JP2020089383A - 免疫リガンド/ペイロード複合体の生産方法 - Google Patents
免疫リガンド/ペイロード複合体の生産方法 Download PDFInfo
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- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
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- 108091008104 nucleic acid aptamers Proteins 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
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- 108700015048 receptor decoy activity proteins Proteins 0.000 description 1
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- 238000005215 recombination Methods 0.000 description 1
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- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008337 systemic blood flow Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 238000002723 toxicity assay Methods 0.000 description 1
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- 238000006276 transfer reaction Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
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- 239000003656 tris buffered saline Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
Classifications
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- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
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Abstract
Description
定義
a)主にタンパク質またはペプチドからなる、
b)少なくとも1つのタンパク質もしくはペプチドドメインを含む、または
c)少なくとも1つのペプチド鎖を含む、
のいずれかであって、
さらに、タンパク質またはペプチドもしくはドメインは好ましくは、配列特異的トランスペプチダーゼまたはその触媒ドメインが検出可能なアミノ酸配列を含む。
・抗体、修飾された抗体フォーマット、抗体誘導体または断片、および/または
・抗体模倣物、
からなる群より選択されるもののうちの少なくとも1つである。
・受容体、
・抗原、
・成長因子、
・サイトカイン、および/または
・ホルモン、
からなる群より選択される実体のうちの少なくとも1つに結合する。
・ソルターゼまたは1つ以上のその断片もしくは誘導体、
・スプリットインテインまたは1つ以上のその断片もしくは誘導体、
からなる群より選択されるものの少なくとも1つである。
・マーカー、
・処理用タグ、および/または
・薬物、
からなる群より選択されるもののうちの少なくとも1つである。
・放射性標識、好ましくは放射性標識で標識したペプチドまたはタンパク質、
・蛍光標識、好ましくは蛍光ペプチドまたはタンパク質、および/または、
・酵素標識、好ましくはペルオキシダーゼ
からなる群より選択されるものの少なくとも1つである。
・サイトカイン、
・放射性標識、
・抗炎症剤、
・毒素、および/または、
・化学療法剤、
からなる群より選択される実体のうちの少なくとも1つに結合する。
a)免疫リガンドは複合体をペイロードがその毒性機能を発揮する特定の部位、例えば病原性の実体、例えば癌細胞に誘導する。従って、ペイロードの全身に及ぼす毒性が低減され、後者の作用部位での局所濃度が上昇し、そのため、副作用を低減させながら、より高い効力がもたらされる。
b)内部移行の後にペイロードが放出され、そのときになってその望まれる細胞毒性機能を発揮する、つまり、周辺の細胞または組織には影響を及ぼさないという様式で病原性の実体に内部移行する複合体が提供される可能性がある。
・所与の病態のインビトロまたはインビボでの診断
・所与の病態に関するインビトロまたはインビボでの予測または予後予測
・所与の病態に罹患しているまたは発症する危険性のあるヒトまたは動物対象の治療、および/または
・研究および/または開発目的
における使用を提供する。
・腫瘍性疾患
・自己免疫疾患
・神経変性疾患、および/または
・感染症
からなる群より選択されるものの少なくとも1つである。
・マーカー、
・処理用タグ、および/または
・薬物
からなる群より選択されるものの少なくとも1つである。
・放射性標識、好ましくは放射性標識で標識したペプチドまたはタンパク質、
・蛍光標識、好ましくは蛍光ペプチドまたはタンパク質、および/または、
・酵素標識、好ましくはペルオキシダーゼ
からなる群より選択されるものの少なくとも1つである。
・サイトカイン、
・放射性標識、
・毒素、および/または、
・化学療法剤、
からなる群より選択されるものの少なくとも1つである。
・メイタンシン
・モノメチルアウリスタチン、および/または
・アルファ−アマニチン
からなる群より選択されるものの少なくとも1つ、もしくはこれらの誘導体である。このようなGlynで修飾された毒素の例を、図14A〜14Cの構造1〜9に示す。
実験および図
Me=メチル(−CH3)基
G=グリシンアミノ酸残基
Me=メチル(−CH3)基
GVFVHNSAGSGK=グリシン−バリン−フェニルアラニン−バリン−ヒスチジン−アスパラギン−セリン−アラニン−グリシン−セリン−グリシン−リシン配列
G=グリシン残基
30mgのアルファ−アマニチン(構造1)(シグマ・アルドリッチ、注文番号A2263)を1mlの無水DMSOに溶解した。この溶液に19mgのNH−Boc−アミノ−ヘキシルブロミドを、次いでカリウムtert−ブトキシド(1MのTHF溶液、35μl)を加えた。反応混合液を室温で6時間撹拌し、さらにカリウムtert−ブトキシド(1MのTHF溶液、20μl)を加えた。この反応物を16時間室温に維持した。酢酸(10μl)を加え、粗混合液を直接、RP−HPLC(サンファイヤー(Sunfire)C18 5μ 3cm×10cmカラム、50mL/分、5〜50%アセトニトリル/水、15分勾配)で精製した。所望の画分を回収し、凍結乾燥して構造2を白色粉末として得た(15mg)。これをTFA/DCM溶液(1/1、容積比、1ml)により、室温で30分間処理した。揮発性物質を減圧下で除去し、構造3を黄みがかったゴムとして得た。これを精製せずに次の工程に用いた。
メイタンシノール(0.6g、1.1mmol)(クリアシンス研究所(Clearsynth Labs)、ムンバイ、インド)を無水THF(6ml)と無水DMF(3ml)に溶解し、その後、1.2mlのDIEA(シグマ・アルドリッチ、注文番号496219)を加えた。この溶液をアルゴン雰囲気下においた。亜鉛トリフラート(1.2g)とNMeAla NCA(0.7g)を一度に加えた。この混合物を固体が溶解するまで超音波で処理した。反応混合物を室温で2日間撹拌し、その後、酢酸エチル(100ml)で希釈した。これを飽和NaHCO3(水溶液、2×50ml)および塩水(50ml)で洗浄した。有機相をMgSO4で乾燥させ、濃縮して粗メイタンシノール3−(S)−アルファ−N−メチルアミノプロピオン酸(8)を得た。これを精製せずに直接次の工程に用いた。
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Claims (24)
- 免疫リガンド/ペイロード複合体の生産方法であって、配列特異的トランスペプチダーゼまたはその触媒ドメインを使って、ペイロードを免疫リガンドに結合させることを包含する、生産方法。
- 前記ペイロードおよび/または前記免疫リガンドが、
a)主にタンパク質またはペプチドからなる、
b)少なくとも1つのタンパク質もしくはペプチドドメインを含む、または
c)少なくとも1つのペプチド鎖を含む、
のいずれかであって、
さらに、前記タンパク質またはペプチドもしくはドメインが前記配列特異的トランスペプチダーゼまたはその触媒ドメインによって検出可能なアミノ酸配列を含む、請求項1に記載の方法。 - 前記免疫リガンド/ペイロード複合体に含まれる前記免疫リガンドが、抗体、修飾された抗体フォーマット、抗体誘導体または断片、および/または抗体模倣物からなる群より選択されるもののうちの少なくとも1つである、請求項1または2の方法。
- 前記免疫リガンドが、
・受容体、
・抗原、
・成長因子、
・サイトカイン、および/または
・ホルモン、
からなる群より選択される実体のうちの少なくとも1つに結合する、請求項1〜3のいずれか1項に記載の方法。 - 前記配列特異的トランスペプチダーゼの少なくとも1つの触媒ドメインが、前記免疫リガンドまたは前記ペイロードいずれかのN末端もしくはC末端に融合されている、請求項1〜4のいずれか1項に記載の方法。
- 前記配列特異的トランスペプチダーゼが、
・ソルターゼ酵素または1つ以上のその断片もしくは誘導体、
・スプリットインテインまたは1つ以上のその断片もしくは誘導体、
からなる群より選択されるもののうちの少なくとも1つである、請求項1〜5のいずれか1項に記載の方法。 - 前記免疫リガンド/ペイロード複合体に含まれる前記ペイロードが、
・マーカー、
・処理用タグ、および/または
・薬物、
からなる群より選択されるもののうちの少なくとも1つである、請求項1〜6のいずれか1項に記載の方法。 - 前記マーカーが、
・放射性標識、好ましくは放射性標識で標識したペプチドまたはタンパク質、
・蛍光標識、好ましくは蛍光ペプチドまたはタンパク質、および/または、
・酵素標識、好ましくはペルオキシダーゼ、
からなる群より選択されるもののうちの少なくとも1つである、請求項1〜7のいずれか1項に記載の方法。 - 前記薬物が、
・サイトカイン、
・放射性標識、
・抗炎症剤、
・毒素、および/または、
・化学療法剤、
からなる群より選択されるもののうちの少なくとも1つである、請求項1〜8のいずれか1項に記載の方法。 - 前記免疫リガンドが、それぞれがペイロードに結合している少なくとも2つのサブユニットを含む、請求項1〜9のいずれか1項に記載の方法。
- 少なくとも2つのサブユニットを有する前記免疫リガンドが、1つ以上の細胞経路を干渉する2種類の異なるペイロード、好ましくは毒素ペイロードに結合している、請求項10に記載の方法。
- 少なくとも2つのサブユニットを有する前記免疫リガンドが、結合部位1カ所当たり少なくとも80%の効率で結合している、請求項10または11に記載の方法。
- 少なくとも2つのサブユニットを有する前記免疫リガンドが、前記2つのサブユニットのうちの少なくとも一方のC末端に付加されている少なくとも2個のアミノ酸、好ましくは2〜5個のアミノ酸から構成されているペプチドスペーサー配列を含む、請求項10〜12のいずれか1項に記載の方法。
- 免疫リガンドとペイロードの間の関係を化学量論的に規定することができる、請求項1〜13のいずれか1項に記載の方法。
- 免疫リガンドとペイロードとの間の前記化学量論的に規定された関係が、部分的に反応したC末端に修飾を有する免疫リガンド基質を除去することで達成される、請求項14に記載の方法。
- ペイロードを前記免疫リガンドに部位特異的に結合させることができる、請求項1〜15のいずれか1項に記載の方法。
- 請求項1〜16のいずれか1項に記載の方法によって得られた免疫リガンド/ペイロード複合体。
- 抗体/薬物複合体および/または抗体/マーカー複合体からなる群より選択される、請求項17の免疫リガンド/ペイロード複合体。
- 請求項1〜18のいずれか1項による免疫リガンド/ペイロード複合体の、
・所与の病態のインビトロまたはインビボでの診断
・所与の病態に関するインビトロまたはインビボでの予測または予後予測
・所与の病態に罹患しているまたは発症する危険性のあるヒトまたは動物対象の治療、および/または
・研究および/または開発目的、
における使用。 - 前記病態が、
・腫瘍性疾患
・自己免疫疾患
・神経変性疾患、および/または
・感染症、
からなる群より選択されるもののうちの少なくとも1つである、請求項19に記載の方法。 - Glyn修飾で修飾された低分子量ペイロードであって、ここでnは1より大きく、好ましくは、nが3またはnが5である、低分子量ペイロード。
- 前記ペイロードが、
・サイトカイン、
・放射性標識、
・毒素、および/または、
・化学療法剤、
からなる群より選択されるもののうちの少なくとも1つである、請求項21に記載の低分子量ペイロード。 - 請求項21または22の低分子量ペイロードの、それを免疫リガンドに結合させるための使用。
- 前記免疫リガンド−ペイロード結合を粗細胞培養上清中で行う、請求項1〜16のいずれか1項に記載の方法。
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