WO2004014945A1 - Epitope de la gp41 et utilisations de celui-ci pour le traitement d'infections au vih - Google Patents

Epitope de la gp41 et utilisations de celui-ci pour le traitement d'infections au vih Download PDF

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Publication number
WO2004014945A1
WO2004014945A1 PCT/IB2003/003149 IB0303149W WO2004014945A1 WO 2004014945 A1 WO2004014945 A1 WO 2004014945A1 IB 0303149 W IB0303149 W IB 0303149W WO 2004014945 A1 WO2004014945 A1 WO 2004014945A1
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hiv
iga
peptide
peptides
specific
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PCT/IB2003/003149
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English (en)
Inventor
Lucia Lopalco
Mario Clerici
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Fondazione Centro S. Raffaele Del Monte Tabor
Istituto Superiore Di Sanita'
Universita' Degli Studi Di Milano
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Priority to AU2003255866A priority Critical patent/AU2003255866A1/en
Publication of WO2004014945A1 publication Critical patent/WO2004014945A1/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
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention regards the identification of a gp41 epitope recognized by the IgA present in the serum and mucosa of individuals with natural immunity to HIV. More specifically the invention is directed to pharmaceutical compositions containing the peptides corresponding to the novel gp41 epitope, the use of said peptides and of antibodies thereto in the immunoprevention or immunotherapy of individuals exposed or at risk of exposure to HIV virus, HIV-infected subjects or AIDS patients.
  • the cell mediated immune responses observed over time in EU include: a) CD4+ and type 1 cytokine- secreting T helper cells; b) CD4+ beta chemokine-producing T helper cells and c) CD8+ and MCH class I-restricted cytotoxic T lymphocytes.
  • HIV- specific humoral immune responses consist in the production of anti cell antibodies and urinary, cervico-vaginal and serum IgA that have the capability of neutralizing primary HIV isolates. Genetic factors can also modulate susceptibility to HIV infection. The first evidence of such factors was provided by the observation that rare individuals homozygous for a deletion ( ⁇ 32) within the CCR5 receptor gene are resistant to R5 HIV strains- supported infection.
  • the antibody 2F5 produced against the epitope ELDKWA has been the only monoclonal antibody against gp41 to effectively inhibit HIV replication in vitro; therefore 2F5 has been used "in vivo" for the passive immunotherapy of SIV infection in primates(the SIV virus, which is similar to HIV, is primate- specific). Passive immunotherapy with a combination of monoclonal antibodies against gp60 - including 2F5 - proved able to protect primates against mucosal and systemic SIV infection (Nat. Med. 2000; 6:200-206 and 207-210). DESCRIPTION OF THE INVENTION
  • IgA isolated from sera of HIV-exposed uninfected individuals (EU) and HIV-seropositive individuals (HIV+) were analyzed to establish which region in the HIV envelope is recognized by IgA, and to verify whether different epitopes are responsible for virus neutralization in HIV-resistant and HIV- infected individuals.
  • Sera from heterosexual couples discordant for HIV serostatus and from HIV-infected subjects were analyzed, using sera from healthy subjects (HC) as negative controls. IgA binding on HIV-env recombinant proteins was assayed. Serum IgA from EU and HIV+ were affinity purified on specific peptides corresponding to different regions of viral envelope, and tested in an HIV neutralization assay using resting and activated PBMC as target cells. Mab 2F5 was used as neutralizing positive control. While IgA of HIV+ patients recognized epitopes expressed in both gpl20 and gp41 env-proteins, IgA of EU exclusively bound epitopes within gp41.
  • IgA from EU specifically bound a gp41 epitope located in the "leucin-zip" motif in the alpha helix region, corresponding to the peptide with sequence QARILAV (aa 582-588).
  • This peptide (“peptide 1"), as well as the gp41 nona-peptide of sequence LQARILAVE (“peptide 2”), proved particularly effective in terms of immunogenicity and HIV-neutralizing activity.
  • antisera from Balb/C mice immunized with peptides 1 and 2 blocked syncytia formation and viral replication.
  • IgA purified from human sera using peptides 1 and 2 neutralized the infectivity of different primary isolates derived from lymphocytes of HIV-seropositive patients.
  • peptide-specific IgA inhibited the replication of different viral strains (from different Continents).
  • the dose-response neutralization curve was very similar to that obtained with the monoclonal antibody Mab 2F5.
  • the invention regards the peptides QARILAV (Gin Ala Arg He Leu Ala Val) and LQARILAVE (Leu Gin Ala Arg He Leu Ala Val Glu) isolated from gp41, and their use for the prevention and immunotherapy of HIV-infections. Since the region containing the gp41 epitope is highly conserved in all HIV and lentivirus strains as well, the invention peptides can be used to prevent or treat infections caused by different HIV and lentivirus strains.
  • QARILAV Ga Ala Arg He Leu Ala Val
  • LQARILAVE Leu Gin Ala Arg He Leu Ala Val Glu
  • the peptides can be synthetically prepared, following the procedures described in Merrifield, (1986) Science 232:341-347, and Barany and Merrifield, The Peptides, Gross and Meienhofer, eds (N.Y., Academic Press), pp. 1-284 (1979).
  • the synthesis can be carried out in solution or in solid phase or with an automatic synthesizer (Stewart and Young, Solid Phase Peptide Synthesis, 2 nd ed., Rockford 111., Pierce Chemical Co., 1984).
  • the peptide amino and carboxyl ends can be added with one or more amino acids, or the peptide can be conjugated to different molecules to increase the immunogenicity or improve the pharmacokinetics, provided that these modifications do not cause reduction or loss of the neutralizing activity of the peptide.
  • modifications include amidation or esterification of the carboxyl terminus, addition of lipophilic groups (e.g. myristyl group) and glycosylation.
  • a further embodiment of the invention regards monoclonal or polyclonal antibodies specific for the peptides QARILAV and LQARILAVE.
  • the antibodies can be produced by animal immunization followed by purification, or with genetic engineering techniques, after isolating and identifying the sequence of a specific antibody, preferably a human antibody immunore acting with the invention peptide.
  • Techniques for producing polyclonal antibodies are known in the art and are described for example in Mayer and Walker eds., "Immunochemical Methods in Cell and Molecular Biology", Academic Press London (1987).
  • Methods for purifying antibodies are known in the art and comprise immunoaffinity chromatography.
  • the antibodies may be further manipulated, e.g.
  • human antibodies are used, preferably of the IgA type.
  • the antibodies to the invention peptides can be used for passive-immunization of subjects exposed or at risk of exposure to HIV, or for immunotherapy of HIV-infected patients.
  • the invention provides pharmaceutical compositions containing an effective amount of at least one of the peptides herein disclosed, or antibodies thereto.
  • the compositions can be administered by the oral, parenteral or topical routes.
  • the topical route especially the transmucosal route, is particularly preferred, since the HIV infection is mainly transmitted through the genital mucosa, which is the first physiological barrier to virus entry, and because of IgA blocking of HIV transcytosis from the mucosal to the systemic repertoire.
  • the parenteral administration e.g. by the intravenous or intramuscular routes, is preferred.
  • the techniques for preparing pharmaceutical compositions are known to the skilled person and can be found for instance in Remington's Pharmaceutical Science, 17° ed., Mack Publishing Company, Easton, PA (1985), herein incorporated by reference.
  • the invention peptides or derivatives thereof are prepared and administered in the form of vaccine.
  • Theory and practice of vaccination are known to anyone skilled in the art, see for example Paul, "Fundamental Immunology” Raven Press, New York (1989) or Cryz, S. J., "Immunotherapy and vaccines", VCH Verlagsgesselshaft (1991).
  • Vaccines are conventionally prepared in the form of injectables, suspensions or solutions, but they can also be used in the form of solid preparations or liposomes.
  • the peptides of the invention, or their derivatives, can be mixed with pharmacologically acceptable excipients, such as emulsifiers, buffering agents and adjuvants which increase the efficacy of the vaccine.
  • pharmacologically acceptable excipients such as emulsifiers, buffering agents and adjuvants which increase the efficacy of the vaccine.
  • the latter can be administered according to single or multiple dosage schedule. Multiple dose provides 1 to 10 separate doses, each containing a quantity of antigen varying from 1 ⁇ g to 1000 ⁇ g, preferably from 5 to about 250 ⁇ g, followed by further doses at subsequent time intervals, necessary to maintain or to reinforce the immune response and, if required, a further dose after several months.
  • the treatment regimen will depend on the response of the treated patient and on his general health conditions.
  • the immunization with preparations containing an invention peptide or derivatives thereof can be applied to subjects exposed or at risk of exposure to HIV virus or as a therapeutic support for HIV-infected patients.
  • the invention is also directed to a nucleic acid molecule encoding an invention peptide.
  • the sequences encoding peptides 1 and 2 are preferably CAGGCAAGAATCCTGGCTGTG and CTCCAGGCAAGAATCCTGGCTGTGGAA, respectively.
  • the choice of the coding nucleotide sequence depends on the expression system to be used, and can be varied by virtue of genetic code degeneracy.
  • the invention further comprises an expression vector wherein said nucleic acid sequence is operatively linked to a heterologous promoter, and a host cell for peptide production containing said expression vector.
  • the DNA molecules coding for the invention peptides and their genetic constructs can be used in the vaccination of subjects exposed or at risk of exposure to HIV, or in the treatment of HIV-infected patients.
  • the DNA immunization can be carried out according to known procedures (Donnelly J.J. et al., 1994, The immunologist 2: 1).
  • the intramuscular administration route is preferred, but the parenteral and mucosal routes can be used as well (PNAS 1986, 83, 9551; WO90/11092).
  • the DNA can be adsorbed onto gold particles and transdermally administered with a biolistic apparatus (Johnston, 1992 Nature, 356, 152).
  • the peptide-specific amino acid and nucleotide sequences can be used for the development of a prognostic test. Accordingly, the peptide may represent a marker of previously-occurred exposure without viral transmission. This prognostic test could be applied to any population at risk of exposure to HIV, so as to exactly determine the number and type of individuals that should be subjected to therapeutic prophylaxis.
  • Fig. 1 Neutralizing activity of i) total IgA from EU and HIV+, ii) purified fraction containing anti-peptide 1 and 2 (pep#l/2) IgA from EU, and iii) fraction without anti-peptide 1/2 IgA from HIV+; total IgA from HC
  • Fig. 2 Binding to gp41 of mouse antisera against peptides 1 and 2. A non-correlated mouse serum was used as negative control.
  • Fig. 3 Modulation of HIV-1 infectivity by mouse antisera against peptides 1-2. A non-correlated mouse serum was used as negative control.
  • Fig. 5 In vitro model of transcytosis inhibition.
  • Fig. 6 Transcytosis inhibition by IgA specific for the sequence
  • Fig. 7 Titration of sera from mice immunized with Leu581 peptide, corresponding to the III, V, VII and XI immunization.
  • Fig. 8 Titration of sera from mice immunized with peptide QUARILAV, corresponding to immunization III, V, VII and XI.
  • Fig. 9 Quantitative analysis of total antibodies and antibodies specific for different peptides after immunizations of two different mice.
  • Sepharose 4B CNBr activated (Pharmacia, Uppsala, Sweden) was coupled with rabbit anti human IgA (2mg/ ⁇ l) (Aldrich, Milan, Italy) by standard methods. In brief, 96 ⁇ l of serum were incubated at room temperature for 15' on columns containing 2400 ⁇ l of sepharose -anti IgA. The columns were washed, IgA were eluted with Glycine/NaCl 0.2 M, and the solution was neutralized with 1M Tris pH 11. Purified IgA were concentrated on Ultrafree- 15 Biomax30 membranes (cut off 30kDa)(Milli ⁇ ore, Bedford, MA, USA). IgA were also purified on sheep anti human IgA sepharose-conjugated columns to exclude the presence of cross-reactive material using the same procedure.
  • HIV peptides were directly coated onto Dynabeads M280 tosylactivated (Dynal, Oslo, Norway) by standard procedures. Briefly, 3x10 ⁇ beads were incubated with 9 ⁇ g of each peptide in borate buffer pH 9.5 for 16 h at 37°C. After 4 washes (in PBS), the peptide-conjugated beads were ready for use.
  • Binding of IgA from EU, healthy donors and HIV-seropositive subjects to each env peptide/bead was obtained by incubating 9 ⁇ g of purified IgA to 9 ⁇ g peptide/bead for lh at 4°C. Beads-conjugated IgA were eluted from the beads in acetic acid 0.5 M and dialized.
  • IgA/peptide depleted were tested in ELISA assay. Microwells plates were coated with all fractions at different dilutions (starting from 1/1 to 1/16 by two-fold dilutions). IgA binding was revealed with HRP conjugated rabbit anti human IgA (Dako, Santa Barbara, CA).
  • the IgA eluted from each peptide/bead complex were tested in ELISA (Table). Microwells plates were coated with gp41/gpl20 recombinant proteins at 0.1 ⁇ g/wells by overnight incubation in NaHC0 3 /Na 2 C0 3 buffer. The plates were satured for lh with PBS and 3% BSA. Eluted IgA were added and incubated for lh at 37°C. IgA binding was revealed with HRP conjugated rabbit anti human IgA (Dako, Santa Barbara, CA). The enzymatic reaction was developed and read at 492nm. Competition assays were performed by preincubating IgA (1.5 nM) with 100 fold in excess of specific synthetic peptides (150 nM) for 30 min at 37°C prior to addition to the microplates.
  • mice were immunized i.p. every 15 days with peptides QARILAV or LQARILAVE (three mice per peptide) or with an unrelated control peptide (VQGEESNDK) (two mice); both peptides had previously been conjugated to KLH (50 ⁇ g/dose). Serum was monitored for the presence of antibodies against the immunogens. When the specific serum titer was > 1 :
  • mice 1,500 dilution, mice were sacrificed and sera were tested in neutralization assay.
  • HIV was isolated from PBMC of HIV-seropositive individuals by co- coltivation with PHA- stimulated PBMC from two healthy donors. The cultures were maintained as long as increasing levels of HIV-p24 antigen were detectable in two consecutive determinations (ranging from 10 to 18 days). The infectivity (LD50) of each virus isolate was determined on PBMC from a single donor. Virus was diluted by five-fold dilutions, beginning with 1/5.
  • ID 50 titers were defined as the reciprocal of the virus dilution resulting in
  • Virus neutralization assays Neutralization activity of purified IgA was measured by standardized methods. Briefly, 2x10 resting or activated (in this latter case, the cells were cultured in medium containing PHA and IL2 for 48h before the neutralizing assay) PBMC from a healthy donor were added to 96 microplate wells. Seventy-five ⁇ l of primary virus dilutions containing TCID50 (range 10 to 32) of each HIV-1 primary isolate was added to 75 ⁇ l of serial dilutions of serum purified IgA fraction (30, 10, 3, 1 ⁇ g/ml) and serum IgA depleted fraction, incubated for lh and added to the PBMC.
  • TCID50 range 10 to 32
  • 8E5 (LAV) cells and MOLT3 cells were grown in RPMI 1640 at lO ⁇ /ml, washed, mixed in 1:2 proportion, and distributed in V-shaped microtiter wells (1.6x10 ⁇ cells/well) together with IgA from EU or from healthy controls or mouse antisera in appropriate dilutions. After 30 min incubation at 37°C, the cells were sedimented by centrifugation and incubated as a pellet for 3h at 37°C. Syncytia (10 to more than 100 cells) were scored with an inverted microscope after transfer of the pellet to flat-bottom well microtiter plates. In uninhibited control samples, 100-130 large syncytia per well were counted.
  • IgA purified from EU or HIV+ patients were coupled to dynabeads previously conjugated to peptides corresponding to the proteins of the HIV envelope. Specific binding to gp41 was observed with IgA from EU. IgA coupled to the different peptides were eluted and utilized in gp41 binding assays at a concentration of 4 ⁇ g/ml. When IgA of EU were analyzed, specific binding to gp41 was observed only when antibodies eluted from peptide 1/2- coated beads were employed (Table). In contrast, when IgA obtained from EU or HIV+ patients were coupled to dynabeads previously conjugated to peptides corresponding to the proteins of the HIV envelope. Specific binding to gp41 was observed with IgA from EU. IgA coupled to the different peptides were eluted and utilized in gp41 binding assays at a concentration of 4 ⁇ g/ml. When IgA of EU were analyzed, specific binding to gp41 was observed only when antibodies e
  • HIV-infected individuals were analyzed, gp41 binding was observed with antibodies eluted from peptide# 13 -coated beads (Table).
  • Total IgA samples from 2 healthy donors were pooled and used as negative controls (Table).
  • Peptide pep#13 (NYTSLIHSLIEESQNQQEKNEQELLELDKWAS) corresponds to the gp41 region recognized by the monoclonal antibody 2F5. The results are expressed as O.D. value (optical density) obtained with samples from 6 EU, 12 HIV+ and 6 HC.
  • Affinity-purified anti-peptide 1/2 human IgA inhibit HIV- 1 replication
  • IgA bound to these same peptides were eluted and evaluated in neutralization assay.
  • Peptide-specific human IgA, affmity- purified from sera, were tested in HIV neutralization assay using the primary isolates of HIV.
  • the neutralizing titers obtained with IgA eluted from peptides 1/2 were higher (IC 50 of 1.8 ⁇ g/ml) than those of total IgA (IC 50 of 10 ⁇ g/ml).
  • the IC 50 obtained with total IgA was of > 100 ⁇ g/ml ( Figure 1).
  • a neutralization assay using activated PBMC as target cells was used.
  • total IgA from representative EU, HC and HIV+ samples, as well as peptidel/2 specific EU IgA purified fraction and pepl/2-IgA depleted fraction from both EU and HIV+ subjects were utilized.
  • a neutralizing anti gp41 monoclonal antibody (2F5) (Muster T. et al., J Vitol. 1994, 68:4031-4034) was used as positive control.
  • mice were immunized with either 50 ⁇ g of peptides 1 or 2 or a control - peptide.
  • the binding to gp41 by the corresponding antisera was evaluated with ELISA assay.
  • a dose-dependent binding specific for all the three sera was observed (Fig. 2).
  • the specific sera were then tested in a neutralization assay where activated PBMC cells were infected with the HIV-1 primary isolate
  • HIV#40 ( Figure 3) in the presence of four different antiserum dilutions (ranging from 1/40 to 1/1080). As shown in Figure 3, the specific mouse antisera inhibited HIV replication in a dose-dependent manner. No inhibition was observed using sera from mice immunized with the control peptide.
  • Antibodies to peptides 1 and 2 inhibit HIV- 1 viral entry
  • IgA specific for QARILAV from the vaginal fluids of two EU were assayed in an in vitro model mimicking the in vivo pattern of HIV transmission through the genital mucosa, whereby the IgA should block the passage of HIV virus from the mucosal to the systemic repertoire. Since the studied EU had multiple sexual intercourses with HIV-positive subjects, the analysis of their mucosal system is of particular relevance.
  • Figures 4 and 5 illustrate an in vivo and, respectively, in vitro- reproduced mucosa model.
  • Figure 6 shows the in vitro HIV inhibition by QARILAV-specific IgA.
  • mice were immunized through the intraperitoneal route with the peptide QARILAV, or with QARILA VERYLKDQQLLG (leu 581) peptide, already described in the literature as immunogenic (i.e. inducing specific antibodies).
  • the QARILAV peptide immunogenicity and ability to induce neutralizing antibodies was evaluated in comparison with leu 581. Eleven immunizations were performed with intervals of 10 days and hyperimmune sera were analysed either in peptide-binding assays (to determine the immunogenicity) or in viral infection inhibition assays (syncytia formation inhibition assay).
  • Figures 7 and 8 show the titration curves of the peptide-specific antibodies against Leu 581 and QARILAV, respectively, after several immunizations.
  • Figure 9 reports the concentrations of total antibodies and of the antibodies specific for the peptides leu 581 and QARILAV. Serum immunoglobulins from non-hyperimmune mouse were used as control. As shown in Figure 2, the QARILAV peptide is able to induce a stronger immune response as compared with that induced by Leu 581 (12% and 9% Ig specific for QARILAV and for Leu581, respectively). Viral infection inhibition test
  • the immunoglobulins specific for the two peptides possess a higher syncytia-formation inhibitory activity than that of antibodies specific for the Leu581 peptide.

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Abstract

L'invention concerne des peptides renfermant un épitope de la gp41 reconnu par IgA d'individus possédant une immunité naturelle contre le VIH, des anticorps contre de tels peptides et l'utilisation de ceux-ci pour le traitement préventif ou thérapeutique d'infections au VIH.
PCT/IB2003/003149 2002-08-06 2003-08-05 Epitope de la gp41 et utilisations de celui-ci pour le traitement d'infections au vih WO2004014945A1 (fr)

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IT001781A ITMI20021781A1 (it) 2002-08-06 2002-08-06 Epitopo di gp41 e suoi usi nel trattamento delle infezioni da hiv.

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Cited By (1)

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WO2013110790A1 (fr) * 2012-01-26 2013-08-01 Institut National De La Sante Et De La Recherche Medicale (Inserm) Compositions vaccinales utilisables dans le cadre de la prévention et du traitement anti-vih

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CHEN Y ET AL: "A common epitope on gp41, IFN-alpha and IFN-beta induces protective activity", IMMUNOLOGY TODAY, ELSEVIER PUBLICATIONS, CAMBRIDGE, GB, vol. 19, no. 12, December 1998 (1998-12-01), pages 586 - 587, XP004149700, ISSN: 0167-5699 *
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DEVITO C ET AL: "Mucosal and plasma IgA from HIV-1-exposed uninfected individuals inhibit HIV-1 transcytosis across human epithelial cells.", JOURNAL OF IMMUNOLOGY (BALTIMORE, MD.: 1950) UNITED STATES 1 NOV 2000, vol. 165, no. 9, 1 November 2000 (2000-11-01), pages 5170 - 5176, XP002263713, ISSN: 0022-1767 *
DING JIAN ET AL: "Candidate multi-epitope vaccines in aluminium adjuvant induce high levels of antibodies with predefined multi-epitope specificity against HIV-1", FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, vol. 29, no. 2, October 2000 (2000-10-01), pages 123 - 127, XP002263715, ISSN: 0928-8244 *
MAZZOLI SANDRA ET AL: "Human immunodeficiency virus (HIV)-specific IgA and HIV neutralizing activity in the serum of exposed seronegative partners of HIV-seropositive persons", JOURNAL OF INFECTIOUS DISEASES, vol. 180, no. 3, September 1999 (1999-09-01), pages 871 - 875, XP002263714, ISSN: 0022-1899 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013110790A1 (fr) * 2012-01-26 2013-08-01 Institut National De La Sante Et De La Recherche Medicale (Inserm) Compositions vaccinales utilisables dans le cadre de la prévention et du traitement anti-vih

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