JP7516369B2 - トランスサイトーシスのための送達構築物および関連する方法 - Google Patents
トランスサイトーシスのための送達構築物および関連する方法 Download PDFInfo
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Description
本願は、2018年11月7日に出願された米国特許仮出願第62/756,889号、2019年8月16日に出願された米国特許仮出願第62/888,133号および2019年8月16日に出願された米国特許仮出願第62/888,238号、2019年9月11日に出願された国際出願番号PCT/US2019/050708、および2019年3月8日に出願された国際出願番号PCT/US2019/021474の利益を主張し、これらの出願は、それらの全体を参照により本明細書に組み込む。
参照による援用
ペイロードおよび送達構築物
精製方法および組成物
タンパク質解析
処置方法
(実施例1)
送達構築物の発現
(実施例2)
上皮細胞単層を越えたペイロードの輸送を査定するin vitroモデル
(実施例3)
極性化された腸上皮細胞を越えたIL-22の担体媒介性輸送
(実施例4)
組換えヒトIL-22は、マウスIL-22受容体に結合する
(実施例5)
大腸炎モデルにおける配列番号15を有する送達構築物のin vivo有効性
(実施例6)
タンパク質可溶化
(実施例7)
タンパク質リフォールディング
(実施例8)
TFF UF/DFによるタンパク質濃縮および緩衝液交換
(実施例9)
捕捉ステップNH2-750F(登録商標)樹脂を使用したタンパク質クロマトグラフィー
CaPure(登録商標)手順を使用したタンパク質クロマトグラフィー
TFF UF/DFによるタンパク質濃縮
(実施例12)
精製された融合分子のin vivo活性の評価
(実施例13)
融合タンパク質精製のスケールアップ
(実施例14)
プロセスステップ回収の間の一貫性
(実施例15)
配列番号15および配列番号17の比較
(実施例16)
送達構築物のin vivo査定
(実施例17)
スペーサーの長さ、および担体のNまたはC末端へのペイロードのカップリングは、ペイロードの生物活性に有意に影響を与えない
本発明は、例えば、以下の項目を提供する。
(項目1)
配列番号15または配列番号17に示すアミノ酸配列を含む送達構築物。
(項目2)
配列番号15に示すアミノ酸配列を含む、項目1に記載の送達構築物。
(項目3)
配列番号17に示すアミノ酸配列を含む、項目1に記載の送達構築物。
(項目4)
担体を含む送達構築物であって、前記担体が、
195~347位のいずれか1つの位置にそのC末端を有し、
3位にグルタミン酸を、4位にアラニンを有し、
極性化された上皮細胞を越えたトランスサイトーシスが可能である、送達構築物。
(項目5)
前記担体が、266アミノ酸の長さである、項目4に記載の送達構築物。
(項目6)
前記担体が、配列番号7もしくは配列番号9に示すアミノ酸配列、またはそれに対して少なくとも90%、95%もしくは99%配列同一性を有するアミノ酸配列からなる、項目4または項目5に記載の送達構築物。
(項目7)
前記担体が、配列番号7に示すアミノ酸配列からなる、項目6に記載の送達構築物。
(項目8)
前記担体が、配列番号9に示すアミノ酸配列からなる、項目6に記載の送達構築物。
(項目9)
前記担体が、ペイロードにカップリングされている、項目4~8のいずれか一項に記載の送達構築物。
(項目10)
前記ペイロードが、IL-22である、項目9に記載の送達構築物。
(項目11)
前記IL-22が、配列番号11に示すアミノ酸配列からなる、項目10に記載の送達構築物。
(項目12)
前記担体が、前記IL-22に非共有結合によりカップリングされている、項目9~11のいずれか一項に記載の送達構築物。
(項目13)
前記担体が、前記IL-22に共有結合によりカップリングされている、項目9~11のいずれか一項に記載の送達構築物。
(項目14)
前記担体が、スペーサーを介して前記IL-22に共有結合によりカップリングされている、項目13に記載の送達構築物。
(項目15)
前記スペーサーが、配列番号13に示すアミノ酸配列からなる、項目14に記載の送達構築物。
(項目16)
配列番号15または配列番号17に示すアミノ酸配列からなる、項目1~15のいずれか一項に記載の送達構築物。
(項目17)
対象における炎症性疾患を処置する方法であって、前記対象に、有効量の項目1~16のいずれか一項に記載の送達構築物を投与するステップを含む方法。
(項目18)
前記炎症性疾患が、肝炎、肥満、脂肪性肝疾患、肝臓の炎症または膵炎、クローン病、潰瘍性大腸炎、嚢炎、直腸炎、多発性硬化症、全身性エリテマトーデス、移植片対宿主病、関節リウマチまたは乾癬である、項目17に記載の方法。
(項目19)
前記疾患が、クローン病または潰瘍性大腸炎である、項目18に記載の方法。
(項目20)
精製された天然に存在しない融合タンパク質を得るための方法であって、
前記天然に存在しない融合タンパク質を含む混合物に対してアニオン交換クロマトグラフィーを行って、前記天然に存在しない融合タンパク質を含む第1の画分を得るステップを含み、
前記天然に存在しない融合タンパク質が、IL-22および担体を含む、方法。
(項目21)
アニオン交換クロマトグラフィーを行うステップが、前記天然に存在しない融合タンパク質をアニオン性交換樹脂に結合させるステップと、前記天然に存在しない融合タンパク質のその後の溶出のための増加する塩勾配を提供して、前記第1の画分を得るステップとを含む、項目20に記載の方法。
(項目22)
アニオン交換クロマトグラフィーを行うステップが、前記混合物を、アミン官能化ポリメタクリレートビーズを含む樹脂と接触させるステップを含む、項目20~21のいずれか一項に記載の方法。
(項目23)
前記樹脂が、NH 2 -750F樹脂である、項目22に記載の方法。
(項目24)
アニオン交換クロマトグラフィーを行うステップに先立ち、前記天然に存在しない融合タンパク質をリフォールディングするステップをさらに含む、項目20~23のいずれか一項に記載の方法。
(項目25)
前記天然に存在しない融合タンパク質をリフォールディングするステップが、封入体由来のカオトロープ可溶化タンパク質をリフォールディング溶液と接触させるステップを含み、前記リフォールディング溶液が、
アルギニン(0.75M~1.25M)、
グリセロール(2%~20%v/v)、
システイン(0.5mM~10mM)および
シスタミン(0.2mM~10mM)
を含み、前記リフォールディング溶液が、7.5~8.5の間のpHを有する、項目24に記載の方法。
(項目26)
アルギニンが、前記リフォールディング溶液中に、0.9M~1.1Mの間の濃度で存在し、
グリセロールが、前記リフォールディング溶液中に、7%~13%(w/w)の間の濃度で存在し、
システインが、前記リフォールディング溶液中に、1.5mM~6mMの間の濃度で存在し、
シスタミンが、前記リフォールディング溶液中に、0.6mM~3mMの間の濃度で存在し、
前記リフォールディング溶液が、7.8~8.2の間のpHを有する、
項目25に記載の方法。
(項目27)
前記第1の画分を含む試料をヒドロキシアパタイト樹脂に供して、前記天然に存在しない融合タンパク質を含む第2の画分を得るステップをさらに含む、項目20~26のいずれか一項に記載の方法。
(項目28)
前記ヒドロキシアパタイト樹脂が、CaPure-ヒドロキシアパタイト樹脂である、項目27に記載の方法。
(項目29)
前記第1の画分を含む試料に対してカチオン交換クロマトグラフィーを行うステップをさらに含む、項目20~26のいずれか一項に記載の方法。
(項目30)
カチオン交換クロマトグラフィーを行うステップが、前記第1の画分を含む前記試料を、サルフェート官能化ポリメタクリレートビーズを含む樹脂と接触させるステップを含む、項目29に記載の方法。
(項目31)
前記樹脂が、TOYOPEARLサルフェート-650F樹脂である、項目30に記載の方法。
(項目32)
細胞との接触時に、前記担体が、前記天然に存在しない融合タンパク質のエンドサイトーシスまたはトランスサイトーシスを促進する、項目20~31のいずれか一項に記載の方法。
(項目33)
前記細胞との接触時に、前記担体が、前記天然に存在しない融合タンパク質のトランスサイトーシスを促進する、項目32に記載の方法。
(項目34)
前記細胞が、腸上皮細胞である、項目32または項目33に記載の方法。
(項目35)
前記腸上皮細胞が、極性化された腸上皮細胞である、項目34に記載の方法。
(項目36)
前記担体が、天然に存在するまたは天然に存在しないコリックスポリペプチドのトランケートバリアントである、項目20~35のいずれか一項に記載の方法。
(項目37)
前記担体が、配列番号2、3、4、5、6、7、8、9、22または23のいずれか1種に対して少なくとも70%、80%、85%、90%、95%、98%、99%または100%配列同一性を有する、項目20~36のいずれか一項に記載の方法。
(項目38)
前記天然に存在しない融合タンパク質が、配列番号14~21のいずれか1種の配列に対して少なくとも70%、80%、85%、90%、95%、98%、99%または100%配列同一性を有する、項目20~37のいずれか一項に記載の方法。
(項目39)
前記IL-22が、配列番号10、11または12のいずれか1種に対して少なくとも85%、90%、95%、98%、99%または100%配列同一性を有する、項目20~38のいずれか一項に記載の方法。
(項目40)
前記担体が、それ自体、第1の等電点(pI)を有し、前記IL-22が、それ自体、第2の等電点を有し、前記第1の等電点が、前記第2の等電点よりも少なくとも1pH単位、少なくとも1.5pH単位、少なくとも1.7pH単位または少なくとも2pH単位低い、項目20~39のいずれか一項に記載の方法。
(項目41)
項目20~41のいずれか一項に記載の方法によって得られる、天然に存在しない融合タンパク質。
(項目42)
担体およびIL-22を含む天然に存在しない融合タンパク質をリフォールディングする方法であって、
(i)前記天然に存在しない融合タンパク質を含む封入体を、カオトロピック剤を含む可溶化溶液と接触させて、可溶性の天然に存在しない融合タンパク質を産生するステップと、
(ii)前記天然に存在しない融合タンパク質をリフォールディング溶液と接触させるステップとを含み、前記リフォールディング溶液が、
アルギニン(0.75M~1.25M)、
グリセロール(2%~20%v/v)、
システイン(0.5mM~10mM)および
シスタミン(0.2mM~10mM)
を含み、前記リフォールディング溶液が、7.5~8.5の間のpHを有する、方法。
(項目43)
アルギニンが、前記リフォールディング溶液中に、0.9M~1.1Mの間の濃度で存在し、
グリセロールが、前記リフォールディング溶液中に、7%~13%(w/w)の間の濃度で存在し、
システインが、前記リフォールディング溶液中に、1.5mM~6mMの間の濃度で存在し、
シスタミンが、前記リフォールディング溶液中に、0.6mM~3mMの間の濃度で存在し、
前記リフォールディング溶液が、7.8~8.2の間のpHを有する、
項目42に記載の方法。
(項目44)
ペイロードにカップリングされたコリックスポリペプチドを含む送達構築物であって、前記コリックスペプチドが、195~347位のいずれか1つの位置にそのC末端を有し、極性化された上皮細胞を越えたトランスサイトーシスが可能である、送達構築物。
(項目45)
前記コリックスポリペプチドが、前記ペイロードに異種カップリングされている、項目44に記載の送達構築物。
Claims (28)
- ヒトIL-22にカップリングされている担体を含む送達構築物であって、前記担体が、配列番号7または9に示すアミノ酸配列からなる、送達構築物。
- 前記ヒトIL-22が、配列番号11に示すアミノ酸配列からなる、請求項1に記載の送達構築物。
- 前記担体が、前記ヒトIL-22に共有結合により、または非共有結合によりカップリングされている、請求項1~2のいずれか一項に記載の送達構築物。
- 前記担体が、スペーサーを介して前記ヒトIL-22に共有結合によりカップリングされている、請求項3に記載の送達構築物。
- 前記スペーサーが、配列番号13に示すアミノ酸配列からなる、請求項4に記載の送達構築物。
- 配列番号15または17に示すアミノ酸配列からなる、請求項1~5のいずれか一項に記載の送達構築物。
- 配列番号15に示すアミノ酸配列からなる、請求項6に記載の送達構築物。
- 配列番号17のアミノ酸配列からなる、請求項6に記載の送達構築物。
- 配列番号15または配列番号17に示すアミノ酸配列、あるいは配列番号15または配列番号17に対して少なくとも95%の配列同一性を有するアミノ酸配列を含む送達構築物。
- 前記アミノ酸配列が、配列番号15または配列番号17に対して少なくとも99%の配列同一性を有する、請求項9に記載の送達構築物。
- ペイロードにカップリングされている担体を含む送達構築物であって、前記送達構築物が、配列番号17に対して少なくとも90%の配列同一性を有し、前記担体が、配列番号7または配列番号9に示すアミノ酸配列、あるいは配列番号7または配列番号9に対して少なくとも95%の配列同一性を有するアミノ酸配列からなる、送達構築物。
- 前記送達構築物が、配列番号17に示すアミノ酸配列を含む、請求項11に記載の送達構築物。
- 前記送達構築物が、配列番号15に示すアミノ酸配列を含む、請求項11に記載の送達構築物。
- 前記送達構築物が、3位にグルタミン酸を、4位にアラニンを有する、請求項11~13のいずれか一項に記載の送達構築物。
- 前記担体が、266アミノ酸の長さである、請求項14に記載の送達構築物。
- 前記担体が、配列番号7に示すアミノ酸配列からなる、請求項11~15のいずれか一項に記載の送達構築物。
- 前記担体が、配列番号9に示すアミノ酸配列からなる、請求項11~15のいずれか一項に記載の送達構築物。
- 前記担体が、配列番号7または配列番号9に示すアミノ酸配列、あるいは配列番号7または配列番号9に対して少なくとも99%の配列同一性を有するアミノ酸配列からなる、請求項16~17のいずれか一項に記載の送達構築物。
- 前記ペイロードが、配列番号11に示すアミノ酸配列からなる、請求項11~18のいずれか一項に記載の送達構築物。
- 前記担体が、配列番号13に示すアミノ酸配列からなるスペーサーを介して前記ペイロードに共有結合によりカップリングされている、請求項19に記載の送達構築物。
- 請求項1~20のいずれか一項に記載の送達構築物および薬学的に許容される担体を含む医薬組成物。
- 請求項1~20のいずれか一項に記載の送達構築物を含む、対象における炎症性疾患を処置するための組成物。
- 前記炎症性疾患が、肝炎、肥満、脂肪性肝疾患、肝臓の炎症、膵炎、クローン病、潰瘍性大腸炎、嚢炎、直腸炎、多発性硬化症、全身性エリテマトーデス、移植片対宿主病、関節リウマチまたは乾癬である、請求項22に記載の組成物。
- 前記炎症性疾患が、胃腸管の炎症性疾患である、請求項22または請求項23に記載の組成物。
- 前記炎症性疾患が、クローン病、潰瘍性大腸炎、嚢炎、直腸炎、または移植片対宿主病である、請求項22または請求項23に記載の組成物。
- 前記炎症性疾患が、クローン病である、請求項22または請求項23に記載の組成物。
- 前記炎症性疾患が、潰瘍性大腸炎である、請求項22または請求項23に記載の組成物。
- 前記組成物が、前記対象に経口投与されることを特徴とする、請求項22~27のいずれか一項に記載の組成物。
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EP4083058A2 (en) | 2022-11-02 |
DK3650037T3 (da) | 2022-05-02 |
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MX2021005346A (es) | 2021-10-13 |
EP3650037A1 (en) | 2020-05-13 |
CL2021001209A1 (es) | 2021-11-19 |
SG11202104721RA (en) | 2021-06-29 |
CA3119060A1 (en) | 2020-05-14 |
EA202191280A1 (ru) | 2021-12-27 |
EP4083058A3 (en) | 2023-01-11 |
US20240238429A1 (en) | 2024-07-18 |
KR20210110294A (ko) | 2021-09-07 |
TW202031678A (zh) | 2020-09-01 |
AU2019377117A1 (en) | 2021-06-10 |
CN113423722A (zh) | 2021-09-21 |
US20200306383A1 (en) | 2020-10-01 |
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CO2021007402A2 (es) | 2021-09-30 |
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