JP6608282B2 - 新規免疫療法用分子およびその使用 - Google Patents
新規免疫療法用分子およびその使用 Download PDFInfo
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- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 238000010181 skin prick test Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 208000034280 venom allergy Diseases 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K39/001—Preparations to induce tolerance to non-self, e.g. prior to transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- 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
- A61K38/10—Peptides 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
- A61K39/35—Allergens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
-
- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Mycology (AREA)
- Transplantation (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
Description
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)FGKLFEVK (配列番号4)
(iv) EVKPDKKNPQLQ (配列番号5)
(v) EGALML (配列番号6)
(vi) PHFNSKAMVIV (配列番号7)
(vii)IVVVN (配列番号8)
(viii)VVNKGTGNLEL (配列番号9)
(ix) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) PHFNSKAMVIV (配列番号7)
(vii)IVVVN (配列番号8)
(viii)VVNKGTGNLEL (配列番号9)
(ix) IMPAAHP (配列番号10)
(i) FQNLQNHRIV(配列番号12)
(ii)RIVQIEAKPNTLV(配列番号13)
(iii)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(iv)WSTRSSENNEGVIVKVSKE(配列番号15)
(v) STRSSENNEGVIVKVSKE(配列番号16)
(vi)ENNEGVIVKVSKE(配列番号17)
(vii)NNFGKLFEVKPDKKNPQ(配列番号18)
(viii)SNNFGKLFEVKPDKKNPQ(配列番号19)
(ix)EVKPDKKNPQLQ(配列番号20)
(x) NNFGKLFEVKPDKKNPQLQ(配列番号21)
(xi)SNNFGKLFEVKPDKKNPQLQ(配列番号22)
(xii)VEIKEGALMLPHFNSKA(配列番号23)
(xiii)ALMLPHFNSKAMVIVVV(配列番号24)
(xiv)KAMVIVVVNKG(配列番号25)
(xv)AMVIVVVNKGTGNLELVAV(配列番号26)
(xvi)VVNKGTGNLELVAVRK(配列番号27)
(xvii)AMVIVVVNKGTGNLELV(配列番号28)
(xviii)KAMVIVVVNKGTGNLELVAV(配列番号29)
(xix)GDVFIMPAAHPVAINASS(配列番号30)
(xx)VFIMPAAHPVAINASSE(配列番号31)
(xxi)GDVFIMPAAHPVAINASSE(配列番号32)
(xxii)VFIMPAAHPVAINASS(配列番号33)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) EGALML (配列番号6)
(vii)PHFNSKAMVIV (配列番号7)
(viii)IVVVN (配列番号8)
(ix) VVNKGTGNLEL (配列番号9)
(x) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)FGKLFEVK (配列番号4)
(iv) EVKPDKKNPQLQ (配列番号5)
(v) EGALML (配列番号6)
(vi) PHFNSKAMVIV (配列番号7)
(vii)IVVVN (配列番号8)
(viii)VVNKGTGNLEL (配列番号9)
(ix) IMPAAHP (配列番号10)
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) PHFNSKAMVIV (配列番号7)
(vii)IVVVN (配列番号8)
(viii)VVNKGTGNLEL (配列番号9)
(ix) IMPAAHP (配列番号10)
(i) FQNLQNHRIV(配列番号12)
(ii)RIVQIEAKPNTLV(配列番号13)
(iii)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(iv)WSTRSSENNEGVIVKVSKE(配列番号15)
(v) STRSSENNEGVIVKVSKE(配列番号16)
(vi)ENNEGVIVKVSKE(配列番号17)
(vii)NNFGKLFEVKPDKKNPQ(配列番号18)
(viii)SNNFGKLFEVKPDKKNPQ(配列番号19)
(ix)EVKPDKKNPQLQ(配列番号20)
(x) NNFGKLFEVKPDKKNPQLQ(配列番号21)
(xi)SNNFGKLFEVKPDKKNPQLQ(配列番号22)
(xii)VEIKEGALMLPHFNSKA(配列番号23)
(xiii)ALMLPHFNSKAMVIVVV(配列番号24)
(xiv)KAMVIVVVNKG(配列番号25)
(xv)AMVIVVVNKGTGNLELVAV(配列番号26)
(xvi)VVNKGTGNLELVAVRK(配列番号27)
(xvii)AMVIVVVNKGTGNLELV(配列番号28)
(xviii)KAMVIVVVNKGTGNLELVAV(配列番号29)
(xix)GDVFIMPAAHPVAINASS(配列番号30)
(xx)VFIMPAAHPVAINASSE(配列番号31)
(xxi)GDVFIMPAAHPVAINASSE(配列番号32)
(xxii)VFIMPAAHPVAINASS(配列番号33)
(i)FQNLQNHRIV(配列番号12)
(ii)RIVQIEAKPNTLV(配列番号13)
(iii)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(iv)WSTRSSENNEGVIVKVSKE(配列番号15)
(v)STRSSENNEGVIVKVSKE(配列番号16)
(vi)NNFGKLFEVKPDKKNPQ(配列番号18)
(vii)SNNFGKLFEVKPDKKNPQ(配列番号19)
(viii)EVKPDKKNPQLQ(配列番号5)
(ix)NNFGKLFEVKPDKKNPQLQ(配列番号21)
(x)SNNFGKLFEVKPDKKNPQLQ(配列番号22)
(xi)VEIKEGALMLPHFNSKA(配列番号23)
(xii)ALMLPHFNSKAMVIVVV(配列番号24)
(xiii)KAMVIVVVNKG(配列番号25)
(xiv)AMVIVVVNKGTGNLELVAV(配列番号26)
(xv)AMVIVVVNKGTGNLELV(配列番号28)
(xvi)KAMVIVVVNKGTGNLELVAV(配列番号29)
(xvii)GDVFIMPAAHPVAINASS(配列番号30)
(xviii)GDVFIMPAAHPVAINASSE(配列番号32)
(xix)VFIMPAAHPVAINASSE(配列番号31)
(i)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(ii)WSTRSSENNEGVIVKVSKE(配列番号15)
(iii)NNFGKLFEVKPDKKNPQLQ(配列番号21)
(iv)VEIKEGALMLPHFNSKA(配列番号23)
(v)ALMLPHFNSKAMVIVVV(配列番号24)
(vi)KAMVIVVVNKGTGNLELVAV(配列番号29)
(vii)GDVFIMPAAHPVAINASS(配列番号30)
(i)配列番号12および13により定義されるペプチド;
(ii)配列番号12により定義されるペプチド;または、
(iii)配列番号13により定義されるペプチド。
(i)配列番号22により定義されるペプチド;
(ii)配列番号18および20により定義されるペプチド;
(iii)配列番号20および19により定義されるペプチド;
(iv)配列番号18により定義されるペプチド;
(iv)配列番号19により定義されるペプチド;または、
(iv)配列番号20により定義されるペプチド。
(i)配列番号25、28および27により定義されるペプチド;
(ii)配列番号25および26により定義されるペプチド;
(iii)配列番号25および28により定義されるペプチド;
(iv)配列番号25および27により定義されるペプチド;
(v)配列番号25により定義されるペプチド;
(vi)配列番号28により定義されるペプチド;
(vii)配列番号27により定義されるペプチド;または、
(viii)配列番号26により定義されるペプチド。
(i)配列番号32により定義されるペプチド;
(ii)配列番号33により定義されるペプチド;または、
(iii)配列番号31により定義されるペプチド。
(i)Ara h1またはAra h1様分子に対する脱感作または免疫学的寛容の導入の手段としての、患者に対する本ペプチドまたはその変異体の投与。これは、たとえば、Th2アネルギーまたはアポトーシスに向かわせるAra h1を導入することにより達成される。そのような結果は、T細胞エピトープ反応性は維持しているが、自然に、または変異の結果として、IgE結合が出来なくなったペプチドの使用を含む、多くの技術の内の任意の1つにより達成されうる。あるいは、寛容を導入するための特定のレジメンに従った、所与のペプチドの特定の濃度の投与に基づいた脱感作/治療プロトコールを使用しても良い。そのような技術により、Ara h1過感受性を排除し、またはAra h1過感受性またはAra h1を含有する組成物に存在するアレルゲンに対する感受性(たとえば、ピーナッツアレルギー)の重篤度を減少しうる。本明細書における、Ara h1感受性の治療に対する言及は、たとえ、当該感受性がAra h1以外のアレルゲンに対するものであったとしても、Ara h1を含有する組成物(たとえば、通常、ピーナッツ)に対する感受性により特徴付けられる状態の治療の範囲内を包含し、理解されたい。
(i)Ara h1に対する対象細胞の反応性を測定すること。これは、たとえば、Ara h1に対する異常な、望ましくない、または不適切な免疫応答により特徴付けられる状態を診断および/またはモニタリングすることに関する使用である。ペプチドは、分画されていない、もしくは分画された、もしくは連続細胞株として誘導された、のいずれかの末梢血由来の細胞または、組織生検由来の細胞と共に固形支持体に結合されてもよく、または、溶液に添加されてもよい。次いで、対象ペプチドに対する反応性は、たとえばH3チミジンの取り込み等の標準的な増殖アッセイ、たとえば表面マーカー、サイトカイン等の分子発現または分子分泌の測定、または当分野公知の細胞活性の他の標準的なアッセイにより測定されてもよい。
(ii)対象由来のT細胞試料を利用する、T細胞増殖アッセイと共に、ペプチドを含有するT細胞エピトープを使用することにより、たとえば、T細胞応答性群の同定が促進される。
ピーナッツアレルギーの成人を、オーストラリア、メルボルンのThe Alfred Allergy Clinicから採用した(表4)。すべての対象は、IgE介在性ピーナッツアレルギーの臨床症状を有しており、ピーナッツ特異的IgEのCAPスコアは、>1(>0.49 kUA/1;Pharmacia CAP System(登録商標)、Pharmacia Diagnostics, Uppsala, Sweden)であった。T細胞株(TCL)の作製に用いた対象は、Victorian TransplantationおよびImmunogenetics Serviceにより遺伝子型(HLA−DRB1、−DQB1および−DPB1、エクソン2)の決定がなされた(表5)。実験は、The Alfred and Monash University Ethics Committeesにより承認され、各対象より、インフォームドコンセントを得た。
粗ピーナッツ抽出物(CPE)を、市販の無塩でドライローストされたピーナッツから、Prickett et al. 2011 supra; de Leon et al. Clin Exp Allergy. 2003; 33(9):1273-80に記述されるように調製した。Ara h1およびAra h1は、Prickett et al. 2011(上述)に記述されるように、液体クロマトグラフィーによりCPEから富化した。エンドトキシン含有量は、CPE、Ara h1およびAra h1のそれぞれに対して、1.7、4.0および、78.0EU/mgであった(Endpoint Chromogenic LAL assay, Lonza, Walkersville, USA)。Ara h1ペプチド(Mimotopes, Victoria, Australia and GenScript USA Inc, New Jersey, USA;表6)は、10%ジメチルスルホキシド/PBSにて2mg/mlで再構成し(20merであり、断片化ペプチドセット)、または、PBS単独で2mg/mlで溶解して再構成した(カスタム合成コアエピトープペプチド)。全ての抗原は、Eusebius et al. Int Arch Allergy Immunol. 2002; 127(3):234-44に記述されるように、マイトジェンでもなく、毒性も無いことを確認した。
Ara h1特異的CD4+T細胞株(TCL)
全ての培養は、2mM L−グルタミン、100IU/mLのペニシリン−ストレプトマイシン、および5%の熱不活化ヒトAB血清(Sigma−Aldrich, St Louis, USA))を含有するRPMI−1640(cRPMI)中で行われた。抗原誘導性TCL増殖は、Prickett et al. 2011(上述)に記述されるように、3Hチミジン(3H−TdR)取り込みアッセイにより分析された。刺激指数(SI;cpm抗原刺激T細胞/cpm無刺激T細胞)>2.5を、陽性とみなし、すべての陽性応答が、2超のアッセイで確認された。TCLによるHLA拘束性エピトープ認識は、Prickett et al. 2011(上述)に記述されるように、エピトープ提示をブロックする、HLA−DR(L243)、HLA−DQ(SVP−L3)、または、HLA−DP(B7/21)に対するモノクローナル抗体(mAb)を用いて評価した。全PBMC内のペプチド誘導性CD4+T細胞増殖の検出を行うために、CFSEで標識したPBMCの7日間培養物を、TCL作製に関してPrickett et al. 2011(上述)に記述されるように、設定した。少なくとも10,000のCD4+T細胞を、試料毎に分析し、抗原有りのCD4+CSFElo(増殖した)のパーセンテージ/抗原無しのCD4+CSFElo(バックグラウンド)のパーセンテージとして、SIを算出した。本アッセイの特異的応答に対する検出閾値は、3人の対象の様々なSI値にわたり、増殖CD4+細胞からのペプチド特異的TCL増殖により評価した。特異的TCLは、3人全ての対象において1.1という低いSIを有する分裂T細胞から作製され(データは示さず)、SI>1.1を陽性として指定した。
好塩基球活性を、フローサイトメトリーにより検出されるCD63の上方調節により評価した(Drew et al. J Immunol. 2004; 173(9):5872-9に記述される)。陽性対照は、ウサギ抗ヒトIgE抗体(7.5ug/mL;DAKO Corporation,CA,USA)、N−ホルミル−メチオニン−ロイシン−フェニルアラニン(fMLP)(0.4ug/mL;Sigma)およびCPEであった。CPE、Ara h1およびペプチドは、3−log濃度範囲にわたり検証された(5、0.5および0.05ug/mL)。
ピーナッツアレルギー対象により認識される主要CD4T細胞エピトープを有するAra h1 20merペプチドの選択
CPE、Ara h1、または、Ara h1の20merペプチドのプール(集合的に、Ara h1配列全体にわたる)を用いて刺激されたCFSE標識PBMCの7日間培養物から抗原特異的(増殖)CD4+CSFEloT細胞を単離および増殖させることにより、HLAが多様な18人のピーナッツアレルギー対象(表4および表5)から、総計145個のAra h1特異的T細胞株(TCL)を作製した(表6)。各対象により認識された(SI>2.5)20merのペプチド(複数含む)を表7に示し、図1にデータを要約する。一部の対象については、CPEまたはAra h1刺激によりほとんどのTCLが生成されたが、他の対象については、ペプチドプールにより生成された。TCLが異なる抗原調製物(CPE、Ara h1、またはペプチドプール)を用いて所与の対象から作製された場合、TCL 20merの特異性は同等であった。全体として、抗原調製物により生じたTCL 20merの特異性に、バイアスは無かった。
最小限の長さのペプチドとすることにより、臨床投与の間に、炎症細胞上の細胞結合型IgEに架橋するリスクが減少し、および、医薬製造が容易となる。各選択された20mer内の最小限のT細胞刺激性配列(コアエピトープ)は、異なる対象由来の反応性TCLの、断片化ペプチドセットに対する増殖を検証することにより決定された(たとえば、図2および表2)。最大限のT細胞増殖を誘導するために必要とされる残基の数は、別々のTCLおよび/または対象の間で、6〜19個のアミノ酸と変動しており(表2)、このことは、CD4+T細胞エピトープに関する従前の報告と一致する(Hemmer et al. Int Immunol. 2000; 12(3):375-83; Suri et al. Curr Opin Immunol. 2006; 18(1):70-7)。最適エピトープ認識に必要とされる隣接残基の数における変動のために(Suri et al. 2006、上記)、TCLは、もし共通コア配列を含有するペプチドが認識を誘導した場合、当該同じエピトープを認識すると考えられていた。この基準に基づいて、5〜12個のアミノ酸に変動する共通のコア(下線を引いた配列、表2)を有する、10種の異なるCD4+T細胞エピトープが特定された(強化エピトープ、表2)。「強化エピトープ」配列は、最も広い、起こりうる認識を得るために検証されたすべての特異的TCLの最大刺激に必要とされる残基を包含するように選択された。
ピーナッツアレルギーとHLA−IIの関連性は明らかにされておらず(Shreffler et al. Ann Allergy Asthma Immunol 2006; 96(6):865-9)、それゆえ、治療のために選択されたペプチドは、広範な適用可能性のために、多様なHLA−II分子に結合するものでなくてはならない。各エピトープを提示するHLA−II型を決定するために、抗HLA−DR、DP、またはDQのmAbを用いて、T細胞に対する個々のエピトープ提示を阻害した。検証した各TCLに対して、エピトープ認識は、用量依存性に1種または複数種のHLA−mAbにより阻害され(例えば図5)、同じmAbがCPEの認識も阻害し(データは示さず)、このことから、自然処理されたエピトープと合成されたエピトープの提示が一致していることが示された。エピトープごとに、少なくとも2人の対象および/またはTCLが検証された(表3)。上述のHLA−IIアルゴリズムの予測と一致して(Singh et al. 2001、上述; Vita et al. 2010、上述)、抗HLA−DRは、1つ(353〜371)以外のすべてのエピトープ認識を阻害し、その1つは検証された両方の対象において抗HLA−DQにより阻害された。エピトープ(436−452)および(507−524)に対しては、一部のTCLについては抗HLA−DRにより認識が阻害されたが、他については抗HLA−DQにより阻害されたことから、これらエピトープに関するHLA結合の重複性が確認された。
全アレルゲンに対する安全な代替法を開発するためには、ペプチドは、細胞結合型IgEに結合および架橋してはならない。ペプチドに対する好塩基球の反応性が、本研究のために採用された7人のピーナッツアレルギーの対象から得た新鮮な血液中で評価された(表4)(図3)。7人すべての対象が、濃度範囲にわたって、CPEに対する高レベルの好塩基球活性化を示した。Ara h1に対する反応は、最も低い用量では対象間で異なっていたが、最も高い濃度では全ての対象において高い活性化が誘導された。しかしながら、候補ペプチドは、検証されたいずれの濃度でも、活性化を誘導しなかった。1人の対象が、ペプチド(409〜427)に対して非常に低いレベルの反応性(8%)を示したが、これは、活性化陽性の閾値を下回るものであり(Boumiza et al. Clin Mol Allergy. 2005; 3:9)、この対象において、Ara h1(80〜90%)またはCPE(74〜76%)により誘導された活性化と比較して無視できるほど低いものであった。
*抗原無しのバックグラウンドの増殖は、総CD4+T細胞中のCD4+CFSEloT細胞の%。∧は、富化Ara h1とAra h1(それぞれ、101.tg/mL)の組み合わせが、これら対象に対し、CPEの代わりに用いられた。
*治療剤として提案される、7つの候補ペプチド
HLA−DR結合モチーフ(灰色の陰影)は、ProPredアルゴリズム(http:www.immuneepitope.org、2012年1月30日にアクセスした)を用いて予測された。予測主要アンカー残基は、太字とし下線を付す。ペプチド40(352〜371)は、このペプチドに対するHLA−DR結合モチーフがこのアルゴリズムでは予測されなかったため、示していない。
*抗原無しのバックグラウンドの増殖は、総CD4+T細胞中のCD4+CFSEloT細胞の%。
∧は、富化Ara h1とAra h1(それぞれ、101.tg/mL)の組み合わせが、これら対象に対し、CPEの代わりに用いられた。
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Claims (15)
- 30個以下の長さのアミノ酸であり、かつアミノ酸配列VEIKEGALMLPHFNSKA(配列番号23)を有する第1のペプチドを含有する組成物。
- 以下の(i)乃至(ix)からなる群から選択される配列番号により定義されるアミノ酸配列を含む第2のペプチドをさらに含有する請求項1に記載の組成物:
(i) FQNLQNHR (配列番号1)
(ii) IVQIEA (配列番号2)
(iii)NEGVIVKVSK (配列番号3)
(iv) FGKLFEVK (配列番号4)
(v) EVKPDKKNPQLQ (配列番号5)
(vi) PHFNSKAMVIV (配列番号7)
(vii)IVVVN (配列番号8)
(viii)VVNKGTGNLEL (配列番号9)
(ix) IMPAAHP (配列番号10) - 少なくとも3種のペプチド、少なくとも4種のペプチド、少なくとも5種のペプチド、少なくとも6種のペプチド、少なくとも7種のペプチド、少なくとも8種のペプチド、少なくとも9種のペプチド、または10種のペプチドを含有する、請求項1又は2に記載の組成物。
- 前記第1のペプチドは、17、18、19、20、21、22、23、24、25、26、27、28、29、または30個の長さのアミノ酸である、請求項1〜3のいずれか1項に記載の組成物。
- 前記第1のペプチドは、17〜25個の長さのアミノ酸である、請求項4に記載の組成物。
- 前記第2のペプチドは、以下のリストから選択される、請求項2〜5のいずれか1項に記載の組成物:
(i)FQNLQNHRIV(配列番号12)
(ii)RIVQIEAKPNTLV(配列番号13)
(iii)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(iv)WSTRSSENNEGVIVKVSKE(配列番号15)
(v)STRSSENNEGVIVKVSKE(配列番号16)
(vi)ENNEGVIVKVSKE(配列番号17)
(vii)NNFGKLFEVKPDKKNPQ(配列番号18)
(viii)SNNFGKLFEVKPDKKNPQ(配列番号19)
(ix)EVKPDKKNPQLQ(配列番号20)
(x)NNFGKLFEVKPDKKNPQLQ(配列番号21)
(xi)SNNFGKLFEVKPDKKNPQLQ(配列番号22)
(xiii)ALMLPHFNSKAMVIVVV(配列番号24)
(xiv)KAMVIVVVNKG(配列番号25)
(xv)AMVIVVVNKGTGNLELVAV(配列番号26)
(xvi)VVNKGTGNLELVAVRK(配列番号27)
(xvii)AMVIVVVNKGTGNLELV(配列番号28)
(xviii)KAMVIVVVNKGTGNLELVAV(配列番号29)
(xix)GDVFIMPAAHPVAINASS(配列番号30)
(xx)VFIMPAAHPVAINASSE(配列番号31)
(xxi)GDVFIMPAAHPVAINASSE(配列番号32)
(xxii)VFIMPAAHPVAINASS(配列番号33) - 配列番号12〜22または24〜33により定義される第2のペプチドの1種または複数種を含有する、請求項6に記載の組成物。
- 前記第2のペプチドは、以下のリストから選択される、請求項2〜7のいずれか1項に記載の組成物:
(i)FQNLQNHRIVQIEAKPNTLV(配列番号14)
(ii)WSTRSSENNEGVIVKVSKE(配列番号15)
(iii)NNFGKLFEVKPDKKNPQLQ(配列番号21)
(v)ALMLPHFNSKAMVIVVV(配列番号24)
(vi)KAMVIVVVNKGTGNLELVAV(配列番号29)
(vii)GDVFIMPAAHPVAINASS(配列番号30)
(viii)EVKPDKKNPQLQ(配列番号20)
(ix)STRSSENNEGVIVKVSKE(配列番号16)
(x) VFIMPAAHPVAINASS(配列番号33) - 配列番号14、16、20、または33により定義される第2のペプチドの1種を含有する、請求項8に記載の組成物。
- 請求項1に記載の第1のペプチドをコードするアミノ酸配列をコードするヌクレオチドの配列、または、
請求項1に記載の第1のペプチドをコードするアミノ酸配列をコードするヌクレオチドの配列に対して相補的なヌクレオチドの配列である、核酸分子。 - 哺乳類における疾患の治療または予防に使用される、請求項1〜9のいずれか1項に記載の組成物であって、前記疾患は、Ara h1に対する異常な、望ましくない、または不適切な免疫反応、または、Ara h1を含有する組成物中に存在するアレルゲンに対する異常な、望ましくない、または不適切な免疫反応により特徴付けられる、組成物。
- 前記疾患は、ピーナッツまたはAra h1もしくはAra h1様分子を含有する樹木性堅果に対して過感受性である、請求項11に記載の組成物。
- 前記樹木性堅果は、ヘーゼルナッツ、アーモンド、またはブラジルナッツである、請求項12に記載の組成物。
- Ara h1に対して脱感作させる、または免疫寛容を誘導する、請求項11〜13のいずれか1項に記載の組成物。
- 哺乳類における疾患の有無を試験するインビトロの方法であって、請求項1〜9のいずれか1項に記載の第1のペプチド及び第2のペプチドを利用して、Ara h1反応性T細胞に対するスクリーニングを行うステップを含み、
前記スクリーニングを行うステップは、Ara h1反応性T細胞の検出強度が、第1のペプチドを用いない場合の検出強度よりも強い場合に、前記哺乳類が前記疾患を有していると決定するステップである、方法。
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