EP0758902A1 - Zusammensetzungen und eine behandlung fuer multiple sklerose - Google Patents

Zusammensetzungen und eine behandlung fuer multiple sklerose

Info

Publication number
EP0758902A1
EP0758902A1 EP95918988A EP95918988A EP0758902A1 EP 0758902 A1 EP0758902 A1 EP 0758902A1 EP 95918988 A EP95918988 A EP 95918988A EP 95918988 A EP95918988 A EP 95918988A EP 0758902 A1 EP0758902 A1 EP 0758902A1
Authority
EP
European Patent Office
Prior art keywords
peptide
mbp
amino acid
acid residues
human mbp
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.)
Withdrawn
Application number
EP95918988A
Other languages
English (en)
French (fr)
Inventor
Di-Hwei Hsu
Dawn Smilek
Jia Dong Shi
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.)
Immulogic Pharmaceutical Corp
Original Assignee
Immulogic Pharmaceutical Corp
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 Immulogic Pharmaceutical Corp filed Critical Immulogic Pharmaceutical Corp
Publication of EP0758902A1 publication Critical patent/EP0758902A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Autoimmune diseases are a significant human health problem and are relatively poorly understood. As there is no microbial or viral culprit apparently directly responsible, prevention, treatment and diagnosis of such diseases must be based on the etiology of the disease. This invariably involves a complex series of reactions of endogenous metabolic intermediates, structural components, cells and so forth. Implicit however in the nature of an autoimmune condition is the notion that at least one autoantigen must be involved in creating the sequence of events that results in the symptoms. Autoimmune demyelinating diseases such as multiple sclerosis are no exception.
  • EAE allergic encephalomyelitis
  • MBP myelin basic protein
  • T cell epitopes T cell epitopes
  • MBP amino acid residues 84-102 Minor epitopes (MBP amino acid residues 143-168, 61-82, 124-142 and 31- 50 recognized by T cells from MS patients were also described. Zamvil et al., supra have shown that MBP amino acid residues 1-11 contain the major T cell epitope(s) causing EAE, in susceptible rodent strains.
  • compositions of the invention comprise at least one peptide or modified peptide of myelin basic protein (MBP) which comprise at least one T cell epitope, and IFN- ⁇ in an appropriate pharmaceutically acceptable medium for either oral, subcutaneous or intravenous administration.
  • Methods of the invention include treatment of individuals who either have MS or are suspected of being susceptible to MS by administering a therapeutically effective amount of a composition of the invention or by administering in a therapeutic regimen, a composition comprising at least one peptide or modified peptide of MBP which comprises at least one T cell epitope and further administering IFN- ⁇ .
  • MCS mean clinical score
  • Fig. lb is a graphic depiction of an experiment showing the effects of MBP peptide Ac 1-11 in two groups of 10 (SJL x TLP) Fj adult female mice who were induced EAE with guinea pig MBP in complete adjuvant plus pertussis toxin on day 0 and were administered either PBS (control) or were treated with 250 nmol Ac 1-11 intravenously on days 10, 13, 17, and 21 (indicated by arrows on the x axis), the Y axis represents the average mean clinical score for each group as described for Fig. la.
  • Fig. lc is a graphic depiction of an experiment showing the effects of MBP peptide Ac 1-11 administered in combination with IFN- ⁇ on EAE in two groups of 10 (SJL x TLP) F j adult female mice who were induced EAE with guinea pig MBP in complete adjuvant plus pertussis toxin on day 0 and were administered either PBS
  • control or were treated with 250 nmol Ac 1-11 intravenously on days 10, 13, 17, and 21 (indicated by open arrows on the x axis), and were treated with 2000 units of IFN- ⁇ interperitoneally (i.p.) on days 9, 12, 16, and 20 (indicated by closed arrows on the x axis), the Y-axis indicates the mean clinical score as discussed for Fig. la.
  • Fig. 2 is a graphic depiction of an experiment showing the effects of various doses of IFN- ⁇ (10,000 units and 2,000 units respectively) on induced EAE in two groups of 10 (SJL x TLP) Fj adult female mice who were induced EAE with guinea pig MBP plus pertussis toxin on day 0 and were administered either PBS (control) or were treated with 10,000 units and 2000 units respectively of LFN- ⁇ interperitoneally (i.p.) on days 9, 13, 16, (indicated by closed arrows on the x axis), the Y-axis indicates the mean clinical score as discussed for Fig. la.
  • Fig. 3 shows the full length amino acid sequence of human MBP.
  • Fig. 4 shows the amino acids sequences for selected MBP peptides useful in the practice of the instant invention. Detailed Description of the Invention:
  • the present invention provides methods for treating multiple sclerosis comprising administering a therapeutically effective amount of at least one antigenic peptide of MBP in a treatment regimen which includes a therapeutically effective amount of IFN- ⁇ .
  • peptide refers to an amino acid sequence having fewer amino acid residues than the entire amino acid sequence of the protein from which the peptide was derived.
  • antigenic peptide refers to any peptide comprising at least one T cell epitope or any portion of such peptide comprising at least one T cell epitope.
  • the epitope will be the basic element, or smallest unit of recognition by a receptor, particularly immunoglobulins, histocompatibility antigens and T cell receptors, where the epitope comprises amino acids of the native protein such as the autoantigen which are essential to receptor recognition.
  • T cell epitopes are believed to be involved in initiation and perpetuation of the autoimmune response. These T cell epitopes are thought to trigger early events at the level of the T helper cell by being presented by an appropriate HLA molecule on the surface of an antigen presenting cell, thereby stimulating the T cell subpopulations with the relevant T cell receptor for the epitope. These events lead to T cell proliferation, lymphokine secretion, local inflammatory reaction, recruitment of additional immune cells to the site of antigen/T cell interaction and activation of the B cell cascade leading to the production of antibodies.
  • Exposure of a subject to a peptide or protein which comprises at least one T cell epitope of the autoantigen may modify T cell subpopulations such that they become unresponsive to the autoantigen and do not participate in stimulating an immune response.
  • administration of a protein or peptide which comprises at least one T cell epitope may modify the lymphokine secretion profile as compared with exposure to the naturally occurring autoantigen (e.g. result in a decrease or LL-4 and/or increase in JL-2 causing a modification of TH1 and TH2 populations).
  • exposure to such a peptide may influence T cell subpopulations which normally participate in the response to the autoantigen such that these T cells are drawn away from the sites of normal exposure to the autoantigen (e.g.
  • T cell subpopulations may ameliorate or reduce the ability of the individual's immune system to stimulate the usual immune response at the site of normal exposure to the autoantigen resulting in diminution of symptoms.
  • Any peptides derived from MBP which moderate response of a subject to MBP autoantigen may be included in the methods and compositions of the invention.
  • Such peptides may be identified, for example, by examining the structure and selecting appropriate regions to be produced as peptides (via recombinant expression systems, synthetically or otherwise) to be examined for ability to influence T cell responses to MBP, and selecting peptides containing epitopes recognized by these cells.
  • Many human MBP peptides comprising T cell epitopes are described in the art. Modified antigenic peptides are useful within the scope of the invention.
  • a peptide can be modified so that it maintains the ability to induce T cell anergy and bind MHC protein without the ability to induce a strong proliferative response or possibly, any proliferative response when administered in immunogenic form.
  • critical binding residues for the T cell receptor can be determined using known techniques (e.g. substitution of each residue and determination of the presence or absence of T cell reactivity).
  • residues shown to be essential to interact with the T cell receptor can be modified by replacing the essential amino acid with another, preferably similar amino acid residue (a conservative substitution) whose presence is shown to enhance, diminish but not eliminate or not effect T cell reactivity.
  • amino acid residues which are not essential for T cell receptor interaction can be modified by being replaced by another amino acid whose inco ⁇ oration may enhance, diminish but not eliminate, or not effect T cell reactivity.
  • amino acid residues which are not essential for T cell receptor interaction can be modified by being replaced by another amino acid whose incorporation may enhance diminish or not effect T cell reactivity but does not eliminate binding to relevant MHC.
  • peptides of the invention can be modified by replacing an amino acid shown to be essential to interact with MHC protein complex with another preferably similar amino acid residue (conservative substitution) whose presence is shown to enhance, diminish but not eliminate or not effect T cell activity.
  • amino acid residues which are not essential for interaction with the MHC protein complex can be modified by being replaced by another amino acid whose incorporation may enhance, not effect, or diminish but not eliminate T cell reactivity.
  • Preferred amino acid substitutions for non-essential amino acids include but are not limited to substitutions with alanine, glutamic acid, or a methyl amino acid.
  • peptides may be modified to increase the solubility of a peptide for use in buffered aqueous solutions such as pharmaceutically acceptable carriers or diluents by adding functional groups to the peptide, terminal portions of the peptide, or by not including hydrophobic T cell epitopes or regions containing hydrophobic epitopes in the peptides or hydrophobic regions of the protein or peptide.
  • charged amino acids or charged amino acid pairs or triplets may be added to the carboxy or amino terminus of the peptide.
  • charged amino acids include arginine (R), lysine (K), histidine (H), glutamic acid (E), and aspartic acid (D).
  • peptides comprising "cryptic epitopes” may be determined and are also useful in the methods and compositions of the invention.
  • Cryptic epitopes are those determinants in a protein antigen which, due to processing and presentation of the native protein antigen to the appropriate MHC molecule, are not normally revealed to the immune system.
  • a peptide comprising a cryptic epitope is capable of causing T cells to become non-responsive, and when a subject is primed with the peptide, T cells obtained from the subject will proliferate in vitro in response to the peptide or the protein antigen from which the peptide is derived.
  • Peptides which comprise at least one cryptic epitope derived from a protein antigen are referred to herein as "cryptic peptides".
  • a T cell proliferation assay may be used as is known in the art in which antigen primed T cells are cultured in vitro in the presence of each peptide separately to establish peptide- reactive T cell Unes.
  • a peptide is considered to comprise at least one cryptic epitope if a T cell line can be established with a given peptide and T cells are capable of proliferation upon challenge with the peptide and the protein antigen from which the peptide is derived.
  • Antigenic peptides useful within in the compositions and methods of the present invention include the following peptides or portions thereof having residue numbers which correspond the amino acid residues of the human MBP protein shown in Fig. 3: a peptide comprising all or a portion of amino acid residues 84-106 of human MBP, a peptide comprising all or a portion of amino acid residues 84-102 of human MBP, a peptide comprising all or a portion of amino acid residues 89-101 of human MBP, a peptide comprising all or a portion of amino acid residues 140-172 of human MBP, a peptide comprising all or a portion of amino acid residues 143-168 of human MBP, a peptide comprising all or a portion of amino acid residues 142-167 of human MBP and a peptide comprising all or a portion of amino acids residues 13-25 of human MBP. Sequences of selected peptides are shown in Figure 4. Any of these peptides may be modified as
  • the present invention provides a method of treating individuals who have multiple sclerosis or are susceptible to developing multiple sclerosis, which comprises administering an effective amount of an antigenic peptide derived from MBP in non-immunogenic form (i.e. without adjuvant) in a therapeutic regimen which also includes the administration of IFN- ⁇ .
  • MBP in a therapeutic regimen which includes administration of IFN- ⁇ can be carried out using known procedures at dosages and for periods of time to effectively reduce, eliminate or prevent the symptoms associates with multiple sclerosis.
  • Effective amounts of either antigenic peptide or LFN- ⁇ when administered together in a therapeutic regimen vary according to factors such as the degree of sensitivity and susceptibility of the individual to MS, the age, sex, and weight of the individual, and the ability of the antigenic MBP peptide to elicit an antigenic response in the individual.
  • the active compounds i.e. the MBP peptide or composition thereof and IFN- ⁇
  • the active compound may be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound.
  • a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound For example, preferably about 1 ⁇ g-3mg and more preferably about 20-500 ⁇ g of antigenic peptide derived from MBP per dosage unit may be administered by injection.
  • a dosage unit of 100-10,000 units of IFN- ⁇ may be administered by injection.
  • the dosage regimen of these two compounds may be adjusted to provide the optimum therapeutic response.
  • IFN- ⁇ and a composition comprising antigenic peptide derived from MBP may be administered simultaneously or may preferably be administered at least six hours apart, preferably at least 12 hours apart, or more preferably at least 24 hours apart.
  • the therapeutic regimen of administering both antigenic peptide and IFN- ⁇ may continue over a period of days or weeks and may be reduced or extended as indicated by the exigencies of the therapeutic situation.
  • the present invention also provides a novel composition
  • a novel composition comprising a physical mixture of an antigenic peptide derived from MBP and IFN- ⁇ in a pharmaceutically acceptable carrier or diluent.
  • This composition may be used as part of a therapeutic regimen for treating or preventing multiple sclerosis in an individual.
  • This invention is further illustrated by the following non-limiting example.
  • Mouse MBP peptide Ac 1-11 was synthesized using standard Fmoc/tBoc synthesis and purified by HPLC.
  • the amino acid sequence for peptide Ac 1-11 is as follows:
  • EAE was induced in 6 to 8 week old female (SJL x PL)F j mice (Jackson Labs, Bar Harbor, ME) by immunizing mice with 100 ⁇ g purified guinea pig MBP in CFA (GIBCO Lab., Grand Island, NY) containing 400 ⁇ g H37RA strain M. tuberculosis (DLFCO Lab., Detroit, MI) subcutaneously at the base of the tail. 200 ng Pertussis Toxin (JHL BIOSCJENCE, Lenexa, Kansas) was given twice intravenously (i.v.) on the day of immunization and also 48 hours later.
  • mice MBP peptide Ac 1-11 The effect of mouse MBP peptide Ac 1-11 was determined and the results are shown in Fig. lb.
  • One group of mice was treated i.p. with PBS on days 10, 13, 17, and 21 (control) after EAE induction, and one group of mice was treated i.v. with 250 nmol of peptide Ac 1-11 on days 10, 13, 17, and 21.
  • the mice were monitored as described above. As shown in Fig lb, the mice treated with Ac 1-11 had less severe symptoms than those of the control group.
  • a treatment regimen which includes a combination of peptide and IFN- ⁇ provides an enhanced effect on diminishing the severity of the symptoms of EAE.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rehabilitation Therapy (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP95918988A 1994-05-10 1995-05-04 Zusammensetzungen und eine behandlung fuer multiple sklerose Withdrawn EP0758902A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US24124694A 1994-05-10 1994-05-10
US241246 1994-05-10
US32822494A 1994-10-25 1994-10-25
US328224 1994-10-25
PCT/US1995/005605 WO1995030435A2 (en) 1994-05-10 1995-05-04 Compositions and treatment for multiple sclerosis

Publications (1)

Publication Number Publication Date
EP0758902A1 true EP0758902A1 (de) 1997-02-26

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ID=26934122

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95918988A Withdrawn EP0758902A1 (de) 1994-05-10 1995-05-04 Zusammensetzungen und eine behandlung fuer multiple sklerose

Country Status (11)

Country Link
EP (1) EP0758902A1 (de)
JP (1) JPH10500109A (de)
AU (1) AU2470595A (de)
CA (1) CA2189990A1 (de)
CZ (1) CZ329596A3 (de)
HU (1) HUT76099A (de)
IL (1) IL113661A0 (de)
PL (1) PL317197A1 (de)
SI (1) SI9520059A (de)
SK (1) SK145896A3 (de)
WO (1) WO1995030435A2 (de)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4278296A (en) * 1994-10-25 1996-05-15 Immulogic Pharmaceutical Corporation Compositions and treatment for multiple sclerosis
US6156535A (en) 1995-08-04 2000-12-05 University Of Ottawa Mammalian IAP gene family, primers, probes, and detection methods
EP0922057A1 (de) * 1996-03-28 1999-06-16 Immulogic Pharmaceutical Corporation Glycoproteinpeptide von myelin-oligodendrozytenund verwendung derselben
EP0939826A2 (de) * 1996-08-15 1999-09-08 Agrivax Incorporated Abgabe von tolerogenen antigenen über essbare pflanzen oder deren produkte
AUPP823999A0 (en) * 1999-01-20 1999-02-11 University Of Queensland, The A treatment
US20020025304A1 (en) * 2000-06-16 2002-02-28 Croze Edward M. Novel interferon for the treatment of multiple sclerosis
CN102784385B (zh) * 2000-08-21 2015-11-25 阿皮托普技术(布里斯托尔)有限公司 肽选择方法
GB0202399D0 (en) * 2002-02-01 2002-03-20 Univ Bristol Peptide
DK1490490T3 (da) 2002-03-27 2009-09-07 Aegera Therapeutics Inc Antisense IAP--nukleobase-oligomerer og anvendelser deraf
US8012944B2 (en) 2003-10-30 2011-09-06 Pharmascience Inc. Method for treating cancer using IAP antisense oligomer and chemotherapeutic agent
BG66517B1 (bg) 2008-04-08 2016-02-29 Tigo Gmbh Супресор на ендогенния човешки гама - интерферон
BG1430U1 (bg) * 2010-06-25 2011-04-29 Иван ИВАНОВ Фармацевтично средство
BG67190B1 (bg) 2017-03-29 2020-11-16 Tigo Gmbh Анти-гама мутантен протеин срещу ендогенния човешки гама интерферон

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021222A1 (en) * 1992-04-09 1993-10-28 Autoimmune, Inc. Suppression of t-cell proliferation using peptide fragments of myelin basic protein
JPH08500823A (ja) * 1992-08-17 1996-01-30 オートイミューン インク レトロウィルス関連神経疾患のバイスタンダー抑制

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9530435A2 *

Also Published As

Publication number Publication date
HUT76099A (en) 1997-06-30
SK145896A3 (en) 1997-05-07
WO1995030435A3 (en) 1995-12-07
JPH10500109A (ja) 1998-01-06
SI9520059A (en) 1997-08-31
HU9603116D0 (en) 1997-01-28
WO1995030435A2 (en) 1995-11-16
PL317197A1 (en) 1997-03-17
CZ329596A3 (en) 1997-05-14
AU2470595A (en) 1995-11-29
CA2189990A1 (en) 1995-11-16
IL113661A0 (en) 1995-08-31

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