * 2006-05-15 2012-11-14 Sea Lane Biotechnologies, LLC Anticorps neutralisants des virus de la grippe
WO2007134327A3 (fr) * 2006-05-15 2008-10-02 Sea Lane Biotechnologies Llc Anticorps neutralisants dirigés contre les virus de la grippe
US8148085B2 (en) 2006-05-15 2012-04-03 Sea Lane Biotechnologies, Llc Donor specific antibody libraries
AU2007249160B2 (en) * 2006-05-15 2013-09-12 I2 Pharmaceuticals, Inc. Neutralizing antibodies to influenza viruses
WO2007134327A2 (fr) * 2006-05-15 2007-11-22 Sea Lane Biotechnologies, Llc. Anticorps neutralisants dirigés contre les virus de la grippe
CN103435697A (zh) * 2006-05-15 2013-12-11 航道生物技术有限责任公司 流感病毒的中和抗体
US8367061B2 (en) 2007-01-30 2013-02-05 Pomona Ricera S.R.L. Anti-idiotype monoclonal antibodies mimicking the HIV gp120 CD4-binding (CD4bs)
US10214580B2 (en) 2007-03-27 2019-02-26 I2 Pharmaceuticals, Inc. Constructs and libraries comprising antibody surrogate light chain sequences
US9587011B2 (en) 2008-03-17 2017-03-07 Pomona Ricerca S.R.L. Monoclonal antibodies capable of reacting with a plurality of influenza virus A subtypes
US9200063B2 (en) 2008-03-17 2015-12-01 Pomona Ricerca S.R.L. Monoclonal antibodies capable of reacting with a plurality of influenza virus A subtypes
US9169318B2 (en) 2008-03-28 2015-10-27 Sea Lane Biotechnologies, Inc. Neutralizing molecules to viral antigens
US9243054B2 (en) 2008-05-27 2016-01-26 Pomona Ricerca S.R.L. Monoclonal antibodies having homosubtype cross-neutralization properties against influenza A viruses subtype H1
US8623363B2 (en) 2008-12-22 2014-01-07 Pomona Ricerca S.R.L. Anti-HCV monoclonal antibody as a medicament for the therapeutic treatment and prevention of HCV infections
US9493550B2 (en) 2008-12-25 2016-11-15 Osaka University Human anti-human influenza virus antibody
US8975378B2 (en) 2008-12-25 2015-03-10 Osaka University Human anti-human influenza virus antibody
US9849172B2 (en) 2009-03-30 2017-12-26 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
WO2010132604A3 (fr) * 2009-05-13 2011-03-24 Sea Lane Biotechnologies, Llc Molécules neutralisantes dirigées contre les virus de la grippe
US10017561B2 (en) 2009-05-13 2018-07-10 I2 Pharmaceuticals, Inc. Neutralizing molecules to influenza viruses
US9175069B2 (en) 2009-05-26 2015-11-03 Icahn School Of Medicine At Mount Sinai Monoclonal antibodies against influenza virus generated by cyclical administration and uses thereof
ITTO20090414A1 (it) * 2009-06-01 2010-12-02 Pomona Biotechnologies Llc Anticorpi monoclonali come medicamento per il trattamento terapeutico e/o profilattico delle infezioni da virus influenzale a (h1n1) di origine suina (s-oiv)
WO2010140114A1 (fr) * 2009-06-01 2010-12-09 Pomona Biotechnologies Llc Anticorps monoclonaux en tant que medicament pour le traitement therapeutique et/ou prophylactique d'infections par le virus (s-oiv) de la grippe a (h1n1) d'origine porcine
US8486406B2 (en) 2009-06-01 2013-07-16 Pomona Ricerca S.R.L. Monoclonal antibodies as a medicament for the therapeutic and/or prophylactic treatment of swine-origin influenza A (H1N1) virus (S-OIV) infections
US20130209499A1 (en) * 2010-02-18 2013-08-15 Mount Sinai School Of Medicine Vaccines for use in the prophylaxis and treatment of influenza virus disease
US9701723B2 (en) * 2010-02-18 2017-07-11 Icahn School Of Medicine At Mount Sinai Vaccines for use in the prophylaxis and treatment of influenza virus disease
US10179806B2 (en) 2010-03-30 2019-01-15 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9708373B2 (en) 2010-03-30 2017-07-18 Icahn School Of Medicine At Mount Sinai Influenza virus vaccine and uses thereof
US10300140B2 (en) 2011-07-28 2019-05-28 I2 Pharmaceuticals, Inc. Sur-binding proteins against ERBB3
US10131695B2 (en) 2011-09-20 2018-11-20 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9975956B2 (en) 2011-12-22 2018-05-22 I2 Pharmaceuticals, Inc. Surrogate binding proteins which bind DR4 and/or DR5
US9969794B2 (en) 2012-05-10 2018-05-15 Visterra, Inc. HA binding agents
US10800835B2 (en) 2012-05-10 2020-10-13 Visterra, Inc. HA binding agents
US9096657B2 (en) 2012-05-10 2015-08-04 Visterra, Inc. HA binding agents
US8877200B2 (en) 2012-05-10 2014-11-04 Visterra, Inc. HA binding agents
US9968670B2 (en) 2012-12-18 2018-05-15 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US10137189B2 (en) 2012-12-18 2018-11-27 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US10583188B2 (en) 2012-12-18 2020-03-10 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9371366B2 (en) 2012-12-18 2016-06-21 Icahn School Of Medicine At Mount Sinai Influenza virus vaccines and uses thereof
US9908930B2 (en) 2013-03-14 2018-03-06 Icahn School Of Medicine At Mount Sinai Antibodies against influenza virus hemagglutinin and uses thereof
US10544207B2 (en) 2013-03-14 2020-01-28 Icahn School Of Medicine At Mount Sinai Antibodies against influenza virus hemagglutinin and uses thereof
US10736956B2 (en) 2015-01-23 2020-08-11 Icahn School Of Medicine At Mount Sinai Influenza virus vaccination regimens
US10513553B2 (en) 2015-11-13 2019-12-24 Visterra, Inc. Compositions and methods for treating and preventing influenza
US11266734B2 (en) 2016-06-15 2022-03-08 Icahn School Of Medicine At Mount Sinai Influenza virus hemagglutinin proteins and uses thereof
US11865173B2 (en) 2016-06-15 2024-01-09 Icahn School Of Medicine At Mount Sinai Influenza virus hemagglutinin proteins and uses thereof
US11254733B2 (en) 2017-04-07 2022-02-22 Icahn School Of Medicine At Mount Sinai Anti-influenza B virus neuraminidase antibodies and uses thereof
US11230593B2 (en) 2019-03-25 2022-01-25 Visterra, Inc. Compositions and methods for treating and preventing influenza

Also Published As

Publication number Publication date
AU1947183A (en) 1984-03-07
FI841583A0 (fi) 1984-04-19
KR840006198A (ko) 1984-11-22
EP0116629A4 (fr) 1987-06-29
JPS59501714A (ja) 1984-10-11
EP0116629A1 (fr) 1984-08-29
IL69556A (en) 1988-05-31
ZA836080B (en) 1984-04-25
IL69556A0 (en) 1983-11-30
PT77230B (en) 1986-02-04
NZ205341A (en) 1988-07-28
NO161002C (no) 1989-06-21
PT77230A (en) 1983-09-01
IT1168636B (it) 1987-05-20
NO841540L (no) 1984-04-17
AU570929B2 (en) 1988-03-31
DK203684D0 (da) 1984-04-18
DK203684A (da) 1984-04-18
IT8348868A0 (it) 1983-08-22
ES8505819A1 (es) 1985-06-16
GR78931B (fr) 1984-10-02
ES525088A0 (es) 1985-06-16
PH18872A (en) 1985-10-21
NO161002B (no) 1989-03-13
FI841583A (fi) 1984-04-19
NZ220612A (en) 1988-07-28

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