JP6955324B2 - 医薬化合物を評価するための新規動物モデル - Google Patents
医薬化合物を評価するための新規動物モデル Download PDFInfo
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Description
本発明は、薬物動態学特性および毒性を評価するための動物モデルにおいて評価され得る抗原特性を有する単一の医薬化合物に反応しないように動物を処置することのできる方法に関する。
毎年、数千個の医薬化合物は、臨床上使用される前に、その薬物動態学特性および潜在的な毒性が試験される。これらの試験の多くは、医薬化合物を動物に投与して、さまざまな時点で薬物動態学特性および/または毒性を評価することによって、行われる。しかしながら、多くの医薬化合物が免疫反応を誘発するため、これらの研究は、かなり制限される。このような免疫反応は、通常数日間または数週間以内に発生し、急速であるため、医薬化合物の薬物動態学特性および可能な毒性を評価するために動物を観察することのできる期間を大幅に減少する。明らかには、免疫反応は、医薬化合物の再投与も妨げる。
本発明の一般的な共通理念として、疾病または障害を治療するための医薬化合物は、この医薬化合物に薬用効果を示さない生物モデルに試験される。換言すれば、この医薬化合物は、健康動物、すなわち、症状または兆候を示しておらずもしくは医薬化合物が治療しようとする疾病を罹患していない動物に投与される。
本発明の方法の利点は、動物の全体的な免疫反応に影響を与えることなく、一種類の化合物に対する動物の免疫反応を除去することができることである。
方法の実施形態において、パラメータは、毒性、半減期、体重、移動性、食性、呼吸、水およびその通過性、および毛並み特性からなる群から選択される1つ以上である。
本発明の文脈において、「医薬化合物」という用語は、免疫反応を誘発することができる、実証または期待された有益な医療活性を有する任意の化合物を意味する。医薬化合物の例として、ペプチド、タンパク質および小さな化学物質が挙げられる。これらの小さな化学物質は、アルブミンなどの動物性宿主タンパク質に結合して、部分抗原(hapten)として免疫反応を誘発することができる。
何千個の新しい分子は、治療に使用され、それらの有効性、薬物動態学特性および潜在的な毒性が動物モデルにおいて試験される。マウス、ラットおよびモルモットなどの齧歯類動物は、使用の容易さ、同系株の入手可能性および評価ツールの利用可能性を有するため、モデルとして最も頻繁に使用される。他の動物モデルとして、ウサギ、ブタ、イヌまたはウマなどが挙げられる。これらの動物は、治療用分子に対する免疫反応を高める能力において人間とかなり異なり、多くの場合、人間の病態生理学に関係ない早期応答を示するため、治療用分子の有効性、薬物動態学特性および長期毒性を評価することができない。これによって、これらの動物モデルの有用性は、厳しく制限される。このような問題を緩和するために、非ヒト霊長類動物を使用することができるが、実験に使用される経費によって、試験できる動物の数が大きく制限され、それによって統計評価の信憑性も制限される。また、ヒトのゲノムと非ヒト霊長類動物のゲノムとの間に高い相同性があるが、観察された動物の個体差は、研究成果の価値を制限する。
(1)1つ以上の生体外アルゴリズムを用いて、タンパク質内のT細胞エピトープの配列を同定することができる。適当なアルゴリズムは、以下のウェブサイトに掲載されるものを含むがこれらに限定されない。
http://www.imtech.res.in/raghava/mhcbn/
http://www.syfpeithi.de/home.htm
http://www-bs.informatik.uni-tuebingen.de/SVMHC
http://bio.dfci.harvard.edu/Tools/antigenic.html
http://www.jenner.ac.uk/MHCPred/
これらのアルゴリズムは、以下の刊行物に記載されている。Zhang et al. (2005) Nucleic Acids Res 15, W180-W183 (PREDBALB); Salomon & Flower (2006) BMC Bioinformatics 7, 501 (MHCBN); Schuler et al. (2007) Methods Mol Biol. 409, 75-93 (SYFPEITHI); Donnes & Kohlbacher (2006) Nucleic Acids Res. 34, W194-W197 (SVMHC); Kolaskar & Tongaonkar (1990) FEBS Lett. 276, 172-174 and Guan et al. (2003) Appl Bioinformatics 2, 63-66 (MHCPred)。
小さな化学物質は、アルブミンまたは膜タンパクなどのタンパク質に直接結合することができる。このような小さな化学物質は、T細胞によって認識されるエピトープの一部であるタンパク質の配列に結合すると、免疫反応を引き起こすことができる。
第VIII因子置換療法は、血友病A患者を治療するために使用される。しかしながら、循環系中のFVIIIのt1/2は、わずか90分である。フォンヴィレブランド因子が存在する場合、その生理学的シャペロン分子FVIIIのt1/2は、最大6時間まで増加する。増加したt1/2を有するFVIII分子の作製は、待望の目標である。
イヌなどの動物において、ヒトFVIIIに対抗する抗体も同様に生成される。これらの抗体は、ヒトFVIIIを中和しないが、動物モデルに投与されたヒトFVIIIの生物学的排泄に影響を与える。
その後、イヌは、完全長のヒト第VIII因子の静脈注射により処置される。次いで、ヒト第VIII因子の反復注射によって、ヒト第VIII因子の薬物動態学特性を評価する。
現在、リウマチ性関節炎などの慢性炎症を罹患している患者にヒト化モノクローナル抗体を投与することは、一般的である。一般的に臨床効果が観察されるが、この治療抗体の長期投与は、重篤な副作用および合併症を引き起こす。これらの副作用は、基本的に治療抗体の長期治療を受けた患者から確認されてあるが、前臨床動物毒性評価から予測されなかった。その主な原因は、動物モデル、特にマウスまたはラットの治療抗体に対する高免疫性に関連する。
医薬化合物が一般的に短い半減期(t1/2)を有するため、その活性を延長するために、さまざまな試みが提案されている。現在、ポリエチレングリコール残基による置換は、多くの医薬化合物に使用されている。このような置換が安全であると考えられているが、いくつかの報告によると、マクロファージなどのスカベンジャー細胞内のペグ化分子の蓄積が確認された。実際には、PEG置換は、循環系から医薬化合物のクリアランスに関与する残基をマスクすることによって、t1/2を増加させる。しかしながら、PEG置換は、同時にプロテアソームによる消化を妨げることによって、細胞蓄積を増加する。細胞蓄積の顕著な特徴としては、通常、泡状マクロファージの出現である。
Claims (12)
- 疾病または障害を治療するための医薬化合物のパラメータを決定するための方法であって、
前記疾病または障害を罹患しておらずもしくは前記疾病または障害の症状または兆候を示しておらず、前記医薬化合物に対して免疫反応を誘発しない非ヒト動物を提供するステップを含み、
前記動物は、モチーフ[CTS]−X−X−C(配列番号:8)またはC−X−X−[CST](配列番号:9)からなるオキシドレダクターゼモチーフと、前記医薬化合物のNKTペプチドエピトープまたはMHCクラスII T細胞エピトープとの組み合わせを含むペプチドを投与することによって得られ、前記モチーフと前記エピトープとは、0〜4個のアミノ酸からなるリンカーによって隔てられ、
前記非ヒト動物に前記医薬化合物を投与するステップと、
前記非ヒト動物から前記医薬化合物のパラメータを測定するステップとを含む、方法。 - 前記医薬化合物は、タンパク質であり、
前記エピトープは、前記タンパク質の断片である、請求項1に記載の方法。 - 前記医薬化合物は、立体構造依存性エピトープを有するタンパク質であり、
前記エピトープは、前記立体構造依存性エピトープのミモトープである、請求項1または2に記載の方法。 - 前記医薬化合物は、タンパク質ではなく、
前記ペプチドに含まれる前記エピトープは、前記医薬化合物のミモトープと同様の配列を有する、請求項1に記載の方法。 - 前記モチーフは、C−X−X−Cである、請求項1〜4のいずれか1項に記載の方法。
- 前記NKTペプチドエピトープは、モチーフ[FWTHY]−X2X3−[ILMV]−X5X6−[FWTHY](配列番号:11)を有する、請求項1〜5のいずれか1項に記載の方法。
- 前記動物は、霊長類動物ではない、請求項1〜6のいずれか1項に記載の方法。
- 前記動物は、齧歯類動物である、請求項1〜7のいずれか1項に記載の方法。
- 前記動物は、非近交系動物である、請求項1〜8のいずれか1項に記載の方法。
- 前記パラメータは、毒性、半減期、体重、移動性、食性、呼吸、水およびその通過性、および毛並み特性からなる群から選択される1つ以上である、請求項1〜9のいずれか1項に記載の方法。
- 疾病または障害を治療するための試験医薬化合物に対して免疫反応しないように、非ヒト動物を処置するための非治療的方法であって、
前記疾病または障害を治療するための前記試験医薬化合物に対して健康であり、前記試験医薬化合物を投与していない非ヒト動物を提供するステップと、
ペプチドを前記非ヒト動物に投与するステップとを含み、
前記ペプチドは、モチーフ[CTS]−X−X−C(配列番号:8)またはC−X−X−[CST](配列番号:9)からなるオキシドレダクターゼモチーフと、前記試験医薬化合物のNKTペプチドエピトープまたはMHCクラスII T細胞エピトープとの組み合わせを含み、
前記モチーフと前記エピトープとは、0〜4個のアミノ酸からなるリンカーによって隔てられる、方法。 - 請求項11に記載の方法によって得られた、前記疾病または障害を治療するための前記試験医薬化合物に対して免疫反応しない非ヒト動物。
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JP2016214240A (ja) | 2016-12-22 |
ES2702386T3 (es) | 2019-02-28 |
US20160339121A1 (en) | 2016-11-24 |
EP3096138B1 (en) | 2018-10-03 |
US10729791B2 (en) | 2020-08-04 |
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