JP2019141084A - Baff及びb7rp1に特異的なタンパク質及びその使用 - Google Patents
Baff及びb7rp1に特異的なタンパク質及びその使用 Download PDFInfo
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Abstract
Description
本出願は、2013年3月13日に出願された米国仮特許出願第61/780,260号及び2014年2月21日に出願された同第61/942,776号の利益を主張するものであり、それらの各々は、参照により、その全体が本明細書に組み込まれる。
本発明の実施形態の一部の例が以下の項目として示される。
(項目1)
BAFF媒介性のヒトB細胞の増殖を阻害することができ、
B7RP1媒介性のヒトT細胞の増殖を阻害することができる、二重特異性タンパク質。
(項目2)
前記二重特異性タンパク質は、異なるアミノ酸配列を有する2つの免疫グロブリン重鎖と、異なるアミノ酸配列を有する2つの免疫グロブリン軽鎖と、を含むIgG抗体を含む、項目1に記載の前記二重特異性タンパク質。
(項目3)
前記IgG抗体は、IgG1抗体である、項目2に記載の前記二重特異性タンパク質。
(項目4)
前記IgG抗体は、IgG2抗体である、項目2に記載の前記二重特異性タンパク質。
(項目5)
前記IgG抗体は、IgG4抗体である、項目2に記載の前記二重特異性タンパク質。
(項目6)
前記二重特異性タンパク質は、ヒトまたはヒト化IgG抗体である、項目1〜5のいずれか1項に記載の前記二重特異性タンパク質。
(項目7)
配列番号8のアミノ酸配列を含む軽鎖相補性決定領域1(CDR1)、配列番号9のアミノ酸配列を含む軽鎖相補性決定領域2(CDR2)、配列番号10のアミノ酸配列を含む軽鎖相補性決定領域3(CDR3)、配列番号11のアミノ酸配列を含む重鎖CDR1、配列番号12のアミノ酸配列を含む重鎖CDR2、及び配列番号13のアミノ酸配列を含む重鎖CDR3を含む、項目1〜6のいずれか1項に記載の前記二重特異性タンパク質。
(項目8)
配列番号15を含む重鎖可変領域と、配列番号14を含む軽鎖可変領域と、を含む、項目7に記載の前記二重特異性タンパク質。
(項目9)
(a)式A−L1−P−L2−Pを有するアミノ酸配列を含むポリペプチド(式中、Aは、IgG抗体の免疫グロブリン重鎖であり、L1は、存在しないかまたは3〜40アミノ酸長の第1のリンカーであり、Pは、10〜40アミノ酸長のBAFF結合ペプチドであり、L2は、存在しないかまたは5〜50アミノ酸長のペプチドリンカーである)と、
(b)免疫グロブリン軽鎖と、を含む、項目1に記載の前記二重特異性タンパク質。
(項目10)
(a)の前記免疫グロブリン重鎖及び(b)の前記免疫グロブリン軽鎖は、B7RP1に結合することができる、(a)の前記ポリペプチドの2つの分子及び(b)の前記軽鎖の2つ分子を含むIgG抗体を形成する、項目9に記載の前記二重特異性タンパク質。
(項目11)
前記免疫グロブリン重鎖は、L1のすぐ上流で、そのC末端のリジンを欠損している、項目9または10に記載の前記二重特異性タンパク質。
(項目12)
前記IgG抗体は、ヒトまたはヒト化抗B7RP1IgG1抗体である、項目9〜11のいずれか1項に記載の前記二重特異性タンパク質。
(項目13)
前記抗B7RP1抗体は、ヒトまたはヒト化IgG2抗体である、項目9〜11のいずれか1項に記載の前記二重特異性タンパク質。
(項目14)
前記抗B7RP1抗体は、ヒトまたはヒト化IgG4抗体である、項目9〜11のいずれか1項に記載の前記二重特異性タンパク質。
(項目15)
Pは、配列番号1のアミノ酸配列(LPGCKWDLLIKQWVCDPL)を有する、項目9〜14のいずれか1項に記載の前記二重特異性タンパク質。
(項目16)
L1は、配列番号40のアミノ酸配列(GGGGG)を有する、項目9〜15のいずれか1項に記載の前記二重特異性タンパク質。
(項目17)
L2は、配列番号5のアミノ酸配列を有する、項目9〜16のいずれか1項に記載の前記二重特異性タンパク質。
(項目18)
L2は、配列番号7のアミノ酸配列を有する、項目17に記載の前記二重特異性タンパク質。
(項目19)
L2は、配列番号6のアミノ酸配列を有する、項目17に記載の前記二重特異性タンパク質。
(項目20)
配列番号8(RASQGISNWLA)のアミノ酸配列を含む軽鎖CDR1、配列番号9(AASSLQS)のアミノ酸配列を含む軽鎖CDR2、配列番号10(QQYDSYPRT)のアミノ酸配列を含む軽鎖CDR3、配列番号11(SYWMS)のアミノ酸配列を含む重鎖CDR1、配列番号12(YIKQDGNEKYYVDSVKG)のアミノ酸配列を含む重鎖CDR2、及び配列番号13(EGILWFGDLPTF)のアミノ酸配列を含む重鎖CDR3を含む、項目9〜19のいずれか1項に記載の前記二重特異性タンパク質。
(項目21)
配列番号14のアミノ酸配列を含む免疫グロブリン軽鎖可変領域を含む、項目9〜20のいずれか1項に記載の前記二重特異性タンパク質。
(項目22)
配列番号15のアミノ酸配列を含む免疫グロブリン重鎖可変領域を含む、項目9〜21のいずれか1項に記載の前記二重特異性タンパク質。
(項目23)
(b)の前記免疫グロブリン軽鎖は、配列番号19のアミノ酸配列を含む、項目15〜22のいずれか1項に記載の前記二重特異性タンパク質。
(項目24)
(a)の前記ポリペプチドは、配列番号17または18のアミノ酸配列を含む、項目15〜23のいずれか1項に記載の前記二重特異性タンパク質。
(項目25)
(a)配列番号17または配列番号18のアミノ酸配列を含むポリペプチドと、
(b)配列番号19のアミノ酸配列を含む別のポリペプチドと、を含む、二重特異性タンパク質。
(項目26)
(a)の前記ポリペプチドの2つの分子と、(b)の前記ポリペプチドの2つの分子とを含む四量体である、項目25に記載の前記二重特異性タンパク質。
(項目27)
(a)の前記ポリペプチドは、配列番号17のアミノ酸配列を含む、項目25または26に記載の前記二重特異性タンパク質。
(項目28)
(b)の前記ポリペプチドは、配列番号18のアミノ酸配列を含む、項目25または26に記載の前記二重特異性タンパク質。
(項目29)
配列番号6または配列番号7のアミノ酸配列を含むリンカーを含む、タンパク質。
(項目30)
BAFF媒介性のヒトB細胞の増殖を阻害することができ、かつB7RP1媒介性のヒトT細胞の増殖を阻害することができる、項目29に記載の前記タンパク質。
(項目31)
配列番号1、配列番号14、及び/または配列番号15のアミノ酸配列を含む、項目30に記載の前記タンパク質。
(項目32)
項目1〜28のいずれか1項に記載の前記二重特異性タンパク質、または項目30もしくは31に記載の前記タンパク質、及び生理学的に許容される賦形剤を含む、薬学的組成物。
(項目33)
項目1〜28のいずれか1項に記載の前記二重特異性タンパク質、または項目30もしくは31に記載の前記タンパク質をコードする、核酸。
(項目34)
項目33に記載の前記核酸を含む、ベクター。
(項目35)
項目33に記載の前記核酸及び/または項目34に記載の前記ベクターを含有する、宿主細胞。
(項目36)
項目35に記載の前記宿主細胞を核酸が発現される条件下で培養することと、
細胞集団または培養培地からタンパク質を回収することと、を含む、二重特異性タンパク質の作成方法。
(項目37)
前記宿主細胞は、哺乳動物細胞である、項目36に記載の前記方法。
(項目38)
前記宿主細胞は、CHO細胞である、項目37に記載の前記方法。
(項目39)
前記宿主細胞は、大腸菌細胞である、項目36に記載の前記方法。
(項目40)
治療有効量の項目1〜28のいずれか1項に記載の前記二重特異性タンパク質、項目30もしくは31に記載の前記タンパク質、または項目32に記載の前記薬学的組成物を患者に投与することを含む、全身性エリテマトーデスの治療方法。
(項目41)
別の治療薬が、二重特異性タンパク質の前、後、またはそれと同時に患者に投与され、
他の治療薬は、副腎皮質ステロイド、抗マラリア薬、レチノイン酸、NSAID、シクロホスファミド、デヒドロエピアンドロステロン、ミコフェノール酸モフェチル、アザチオプリン、クロラムブシル、メトトレキサート、タクロリムス、ダプソン、サリドマイド、レフルノミド、またはシクロスポリンである、項目40に記載の前記方法。
(項目42)
前記他の治療薬は、ミコフェノール酸モフェチル、副腎皮質ステロイド、抗マラリア薬、メトトレキサート、またはアザチオプリンである、項目41に記載の前記方法。
(項目43)
治療有効量の項目1〜28のいずれか1項に記載の前記二重特異性タンパク質、項目30もしくは31に記載の前記タンパク質、または項目32に記載の前記薬学的組成物を患者に投与することを含み、前記患者は、ANCA陽性血管炎、関節リウマチ(RA)、クローン病、潰瘍性大腸炎、セリアック病、天疱瘡、類天疱瘡、亜急性皮膚エリテマトーデス(SCLE)、多発性硬化症、慢性炎症性脱髄性多発ニューロパチー(CIDP)、重症筋無力症、グッドパスチャー症候群、糸球体腎炎、自己免疫性溶血性貧血(AIHA)、特発性血小板減少性紫斑病(ITP)、慢性活動性肝炎、原発性胆汁性肝硬変、シェーグレン症候群、全身性硬化症、橋本甲状腺炎、グレーブス病、アジソン病、及び多発性内分泌腫瘍症(MEN)からなる群から選択される疾患を有する、治療方法。
(項目44)
項目1〜28のいずれか1項に記載の前記二重特異性タンパク質、または項目29〜31のいずれか1項に記載の前記タンパク質の薬物としての使用。
(項目45)
項目1〜28のいずれかに記載の前記二重特異性タンパク質、または項目30もしくは31に記載の前記タンパク質を含む、全身性エリテマトーデスの治療のための薬学的組成物。
(項目46)
項目1〜28のいずれかに記載の前記二重特異性タンパク質、または項目30もしくは31に記載の前記タンパク質を含む、ループス腎炎の治療のための薬学的組成物。
本明細書で意味する「抗体」は、重鎖及び/または軽鎖免疫グロブリン可変領域を含むタンパク質である。
Capra,Immunoglobulins:Structure and Function,pp.283−314 in Fundamental Immunology,3rd Ed,Paul,ed.,Raven Press,New York,1993(参照により本明細書に組み込まれる)に概説される。免疫グロブリン軽鎖は、VL領域及びCL領域を含有する。これらの領域の多数の配列が当該技術分野で既知である。例えば、Kabat et al.,Sequences of Proteins
of Immunological Interest,Public Health
Service N.I.H.,Bethesda,MD,1991を参照されたい。いくつかの場合において、免疫グロブリン軽鎖及びいくつかの非免疫グロブリン配列を含むポリペプチド鎖が、本明細書において「軽鎖」と称される。
Fundamental Immunology,3rd Ed,Paul,ed.,Raven Press,New York,1993(参照により本明細書に組み込まれる)に概説される。同様に、本明細書で意味する免疫グロブリン可変領域の中に含まれるのは、天然起源の核酸配列によってコードされる免疫グロブリン可変領域と比較して、20、15、10、または5個以下の単一アミノ酸の挿入、欠失、及び/または置換を有するタンパク質である。免疫グロブリン可変領域は、相補性決定領域1(CDR1)、相補性決定領域2(CDR2)、及び相補性決定領域3(CDR3)として知られる3つの超可変領域を含有する。これらの領域は、抗体の抗原結合部位を形成する。CDRは、可変性のより低いフレームワーク領域(FR1−FR4)内に埋め込まれている。可変領域内におけるこれらの小領域の順序は次の通りである:FR1−CDR1−FR2−CDR2−FR3−CDR3−FR4。免疫グロブリン可変領域の多数の配列が当該技術分野で既知である。例えば、Kabat et al.,Sequences of Proteins of Immunological Interest,Public Health Service N.I.H.,Bethesda,MD,1991を参照されたい。
B7RP1及びBAFFに結合し、かつ/またはin vitroでB7RP1媒介性T細胞増殖及びBAFF媒介性B細胞増殖を阻害することができる二重特異性タンパク質が本明細書に開示される。本明細書に記載の二重特異性タンパク質が結合するBAFF及びB7RP1タンパク質は、ヒトタンパク質であってもよく、かつ/または、特に、カニクイザル、アカゲザル、チンパンジー、マウス、及び/もしくはウサギ等の別の種由来のタンパク質であってもよい。いくつかの実施形態において、本明細書に記載の二重特異性タンパク質は、例えば、ヒト(ホモ・サピエンス)及びカニクイザル(マカク・ファシキュラリス)の両方のB7RP1及びBAFFタンパク質に結合することができる。
それらを含有するタンパク質に好ましい物理的特性を付与する、配列番号5、6、または7のアミノ酸配列を有するリンカーが本明細書に提供される。後述する実施例1に示されるように、2つの特定のリンカー、すなわち、配列番号6及び配列番号7のアミノ酸配列を有するリンカーの使用が、二重特異性分子の発現、安定性、及び粘性等の特性に好ましい影響を与えた。したがって、これらのリンカーを含有する様々なタンパク質は、他のリンカーを含有する同様のタンパク質と比較して、そのような好ましい特性を有する可能性がある。
本明細書に記載のBAFF及びB7RP1に結合する二重特異性タンパク質は、様々な適応症、特に、自己抗体によって駆動される状態ならびに/またはT細胞及びB細胞の両方によって媒介される状態の治療薬として使用することができる。そのような状態は、例えば、SLE、ループス、腎炎、ANCA陽性血管炎、関節リウマチ(RA)、皮膚筋炎、多発性筋炎、クローン病、潰瘍性大腸炎、及びセリアック病等の消化管疾患、天疱瘡、類天疱瘡、及び亜急性皮膚エリテマトーデス(SCLE)等の皮膚の状態、多発性硬化症及び慢性炎症性脱髄性多発ニューロパチー(CIDP)等の神経系の疾患、重症筋無力症等の神経筋疾患、グッドパスチャー症候群及び糸球体腎炎等の腎臓に関与する疾患、自己免疫性溶血性貧血(AIHA)、特発性血小板減少性紫斑病(ITP)、及び自己免疫性好中球減少症等の血液学的状態、慢性活動性肝炎及び原発性胆汁性肝硬変等の肝臓の状態、シェーグレン症候群、全身性硬化症、ならびに橋本甲状腺炎、グレーブス病、アジソン病、及び複数の内分泌性自己免疫不全(一般的に、糖尿病、甲状腺機能低下症、アジソン病、及び性腺機能不全)を含む内分泌状態を含む。本明細書に記載の二重特異性タンパク質の治療有効量は、これらの状態のいずれかを治療するために該状態に罹患する患者に投与することができる。
Dis.55:756−760;Hay et al.(1993),Q.J.Med.86:447−458。BILAGについて記載するこれらの参考文献の一部が、参照により本明細書に組み込まれる。BILAGスコアは、全身(発熱及び疲労等)、皮膚粘膜(他の多くの症状の中でも特に皮疹及び脱毛症)、神経(他の多くの症状の中でも特に発作、偏頭痛、及び精神症状)、筋骨格(関節炎等)、心肺(心不全及び肺機能低下等)、血管炎及び血栓症、腎臓(腎炎等)、ならびに血液の8つの器官に基づく系の各々において、別個の数値及びアルファベットの疾患活動性スコアを与えることによって割り当てられる。同上。本明細書に記載の治療は、BILAG指標によって測定されるようなSLEの症状を軽減もしくは排除する上で、または本明細書に記載の二重特異性タンパク質を用いた治療を開始する前のベースライン値と比較して患者のBILAGスコアを高める上で有用であり得る。
B7RP1媒介性T細胞増殖及びBAFF媒介性B細胞増殖を阻害することができる二重特異性タンパク質をコードする核酸が本明細書に提供される。例えば、配列番号52は、配列番号14のアミノ酸配列を有するVL領域をコードし、配列番号53は、配列番号15のアミノ酸配列を有するVH領域をコードする。同様に、配列番号55及び56は、2つのBAFF結合ペプチドに融合された抗B7RP1抗体の重鎖を含むポリペプチドである配列番号17及び18のアミノ酸配列をそれぞれコードする。配列番号57は、前述のヘテロ四量体の二重特異性IgG抗体または二重特異性融合タンパク質の一部であり得る抗B7RP1抗体の軽鎖をコードする。本明細書に記載の任意のアミノ酸配列をコードする任意の核酸配列が企図される。同様に、本明細書に開示される配列に対するサイレント変異を含むか、または前述のアミノ酸配列変異体をコードするヌクレオチド配列変異体も、本発明の範囲内に含まれる。より具体的には、アミノ酸100個当たり10個以下の単一アミノ酸の挿入、欠失、または置換だけ本明細書に開示されるアミノ酸配列と異なるアミノ酸配列をコードするヌクレオチド配列が企図される。
本明細書に記載の二重特異性タンパク質をコードする核酸は、核酸を発現させる宿主細胞に適切なベクターに挿入することができる。これらの核酸は、当該技術分野で周知のいずれの方法によって宿主細胞に導入されてもよい。使用することができる宿主細胞は、他の多くの細胞の中でも特に、大腸菌を含む細菌、出芽酵母またはピキア・パストリスを含む酵母、ヨトウガ細胞を含む昆虫細胞、植物細胞、ならびにチャイニーズハムスター卵巣(CHO)細胞、ベビーハムスター腎臓(BHK)細胞、サル腎細胞、HeLa細胞、ヒト肝細胞癌細胞、及び293細胞を含む哺乳動物細胞を含む。これらの宿主細胞は、導入した核酸が発現するような、かつ培養上清もしくは細胞集団から二重特異性タンパク質を回収できるような条件下で培養することができる。
本明細書に記載の二重特異性タンパク質を含む薬学的組成物が提供される。そのような組成物は、生理学的に許容される担体、賦形剤、または希釈剤等の1つ以上のさらなる構成成分とともに、治療有効量の二重特異性タンパク質を含むことができる。そのようなさらなる構成成分は、多くの可能性の中でも特に、緩衝剤、炭水化物、ポリオール、アミノ酸、キレート剤、安定剤、及び/または防腐剤を含むことができる。多くのそのようなさらなる構成成分は、例えば、Remington’s Pharmaceutical Sciences,18th Edition,(A.R.Gennaro,ed.),1990,Mack Publishing Company(その関連する部分が、参照により本明細書に組み込まれる)に記載される。
この一連の実験の目的は、(1)BAFF媒介性B細胞増殖及びB7RP1媒介性T細胞増殖を阻害し、(2)生物学的アッセイにおいて高度に活性であり、(3)好ましい生物物理学的特性を有する二重特異性分子を発見することであった。ヒトBAFFを抗ヒトB7RP1 IgG抗体(抗huB7RP1)に結合させるペプチドの融合のための多数の概略的設計を図1に示す。BAFF結合ペプチドの配列は、配列番号1に提供され、抗huB7RP1の免疫グロブリン重鎖及び軽鎖の配列は、それぞれ、配列番号25及び配列番号19に提供される。
マウスにおける前臨床試験を実施するために、マウスB7RP1及びマウスBAFFに結合することができるマウス代替物二重特異性分子(これ以降、「マウス代替物」)を構築した。実施例1に記載した二重特異性構築物を構築するために使用した抗huB7RP1抗体はマウスB7RP1に結合しないが、これらの構築物に使用したBAFF結合ペプチドは、ヒト及びマウス両方のBAFFに結合する。データは示さず。マウス代替物は、マウス免疫グロブリン定常領域及びラット抗マウスB7RP1免疫グロブリン可変領域のキメラである、拮抗性IgG抗マウスB7RP1抗体(本明細書において「抗mB7RP1」と称される)を含む。抗mB7RP1の使用は、Hu et al.(2009),J.Immunol.182:1421(1B7−V2と表記される)に記載されている。マウス代替物は、短いリンカー(5アミノ酸長)を介して抗mB7RP1の免疫グロブリン重鎖のC末端に融合されたBAFF結合ペプチド(配列番号1)の2つのコピーを有する。BAFF結合ペプチドの2つのコピーは、23アミノ酸長の別のリンカーによって分離される。重複PCRを用いてマウス代替物の重鎖をコードする核酸を作製し、αBAFFのBAFF結合部位をコードする核酸を、1B7−V2、すなわち、抗mB7RP1の重鎖をコードする核酸の下流末端に結合した。
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