JP2022082675A - 組織カリクレイン1の剤形 - Google Patents
組織カリクレイン1の剤形 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、2017年10月3日に出願された米国仮特許出願第62/567,406号、2017年6月7日に出願された米国仮特許出願第62/516,463号、および2017年3月9日に出願された米国仮特許出願第62/469,385号に対する優先権を主張するものであり、これらの各々はその全体が参照により本明細書に組み込まれる。
本出願に関連する配列表は、紙のコピーの代わりにテキスト形式で提供されており、参照により本明細書に組み込まれる。配列表を含むこのテキストファイル名は、DIAM_037_03WO_ST25.txtである。本テキストファイルは9KBであり、2018年3月9日に作成され、EFS-Web経由で電子的に提出されている。
技術分野
本開示の実施形態は、約0.1μg/kg~約10.0μg/kgのKLK1ポリペプチド総投与量を有する、1つ以上の組織カリクレイン-1(KLK1)ポリペプチドの剤形に関し、皮下および静脈内剤形が含まれる。また、例えば、虚血性病態および出血性病態を治療するための、関連デバイスおよびその使用方法も提供される。
組織カリクレインはすべて、トリプシンまたはキモトリプシンのそれと同様の基質特異性を有するプロテアーゼ活性を有する。KLK1の最もよく特徴付けられている活性は、直接的にまたは間接的に、両ブラジキニン受容体(BK-B1、BK-B2)のサブタイプを活性化する、キニンと総称されるブラジキニン(BK)様ペプチドを生成するキニノーゲンのその酵素切断である。キニンによるBK受容体の活性化は、体内の虚血に応答して多数の複雑な代謝経路を動かし、これには改善された血流(血管拡張による)、抗炎症反応、血管新生または血管形成による細胞修復、およびアポトーシスの減少が含まれ得る。
組織カリクレイン媒介性放出が、腎臓および心臓を含む種々の組織において血流を増加させ(例えば、Stone et al.,Arterioscler Thromb Vasc Biol.29:657-664,2009を参照のこと)、このことはカリクレイン治療が特定の病態に対処する1つの様式である可能性が高いことを示すかなりの数の科学的研究がある。したがって、KLK1は、患者における血流の再確立および炎症の軽減が脳機能、腎機能、心機能を含む臓器機能の維持に不可欠である広範囲の臨床シナリオを治療する可能性を有すると考えられている。しかし、ヒトにおいてKLK1の治療レベルを達成し維持する最適な剤形および投与経路を同定する必要性が依然としてある。本開示は、これらおよび他の必要性に対処する。
本開示の実施形態は、組織カリクレイン-1(KLK1)の製剤が逆用量曲線を有するという予想外の発見に関し、低用量製剤のある時点までの投与は、高用量製剤と比較して改善された薬物動態および/または活性プロファイルを示す。
第1のKLK1ポリペプチドは、ポリペプチド当たり3つの異なる位置に結合した3つのグリカンを有し、第2のKLK1ポリペプチドは、ポリペプチド当たり2つの異なる位置に結合した2つのグリカンを有し、
第1のKLK1ポリペプチドおよび第2のKLK1ポリペプチドは、約45:55~約55:45の比で剤形中に存在する。
特定の実施形態では、例えば以下の項目が提供される:
(項目1)
約0.5μg/kg~約10.0μg/kgのKLK1ポリペプチド総投与量で製剤される1つ以上の組織カリクレイン(KLK1)ポリペプチドを含む剤形。
(項目2)
皮下または静脈内投与に適している、項目1に記載の剤形。
(項目3)
約0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.75、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、または10μg/kgのKLK1ポリペプチド総投与量を含む、項目1または2に記載の剤形。
(項目4)
約1.0μg/kg~約5.0μg/kg、または約1.0μg/kg~約4.0μg/kg、または約1.0μg/kg~約3.0μg/kg、または約1.0μg/kg~約2.0μg/kg、または約2.0μg/kg~約5.0μg/kg、または約2.0μg/kg~約4.0μg/kg、または約2.0μg/kg~約3.0μg/kg、または約3.0μg/kg~約5.0μg/kg、または約3.0μg/kg~約4.0μg/kg、または約2.5μg/kg~約3.5μg/kg、または約3μg/kgの総KLK1ポリペプチド皮下剤形を含む、項目1~3のいずれか一項に記載の剤形。
(項目5)
約0.5μg/kg~約3.0μg/kg、または約0.5μg/kg~約2.0μg/kg、または約0.5μg/kg~約1.0μg/kg、または約0.5μg/kg~約0.8μg/kg、または約0.5μg/kg~約0.75μg/kg、または約0.75μg/kgの総KLK1ポリペプチド静脈内剤形を含む、項目1~4のいずれか一項に記載の剤形。
(項目6)
第1のKLK1ポリペプチドおよび第2のKLK1ポリペプチドを含み、
前記第1のKLK1ポリペプチドが、ポリペプチド当たり3つの異なる位置に結合した3つのグリカンを有し、前記第2のKLK1ポリペプチドが、ポリペプチド当たり2つの異なる位置に結合した2つのグリカンを有し、
前記第1のKLK1ポリペプチドおよび前記第2のKLK1ポリペプチドが、約45:55~約55:45の比で前記剤形中に存在する、項目1~5のいずれか一項に記載の剤形。
(項目7)
前記グリカンのうちの1つ以上がN-結合グリカンである、項目6に記載の剤形。
(項目8)
前記グリカンのうちの1つ以上が、配列番号3または4によって定義される、KLK1のアミノ酸残基78、84、または141に結合している、項目6または7に記載の剤形。
(項目9)
前記第1のKLK1ポリペプチドの前記3つのグリカンが、残基78、84、および141におけるN-結合グリカンである、項目6~8のいずれか一項に記載の剤形。
(項目10)
前記第2のKLK1ポリペプチドの前記2つのグリカンが、残基78および84におけるN-結合グリカンであるが、残基141においては結合しない、項目6~9のいずれか一項に記載の剤形。
(項目11)
前記第1のKLK1ポリペプチドおよび前記第2のKLK1ポリペプチドが約50:50の比で前記剤形中に存在する、項目1~10のいずれか一項に記載の剤形。
(項目12)
前記剤形がKLK1ポリペプチドの三重グリコフォームおよびKLK1ポリペプチドの二重グリコフォームを含み、前記三重グリコフォームおよび前記二重グリコフォームが約45:55~約55:45の比で前記剤形中に存在する、項目1~5のいずれか一項に記載の剤形。
(項目13)
前記三重グリコフォームが、配列番号3または4によって定義されるKLK1のアミノ酸残基78、84、および141においてN-結合グリカンを含む、項目12に記載の剤形。
(項目14)
前記二重グリコフォームが、配列番号3または4によって定義される、KLK1のアミノ酸残基78および84においてN-結合グリカンを含むが、KLK1のアミノ酸残基141においては含まない、項目12または13に記載の剤形。
(項目15)
前記三重グリコフォームおよび前記二重グリコフォームが、約50:50の比で前記剤形中に存在する、項目12~14のいずれか一項に記載の剤形。
(項目16)
前記1つ以上のKLK1ポリペプチドが、組換えKLKポリペプチド、成熟KLK1ポリペプチド、ヒトKLK1(hKLK1)ポリペプチド、またはそれらの任意の組み合わせである、項目1~15のいずれか一項に記載の剤形。
(項目17)
前記hKLK1ポリペプチドが、配列番号1のアミノ酸残基78~141もしくは配列番号2のアミノ酸残基78~141、またはそれらの活性フラグメント、または配列番号1のアミノ酸残基78~141もしくは配列番号2のアミノ酸残基78~141に対して少なくとも約90、95、96、97、98、もしくは99%の配列同一性を有する活性変異体を含むか、それらからなるか、またはそれらから本質的になる、項目16に記載の剤形。
(項目18)
前記hKLK1ポリペプチドが、配列番号1のアミノ酸残基25~262もしくは配列番号2のアミノ酸残基25~262、またはそれらの活性フラグメント、または配列番号1のアミノ酸残基25~262もしくは配列番号2のアミノ酸残基25~262に対して少なくとも約90、95、96、97、98、もしくは99%の配列同一性を有する活性変異体を含むか、それらからなるか、またはそれらから本質的になる、項目16に記載の剤形。
(項目19)
前記KLK1ポリペプチドが、配列番号2のアミノ酸残基25~262に対して少なくとも約90、95、96、97、98、または99%の配列同一性を有するアミノ酸配列を含み、前記KLK1ポリペプチドが、E145および/またはA188を含む、項目16に記載の剤形。
(項目20)
前記KLK1ポリペプチドが、配列番号2のアミノ酸残基25~262に対して少なくとも約90、95、96、97、98、または99%の配列同一性を有するアミノ酸配列を含み、前記KLK1ポリペプチドが、Q145および/またはV188を含む、項目16に記載の剤形。
(項目21)
薬学的に許容される賦形剤、希釈剤、アジュバント、または担体を含む、項目1~20のいずれか一項に記載の剤形。
(項目22)
KLK1の他のグリコシル化アイソフォーム(グリコフォーム)を実質的に含まない、項目1~21のいずれか一項に記載の剤形。
(項目23)
タンパク質1mg当たり約1EU未満のエンドトキシンレベル、総タンパク質1mg当たり約100ng未満の宿主細胞、総タンパク質1mg当たり約10pg未満の宿主細胞DNAを有し、かつ/または凝集物を実質的に含まない(約95%超がSEC HPLCによって単一ピークとして現れる)、項目1~22のいずれか一項に記載の剤形。
(項目24)
アンジオテンシン受容体遮断薬、エダバロン、ファインレノン、およびバルドキサロンのうち1つ以上(それらの組み合わせを含む)から選択される第2の薬剤をさらに含む、項目1~23のいずれか一項に記載の剤形。
(項目25)
前記アンジオテンシン受容体遮断薬が、ロサルタン、アジシルサルタン、カンデサルタン、エプロサルタン、フィマサルタン、イルベサルタン、オルメサルタン、サプリサルタン、テルミサルタン、およびバルサルタンのうち1つ以上(それらの組み合わせを含む)から選択される、項目24に記載の剤形。
(項目26)
それを必要とする対象を治療する方法であって、項目1~25のいずれか一項に記載の剤形を前記対象に投与することを含む、方法。
(項目27)
前記剤形を前記対象に皮下または静脈内投与することを含む、項目26に記載の方法。
(項目28)
脳虚血(虚血性脳卒中)、心虚血(心筋虚血)、虚血性大腸炎、四肢虚血、および皮膚虚血のうちの1つ以上から任意選択的に選択される、前記対象における虚血性病態を治療するための、項目26または27に記載の方法。
(項目29)
任意選択的に、脳内(脳の内部)出血性脳卒中およびくも膜下出血性脳卒中を含む出血性脳卒中である、前記対象における出血性病態を治療するための、項目26または27に記載の方法。
(項目30)
血管性認知症、糖尿病(任意選択的に2型糖尿病(T2D))、外傷性脳損傷(TBI)、腎臓病(任意選択的に慢性腎臓病、糖尿病性腎臓病、または多発性嚢胞腎症)、全身性エリテマトーデス(SLE)およびループス腎炎を含む関連病態、肺動脈高血圧症(PAH)、巣状分節性糸球体硬化症、ならびに本態性高血圧症のうち1つ以上から選択される疾患を治療するための、項目26または27に記載の方法。
(項目31)
前記剤形を前記対象に皮下投与することを含み、前記剤形の皮下投与が、前記対象において前記1つ以上のKLK1ポリペプチドの治療上有効な血清レベルを達成し、任意選択的に、前記皮下投与後に約もしくは少なくとも約2、4、6、8、10、12、24、23、48、60、72、84、96時間以上、または1、2、3、4、5、6、7、8、9、10、11、12、13、もしくは14日以上の間、前記治療上有効な血清レベルを維持する、項目26~30のいずれか一項に記載の方法。
(項目32)
前記剤形を前記対象に静脈内投与することを含み、前記剤形の静脈内投与が、前記対象において前記1つ以上のKLK1ポリペプチドの治療上有効な血清レベルを、任意選択的に、前記静脈内投与後約0.5、1、2、3、もしくは4時間で、または約0.5、1、2、3、もしくは4時間未満で達成する、項目26~30のいずれか一項に記載の方法。
(項目33)
前記治療上有効な血清レベルが約1.0~約5.0ng/ml、または約1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、もしくは5.0mg/mlである、項目31または32に記載の方法。
(項目34)
前記剤形の投与が、高用量剤形、任意選択的に少なくとも約15μg/kg、または少なくとも約20μg/kg、または少なくとも約50μg/kg、または少なくとも約100μg/kg、または少なくとも約400μg/kg以上のKLK1ポリペプチド総投与量を有する高用量剤形と比較して、改善された薬物動態プロファイルまたは生物学的効果を達成する、項目26~33のいずれか一項に記載の方法。
(項目35)
1日に約1回または2回、2日毎に1回または2回、3日毎に1回または2回、4日毎に1回または2回、5日毎に1回または2回、6日毎に1回または2回、1週間毎に1回または2回の投与計画として、前記剤形を前記対象に投与することを含む、項目26~34のいずれか一項に記載の方法。
(項目36)
任意選択的に皮下投与により、3日毎に1日に約1回の投与計画として前記剤形を前記対象に投与することを含む、項目35に記載の方法。
(項目37)
1つの静脈内剤形を前記対象に静脈内投与し、続いて、任意選択的に1日に約1回または2回、2日毎に1回または2回、3日毎に1回または2回、4日毎に1回または2回、5日毎に1回または2回、6日毎に1回または2回、1週間毎に1回または2回の投与計画として、1つ以上の皮下剤形を前記対象に皮下投与することを含む、項目26~36のいずれか一項に記載の方法。
(項目38)
前記静脈内投与が、前記対象において前記1つ以上のKLK1ポリペプチドの治療上有効な血清レベルを、前記静脈内投与後約0.5、1、2、3、もしくは4時間で、または約0.5、1、2、3、もしくは4時間未満で達成し、前記皮下投与が、前記皮下投与後に約もしくは少なくとも約2、4、6、8、10、12、24、23、48、60、72、84、96時間以上、または1、2、3、4、5、6、7、8、9、10、11、12、13、もしくは14日以上の間、前記治療上有効な血清レベルを維持する、項目37に記載の方法。
(項目39)
任意選択的に同一のまたは異なる剤形または組成物の一部として、アンジオテンシン受容体遮断薬、エダバロン、ファインレノン、およびバルドキサロンのうちの1つ以上(それらの組み合わせを含む)から選択される第2の薬剤を投与することを含む、項目26~38のいずれか一項に記載の方法。
(項目40)
前記アンジオテンシン受容体遮断薬が、ロサルタン、アジルサルタン、カンデサルタン、エプロサルタン、フィマサルタン、イルベサルタン、オルメサルタン、サプリサルタン、テルミサルタン、およびバルサルタンのうちの1つ以上(それらの組み合わせを含む)から選択される、項目39に記載の方法。
(項目41)
項目1~25のいずれか一項に記載の剤形を含むデバイスであって、前記剤形を皮下または静脈内に送達するのに適している、デバイス。
別途定義されない限り、本明細書で使用する技術用語および科学用語はすべて、本発明の属する技術分野の当業者によって通常理解されるのと同じ意味を有する。本明細書に説明されるものと類似のまたは等価の任意の方法および材料を本発明の実施または試験に使用することができ、好ましい方法および材料を説明する。本発明の目的のために、以下の用語を下記に定義する。
本開示の実施形態は、約0.1μg/kg~約5μg/kgまたは約10.0μg/kgのKLK1ポリペプチド総投与量で製剤される1つ以上の組織カリクレイン(KLK1)ポリペプチドを含む剤形に関する。場合によっては、剤形は、対象、例えばヒト対象への皮下または静脈内投与に適している(または適合されている)。
ヒトにおける低用量KLK1製剤の薬物動態
低用量KLK1製剤の薬物動態をヒトで評価した。製剤は、米国特許出願第14/677,122号(参照により組み込まれる)に記載のとおり調製された、成熟ヒトKLK1の二重および三重グリコシル化アイソフォームの混合物で構成される。
Claims (1)
- 明細書に記載の発明。
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- 2018-03-09 KR KR1020197026369A patent/KR20190122706A/ko not_active Application Discontinuation
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WO2018165551A1 (en) | 2018-09-13 |
CN110446501A (zh) | 2019-11-12 |
AU2018230478A1 (en) | 2019-09-12 |
JP2020510023A (ja) | 2020-04-02 |
US11857608B2 (en) | 2024-01-02 |
EP3592377A1 (en) | 2020-01-15 |
EP3592377A4 (en) | 2021-02-17 |
CA3054962A1 (en) | 2018-09-13 |
KR20190122706A (ko) | 2019-10-30 |
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