EP3400235A1 - Méthode de traitement de maladies liées à ses propres protéines - Google Patents

Méthode de traitement de maladies liées à ses propres protéines

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Publication number
EP3400235A1
EP3400235A1 EP16704393.4A EP16704393A EP3400235A1 EP 3400235 A1 EP3400235 A1 EP 3400235A1 EP 16704393 A EP16704393 A EP 16704393A EP 3400235 A1 EP3400235 A1 EP 3400235A1
Authority
EP
European Patent Office
Prior art keywords
protein
peptide
treatment period
self
administrations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16704393.4A
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German (de)
English (en)
Inventor
Lucille DESALLAIS
Jean-François ZAGURY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peptinov
Original Assignee
Peptinov Sas
CNAM Conservatoire National des Arts et Metiers
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptinov Sas, CNAM Conservatoire National des Arts et Metiers filed Critical Peptinov Sas
Publication of EP3400235A1 publication Critical patent/EP3400235A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/52—Cyclic peptides containing at least one abnormal peptide link with only normal peptide links in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • 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
    • A61K39/385—Haptens or antigens, bound to carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to method of treatment of self-protein-related diseases, in particular IL-6 related diseases, in an individual.
  • IL-6 lnterleukin-6
  • IL-6 is a key messenger of immune responses and inflammation processes. It is produced by a wide variety of cell types such as lymphocytes, macrophages, neutrophils or fibroblasts.
  • IL-6 is the major regulator of acute phase protein synthesis in response to injury. It is also involved in the proliferation and differentiation of cytotoxic T cells by inducing the production of IL-2 and its receptor.
  • IL-6 IL-6 serum concentration is increased in sera of rheumatoid arthritis (RA), systemic sclerosis (SSc) and multiple myeloma patients and is correlated with disease severity.
  • RA rheumatoid arthritis
  • SSc systemic sclerosis
  • IL-6R anti-IL-6 receptor
  • Anti-cytokine biologies monoclonal antibodies and soluble receptors
  • These biologies present however several drawbacks including primary and secondary resistances, repeated injections and thus high compliance required from patients, side effects, and prohibitive costs for patients and healthcare systems (up to $20,000 per patient per year).
  • the present inventors have developed anti- cytokine peptide-based active immunization, where cytokine-derived peptides linked to a carrier protein are used as immunogens to induce anti-cytokine autoantibodies production.
  • the present inventors have recently demonstrated the efficacy of anti-IL-6 active immunization in the bleomycin mouse model of SSc, as described in Desallais, L. et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis.
  • Arthritis Res Ther 16, R1 57 (2014) and International Application WO2013/021 284 which is incorporated herein by reference.
  • the present inventors have now made the surprising finding that the efficacy of the treatment by anti-IL-6 active immunization could be improved by performing repeated administrations of the IL-6-derived peptide throughout the treatment.
  • the present invention relates to a method for treatment of self-protein- related diseases, or for vaccinating or immunizing against self-protein related diseases, in an individual during a treatment period, comprising performing several administrations of an effective amount of a peptide derived from the self-protein to the individual, wherein the administrations are distributed all along the treatment period.
  • the present invention also relates to a peptide derived from a self-protein for use in the treatment of self-protein-related diseases, or in the vaccination or immunization against self-protein related diseases, in an individual during a treatment period, wherein several administrations of the peptide derived from the self-protein are performed and the administrations are distributed all along the treatment period.
  • the present invention also relates to the use of a peptide derived from a self-protein for the manufacture of a medicament for the treatment of self-protein-related diseases, or for the vaccination or immunization against self-protein related diseases, in an individual during a treatment period, wherein several administrations of the peptide derived from the self- protein are performed and the administrations are distributed all along the treatment period.
  • the present invention also relates to a method for eliciting an immune response against a self-protein in an individual during a treatment period, comprising performing several administrations of an effective amount of a peptide derived from the self-protein to the individual, wherein the administrations are distributed all along the treatment period.
  • the present invention also relates to a peptide derived from a self-protein for use for eliciting an immune response against the self-protein in an individual during a treatment period, wherein several administrations of the peptide derived from the self-protein are performed and the administrations are distributed all along the treatment period.
  • the present invention also relates to the use of a peptide derived from a self-protein for the manufacture of a medicament for eliciting an immune response against the self- protein in an individual during a treatment period, wherein several administrations of the peptide derived from the self-protein are performed and the administrations are distributed all along the treatment period.
  • the present invention also relates to a method for treating an inflammatory disorder, or for vaccinating or immunizing against an inflammatory disorder, in an individual during a treatment period, comprising performing several administrations of an effective amount of a peptide derived from a pro-inflammatory protein to the individual, wherein the administrations are distributed all along the treatment period.
  • the present invention also relates to a peptide derived from a pro-inflammatory protein for use in the treatment of inflammatory disorders, or for vaccinating or immunizing against an inflammatory disorder, in an individual during a treatment period, wherein several administrations of the peptide derived from the self-protein are performed and the administrations are distributed all along the treatment period.
  • the present invention also relates to the use of a peptide derived from a pro- inflammatory protein for the manufacture of a medicament for the treatment of inflammatory disorders, or for vaccinating or immunizing against an inflammatory disorder in an individual, during a treatment period, wherein several administrations of the peptide derived from the self-protein are performed and the administrations are distributed all along the treatment period.
  • Figure 1 Study design. The monkeys received one priming (d1 ) and 4 boosters (d15, d30, d45, d76). The DTH reaction was evaluated on day 90, 30 days after the priming against TTx (day 59).
  • Figure 2 (a) Evolution of body weight (kg) in the hlS200-immunized group of monkeys, (b) Rectal temperature at week 7. (c) Rectal temperature at week 1 1 .
  • BT before treatment
  • T+6h 6 hours after treatment
  • T+24h 24 hours after treatment.
  • Figure 3 Kinetics of the anti-IL-6 antibody production in the cynomolgus monkeys immunized against the hlS200 peptide immunogen. The control groups did not exhibit any antibodies against IL-6 detected by ELISA and are thus not shown.
  • Figure 4 Neutralizing capacity of the antibodies purified from sera of the immunized monkeys at d-8, d59, d90, d1 05 and d120.
  • Figure 5 Cumulative inflammatory score of the local reactions of the immunized monkeys, based on erythema, dermal thickening, and nodules at the sites challenged with 0.05 ml of TTx vaccine.
  • Figure 6 (a) IL-6 levels in the serum of monkeys were measured by ELISA. Data are presented as mean ⁇ SD for each group at each time point. The mean level is always slightly higher in the hlS200-immunized group at each timepoint. (b) Analysis by the Mann-Whitney test shows that the mean IL-6 concentration over time is significantly higher in hlS200- immunized monkeys compared to the two control groups.
  • the treatment period according to the invention comprises, or is constituted of, a priming period and a booster period.
  • the administrations according to the invention are substantially evenly distributed all along the treatment period.
  • the treatment period according to the invention is of at least 1 , 2, 3, 6, 1 2, 18, 24, or 36 months.
  • the treatment period is of a least 5, 1 0, 15, 20 or 30 years.
  • the treatment period is a lifelong treatment.
  • the treatment period lasts for the duration of the disease.
  • consecutive administrations according to the invention are separated from one another by at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 week(s) all along the treatment period.
  • consecutive administrations according to the invention are separated from one another by at least 1 , 2, or 3 week(s) during the priming period.
  • consecutive administrations according to the invention are separated from one another by at least 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 week(s) during the booster period.
  • consecutive administrations are separated from one another by at most, or less than, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 week(s) all along the treatment period.
  • consecutive administrations are separated from one another by at most 1 ,
  • consecutive administrations according to the invention are separated from one another by at most, or less than, 4, 5, 6, 7, 8, 9, 10, 1 1 or 1 2 week(s) during the booster period.
  • the priming period is of at most, or less than 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 1 2 weeks.
  • the treatment period comprises, or consists of:
  • a booster period preferably of at least one year, during which consecutive administrations are separated from one another by 1 month to less than 3 months, or by about 1 , 1 .2, 1 .4, 1 .6, 1 .8, 2, 2.2, 2.4, 2.6 or 2.8 months.
  • the administrations according to the invention are selected from the group consisting of intramuscular administration, intravenous administration, subcutaneous administration, intradermic administration, transcutaneous administration, topical administration, intraperitoneal administration, oral administration, sublingual administration and nasal administration.
  • self-protein relates to a protein encoded by the genome of the individual. Accordingly, the self-protein according to the invention is not a viral, bacterial or parasitic protein.
  • the self-protein according to the invention is a pro-inflammatory protein. More preferably the self-protein according to the invention is a pro-inflammatory cytokine. Most preferably, the self-protein according to the invention is IL-6.
  • a self-protein-related disease relates to any disease of which an aetiologic agent and/or an symptom-causative agent is a self-protein.
  • the self-protein-related diseases according to the invention are inflammatory diseases.
  • the self-protein-related diseases or the inflammatory diseases or disorders according to the invention are preferably selected from the group consisting of:
  • rheumatoid arthritis in particular rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, arthrosis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, or ankylosing spondylitis,
  • - chronic or IL-6-related inflammatory bone diseases in particular a bone resorption disorder or osteoporosis
  • - chronic or IL-6-related inflammatory diseases associated with an infection such as septic shock, endotoxin shock, septicaemia, HCV hepatitis, malaria, meningitis, AIDS or HIV infections
  • IL-6-related inflammatory diseases of the cardiovascular system such as atherosclerosis, ischaemia-reperfusion lesions, coronary diseases, and vasculitis, such as
  • scleroderma in particular systemic scleroderma (also known as systemic sclerosis), lupus erythematosus, in particular disseminated lupus erythematosus, multiple sclerosis, or psoriasis
  • systemic scleroderma also known as systemic sclerosis
  • lupus erythematosus in particular disseminated lupus erythematosus
  • multiple sclerosis multiple sclerosis
  • psoriasis psoriasis
  • graft-versus-host reactions graft-versus-host reactions
  • graft rejections and traumas graft rejections and traumas
  • CVID common variable immunodeficiency
  • - cancers having a chronic or IL-6-related inflammatory component such as plasmacytoma, colorectal cancer, recurrent ovarian cancer, lymphoproliferative syndrome, multiple myeloma, in particular refractory multiple myeloma, or myeloproliferative syndrome, - diabetes, in particular juvenile diabetes,
  • the self-protein-related diseases or the inflammatory diseases or disorders according to the invention are more preferably selected from the group consisting of rheumatoid arthritis, chronic inflammatory diseases of the intestine, such as Crohn's disease and haemorrhagic rectocolitis, lupus erythematosus, psoriasis, multiple myeloma, and colorectal cancer.
  • the peptide is linked to a carrier protein.
  • the carrier protein is Keyhole Limpet Hemocyanin (KLH), hepatitis B surface antigen (HBsAg), bovine serum albumin (BSA), diphtheria toxoid or toxin (DT), tetanus toxoid or toxin (TT), or a viruslike particle (VLP).
  • KLH Keyhole Limpet Hemocyanin
  • HBsAg hepatitis B surface antigen
  • BSA bovine serum albumin
  • DT diphtheria toxoid or toxin
  • TT tetanus toxoid or toxin
  • VLP viruslike particle
  • the peptide according to the invention is linked to a carrier protein acconrd to the invention by a coupling agent or a cross-linking agent, in particular bis-diazo-benzidine (BDB) or succinimidyl-6-(3-maleimidopropionamido)-hexanoate (SMPH).
  • BDB bis-diazo-benzidine
  • SMPH succinimidyl-6-(3-maleimidopropionamido)-hexanoate
  • the peptide according to the invention is Acetyl- CESSKEALAENNLNLPKCY (SEQ ID NO: 1 ).
  • the peptide according to the invention is cyclized by the formation of an intramolecular disulphide bond between the two cysteine (C) residues.
  • the peptide according to the invention is administered in an amount or at a dose of from 0.5 to 1 00 micrograms per kg of the individual (i.e. ⁇ g kg), more preferably 1 to 10 ⁇ g kg.
  • the peptide according to the invention is administered in an unitary amount or at a unit dose of from 50 ⁇ g to 1 ,000 ⁇ g.
  • the dose or amount of the peptide relate to the total weight of the peptide optionnally associated the carrier protein if present.
  • the peptide according to the invention can be combined with an adjuvant.
  • the adjuvant can be of any type suited to enhancing the immune response, in particular the antibody response, of an individual, animal or human, to the administration of a peptide. It can thus be complete or incomplete Freund's adjuvant, ISA51 or ISA720, alum or calcium phosphate for example, ISA51 or ISA720 being preferred.
  • the adjuvant can be combined with the peptide according to the invention by producing a 1 /2 up to a 1 /10 mixture, in particular a 1 /1 mixture, by volume of a solution of adjuvant and a solution comprising the polypeptide.
  • the individual according to the invention is a mammal, more preferably a primate, and most preferably a human.
  • the individual according to the invention is afflicted with an inflammatory disease.
  • the inventors have tested the hlS200-coupled peptide in cynomolgus monkeys as, in this species, this peptide sequence is identical to the human one. Therefore, the inventors evaluated the ability of the vaccine to induce a strong anti- cytokine antibody response and active immunization efficacy in a delayed-type hypersensitivity (DTH) model (Bouchez, C. et al. Development of a Delayed-Type Hypersensitivity (DTH) Model in the Cynomolgus Monkey. J Toxicol Pathol 25, 183-188 (2012)).
  • DTH delayed-type hypersensitivity
  • the hlS200 peptide was designed using the human IL-6/IL-6Roc/gp130 structure (PDB ID: 1 P9M). This peptide was chosen in loops exposed to the protein surface, which correspond to a region involved in the interaction between the cytokine IL-6 and its receptor IL-6R0C.
  • the hlS200 peptide sequence is: (SEQ ID NO:
  • CESSKEALAENNLNLPK SEQ ID NO: 2
  • SEQ ID NO: 2 The sequence in bold (CESSKEALAENNLNLPK) (SEQ ID NO: 2) is strictly identical between human and cynomolgus monkey IL-6.
  • Peptides were synthesized as previously described in Desallais et al. (2014) op. cit. by Polypeptide Laboratories (Strasbourg, France). They were produced in a cyclized form by the formation of intramolecular disulphide bonds between cysteine residues and coupled with bis-diazobenzidine (BDB) to Keyhole Limpet Hemocyanin (KLH).
  • BDB bis-diazobenzidine
  • KLH Keyhole Limpet Hemocyanin
  • each monkey received a complete health check including clinical examination, tuberculin testing, treatment against parasites and coprology tests.
  • animals were housed in groups in dedicated pens at CIT (Centre International de Toxicologie) animal facilities (Evreux, France). The environment conditions were continuously recorded (temperature 22 ⁇ 3°C and relative humidity 50 ⁇ 30 %).
  • the daily diet during the study consisted of commercial food pellets (Dietex France, SDS, Saint Gratien, France).
  • a fruit supplement was given daily to each animal. Drinking water was provided ad libitum.
  • the monkey W62010 from the hlS200-immunized group, received three sessions of non-steroidal anti-inflammatory drug (NSAID) and antibiotic drug administration (Finadyne® and Suramox® from days 9, 44 and 1 05) following a recurrent dental abscess (which started on day 9 and was not related to the immunization).
  • NSAID non-steroidal anti-inflammatory drug
  • Finadyne® and Suramox® from days 9, 44 and 1 05
  • the first group which received the control peptide (150 ⁇ g/monkey) conjugated to KLH (300 ⁇ g/monkey according to the manufacturer of the conjugate, Polypeptide Laboratories) and the second group, which received KLH only (Pierce, IL, USA), were used as negative controls.
  • the third group of four monkeys was immunized with the hlS200 peptide (150 ⁇ g/monkey) conjugated to KLH (300 ⁇ g/monkey according to the manufacturer of the conjugate, Polypeptide Laboratories). Each treatment was emulsified in Montanide ISA 51 VG (Seppic, France). All monkeys received an injection of 0.3 ml on every immunization day.
  • Serum immunoglobulins were purified to avoid any non-specific serum interference in the IL-6 neutralization assay (see below).
  • the total IgG fractions were purified from the sera of immunized monkeys using a protein A and protein G affinity chromatography (Biotem, Apprieu, France). In brief, 3 ml of each sera were diluted five times in PBS 1 X sodium EDTA 5 mM and injected on the column. After washes, elution of bound IgGs was accomplished with ammonium acetate 500 mM pH3 and neutralized with Tris 1 M pH 8,8. IgG fractions were then concentrated by centrifugation followed by two dialysis of two hours in PBS at 4°C. Final volume of purified IgGs was 3 ml.
  • This neutralization assay is based on the inhibition of the binding of IL-6 to its receptors, in an ELISA-derived assay.
  • Microtitration plates were coated with 300 ng/ml of recombinant human gp130 Fc chimera protein (R&D Systems, Lille, France) in PBS overnight at 4°C.
  • hlL-6 at 1 ,3 ng/ml
  • hlL-6Fta 200 ng/ml (R&D Systems, Lille, France) were preincubated with the antibodies purified from the sera of immunized animals (at a dilution of 1 :3) for two hours at 37°C.
  • the Tetanus vaccine (Sanofi Pasteur, France) was administered by intramuscular injection into the left thigh of the monkey on day 59, at a dose-volume of 0.5 mL per animal.
  • a challenge was performed by intradermal injection on day 90 on two sites of the back of each animal with 0.05 mL of Tetanus vaccine. Animals were slightly anesthetized before the injections. Skin inflammatory reactions at the challenge sites were recorded once daily for each animal before administration, 24h, 48h and 72h after challenge. Three parameters were evaluated at each challenge site: erythema, dermal thickening and nodules.
  • Serum levels of IL-6 were measured in all monkeys, by using U-CyTech sandwich old world monkey IL-6 ELISA kits with a detection limit of 5 pg/ml (U-CyTech Biosciences, Utrecht, The Netherlands).
  • the IL-6 neutralization capacity of the antibodies induced by the immunization of monkeys was assessed by measuring the inhibition of binding of IL-6 to its receptors IL- 6Ra/gp130.
  • the IgG antibodies of the immunized monkeys were purified. Neutralizing antibody responses were observed in all hlS200-immunized monkeys with a maximum neutralizing capacity on d59 which decreased over time. No neutralization was observed for the control groups (Fig. 4).
  • the neutralizing capacity in the h lS200-immunized monkeys along time followed a similar evolution as the anti-IL-6 antibody titersso. Significant decrease of the DTH response clinical signs following immunization against the hlS200-coupled peptide
  • Table 2 Local skin reactions at challenge sites injected with 0.05 ml of Tetanus vaccine (mean for 2 sites: total of 8 sites for 4 animals/group), (a): Grade of erythema and dermal thickening during the DTH evaluation (day 90 up to day 93), 1 : very slight; 2: well-defined, (b) : Mean duration (days) regarding DTH evaluation, (c) : Mean size of nodules (mm), nm: non measurable.
  • the TTx antibody response was also evaluated and was very similar in the three groups. The reduced clinical scores observed in the test group is thus likely not due to a decreased priming against TTx. Mean serum IL-6 levels increase after active immunization
  • the mean serum IL-6 concentration at each time point (e.g. test samples vs. control samples at day 15, or at day 30, etc.) showed no significant difference between the test group and the control groups. However, it can be observed that the mean serum IL-6 concentration for all time points was higher from day 15 to day 120 in the test group than in the two other groups (Fig. 6a).
  • Cynomolgus monkeys were of particular interest because the sequence of the hlS200 peptide (derived from IL-6) is 100 % identical between human and cynomolgus monkey IL-6.
  • the inventors also confirmed that anti-IL-6 active immunization had in vivo effects since it was able to modulate the inflammatory reactions following a DTH response induced by TTx. Indeed, the results showed a significant 57.9 % decrease of the inflammatory reactions in the IL-6-immunized group compared to controls. The inventors did not observe a direct correlation between anti-IL-6 titers and the reduction of the clinical score following TTx challenge within the IL-6 immunized group.
  • the inventors have shown that the response to TTx was very similar in the hlS200-immunized group and in the control groups indicating that the decrease of DTH clinical scores in hlS200 immunized monkeys could not be induced by a decreased priming against TTx, but by the effective neutralization of IL-6 at day 90 due to the immunizations.
  • IL-6 concentration was also observed in patients treated with Tocilizumab, suggesting that this increase is well tolerated in patients treated by anti-IL-6 biologies.
  • the CRP concentration was low in the three monkey groups of the study since they were healthy monkeys with no disease. Since the CRP values were low in all groups to begin with, it could not be reduced more by the vaccine in the h lS200-immunized group.
  • a decrease of CRP levels has been observed in patients treated by anti-IL-6 biologies because they initially had a chronic inflammatory disease with high levels of CRP.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne une méthode de traitement de maladies liées à ses propres protéines, ou de vaccination ou d'immunisation contre des maladies liées à ses propres protéines, chez un individu pendant une période de traitement, consistant à administrer à plusieurs reprises à l'individu une quantité efficace d'un peptide dérivé de ses propres protéines, les administrations étant réparties tout au long de la période de traitement.
EP16704393.4A 2016-01-07 2016-01-19 Méthode de traitement de maladies liées à ses propres protéines Pending EP3400235A1 (fr)

Applications Claiming Priority (2)

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EP16305011 2016-01-07
PCT/EP2016/050935 WO2017118491A1 (fr) 2016-01-07 2016-01-19 Méthode de traitement de maladies liées à ses propres protéines

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EP3400235A1 true EP3400235A1 (fr) 2018-11-14

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EP3845556A1 (fr) * 2019-12-31 2021-07-07 Peptinov SAS Conjugue immunogene destine a induire une reponse immunitaire dirigee contre l interleukine-6

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FR2978964B1 (fr) 2011-08-09 2015-02-20 Conservatoire Nat Arts Composition vaccinale anti-il-6

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