WO2007031100A1 - Immunothérapie active pour inflammation systémique potentiellement mortelle - Google Patents

Immunothérapie active pour inflammation systémique potentiellement mortelle Download PDF

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Publication number
WO2007031100A1
WO2007031100A1 PCT/EP2005/009866 EP2005009866W WO2007031100A1 WO 2007031100 A1 WO2007031100 A1 WO 2007031100A1 EP 2005009866 W EP2005009866 W EP 2005009866W WO 2007031100 A1 WO2007031100 A1 WO 2007031100A1
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Prior art keywords
hmgbl
protein
peptides
administration
peptide
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PCT/EP2005/009866
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English (en)
Inventor
Roberto Ringhini
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Ostini, Marco
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Priority to PCT/EP2005/009866 priority Critical patent/WO2007031100A1/fr
Publication of WO2007031100A1 publication Critical patent/WO2007031100A1/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
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the field of clinical immunology and in particular to the field of immunoprophylaxis and therapy of degenerative disease associated with high expression of pro-inflammatory cytokines.
  • the invention is based on the discovery that prophylactic treatment with the protein known as HMGBl is capable of inducing, in a human subject, the production of circulating antibodies which neutralise the biological activity of the endogenous HMGBl in biological fluids.
  • the HMGBl biological activity comprises HMGB l 's ability to promote the release of the pro-inflammatory cytokine TNF-ce which is present in an abnormal and uncontrolled amount in numerous systemic inflammatory conditions such as, for example, sepsis, septic shock, hemorrhagic shock, and other related pathologic conditions.
  • Sepsis also called septicemia, is a systemic syndrome that develops following the amplification and de-regulation of the immunological response to a massive bacterial infection. Initially, the symptoms of this pathologic condition include fever, mental confusion, hypotension, impaired renal function and thrombocytopenia. Often, it evolves into a clinical stage of severe sepsis which is characterized by non-pharmacologically controllable hypotension, altered coagulation and organ dysfunction affecting in particular the kidney and lungs.
  • a recent epidemiological study of sepsis reported a frequency in the USA of 3 cases every 1.000 inhabitants per year, totaling approximately 750.000 yearly cases, with a mortality rate of 29% (corresponding to 215.000 deaths), mortality rate increasing to 50% in the presence of septic shock (Angus D.
  • LPS lipopolysaccharide
  • the host's immune defense reacts to contain bacterial aggression with an inflammatory response which is followed by an anti-inflammatory response that limits and modulates the intensity of the initial inflammatory response.
  • an anti-inflammatory response that limits and modulates the intensity of the initial inflammatory response.
  • massive activation of phagocytes results in the uncontrolled release into the circulation of inflammatory cytokines. This cytokine release is followed by the activation of endothelial cells which amplifies the inflammation by promoting endothelial adhesion of circulating lymphocytes with subsequent oxidative damage and loss of vascular integrity.
  • HMGBl also known as HMG-I (High Mobility Grou ⁇ -1) (Bustin M.,
  • HMG-Box Its structure is organized into three domains two of which are capable of binding DNA and are defined as HMG-box A and HMG box-B.
  • the third domain is located in the C-terminus and comprises 30 residues of aspartic acid and glutamic acid.
  • the two DNA-binding domains comprise approximately 80 amino acids, 29% of which are identical and 65% similar, and are assembled in three alpha-helix structures which form an L (Read et al., 1993, Nucleic Acids res., 21:3427-3436).
  • HMGBl classified as a chromosomic non-histonic nucleic protein, is stable in acid conditions (perchloric acid 5%) and can be separated from chromatin by saline extraction with sodium chloride 0.35 M. HMGBl is abundant and ubiquitous in the nucleus (106 molecules per nucleus). It binds to DNA with structural non sequential specificity determining a characteristic folding of its helices which facilitates the formation of nucleoprotein complexes capable both of stabilizing the structure and of binding with specific transcription factors.
  • the HMGBl protein was called amphoterin due to the bipolar distribution of the electric charges on its surface.
  • the central nervous system it has been found not only in the nucleus and cytoplasm but also in the extracellular space where it contributes to the neurite outgrowth (Rauwala H. et al., 1987, J. Biol. Chem., 262:16625-16635).
  • This protein was also localized on the membrane of murine erythroleukemia cells from which it is released during the differentiation process (Passalacqua M. al. 1997, FEBS Lett., 400:275-279).
  • HMGBl can be released by necrotic cells or by native immunity cells, for example macrophages and monocytes, following stimulation by bacterial endotoxins and immunomodulatory cytokines (Scaffidi P. et al., 2002, Nature 418(6894): 191-195; Wang H. et al., 1999, Science, 285:248-251).
  • cytokines Rost al., 2002, Nature 418(6894): 191-195; Wang H. et al., 1999, Science, 285:248-251.
  • RAGE Receptor of Advanced Glycosylation End-Products
  • This receptor is present in numerous cell types, including endothelial cells, smooth muscle cells, mononuclear phagocytes and neurons, and it is involved both in a number of pathological conditions, such as diabetes and atherosclerosis, and in numerous physiological processes, such as inflammation and elongation of neurites during embryonic development (Hutten et al., 1999, J. Biol. Chem., 274: 19919-19924).
  • Another effect correlated with the binding of RAGE by HMGBl is tumor growth and formation of metastases.
  • HMGl with RAGE activates endocellular molecules which act as effectors in the mechanisms of cancer proliferation and invasion (Taguchi A. et al., 2000, Nature, 405:354-360).
  • HMGBl stimulates the synthesis and release of TNF-ce subsequent to HMGBl interaction with receptors present in PBMC (peripheral blood mononuclear cells), also defined as mature monocytes (Andersson U. et al., J. Exp. Med., 192:565-570).
  • HMGB 1 and RAGE Various pharmaceutical compounds capable of inhibiting the interaction between HMGB 1 and RAGE have been proposed for the treatment of sepsis and of related conditions. These compounds utilize fragments of HMGBl as direct inhibitors of HMGBl biological activity (WO 02/092004; US 2004/0156851) or exogenous antibodies with affinity for the entire molecule or its parts to be used as passive immunotherapy (WO 00/47104, US 6,448,223).
  • EP 1079849 discloses the cytotoxic activity of HMG and HMG-I proteins.
  • the present invention describes instead a pharmaceutical composition comprising as the active ingredient HMGBl, or an immunogenic peptide thereof, and its use to induce the production of specific endogenous antibodies
  • active immunotherapy capable of blocking RAGE binding in circulating monocytes.
  • HMGBl refers to a protein with a degree of sequence identity of at least 70%, preferably greater than 80%, and even more preferably greater than 90%, with the protein identified in the NCBI-Entrez data-base by the access number P09429 (GI: 123369).
  • peptide is used according to its conventional meaning, to indicate a sequence of amino acids forming a part of a native protein, not limited in terms of number of constituting residues or presence of post-transcriptional modifications, such as glycosylation, acetylation, phosphorylation and other available natural or artificial modifications.
  • the term refers to linear sequences of amino acids containing from 10 to 40 residues, preferably from 10 to 30 residues, and more preferably from 10 to 20 residues, which constitute an immunogenic portion of the protein from which they derive.
  • immunogenic defines the peptide's capacity to induce in the receiving host a specific antibody response to the fragment itself, or to the molecule from which the fragment was derived.
  • peptide variant refers typically to a peptide that differs from the peptide described by one or more deletion, substitution or insertion of amino acids.
  • Peptides variants included in the present invention are typically those that show, in their sequence length, an identity of 70%, preferably of 80%, and more preferably of 90% with the peptides derived from the active molecule.
  • LPS lipopolysaccharide
  • mice weighing 20-25 grams induces lethargy status, pilo erection and diarrhea followed by death within 48 hours.
  • increased serum levels of the cytokine TNF- ⁇ have been reported which reach maximum values 90 minutes after LPS administration and then decrease to non significant levels in the subsequent 10 hours (Van der Poll T. et al., 1999, Infect. Dis. Clin. North Am. 13:413-426).
  • the protein HMGBl can be detected in the serum 8 hours after LPS administration and its concentration increases steadly reaching a plateau 16 to 32 hours after endotoxin administration (Wang H. et al., 2001, Am. J. Crit. Care Med.
  • HMGB 1 modulates, in a dose-dependent manner, the release of TNF-ce from peripheral blood mononuclear cells (PBMC) but not from lymphocytes, and that this effect is lost using peptides derived from the fragmentation of HMGBl (Anderson U. et al., 2000, J. Exp. Med. 192;565-570).
  • PBMC peripheral blood mononuclear cells
  • the invention accordingly provides the use of HMGB 1 or of a protein or peptide having an identity with the human protein of at least 50% for the preparation of a medicament for the treatment of diseases associated with the presence of an abnormal and excessive amount of HMGBl protein in the biological fluids.
  • the selection of peptides capable of inducing the production of neutralizing antibodies may be performed by analyzing the characteristics of the amino acids present in the primary structure of HMGB 1.
  • well known methods allow the characterization of the antigenic profile of the molecule and of related peptides.
  • the antigenic profiles were generated using the software ANTHEPROT 2000 Version 5.2 (institute of Biology and Protein Chemistry UMR 5086 CNRS-UCBL, Lyon, France) and the software ProtScale present in the database ExPASy (Swiss Institute of Bioinformatics, Basel University, Basel, Switzerland).
  • the analysis of the antigenic profiles has allowed the selection of 9 peptides, containing from 13 to 15 amino acids each, having the sequences reported in the Sequence Listing. Other peptides may be prepared by the same method.
  • Said peptides are a further object of the invention.
  • a further embodiment of the invention refers to pharmaceutical compositions comprising HMGBl or peptides derived therefrom.
  • some peptides can be naturally immunogenic, it is often necessary or preferable to conjugate the peptide to high molecular weight molecules in order to induce or enhance the host's immunological response.
  • various known molecules such as Bovine Serum Albumin (BSA), hemocyanin (KLH) and Ovalbumin (OVA) may be used as peptide carriers after chemical conjugation with a bi-functional reagent (e.g. glutaraldehyde, carbodiiimide).
  • BSA Bovine Serum Albumin
  • KLH hemocyanin
  • An alternative to this type of conjugation is the preparation of multiple antigenic peptides (MAPs) by known methods.
  • MAPs multiple antigenic peptides
  • the macromolecule which forms the complex consists of 8 identical peptides covalently bound to an internal heptameric structure (core) of lysine which is non immunologically reactive and has a molecular weight adequate to make the complex highly immunogenic.
  • an appropriate formulation would consists of the native forms of the peptides derived from HMGBl, preferably conjugated to a protein carrier, and preferably assembled as MAPs.
  • the compositions of the invention may be administerd by systemic, inhalation or parenteral route to an animal species, preferably to humans.
  • compositions include saline or parenteral solutions for injectable drugs, e.g. as prescribed by International Pharmacopeias.
  • the quantity of immunogenic substance present in the pharmaceutical composition must be sufficient to guarantee therapeutic benefit to the subject who receives it. In other words, such quantity should be sufficient to induce the production of circulating antibodies endowed with neutralizing activity against the biological/receptorial activity of HMGBl present in circulation.
  • the dose of immunogenic substance depends on the animal species treated. Based on currently used pharmaceutical methods, a dose between 5 ⁇ g/kg and 2 mg/kg of body weight, preferably between 20 ⁇ g/kg and 500 mg/kg of body weight, and even more preferably between 20 ⁇ g/kg and 100 ⁇ g/kg of body weight should be adequate in man.
  • compositions that contains not only the immunogenic substance but also an immunostimulant capable of enhancing the immune response (cell-fixed or circulating) induced by it (Powell M.F., Newman M.J., 1995. "Vaccine Design. The subunit and adjuvant approach", Plenum Press Ed., New York).
  • the immunostimulant to be used in this invention is classified in the category of the adjuvants, including both substances that protect the antigen against a rapid catabolism, such as aluminum hydroxide or mineral oil, and those that stimulate the immune response in a non-specific way, such as lipid A and proteins derived from the microorganism Bordetella pertussis.
  • the adjuvant can be selected from those already commercially available for pharmaceutical use, for example the products ISA-51 and ISA-720 (Seppic, France), SAF and MF-59 (Chiron, USA), SBAS-2 and SBAS-4 (SmithKline Beecham, Belgium), Detox and RC-529 (Corica, USA) or others.
  • the compositions of the invention can contain physiologic buffers, carbohydrates, mannitol, stabilizing proteins, anti- oxidants, bacteriostatics, chelating agents or other substances described in International Pharmacopeias which are generally used for the preparation of drugs or vaccines for warm-blooded animals and preferably for humans.
  • the evaluation of the neutralizing capacity of the endogenous antibodies induced by the administration of the claimed product can be performed using an analytical method and calculating a parametric value known as the Neutralization Index (NI), whose determination is a useful condition for the use of the invention.
  • NI Neutralization Index
  • This assay measures the capacity of the induced antibodies to inhibit the interaction between HMGBl and RAGE on the surface of mononuclear cells of peripheral blood using donor's PBMC obtained applying well known centrifugation methods such as those described in Example 1. Briefly, after separation the cells are incubated with a fixed amount of recombinant protein HMGBl (HMGBIr) and a pre-established volume of complement- free serum obtained from a subject treated with the product claimed in this invention. The presence of anti-HMGBl antibodies in the analyzed serum blocks the interaction between the recombinant molecule and its receptors on the cells thereby inhibiting the release of TNF-a.
  • HMGBIr recombinant protein HMGBl
  • the TNF- ⁇ concentration in the cellular growth medium is measured using a commercially available immunometric assay, such as, for example, the human TNF-ce Quantikine immunoassay produced by R&D SYSTEM (Cat. N. DTA50).
  • the ratio between the TNF- ⁇ amount present in the sample and the maximum release of this cytokine obtained by the addition of a non specific hyperimmune serum gives a normally distributed value comprised between 0 and 1.
  • the clustering of the measured ratio in a numeric scale allows the determination of the sample's neutralization index (NI), which is an index of the assayed serum capacity to neutralize the biological activity of the circulating HMGBl.
  • NI neutralization index
  • the neutralizing capacity of the analyzed serum is considered null for a +1 index, moderate for a +2 index, high for +3 index and very high for a +4 index. This neutralizing capacity is directly correlated with the efficacy of the treatment with the claimed product (active immunotherapy).
  • a NI value greater than 1 unit indicates a good prophylactic effect, indicating the presence in the serum of the treated subject of a significant amount of neutralizing antibodies, whereas indexes equal to or smaller than 1 unit suggest the need for boosters enhancing the anti-HMGBl activity of the serum.
  • mice were treated according to a specific protocol with a prophylactic product containing an adjuvant mixed to a peptide derived from HMGB in the form of MAP or the complete HMGBl recombinant molecule. Subsequently, animals were inoculated with a quantity of LPS sufficient to provoke lethal effects within three days. The two groups treated with the prophylactic agents had a survival rate which was at least 50% greater than that of the reference group treated with adjuvant only.
  • This example shows a model of active immunoprophylaxis against endotoxic shock in Balb/C mice and the evaluation of the neutralizing capacity of mice sera after treatment.
  • mice 16 Balb/C male mice aged 6-7 weeks (weighing 20-25 grams) received an intramuscular injection of the recombinant HMGBl (HMGBIr) protein (SIGMA-ALDRICH, Cat. N. H-4652) or of the peptide SEQ. ID. No.l in the form of octameric MAP supplied by PRIMM srl (Italy).
  • the injection was prepared by adding 10 ⁇ g of HMGBIr (35 ⁇ l physiologic solution) or 25 ⁇ g of MAP (50 ⁇ l phosphate buffer) to 50 ⁇ l of ImmunEasy Mouse Adjuvant (QIAGEN AG, Basel). The reagents were mixed thoroughly and incubated for 5 minutes at room temperature (18-25°C) prior to the intramuscular administration into the quadriceps.
  • the treatment protocol for both groups consisted of three administrations each with a two- week interval period, i.e. primer 38 days, first booster 24 days, and second booster 10 days, before blood sampling, in order to evaluate the presence of neutralizing antibodies.
  • the control group consisted of 8 Balb/C male mice (Group 3), with the same age and average body weight, treated according to the protocol described above with 50 ⁇ l of ImmunEasy Mouse Adjuvant diluted with an equal volume of saline solution. Three days after the last inoculum, blood sampling was performed in order to obtain 150 ⁇ l of serum, treated at 56°C for 30 minutes to remove complement and stored at 4 ⁇ 2°C.
  • mice sera neutralizing capacity was based on the measure of the TNF- ⁇ releases by human monocytes after stimulation with HMGB-I in presence of the mice complement- free sera.
  • Monocytes preparation was obtained by adding 5 ml of phosphate buffer to 3 ml of human venous blood stored in heparin or EDTA vials, mixing by inversion and carefully layering the mixture onto 3 ml of Histopaque-1077 (SIGMA-ALDRICH, Cat. N. H-8889) added to a 5 ml conical centrifuge tube. After centrifugation at 400 x g for 30 minutes the upper layer was removed up to the opaque interface containing the mononuclear cells.
  • the cells were then diluted at the concentration of 106 cells/ml culture medium and 0.5 ml of this suspension was transferred into the well of a sterile polystyrene 24-wells multidish (NUNC, Cat. N. 142475). Each serum sample was analyzed in quadruplicate and further four wells were used totaling 4 for the negative and positive controls (two for each control samples). After distribution of the cells in all the test-wells and incubation for 1 hour at 37°C (5% CO 2 ), 0.4 ml of culture medium of each well was removed to eliminate the lymphocytes in suspension and was substituted with equal volume of RPMI 1640.
  • NUNC sterile polystyrene 24-wells multidish
  • the assay was performed in duplicate and the average concentration of each sample was obtained by multiplying the result by the dilution factor.
  • the mean value of TNF-o; obtained assaying the quadruplicate wells or the duplicate wells associated to the Positive or Negative Controls is reported in the table below.
  • the neutralization index (NI) of each serum sample was assessed calculating the ratio between the value obtained for the tested sample and that obtained for the positive control sample and by classifying the obtained value according to the numerical scale described previously.
  • the described serum analytical assay is considered acceptable only if meets established TNF- ⁇ concentration criteria for Negative and Positive Controls i.e. TNF- ⁇ values ⁇ 100 ng/ml and >4.000 ng/ml for these samples respectively.
  • the evaluation of the NI related to the serum specimens #1 and #3 suggests, respectively, a poor response or no response to the immunoprophylactic treatment.
  • the capacity of their sera to neutralize the monocytes TNF- ⁇ secretion stimulated by the presence of HMGB-I was very low.
  • the treatment efficacy is classified as moderate (#4, #5), good (#2) and very good (#6).
  • mice treated in Example 1 were treated and clustered into three groups receiving HMGBIr (Group 1), MAP derived from the peptide labeled as SEQ.ID.No 1 (Group 2) and an adjuvant (Group 3), respectively.
  • mice received an intraperitoneal injection of a lethal dose of LPS SIGMA-ALDRICH Cat. N. L2262
  • PB S phosphate buffer solution

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Abstract

Cette invention a pour objet l'utilisation de HMGB1 ou de fragments immunogéniques de celui-ci pour immunoprophylaxie active et traitement de conditions inflammatoires systémiques, telles que septicémie, choc endotoxique, choc hémorragique et autres syndromes apparentés. L'administration de HMGB1, ou de peptides qui en sont dérivés, induit une réponse immunitaire caractérisée par la production d'anticorps anti-HMGB1 capables de neutraliser l'activité du HMGB1 circulant en inhibant sa capacité à favoriser la sécrétion de cytokine TNF-α pro-inflammatoire. L'efficacité du traitement préventif peut être déterminée par une méthode qui mesure l’activité neutralisante des anticorps contre l'effet biologique du HMGB1 sur les monocytes humains.
PCT/EP2005/009866 2005-09-14 2005-09-14 Immunothérapie active pour inflammation systémique potentiellement mortelle WO2007031100A1 (fr)

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Cited By (8)

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US20090202500A1 (en) * 2006-10-30 2009-08-13 Genomix Co., Ltd. Pharmaceuticals That Promote Functional Regeneration of Damaged Tissues
US9623078B2 (en) 2012-10-25 2017-04-18 Genomix Co., Ltd. Method for treating cardiac infarction using HMGB1 fragment
US9688733B2 (en) 2012-10-25 2017-06-27 Genomix Co., Ltd. Method for treating spinal cord injury using HMGB1 fragment
US9919010B2 (en) 2008-04-30 2018-03-20 Genomix Co., Ltd. Method for collecting functional cells in vivo with high efficiency
US10364276B2 (en) 2011-04-26 2019-07-30 StemRIM Inc. Peptide for inducing regeneration of tissue and use thereof
US11191786B2 (en) 2009-10-28 2021-12-07 StemRIM Inc. Agents for promoting tissue regeneration by recruiting bone marrow mesenchymal stem cells and/or pluripotent stem cells into blood
US11298403B2 (en) 2017-12-01 2022-04-12 StemRIM Inc. Therapeutic agent for inflammatory bowel disease
US11969459B2 (en) 2017-01-27 2024-04-30 StemRIM Inc. Therapeutic agent for cardiomyopathy, old myocardial infarction and chronic heart failure

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WO2004046345A2 (fr) * 2002-11-20 2004-06-03 Critical Therapeutics, Inc. Utilisation de fragments hmgb en tant qu'agents anti-inflammatoires
WO2004061456A2 (fr) * 2003-01-03 2004-07-22 Alcedo Biotech Gmbh Utilisations de proteines de liaison a l'adn
WO2005025604A2 (fr) * 2003-09-10 2005-03-24 The General Hospital Corporation Utilisation de hmgb et fragments de hmgb pour faire diminuer la reponse immunitaire specifique
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WO2002074337A1 (fr) * 2001-03-16 2002-09-26 Bio3 Research S.R.L. Inhibiteurs et/ou antagonistes de proteines hmgb1 destines au traitement de maladies vasculaires
WO2004004763A2 (fr) * 2002-07-03 2004-01-15 Fondazione Centro San Raffaele Del Monte Tabor Utilisation de hmgb1 dans le traitement des lesions tissulaires et/ou pour activer la reparation des tissus
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090202500A1 (en) * 2006-10-30 2009-08-13 Genomix Co., Ltd. Pharmaceuticals That Promote Functional Regeneration of Damaged Tissues
US9919010B2 (en) 2008-04-30 2018-03-20 Genomix Co., Ltd. Method for collecting functional cells in vivo with high efficiency
US11197895B2 (en) 2008-04-30 2021-12-14 StemRIM Inc. Method for collecting functional cells in vivo with high efficiency
US11191786B2 (en) 2009-10-28 2021-12-07 StemRIM Inc. Agents for promoting tissue regeneration by recruiting bone marrow mesenchymal stem cells and/or pluripotent stem cells into blood
US10364276B2 (en) 2011-04-26 2019-07-30 StemRIM Inc. Peptide for inducing regeneration of tissue and use thereof
US10550165B2 (en) 2011-04-26 2020-02-04 StemRIM Inc. Peptide for inducing regeneration of tissue and use thereof
US9623078B2 (en) 2012-10-25 2017-04-18 Genomix Co., Ltd. Method for treating cardiac infarction using HMGB1 fragment
US9688733B2 (en) 2012-10-25 2017-06-27 Genomix Co., Ltd. Method for treating spinal cord injury using HMGB1 fragment
US11969459B2 (en) 2017-01-27 2024-04-30 StemRIM Inc. Therapeutic agent for cardiomyopathy, old myocardial infarction and chronic heart failure
US11298403B2 (en) 2017-12-01 2022-04-12 StemRIM Inc. Therapeutic agent for inflammatory bowel disease

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