JP2016505008A - ペプチド - Google Patents
ペプチド Download PDFInfo
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- JP2016505008A JP2016505008A JP2015552188A JP2015552188A JP2016505008A JP 2016505008 A JP2016505008 A JP 2016505008A JP 2015552188 A JP2015552188 A JP 2015552188A JP 2015552188 A JP2015552188 A JP 2015552188A JP 2016505008 A JP2016505008 A JP 2016505008A
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- 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
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Abstract
Description
第1の態様において、本発明はペプチドに関する。
「ペプチド」なる語は、典型的には隣接アミノ酸のα-アミノ基とカルボキシル基との間のペプチド結合により互いに連結された一連の残基、典型的にはL-アミノ酸を意味する通常の意味で用いられている。この用語は修飾ペプチドおよび合成ペプチド類似体を含む。
ミエリンオリゴデンドロサイト糖タンパク質(MOG)は、単一の細胞外Ig可変ドメイン(Ig-V)を有するI型内在性膜タンパク質である。MOGのアミノ酸配列は動物種間で高度に保存されており(>90%)、これは重要な生物学的機能を示唆している。MOGは、CNSにおいて、ミエリン鞘の最外ラメラならびにオリゴデンドロサイトの細胞体および突起上で特異的に発現される。
配列番号5
GQFRVIGPRHPIRALVGDEVELPCRISPGKNATGMEVGWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKDAIGEGKVTLRIRNVRFSDEGGFTCFFRDHSYQEEAAMELKVEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYRLRGKLRAEIENLHRTFDPHFLRVPCWKITLFVIVPVLGPLVALIICYNWLHRRLAGQFLEELRNPF
配列番号6
YRPPFSRVVHLYRNGKDQDGD
MOG 41-55: RPPFSRVVHLYRNGK (配列番号1)
MOG 43-57: PFSRVVHLYRNGKDQ (配列番号2)
MOG 44-58: FSRVVHLYRNGKDQD (配列番号3)
MOG 45-59: SRVVHLYRNGKDQDG (配列番号4)。
適応免疫応答においては、Tリンパ球はタンパク質抗原の内部エピトープを認識することができる。抗原提示細胞(APC)はタンパク質抗原を取り込み、それらを短いペプチド断片へと分解する。ペプチドは細胞内で主要組織適合性複合体(MHC)クラスIまたはII分子に結合し、細胞表面に運ばれうる。該ペプチドは、MHC分子と共に細胞表面に提示されると、(T細胞受容体(TCR)を介して)T細胞により認識されることが可能であり、この場合、該ペプチドはT細胞エピトープである。
本発明のペプチドはインビトロでMHC分子に結合することができ、かつ抗原プロセシングを受けることなくT細胞に提示されることができる。
a)固定APC(CD28に対する抗体の存在下または非存在下)、
b)クラスIまたはII MHC分子を含有する脂質膜(CD28に対する抗体の存在下または非存在下)、
c)プレート結合形態の、精製された天然または組換えMHC(CD28に対する抗体の存在下または非存在下)。
本発明のペプチドは、ミエリンオリゴデンドロサイト糖タンパク質(MOG)に対する寛容を誘発しうる。
(a)該ペプチドがインビボにおける標的エピトープである疾患に罹る感受性の低下;
(b)CD4+ T細胞におけるアネルギーの誘導(これはインビトロにおける抗原での後続チャレンジにより検出されうる);
(c)以下のものを含むCD4+ T細胞集団における変化:
(i)増殖の低減;
(ii)IL-2、IFN-γおよびIL-4の産生のダウンレギュレーション;
(iii)IL-10の産生の増加。
本発明のペプチドは疾患の治療および/または予防において使用されうる。該疾患は脱髄疾患、例えば副腎白質ジストロフィー、VWM型白質脳症(vanishing white matter disease)または多発性硬化症(MS)でありうる。
第2の態様において、本発明は、本発明の第1の態様の1以上のペプチドを含む医薬組成物に関する。
該ペプチドはアジュバントの非存在下で可溶性形態で投与されうる。
材料および方法
抗原
細胞外ドメインに相当するヒトMOGの125アミノ酸のN末端部分をコードする核酸配列を細菌発現ベクター(pET系)内にクローニングした。この組換えヒトMOG細胞外ドメイン(rhMOGED)をC末端にHisタグを有する融合タンパク質として細菌系内で発現させた。
MOG特異的ハイブリドーマT細胞クローンをDR2+マウスの免疫化により作製した。DR2+マウスを完全フロイントアジュバント(CFA)中のrhMOGEDまたはMOG重複ペプチドのプールで免疫化した。10日後、脾臓および流入領域リンパ節を摘出し、CD4+ T細胞を精製し、インビトロで抗原/CFAで再刺激した。1週間後、T細胞をインビトロで抗原で再刺激して、活性化抗原特異的細胞の数を増加させた。
生きた又はp-ホルムアルデヒド固定Mgar(HLA-DR2 +ve)細胞を、T細胞と共に、血清単体中、または血清中のペプチドと共に48時間インキュベートした。T細胞増殖応答をIL-2産生により測定した。
ネスティッドMOGペプチドの提示に対する種々のMOG特異的ハイブリドーマクローンの応答を図1に示す。ペプチドMOG 41-55(「ROK5」)はアピトープと定められたが、それは、更なるプロセシングを受けることなく、固定APCによりT細胞に提示されることが可能だったからである。ついで、1つのアミノ酸ずつずれているペプチド群を使用して、領域25-60における重複ペプチドを使用して詳細な研究を行った。ペプチドMOG 41-55、43-57、44-58および45-59がアピトープとして同定された(図1)。
アピトープとして同定されたペプチドが抗原に対する寛容を誘発できるかどうかを決定するために、エクスビボ(ex vivo)研究を行った。HLA-DR2トランスジェニックマウスを100μgのROK5 (MOG 41-55)、100μgのMOG 35-55またはPBSで第-8日、第-4日および第-2日に免疫化した。第0日に、尾基底部への注射により、CFAと組み合わせた100μgのMOG 35-55でマウスをチャレンジした。
EAE(実験的自己免疫脳脊髄炎)は、広範に研究されているMSモデルであり、強力なアジュバント中のミエリンまたはミエリン成分(MOGを含む)での免疫化により多種多様な遺伝的感受性の実験動物種(げっ歯類および霊長類を含む)において誘発されうる。
実験2: 5回用量ROK5前処理およびそれに続くmMOG35-55での免疫化。
mMOG35-55: MEVGWYRSPFSRVVHLYRNGK (配列番号7)
hROK5 (41-55): RPPFSRVVHLYRNGK (配列番号1)
mROK5 (41-55): RSPFSRVVHLYRNGK (配列番号8)
2群のDR2トランスジェニックマウスを準備し、第0日に、「100μg」群の動物(n=7)には完全フロイントアジュバント(CFA)中の100μgのmMOG35-55を投与し(100μl, 皮下(s.c.), 尾基底部への注射)、「200μg」群の動物(n=8)にはCFA中の200μgのmMOG35-55を投与した。第0日および第2日に、全ての動物に百日咳毒素(PBS中の200mg, 腹腔内(i.p.))の注射を行った。毎日、臨床的EAEを評価し、動物の体重を測定した。
これに基づいて、MOG誘発性EAEを予防するROK5の能力を試験した。
第1実験を行った。この実験では、マウスROK5、ヒトROK5またはPBS(CFA中の100μl中の100μg)で動物を3回(3日間隔)前処理し(脇腹への皮下(s.c.)注射)、ついで第0日および第2日に、全ての動物をCFA中の200μgのmMOG35-55(尾基底部への皮下(s.c.)注射)で、および200ngの百日咳毒素(PBS中の200ng, 腹腔内(i.p.))で免疫化した。
第2実験を行った。この実験では、ヒトROK5またはPBS(CFA中の100μl中の100μg)で動物を5回(3日間隔)前処理し(脇腹への皮下(s.c.)注射)、ついで第0日および第2日に、全ての動物をCFA中の200μgのmMOG35-55(尾基底部への皮下(s.c.)注射)で、および200ngの百日咳毒素(PBS中の200ng, 腹腔内(i.p.))で免疫化した。毎日、臨床的EAEをスコアリングした。
Claims (10)
- インビトロでMHC分子に結合することができ、かつ抗原プロセシングを受けることなくT細胞に提示されることができるペプチドであって、ミエリンオリゴデンドロサイト糖タンパク質(MOG)の領域40-60の一部を含むペプチド。
- 以下のミエリンオリゴデンドロサイト糖タンパク質ペプチド: MOG 41-55、43-57、44-58および45-59から選択される、請求項1または2記載のペプチド。
- MOG 41-55である、請求項2記載のペプチド。
- 脱髄疾患の治療および/または予防における使用のための、請求項1〜3のいずれか1項記載のペプチド。
- 該疾患が多発性硬化症である、請求項4記載のペプチド。
- 請求項1〜5のいずれか1項記載の1以上のペプチドを含む医薬組成物。
- 脱髄疾患の治療および/または予防を要する対象における脱髄疾患の治療および/または予防方法であって、請求項1〜5のいずれか1項記載のペプチドを該対象に投与する工程を含む方法。
- 該疾患が多発性硬化症である、請求項7記載の方法。
- 脱髄疾患の予防および/または治療における使用のための医薬の製造における、請求項1〜5のいずれか1項記載のペプチドの使用。
- 該疾患が多発性硬化症である、請求項9記載の使用。
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AU2014206592A1 (en) | 2015-07-23 |
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MX369414B (es) | 2019-11-07 |
CN105121463B (zh) | 2020-11-27 |
KR102169902B1 (ko) | 2020-10-26 |
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US20150353616A1 (en) | 2015-12-10 |
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MX2015009085A (es) | 2016-02-16 |
GB201300684D0 (en) | 2013-02-27 |
WO2014111840A2 (en) | 2014-07-24 |
JP6347065B2 (ja) | 2018-06-27 |
AU2014206592B2 (en) | 2018-01-04 |
US9862751B2 (en) | 2018-01-09 |
US10377800B2 (en) | 2019-08-13 |
EP2945966A2 (en) | 2015-11-25 |
CN105121463A (zh) | 2015-12-02 |
CA2897655A1 (en) | 2014-07-24 |
KR20150105365A (ko) | 2015-09-16 |
EP2945966B1 (en) | 2019-07-03 |
SG11201505526TA (en) | 2015-08-28 |
IL239871B (en) | 2018-12-31 |
BR112015016780A2 (pt) | 2017-08-15 |
RU2015134356A (ru) | 2017-02-22 |
WO2014111840A3 (en) | 2014-10-30 |
HK1211596A1 (en) | 2016-05-27 |
IL239871A0 (en) | 2015-08-31 |
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