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WO1999015552A1 - Composes oligopeptidiques - Google Patents

Composes oligopeptidiques Download PDF

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Publication number
WO1999015552A1
WO1999015552A1 PCT/JP1998/004203 JP9804203W WO9915552A1 WO 1999015552 A1 WO1999015552 A1 WO 1999015552A1 JP 9804203 W JP9804203 W JP 9804203W WO 9915552 A1 WO9915552 A1 WO 9915552A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pro
oligopeptide
gly
cys
Prior art date
Application number
PCT/JP1998/004203
Other languages
English (en)
Japanese (ja)
Inventor
Tadao Okamoto
Junko Wada
Yoshihisa Inoue
Naoki Sugiyama
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
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 Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU90954/98A priority Critical patent/AU9095498A/en
Publication of WO1999015552A1 publication Critical patent/WO1999015552A1/fr

Links

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
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
    • 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 oligopeptide compounds. More specifically, the present invention relates to a novel oligopeptide compound useful as a B7 inhibitor. The present invention also relates to a compound having a B7 inhibitory action and a method for screening the same. Further, the present invention relates to a pharmaceutical composition and a B7 inhibitor containing the compound. It also relates to methods for inhibiting B7 and the use of these compounds for producing B7 inhibitors. Background art
  • B7 inhibitors substances that inhibit the action of the B7 molecule family (referred to as B7 inhibitors) are expected to act as antigen-specific immunosuppressants, and research on B7 inhibitors has been conducted.
  • B7 inhibitors include anti-B7 antibodies and CTLA4-Ig (CTLA4 is a molecule expressed on activated T cells, CTLA4-Ig is a fusion protein of CTLA4 and immunoglobulin ) Is only reported. See Finck, BK, Linsley, PS and Wofsy, D., Science, 265, pl225-1227 (1994).
  • CTL A 4—Ig is under development by Bristol-Myers Squibb o
  • oligopeptide compound or a salt thereof according to the above (1) which is represented by:
  • oligopeptide compound or salt thereof according to any one of the above-mentioned 1 to ⁇ ⁇ ⁇ , which is a compound having a B7 inhibitory action;
  • the T fine A method of screening for a compound having a B7 inhibitory action (target drug) by using a system for analyzing the degree of inhibition of the costimulatory reaction of the target drug by measuring the amount of 3 H-thymidine incorporated into the cells;
  • T cells (1 ⁇ 2) X 1 0 5 cells Z Ueru,? (3) Activated 8 cells are used in an amount of (1 to 40) ⁇ 10 4 cells / ⁇ l, anti-CD3 antibody is used in an amount of about 1 ng / m 1, and culture days are 1 to 3 days.
  • the present invention is a.
  • the oligopeptide compound of the present invention includes various compounds as long as it is the above-mentioned oligonucleotide having an amino acid sequence, and any amino acid or any amino acid or A plurality of arbitrary amino acid peptide chains may be bonded, and the N-terminal amino group and / or the C-terminal carboxy group of these oligopeptides may have a substituent; and It may be a cyclic oligopeptide having an N-terminal and a C-terminal bonded, and when the oligopeptide contains two or more cysteines, those cysteines are linked by a disulfide (—S—S—) bond. It may be cyclized.
  • the number of amino acids of the oligopeptide compound of the present invention is about 6 to 25, preferably about 6 to 20, and more preferably about 6 to 10.
  • a preferred compound of the oligopeptide compound of the present invention has the following general formula (1) or general formula (2)
  • 1 and 2 and 3 and 4 are the same or different and are each a single bond, an amino acid residue or a peptide chain composed of a plurality of amino acids, and X and chi Examples 2 and chi peptide chain composed of 3 and chi 4 amino acid residue or a plurality of amino acids, to select a peptide chain of arbitrary amino acid residue or a plurality of any amino acid Possible force X, preferably -Lys-Val-Glu-Leu-, -Cys-Lys-Val-Glu-Leu-, -Cys-Gly-, -Cys-Gly-Gly-, -Cys-Gly- Gly-Gly-, -Cys-, etc.
  • R and R 3 represent N-terminal H or a substituent thereof.
  • substituents include an acyl group (for example, an alkanol group such as acetyl (Ac), propionyl, butyryl, lauroyl, benzoyl, Aromatic acyl groups such as naphthoyl, heterocyclic acyl groups such as furoyl, tenyl and nicotinyl), alkyl groups such as methyl, ethyl and propyl, and aralkyl groups such as benzyl and benzhydryl.
  • the substituent may be substituted with, for example, an alkyl group, a hydroxyl group, a nitro group, a halogen, or the like.
  • R 2 and R 4 each represent C-terminal OH or a substituent thereof.
  • the substituent include an amide group and an ester group.
  • R 2 includes, for example, amino
  • examples thereof include an amino group which may have a substituent such as alkylamino (for example, methylamino and ethylamino), benzylamino and the like, and an alkoxy group such as methoxy, ethoxy, butoxy and benzyloxy.
  • Chemical synthesis methods include known peptide synthesis methods, for example, a method in which amino acids are coupled stepwise from the C-terminus or a method in which amino acids are coupled stepwise from the N-terminus, and oligopeptides having a partial sequence.
  • Examples of the method include a binding method, a liquid phase method or a solid phase method, manual synthesis, and synthesis using an automatic synthesizer.
  • DNA having a base sequence corresponding to the target oligopeptide is synthesized, and the DNA is incorporated into an appropriate expression system, expressed, and produced as a recombinant substance.
  • a genetic engineering technique is already known and can be performed according to a conventional method.
  • the compound having a B7 inhibitory activity of the present invention is a compound that can be selected in a screening system described in Experimental Examples described later, and more specifically, a medium containing T cells derived from C57BL / 6 mouse.
  • the anti-CD 3 antibody, teeth 8 activation 8 cells were mixed 3 H- thymidine ⁇ beauty target drug, after cell culture, by measuring 3 H- thymidine amount incorporated into said T cells, the subject It can be obtained by a screening method using a system for analyzing the degree of inhibition of the costimulatory reaction of a drug.
  • the target drug includes an arbitrary compound that is to be screened, and includes an oligonucleotide compound other than the oligonucleotide compound having the above-mentioned structure and other arbitrary compounds.
  • the use concentration of the target drug is preferably about 100 to 300.
  • the amount of 3 H-thymidine incorporation can be measured by a liquid scintillation 'counting method or a bio-imaging analyzer (BAS) method according to a conventional method.
  • Example 2 The compounds of Examples 2 to 4 were synthesized in the same manner as in Example 1.
  • Example 2 The compounds of Examples 2 to 4 were synthesized in the same manner as in Example 1.
  • Example 6′13 was synthesized in the same manner as in Example 5.
  • the concentration of the test drug was 300 ⁇ M, and the amount of 3 3- thymidine was 2 nC i. Radioactivity was measured by liquid scintillation 'counting method or bio-imaging analyzer (BAS) method. Table 1 shows the results.
  • the anti-CD3 monoclonal antibody and LPS-activated B cells were prepared according to the method described in the literature (Int. J. Cancer 70, 1-8, 1997).
  • the compound of the present invention has reduced costimulatory activity
  • the B7 inhibitory activity was measured in the presence of an anti-CD288 monoclonal antibody (1 g Zm1) according to Experimental Example 2. went. If the inhibitory activity of the compound of the present invention is B7-specific, the presence of the anti-CD28 monoclonal antibody will restore the costimulatory activity. As a result of this test, the inhibitory effect of the compound of the present invention was completely released by the anti-CD28 monoclonal antibody. In addition, it was similarly released when a 5-fold amount of LPS-activated B cells was used. That is, it was found that the B7 inhibitory action of the compound of the present invention was B7-specific.
  • the compound of the present invention (the compound of Example 2) was mixed with 1 g of lactose to prepare a powder.
  • the compound of the present invention can have a B7 inhibitory effect, it is expected to be used in the immune field. That is, it can be applied to autoimmune diseases, allergies, rejection at the time of organ transplantation, bacterial infection, cancer, tumor, AIDS, and the like.
  • the oligopeptide compound of the present invention has a lower molecular weight than conventional protein-based inhibitors (anti-B7 antibody, CTLA4-Ig, etc.), it has reduced immunogenicity and tissue permeability. Improvement and reduction of side effects can be achieved.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Cell Biology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention a trait à des composés oligopeptidiques comportant un reste oligopeptidique représenté par la séquence -Met-Tyr-Pro-Pro-Pro-Tyr- ou -Pro-Ser-His-Asn-Thr-Asp-Glu-Val et, notamment, à de nouveaux composés oligopeptidiques efficaces en tant qu'inhibiteurs de B7 ou à des composés dotés d'une telle activité. Elle concerne également une méthode de criblage de ces composés et porte sur des préparations médicinales renfermant ces composés et relevant du domaine de l'immunologie (maladies auto-immunes, allergies, réactions de rejet après une transplantation d'organe, infections bactériennes, cancers, tumeurs, SIDA, etc.).
PCT/JP1998/004203 1997-09-19 1998-09-18 Composes oligopeptidiques WO1999015552A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU90954/98A AU9095498A (en) 1997-09-19 1998-09-18 Oligopeptide compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/273704 1997-09-19
JP27370497 1997-09-19

Publications (1)

Publication Number Publication Date
WO1999015552A1 true WO1999015552A1 (fr) 1999-04-01

Family

ID=17531402

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/004203 WO1999015552A1 (fr) 1997-09-19 1998-09-18 Composes oligopeptidiques

Country Status (2)

Country Link
AU (1) AU9095498A (fr)
WO (1) WO1999015552A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06508989A (ja) * 1991-06-27 1994-10-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃｔｌ４ａレセプター、それを含有する融合タンパク質およびそれらの使用
JPH0847391A (ja) * 1994-04-15 1996-02-20 Bristol Myers Squibb Co Ｃｔｌａ４分子及びｉｌ４結合分子並びにそれらの使用
JPH09202800A (ja) * 1995-07-21 1997-08-05 Bristol Myers Squibb Co Ｃｔｌａ４変異体分子およびそれの使用
WO1997028267A1 (fr) * 1996-02-02 1997-08-07 Repligen Corporation Anticorps et proteines de fusion d'immunoglobuline presentant des fonctions d'effecteur modifiees et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06508989A (ja) * 1991-06-27 1994-10-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃｔｌ４ａレセプター、それを含有する融合タンパク質およびそれらの使用
JPH0847391A (ja) * 1994-04-15 1996-02-20 Bristol Myers Squibb Co Ｃｔｌａ４分子及びｉｌ４結合分子並びにそれらの使用
JPH09202800A (ja) * 1995-07-21 1997-08-05 Bristol Myers Squibb Co Ｃｔｌａ４変異体分子およびそれの使用
WO1997028267A1 (fr) * 1996-02-02 1997-08-07 Repligen Corporation Anticorps et proteines de fusion d'immunoglobuline presentant des fonctions d'effecteur modifiees et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRUNET J.-F., ET AL.: "A NEW MEMBER OF THE IMMUNOGLOBULIN SUPERFAMILY-CTLA-4.", NATURE, NATURE PUBLISHING GROUP, UNITED KINGDOM, vol. 328., 1 January 1987 (1987-01-01), United Kingdom, pages 267 - 270., XP002915323, ISSN: 0028-0836, DOI: 10.1038/328267a0 *

Also Published As

Publication number Publication date
AU9095498A (en) 1999-04-12

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