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WO1993003766A1 - Peptides antigeniques multiples destines a etre utilises comme vaccins contre le vih - Google Patents

Peptides antigeniques multiples destines a etre utilises comme vaccins contre le vih Download PDF

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Publication number
WO1993003766A1
WO1993003766A1 PCT/US1992/006688 US9206688W WO9303766A1 WO 1993003766 A1 WO1993003766 A1 WO 1993003766A1 US 9206688 W US9206688 W US 9206688W WO 9303766 A1 WO9303766 A1 WO 9303766A1
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WIPO (PCT)
Prior art keywords
peptide
sequence
seq
multiple antigen
maps
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PCT/US1992/006688
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English (en)
Inventor
James P. Tam
Albert T. Profy
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Repligen Corporation
The Rockefeller University
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Publication of WO1993003766A1 publication Critical patent/WO1993003766A1/fr

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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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/735—Fusion polypeptide containing domain for protein-protein interaction containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)
    • 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

  • MULTIPLE ANTIGEN PEPTIDES FOR USE AS HIV VACCINES Background of the Invention is vaccines for prevention and treatment of HIV infection.
  • Highly specific and immunogenic antigens are preferred as vaccines. While the i munogenicity of an antigen can be increased by coupling a protein carrier to the antigen, this approach has several drawbacks. First, if the carrier is large, significant humoral immune response can be directed against the carrier rather than the antigen. Second, a large carrier can suppress humoral response to the antigen. Finally, the coupling of an antigen to a protein carrier can alter the immunogenic determinants of the antigen.
  • MAPS Multiple antigen peptide systems
  • Most MAPS are composed of several peptide antigens covalently linked to a branching, dendritic core composed of bifunctional units (e.g., lysines) .
  • a cluster of antigenic epitopes form the surface of a MAPS and a small matrix forms its core.
  • the core is not immunogenic.
  • MAPS have been used to prepare experimental vaccines against hepatitis (Tam et al., Proc. Natl . Acad. Sci . USA 86:9084, 1989), malaria (Tam et al. , J. Exp. Med. 171:299, 1990), and foot-and-mouth disease.
  • a further advantage of MAPS is that they are chemically unambiguous. This allows different epitopes, such as B cell and T cell epitopes, to be arranged and a particular arrangement and stoichiometry.
  • European Patent Application 89200145.4 describes a process for preparing MAPS by reacting a branched structure based on an a ino acid such as lysine with a separately synthesized antigenic compound.
  • European Patent Application 89301288.0 describes peptides (CRIKQIINMWQEVGKAMYAPPISGQIRC (SEQ ID NO: 1), QSVEINCRTPNNNTRKSIRIQRGPGRAFVTIGK (SEQ ID NO: 2), and analogs thereof) which are specifically immunoreactive with antibodies to HIV and suggests that MAPS which include these peptides can be used for immunization to prevent HIV infection.
  • CAPS CAPS which include these peptides
  • PCT Application PCT/US90/02039 discloses multiple antigen peptide systems in which a large number of each of T cell and B cell malarial antigens are bound to the functional groups of a dendritic core molecule.
  • the invention features a multiple antigenic peptide system including a dendritic core and a peptide, wherein the peptide includes the se uence IGPGR (SEQ ID NO: 3) , and the multiple antigen peptide system, when injected into a mammal, is capable of eliciting an immune response.
  • the peptide includes a pair of six amino acid sequences flanking the sequence IGPGR (SEQ ID NO: 3) , the flanking sequences taken together having at least 36% ho ology to the pair of six amino acid sequences flanking the sequence IGPGR within the V3 loop of HIV-I-MN prototype virus.
  • the V3 loop sequence of the gpl20 envelope protein of HIV-I-MN includes the 35 amino acids of HIV-I-MN from the invariant cysteine at position 303 to the invariant cysteine at position 3-8, inclusive.
  • the HIV-I-MN prototype virus is defined by a particular amino acid subsequence within the V3 loop region of the gpl20 envelope protein having the sequence KRKRIHIGPGRAFYTTK (SEQ ID NO: 4) . (Amino acid sequences are presented in the standard single-letter code throughout.)
  • the peptide includes the sequence KRKRIHIGPGRAFYTTK (SEQ ID NO: 4).
  • the multiple antigenic peptide system includes a T cell epitope.
  • the T cell epitope is covalently linked in tandem to the peptide; the T cell epitope includes the sequence QIINMWQEVGKAMYA (SEQ ID NO: 5) .
  • T cell epitope is meant a peptide capable of eliciting a proliferative T cell response.
  • the T cell epitope is at least seven amino acids long.
  • the dendritic core includes lysine; the dendritic core is tetravalent.
  • the peptide is between 10 and 40 amino acids long.
  • the peptide includes the sequence HIGPGR (SEQ ID NO: 6) ; the peptide includes the sequence IHIGPGR (SEQ ID NO: 7) , the peptide includes the sequence RIHIGPGR (SEQ ID NO: 8) ; the peptide includes the sequence IGPGRA (SEQ ID NO: 9) ; the peptide includes the sequence IGPGRAF (SEQ ID NO: 10) ; the peptide includes the sequence KRKRIHIGPGRAFYTTKN (SEQ ID NO. 11) .
  • the invention features a method of immunizing a mammal to inhibit HIV infection.
  • the method includes administering to the mammal the multiple antigen peptide system described above.
  • the invention features a method for eliciting an immune response against HIV in a mammal.
  • the method includes administering to the mammal the multiple antigen peptide system described above.
  • the invention features a vaccine which includes an immunologically effective amount of the multiple antigen peptide system described above.
  • the invention features a method for generating antibodies. The method includes administering to a mammal an antibody-generating amount of the multiple antigen peptide system described above.
  • Multiple antigen peptide system is the commonly used name for a molecule composed of two or more, usually identical, antigenic molecules covalently attached to a dendritic core which is composed of bifunctional units.
  • the dendritic core molecule is a branching molecule in which a first bifunctional unit is linked to two additional bifunctional units each of which may be attached to two additional bifunctional units to form a third generation molecule.
  • This pattern may be repeated any number of times to form higher generation molecules.
  • the number of free functional groups is equal to 2 n , where n is equal to the generation of the molecule.
  • a third generation molecule thus has 8 free functional groups which can be attached to 8 peptides.
  • Figure 1 is a schematic representation of several tetravalent MAPS and the sequences of the peptides attached to the lysine core.
  • T cell epitopes are represented by the shaded rectangles in the schematic drawings;
  • B cell epitopes are represented by unshaded rectangles.
  • the amino acid sequences of peptides B1-B9 and T are listed.
  • Figure 2 is a pair of graphs which depict the results of ELISA assays used to measure mouse antisera binding to HIV-I-III B peptides (panel A) and HIV-I-III B gpl20 (panel B) .
  • Antisera were raised using Bl peptide (filled circles) , B2 peptide (open circles) , and B3 peptide (filled squares) .
  • Antisera, serially diluted, were tested for their binding activity to wells coated either with 5 ⁇ g of the same peptide used to raise the antisera (panel A) or 0.1 /g of recombinant gpl20 (panel B) .
  • Goat anti-mouse IgG was used as secondary antibody.
  • the mean absorbance (405 nm) is plotted as a function of the reciprocal dilution of antisera.
  • Figure 3 is a graph which depicts the results of ELISA assays used to measure mouse antisera binding to peptide B4T. Antisera were obtained after three intraperitoneal immunizations with MAP-B4T (solid circles) or B4T peptide (open squares) .
  • the mean absorbance (405 nm) is plotted as a function of the reciprocal dilution of antisera.
  • HIV-I-MN and HIV-I-MN Viral Variant Peptides in MAPS
  • MAPS which include peptides derived from the V3 loop of the HIV-I external envelope protein (gpl20) were used to raise antisera in mice, rabbits and guinea pigs.
  • the V3 loop of gpl20 includes all of the amino acids from cysteine 303 to cysteine 338 of HIV-I. In intact gpl20 a disulfide bond between these two cysteines forms a loop (V3 loop) .
  • the V3 loop represents one of the most variable regions of the envelope protein.
  • sequence of the V3 loop varies by as much as 50%.
  • Multiple antigen peptide system is the commonly used name for a combination antigen/antigen carrier that is composed of two or more, usually identical, antigenic molecules covalently attached to a dendritic core which is composed of bifunctional units.
  • the dendritic core of a multiple antigen peptide system can be composed of lysine molecules.
  • a lysine is attached via peptide bonds through each of its amino groups to two additional lysines.
  • This second generation molecule has four free amino groups each of which can be covalently linked to an additional lysine to form a third generation molecule with eight free amino groups.
  • a peptide may be attached to each of these free groups to form an octavalent multiple peptide antigen.
  • the second generation molecule having four free amino groups can be used to form a tetravalent MAPS, i.e. , a MAPS having four peptides covalently linked to the core.
  • Many other molecules, including aspartic acid and glutamic acid, can be used to form the dendritic core of a multiple peptide antigen system.
  • the dendritic core, and the entire MAPS may be conveniently synthesized on a solid resin using the classic Merrifield synthesis procedure.
  • antigen carrier systems have many advantages as antigen carrier systems. Their exact structure and composition is known; the ratio of antigen to carrier is quite high; and several different antigens, e.g., a B cell epitope and a T cell epitope, may be attached to a single dendritic core. When both a B cell epitope and a T cell epitope are present it is preferable that they are linked in tandem on the same functional group of the dendritic core. Alternatively the T cell epitope and the B cell epitope may be on separate branches of the dendritic core. Preferably, the T cell epitope is a helper T cell epitope; however a cytotoxic T cell epitope may also be used.
  • T cell epitopes may be derived from the HIV-I envelope protein. However, it is not necessary that the B cell epitope and the T cell epitope both be derived from the HIV-I gpl20 envelope protein. T cell epitopes from different HIV-I proteins (e.g., those encoded by the nef , gag, tat, rev, vif, pol , vpr, vpu , or vpx genes), different retrovirus, or unrelated organisms (e.g., malarial antigens or tetanus toxoid) may be used. T cell epitopes can be identified by a T cell proliferation assay (described herein below) .
  • Synthesis of peptides Synthetic peptides were prepared manually by a stepwise solid-phase peptide synthesis (Tam, Proc. Nat 'l . Acad . Sci . USA 85:5409, 1988; Merrifield, Science 232:341, 1986) on t-butoxycarbonyl (Boc)-Ala-OCH 2 -Pam resin (Mitchell et al., J. Am . Chem .
  • a resin coupled to a t-butoxycarbonyl-substituted (Boc-substituted) amino acid is reacted with 50% trifluoroacetic acid to remove Boc and the resulting salt is neutralized with diisopropoylethylamine.
  • the first part of the lysine core is then added by reacting the amino acid-coupled resin with Boc-Lys(Boc) in dimethylformamide followed by reaction with dicyclohexylcarbodiimide and CH 2 C1 2 -
  • a second such synthetic cycle yields a branched tetrapeptide on which four peptides may be synthesized using conventional solid-phase synthesis techniques. It is also possible to separately synthesize the lysine core and the peptides and then couple the peptides to the core in a subsequent step (European Patent Application 89200145.4) .
  • peptides which have been circularized prior to attachment to the dendritic backbone. This circularization can be accomplished via disulfide bond formation between cysteines present in the peptide. Such an arrangement is particularly desirable for peptides derived from the V3 loop of gpl20 since the sequence in this region forms a loop in the intact virus.
  • Immunization procedure The animals were injected four times, at two week intervals, using complete Freund's adjuvant (Sigma, St. Louis, MO) for the first injection, and incomplete Freund's adjuvant for the booster injections. Mice (five for each peptide) received intraperitoneally 50 ⁇ g of the peptide for each injection.
  • Guinea pigs received subcutaneously 100 ⁇ g of the peptides the first and second injections and 50 ⁇ g for the last two injections. Rabbits (two for each peptide) were injected intradermally with 400 ⁇ g (first injection, day 0) and 200 ⁇ g (second injection, day 14) and subsequently intramuscularly with 200 ⁇ g of the peptides at day 28 and day 42. The animals were bled immediately before each injection. The antisera used for the reported experiments were obtained fifteen days after the last injection.
  • ELISA Assays Mouse and rabbit antisera were analyzed by standard direct ELISA using flat-bottomed microplates (Maxisorp, Nunc, Denmark) coated with 5 g/well of each peptide or 0.1 ⁇ g/well of purified recombinant gpl20 (Repligen, Cambridge, MA) . The assays of the guinea pig sera were performed using plates coated with the 24 amino acid peptides, RP135 (III B ) , RP139 (RF) , and RP142 (MN) (Rusche et al., Proc . Nat 'l Acad Sci . USA 85:3198, 1988).
  • the plates were blocked for 90 min at 37°C with the diluent buffer (PBS + 1% calf serum) .
  • Phosphatase- conjugated goat secondary antibody (Sigma) , diluted 1:1000, was then added for 2 hr at 37°C. After an additional three washes, the substrate p-nitrophenyl phosphate (1 mg/ l; Sigma) in diethanolamine buffer (pH 9.8) was added, and the bound secondary antibody was detected at 405 nm.
  • the antibody titer was calculated as the reciprocal of the antiserum dilution giving the half maximal response.
  • the optical density obtained with preimmunization sera was always less than 0.1 units.
  • the recombinant virus expressing the env gene is used to infect CD4+ cells (e.g., CEM, M0LT4, or SUP-T1 cells) .
  • CD4+ cells e.g., CEM, M0LT4, or SUP-T1 cells
  • the HIV envelope protein presented on the surface of these cells will bind to the cell surface receptor, CD4, resulting in the fusion of the cells and the formation of giant multinucleated cells called syncytia.
  • Syncytium formation can be assayed in the presence or absence of antiserum at a series of dilutions. The number of syncytia that are formed are quantified at an appropriate time post-infection.
  • the preferred MAPS are those which raise antisera that inhibits syncy
  • CD4-positive CEM cells (Accession Number CCL119, American Type Culture Collection, Rockville MD) were infected with recombinant vaccinia viruses expressing full length gpl60 at a multiplicity of infection of 1.
  • HIV-I-III B and HIV-I-RF the recombinant virus expressed the entire envelope gene.
  • HIV-I-MN the recombinant virus expressed the V3 region of HIV-I-MN inserted into the gpl60 of HIV-I-III B as described by Scott et al. (Proc. Nat 'l . Acad. Sci . USA 87:8597, 1990).
  • Immune sera were added to the cultures 1 hr post-infection and syncytia were counted 24 hr post-infection.
  • the fusion inhibition titer for each immune serum is defined as the reciprocal of the dilution which reduces the number of syncytia to 10% of the number observed in the presence of a normal serum control.
  • Antisera can also be assessed using a viral neutralization assay.
  • viral reverse transcriptase activity is used as a measure of viral activity. Dilutions of antiserum are incubated with HIV and are than added to HIV susceptible CD4+ cells.
  • Such an assay is described by Robey et al., Proc . Nat 'l . Acad. Sci . USA 83:7023, 1986; Popovic et al., Science 224:497, 1984; and Robert-Guroff, Nature 316:72, 1985).
  • PEPSCAN Antigen domains can be identified by pepscan analysis as described by Geyson et al. (J. Immunol . Methods 102:259, 1987).
  • overlapping peptides derived from the sequence of a peptide to be analyzed can be synthesized on the tips of polyethylene rods.
  • the rods are then assembled into a holder with the format of a microtiter plate. All the subsequent reactions can be carried out at the tips of the rods using a microtiter plate. Nonspecific binding can be avoided by the incubation for 1 hr at room temperature with diluent buffer.
  • the rods are then incubated with diluted antiserum for 16 hr at 4°C, washed 4 times in 0.05% Tween 20 in PBS and incubated with a secondary antibody, (e.g., goat anti-mouse or anti-rabbit IgG) coupled to alkaline phosphatase for 1 hr at room temperature.
  • a secondary antibody e.g., goat anti-mouse or anti-rabbit IgG
  • the presence of the conjugate antibody on the tips can then be detected by reaction with substrate solution.
  • Syncytia Inhibition Assay A recombinant vaccinia virus syncytium inhibition assay can be used to assess the effectiveness of antisera raised using the MAPS herein described.
  • This assay can be performed using cells infected with a vaccinia virus expressing an HIV env gene rather than actual HIV infected cells. Construction of a recombinant vaccinia virus capable of expressing the full-length HIV envelope gene from a vaccinia virus promoter is described in EP Publication No. 0 243 029, hereby incorporated by reference.
  • Antibody Response to Mono-Epitope MAPS Nine peptides from the V3 regions of HIV-I isolates III B , RF and MN were incorporated into tetravalent MAPS (prepared as described above) . These MAPS are designated MAP Bl through B9 to indicate that they include a B cell epitope. Referring to Fig.
  • ELISA assays demonstrated that antisera titers in mice were closely related to the length of the III B peptide used for the immunization, with the MAPS using the longest peptide (Bl, amino acids 308-331) inducing the strongest response, followed by the MAPS using the intermediate peptide (B2, amino acids 312-328) which elicited a reduced reactivity, while the MAPS using the shortest peptide (B3, amino acids 315-325) was completely non- immunogenic. The same pattern of ELISA reactivity was observed against native gpl20 protein (Fig. 2, panel B) .
  • ELISA assay of the rabbit antisera showed that nearly all of the mono-epitope MAPS were able to elicit strong responses; antibody titers varied from the highest value (1.2 x 10 6 ) in the antisera of rabbits immunized by the B2 and B8 peptides, to the lowest (2.3 x 10 4 ) found in the antisera of rabbits injected with the shortest peptide of the RF series (B6) .
  • Synthetic HAP peptides containing HIV-I B cell or B cell and T cell epitopes from different HIV- i isolates were used to inoculate animals.
  • the resulting immune sera were assayed by ELISA against the immunizing peptide; the antibody titers are presented as the geometric mean ( ⁇ SEM) of endpoint dilutions corresponding to antisera from five (mice) or two (rabbits) animals.
  • ELISA with guinea pig antisera was performed using plates coated with 24 amino acid peptides RP135 (IIIB), RP139 (RF), or RP142 (MN). Titers are the geometric mean ( ⁇ SEM) of endpoint dilutions of the antisera from three animals.
  • Each di- epitope MAPS contains a tandem configuration in which a T-helper cell peptide derived from HIV-I envelope protein was added at the carboxyl-end of each B cell peptide. Accordingly, these MAPS are referred to as MAP BIT through MAP B9T to indicate that they include a T cell epitope in addition to one of the B cell epitope peptides, B1-B9.
  • Peptide blocking ELISA assays were performed with a dilution of rabbit antisera giving an absorbance between 1.3 and 1.6. The wells were coated with 5 ⁇ g of the indicated peptide. The competing peptide was present at 50 g/ml.
  • a T cell poliferation assay was performed using BIT MAPS and B3T MAPS. Lymph node cells from antigen-primed
  • mice were cultured in vitro with the same BT MAPS used for the immunization or with the corresponding B cell epitope MAPS. As shown in Table 5, lymph node cells from mice immunized with BIT MAPS proliferated when cultured with Bl MAPS (which appears to have a helper deteminant) and even more strongly when the BIT MAPS was used for the in vitro stimulation. Further, the B3T
  • MAPS-primed cells exhibited a high level of proliferation following stimulation with the di-epitope B3T MAPS. In contrast, the B3 peptide did not induce proliferation.
  • mice (3 Balb/c per group) were injected with 50/ ⁇ g MAPS in Fruend's complete adjuvant. Restimulated with 10/ ⁇ g/ml MAPS in virto.
  • Table 6 demonstrates that the majority of the rabbits developed antisera that inhibited syncytia formation in a culture expressing envelop of the same strain used as an immunogen.
  • the data suggest that inhibitory antibodies are elicited primarily by the di- epitope MAPS for the RF series and to some extent for the III B series.
  • the T cell epitope does not seem to influence the response of MAPS in the MN series which appears to be significantly greater than the response elicited by MAPS in the III B and RF series.
  • BIT MAP induced an antisera which was better at inhibiting syncytia formation than Bl MAP.
  • a clear correlation between the titer observed in ELISA assay and the syncytium inhibition activity of the antibodies was not evident, since antisera which show very high peptide binding capacity were less effective than others in inhibiting syncytium formation.
  • Table 7 presents the results of similar syncytium inhibition assays in guinea pigs. These data show that MAPS in the MN series elicit a better immune response than MAPS in the RF or III B series and that the B8 peptide appears to be the most effective peptide in the MN series. Table 7: MAPS-Induced Guinea Pig antisera syncytia inhibition titers against different HIV-I isolates **1
  • Fusion inhibition titer is the reciprocal of the dilution that reduces the number of syncytia by 90%. Serum from three guinea pigs in each group was analyzed.
  • the MAPS of the invention may be administered by direct injection into the blood stream. They may also be incorporated into polymeric microcapsules (e.g., liposomes) and/or administered with an adjuvant (e.g., alum) . Liposome-encapsulated antigens often elicited a higher antibody titer than non-encapsulated antigens.
  • polymeric microcapsules e.g., liposomes
  • an adjuvant e.g., alum
  • Lys Arg Lys Arg lie His lie Gly Pro Gly Arg Ala Phe Tyr Thr Thr

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Abstract

L'invention présente en général un système de peptides antigéniques multiples comprenant un noyau dendritique et un peptide, ce dernier comprenant la séquence IGPGR (SEQ ID NO:3). Lorsqu'on l'injecte dans un mammifère, ce système de peptides antigéniques est à même de provoquer une réponse immunitaire.
PCT/US1992/006688 1991-08-13 1992-08-11 Peptides antigeniques multiples destines a etre utilises comme vaccins contre le vih WO1993003766A1 (fr)

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Cited By (12)

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WO1995007929A1 (fr) * 1993-09-13 1995-03-23 Armel S.A. Constructions de peptides a branches multiples destines a etre utilises contre le vih
GB2282378A (en) * 1993-09-30 1995-04-05 Merck & Co Inc Conjugates of epitopes of HIV with a protein complex from Neisseria
US5622933A (en) * 1993-09-13 1997-04-22 Armel S.A. Multiple branch peptide constructions for use against HIV
EP0765357A4 (fr) * 1994-06-15 1997-07-30 Biomolecular Res Inst Ltd Dendrimeres antiviraux
US5674977A (en) * 1993-02-05 1997-10-07 The Ontario Cancer Institute Branched synthetic peptide conjugate
WO1998029443A1 (fr) * 1996-12-31 1998-07-09 Armel S.A. Constructions de peptides a plusieurs ramifications
US6355238B1 (en) 1992-11-18 2002-03-12 Yale University Specific immune system modulation
US6582700B1 (en) 1997-11-18 2003-06-24 Medical University Of South Carolina Linear antigen supporting units
US6607722B2 (en) 1999-04-20 2003-08-19 Richard Leslie Edelson Methods for inducing the differentiation of monocytes into functional dendritic cells
US7618637B2 (en) 1995-08-18 2009-11-17 Sloan-Kettering Institute For Cancer Research Heat shock protein-based vaccines and immunotherapies
US8524461B2 (en) 2003-04-11 2013-09-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Multiple antigenic peptide assay for detection of HIV or SIV type retroviruses
EP2367567A4 (fr) * 2008-08-05 2014-12-03 Univ Queensland Squelettes présentant un antigène

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EP0328403A2 (fr) * 1988-02-12 1989-08-16 United Biomedical Inc. Peptides synthétiques relatifs à la protéine HIV-GP120-env. et leur application
EP0339695A2 (fr) * 1988-04-29 1989-11-02 Stichting Voor De Technische Wetenschappen Procédé de préparation d'un conjugué antigénique ou immunogénique ainsi que l'utilisation de tels conjugués

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Publication number Priority date Publication date Assignee Title
EP0328403A2 (fr) * 1988-02-12 1989-08-16 United Biomedical Inc. Peptides synthétiques relatifs à la protéine HIV-GP120-env. et leur application
EP0339695A2 (fr) * 1988-04-29 1989-11-02 Stichting Voor De Technische Wetenschappen Procédé de préparation d'un conjugué antigénique ou immunogénique ainsi que l'utilisation de tels conjugués

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PROC. NATL. ACAD. SCI. USA, Vol. 87, issued November 1990, C.F. SCOTT JR. et al., "Human Monoclonal Antibody that Recognizes the V3 Region of Human Immunodeficiency Virus gp120 and Neutralizes the Human T-Lymphotropic Virus type IIIMN Strain", pages 8597-8601. *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 263, No. 4, issued February 1988, D.N. POSNETT et al., "A Novel Method for Producing Anti-Peptide Antibodies", pages 1719-1725. *
THE JOURNAL OF IMMUNOLOGY, Vol. 142, No. 10, issued 15 May 1989, T.J. PALKER et al., "Polyvalent Human Immunodeficiency Virus Synthetic Immunogen Comprised of Envelope gp120 T Helper Cell Sites and B Cell Neutralization Epitopes", pages 3612-3619. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6355238B1 (en) 1992-11-18 2002-03-12 Yale University Specific immune system modulation
US5674977A (en) * 1993-02-05 1997-10-07 The Ontario Cancer Institute Branched synthetic peptide conjugate
AP502A (en) * 1993-09-13 1996-06-07 Cellpep Sa Multiple branch peptide constructions for use against HIV.
US5622933A (en) * 1993-09-13 1997-04-22 Armel S.A. Multiple branch peptide constructions for use against HIV
WO1995007929A1 (fr) * 1993-09-13 1995-03-23 Armel S.A. Constructions de peptides a branches multiples destines a etre utilises contre le vih
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