JP5701064B2 - フェロポーチン抗体およびその使用方法 - Google Patents
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- JP5701064B2 JP5701064B2 JP2010544443A JP2010544443A JP5701064B2 JP 5701064 B2 JP5701064 B2 JP 5701064B2 JP 2010544443 A JP2010544443 A JP 2010544443A JP 2010544443 A JP2010544443 A JP 2010544443A JP 5701064 B2 JP5701064 B2 JP 5701064B2
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Description
本出願は、2008年12月11日に出願された米国仮出願第61/121,729号の優先権、および2008年1月25日に出願された米国仮出願第61/023,693号の優先権を主張する。各優先出願の開示は、参照によりその全体が本明細書に組み込まれる。
本発明は、フェロポーチン抗体およびその使用に関する。
鉄はすべての生命体の成長および発達のために必要となる、必須微量元素である。哺乳動物の鉄含有量は、鉄吸収、鉄循環、および鉄を貯蔵する細胞からの鉄放出を制御することによって、調節される。鉄放出は、血漿に鉄を放出することが可能な主細胞である、腸細胞、マクロファージおよび肝細胞の細胞表面上に位置する主要な鉄輸出タンパク質であるフェロポーチンによって制御される。MTP1またはフェロポーチン−1としても知られているフェロポーチンは、細胞内鉄排出を媒介する複数回貫通型膜タンパク質である(Donovan et al.,Nature,403:776−781,2000、Abboud et al.,J.Biol.Chem.,275:19906−19912,2000)。フェロポーチンは、十二指腸の腸細胞および細網内皮系のマクロファージに高度に発現し、食事からの鉄の輸送および老化赤血球からの循環利用にそれぞれ関与する(Yang et al.,J.Biol.Chem.,277:39786−39791,2002)。フェロポーチンは、鉄調整ホルモンであるヘプシジンによって負に調整される。ヘプシジンは、フェロポーチンに結合し、フェロポーチンの内部移行および分解をもたらすことが示されている(Nemeth et al.,Blood,107:328−333,2006;Nemeth et al.,Science,306:2090−2093,2004;de Domenico et al.,Mol.Biol.Cell.,8:2569−2578,2007)。この機序は、マクロファージ、肝細胞および腸細胞からの鉄の放出を遮断する(Knutson et al.,Proc.Natl.Acad.Sci.USA,102:1324−1328,2008、Nemeth et al.,Blood,107:328−333,2006、Knutson et al.,Blood,102:4191−4197,2003)。
本発明の種々の実施形態は、以下に記載されるように、ヒトフェロポーチンに結合するモノクローナル抗体を含む抗体、かかる抗体を産生する方法、フェロポーチンを検出するためにかかる抗体を使用する方法、かかる抗体を含む医薬製剤、該医薬製剤を調製する方法、ならびに赤血球生成刺激剤および/または鉄キレート剤との併用療法を含む、該医薬製剤により患者を治療する方法を提供する。かかる抗体をコードする核酸、かかる核酸を含むベクターおよび組換え宿主細胞、ならびにかかる抗体を産生する方法も提供する。
フェロポーチン(配列番号16)は、10あるいは12の膜貫通ドメインを有することが予測されるマルチ膜貫通タンパク質である。トポロジー図に基づいて、20%未満の残基が、細胞外であることが予測され、最長細胞外ループは、わずか57残基長さであることが予測される。図1は、フェロポーチン膜貫通および細胞外ドメインの2つの概略図を示す。図1Aにおいて、細胞外ドメインは、配列番号16のアミノ酸46〜60(ループ1)、116〜126(ループ2)、204〜205および325〜342(ループ3)、394〜449(ループ4)ならびに513〜517(ループ5)に対応する。図1Bにおいて、細胞外ドメインは、配列番号16のアミノ酸35〜57(ループ1)、116〜124(ループ2)、332−340(ループ3)、393−449(ループ4)および515−518(ループ5)に対応する。
「抗体」という用語は、最も広範な意味で使用され、完全に組み立てられた抗体、モノクローナル抗体、ポリクローナル抗体、多重特異性抗体(二重特異性抗体を含む)、抗原(Fab’、F’(ab)2、Fv、単鎖抗体、ダイアボディ(diabodies)を含む)に結合することができる抗体フラグメント、ならびにそれらが所望の生物活性を示す限り、前述のものを含む組換えペプチドを含む。化学的に誘導体化された抗体を含む、無傷分子および/またはフラグメントのマルチマーまたは会合体が、企図される。IgG、IgM、IgD、IgA、およびIgE、IgG1、IgG2、IgG3、IgG4、IgA1およびIgA2を含む、任意のアイソタイプクラスもしくはサブクラスの抗体、または任意のアロタイプの抗体が、企図される。異なるアイソタイプは、異なるエフェクター機能を有する、例えば、IgG1およびIgG3アイソタイプは、抗体依存性細胞傷害(ADCC)活性を有する。
1)抗体31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6の任意の1つ、2つ、3つ、4つ、5つ、または6つのCDRH1、CDRH2、CDRH3、CDRL1、CDRL2もしくはCDRL3を保有し、任意に、かかる単数または複数のCDRにおける、1つまたは2つの変異体を含む、モノクローナル抗体、
2)抗体31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6のすべてのCDRH1、CDRH2、CDRH3、または重鎖可変領域を保有し、任意に、かかる単数または複数のCDRにおける、1つまたは2つの変異体を含む、モノクローナル抗体、
3)抗体31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6のすべてのCDRH1、CDRH2、CDRH3、または軽鎖可変領域を保有し、任意に、かかる単数または複数のCDRにおける、1つまたは2つの変異体を含む、モノクローナル抗体、
4)例えば、X線結晶学または重水素交換質量分析、アラニンスキャニングおよびペプチドフラグメントELISA等の他の生物物理学的もしくは生化学的技法を通して決定される、抗体31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6と同一のフェロポーチンの線状もしくは立体的エピトープに結合するモノクローナル抗体、
5)フェロポーチン(配列番号16)のアミノ酸残基393〜446からなるペプチドに結合し、いくつかの実施形態において、配列番号16のアミノ酸残基75〜96、152〜183、330〜338または542〜571に結合しない、モノクローナル抗体、
6)フェロポーチン(配列番号16)のアミノ酸残基439〜449からなるペプチドに結合するモノクローナル抗体、ならびに
7)約75%以上、約80%以上、または約81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、または95%以上でヒトフェロポーチンに結合するために、抗体31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6のうちのいずれか1つと競合するモノクローナル抗体。
本明細書に記載のモノクローナル抗体をコードし、任意に、核酸を含む、宿主細胞、ベクターおよび宿主細胞によって認識される配列を制御するように作用可能に連結される、単離された核酸、ならびに抗体の産生のための組換え技法も提供し、これには、核酸を発現するように宿主細胞を培養することと、任意に、宿主細胞培養または培地から抗体を回収することを含み得る。
キメラ化またはヒト化抗体は、親齧歯類モノクローナル抗体よりもヒトにおいて免疫原性が少ないため、それらは、過敏症の危険性がはるかに少ないヒトの治療のために使用することができる。したがって、これらの抗体は、ヒトへの生体内投与に関与する治療への適用に企図される。
「ヒト改変(Human Engineered(商標))抗体」という句は、非ヒト抗体、一般的に、齧歯類モノクローナル抗体またはあるいは、キメラ化抗体に由来する抗体を指す。抗体可変ドメインのヒト改変(Human Engineered(商標))は、抗体分子の結合活性を維持しながら、免疫原性を低下させる方法として、Studnickaによって記載されている(例えば、Studnicka et al.米国特許第5,766,886号、Studnicka et al.Protein Engineering 7:805−814,1994を参照のこと)。該方法によると、各可変領域アミノ酸は、置換の危険度が割り当てられる。アミノ酸置換は、3つの危険度カテゴリーの1つによって識別される:(1)低危険度変化は、免疫原性を低下させる最大の潜在的可能性を有し、抗原結合を妨げる可能性が最も低いものである、(2)中危険度変化は、免疫原性をさらに低下させるが、抗原結合またはタンパク質の折り畳みに影響を及ぼす可能性がより大きいものである、(3)高危険度残基は、抗体構造に結合するまたは抗体構造を維持するために重要であり、抗原結合またはタンパク質の折り畳みが影響を受ける危険度が最も高いものである。プロリンの三次元構造上の役割のゆえに、プロリンにおける修飾は、その位置が一般的には低危険度位置である場合でも、一般に少なくとも中危険度変化とみなされる。
フェロポーチンに対する抗体はまた、内因性免疫グロブリンを産生せず、ヒト免疫グロブリン遺伝子座を含むように改変されたトランスジェニック動物を用いて、産生することもできる。例えば、WO98/24893は、ヒトIg遺伝子座を有するトランスジェニック動物を開示しており、該動物は、内因性重鎖および軽鎖遺伝子座の不活性のために機能性内因性免疫グロブリンを産生しない。WO91/741もまた、免疫原に対する免疫応答を開始させることができるトランスジェニック非霊長類哺乳動物宿主を開示しており、該抗体は、霊長類定常および/または可変領域を有し、内因性免疫グロブリンをコードする遺伝子座は置換または不活性化されている。WO96/30498は、修飾抗体分子を形成するために定常または可変領域の全部または一部を置換することのような、哺乳動物における免疫グロブリン遺伝子座を修飾するためのCre/Lox系の使用を開示する。WO94/02602は、不活性化内因性Ig遺伝子座および機能的ヒトIg遺伝子を有する非ヒト哺乳動物宿主を開示する。米国特許第5,939,598号は、マウスが内因性重鎖を欠き、1つ以上の異種定常領域を含む外来性免疫グロブリン遺伝子座を発現するトランスジェニックマウスを作製する方法を開示する。
組換えヒト抗体遺伝子のレパートリーを作製するための技術の開発、および糸状バクテリオファージの表面上でのコードされる抗体フラグメントの提示は、ヒト由来抗体を生成するための別の手段を提供している。ファージディスプレイは、例えば、Dower et al.、WO91/17271、McCafferty et al.、WO92/01047、およびCaton and Koprowski,Proc.Natl.Acad.Sci.USA,87:6450−6454(1990)に記載され、これらのそれぞれは、参照によりその全体が本明細書に組み込まれる。ファージ技術によって産生される抗体は、通常、細菌において抗原結合フラグメント、例えば、FvまたはFabフラグメントとして産生され、したがって、エフェクター機能を欠く。エフェクター機能は、2つの戦略のいずれかによって導入することができる。すなわち、フラグメントを、哺乳動物細胞における発現のために完全抗体に改変するか、またはエフェクター機能誘発することが可能な第2の結合部位を備えた二重特異性抗体フラグメントに改変することができる。
上記のように、抗体フラグメントは、無傷全長抗体の一部分、好ましくは、無傷抗体の抗原結合もしくは可変領域を含み、抗体フラグメントから形成される線状抗体および多重特異性抗体を含む。抗体フラグメントの限定されない例には、Fab、Fab’、F(ab’)2、Fv、Fd、ドメイン抗体(dAb)、相補的決定領域(CDR)フラグメント、単鎖抗体(scFv)、単鎖抗体フラグメント、ダイアボディ、トリアボディ、テトラボディ、ミニボディ、線状抗体、キメラ化組換え抗体、トリボディもしくはバイボディ、細胞内抗体、ナノボディ、小モジュール免疫薬剤(SMIP)、抗原結合ドメイン免疫グロブリン融合タンパク質、ラクダ化抗体、VHH含有抗体、またはこれらの変異タンパク質もしくは誘導体、ならびに抗体が、所望の生物学的活性を保持する限り、CDR配列等のポリペプチドに結合する特異性抗原を与えるのに十分な免疫グロブリンの少なくとも一部分を含有するポリペプチドが含まれる。かかる抗原フラグメントは、全抗体の修正によって産生され得るか、または組換えDNA技法またはペプチド合成を用いて新たに合成され得る。
いくつかの実施形態において、多価またはさらに多重特異性(例えば、二重特異性、三重特異性等)モノクローナル抗体を生成することが望ましいとされ得る。かかる抗体は、標的抗原の少なくとも2つの異なるエピトープに対して結合特異性を有し得る、または代替として、2つの異なる分子、例えば、標的抗原および細胞表面タンパク質もしくは受容体に結合し得る。例えば、二重特異性抗体は、細胞防御機構を標的発現細胞に集中させるために、標的に結合する腕と、T細胞受容体分子(例えば、CD2またはCD3)等の白血球上の引き金分子、またはFcγRI(CD64)、FcγRII(CD32)およびFcγRIII(CD16)等のIgG(FcγR)についてのFc受容体に結合する別の腕を含み得る。別の例として、二重特異性抗体は、細胞傷害性薬を、標的抗原を発現する細胞に局在化させるために使用し得る。これらの抗体は、標的結合腕と、細胞傷害性薬(例えば、サポリン、抗インターフェロン60、ビンカアルカロイド、リシンA鎖、メトトレキサートまたは放射性同位体ハプテン)に結合する腕を有する。多重特異性抗体は、完全長抗体または抗体フラグメントとして調製され得る。
他のフェロポーチン特異的結合剤は、例えば、抗体からのCDRに基づいて、またはヒトフェロポーチンについて所望の結合特性を示すペプチドもしくは化合物のために、種々のペプチドもしくは有機化学化合物のライブラリーをスクリーニングすることによって、調製することができる。フェロポーチン特異的結合剤には、ヒト抗体31A5(配列番号5〜10)、ヒト抗体37A2(配列番号29〜34)、ヒト抗体37B9(配列番号39〜44)、ヒト抗体37C8(配列番号49〜54)、ヒト抗体37G8(配列番号59〜64)、ヒト抗体38A4(配列番号69〜74)、ヒト抗体38C8(配列番号79〜84)、ヒト抗体38D2(配列番号89〜94)、ヒト抗体38E3(配列番号99〜104)、またはヒト抗体38G6(配列番号109〜114)のうちの1つ以上のCDRに、少なくとも80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%もしくはそれ以上同一である、ペプチド含有アミノ酸配列が含まれる。
本発明の抗フェロポーチン抗体は、当業者には公知の技法によって容易に修飾することができる。可能な変異には、1つ以上の残基の挿入、欠失、または置換が含まれる。挿入または欠失は、好ましくは、約1〜5個のアミノ酸の範囲、さらに好ましくは1〜3個、および最も好ましくは1〜2個のアミノ酸である。
(1)疎水性:ノルロイシン、met、ala、val、leu、ile;
(2)中性の親水性:cys、ser、thr;
(3)酸性:asp、glu;
(4)塩基性:asn、gln、his、lys、arg;
(5)鎖配向に影響する残基:gly、pro;および
(6)芳香族:trp、tyr、phe。
ある例において、抗体変異体は、エピトープ結合に直接関与するアミノ酸残基を修飾する目的で、調製される。他の実施形態において、本明細書で論じられる目的のために、エピトープ結合に直接関与しない残基、またはいずれの方法でもエピトープ結合に関与しない残基の修飾が、望ましい。CDR領域および/またはフレームワーク領域のいずれの内の突然変異も、企図される。
親抗体と比較して修飾されたグリコシル化パターンを有する抗体変異体を産生することもでき、例えば、特異的結合剤もしくは抗体に結合する1つ以上の炭水化物部分を付加もしくは欠失させる、および/または特異的結合剤もしくは抗体における1つ以上のグリコシル化を付加もしくは欠失させることにより行われる。
システイン残基は、抗体またはFc含有ポリペプチドのFc領域において除去または導入され得、それによって、この領域における鎖間ジスルフィド結合を排除するか、または増加させる。そのようにして生成されたホモ二量体型特異的結合剤または抗体は、改善された内在化能力および/またはより高い補体媒介性細胞致死作用および抗体依存性細胞傷害作用(ADCC)を有し得る。Caron et al.,J.Exp Med.176:1191−1195(1992)およびShopes,B.J.Immunol.148:2918−2922(1992)を参照のこと。ホモ二量体型特異的結合剤または抗体はまた、Wolff et al.,Cancer Research 53:2560−2565(1993)に記載されるように、ヘテロ二官能性架橋剤を用いて調製され得る。代替として、2つのFc領域を有し、それゆえ高い補体融解およびADCC能力を有し得る特異的結合剤または抗体を作り出すことができる。Stevenson et al.,Anti−CancerDrug Design,3:219−230(1989)を参照のこと。
抗体の共有結合修飾もまた、本発明の範囲内に含まれる。それらは、該当する場合、ポリペプチドもしくは抗体の化学合成によってまたは酵素もしくは化学分解によってなされ得る。共有結合修飾の他のタイプは、標的とされたアミノ酸残基を、選択された側鎖またはNもしくはC末端残基と反応させることが可能な有機誘導体化剤と反応させることによって導入され得る。
本明細書の例示的な抗体を交差遮断する、および/またはフェロポーチン活性を阻害する、フェロポーチンを結合する抗体を同定する方法も提供する。
フェロポーチンを検出するための方法も提供する。試料における、フェロポーチンの存在または不在を決定するために、患者からの生体試料は、免疫複合体を形成させるのに十分な条件下および時間で、本明細書に開示される1つ以上の抗フェロポーチン抗体と接触させる。その後、生体試料内の抗フェロポーチン抗体とフェロポーチンとの間に形成された免疫複合体を検出する。試料内のフェロポーチンの量は、抗体とフェロポーチンとの間に形成された免疫複合体の量を測定することによって定量化される。
フェロポーチンに結合する本明細書に記載の抗体を、それを必要とする対象を治療するために使用することも提供する。例示的な実施形態において、該対象は、鉄ホメオスタシスの障害、ヘプシジンレベルの上昇、ヘプシジン関連障害、アテローム性動脈硬化症または貧血を起こす危険性がある、または罹患している場合がある。
(同一または異なる標的抗原に結合する)2つ以上の抗体とともに混合する、または第2の治療剤と本明細書に記載される抗体と併用して、さらに改善された効力を提供し得ことは、さらに有利である。いくつかの実施形態において、本明細書に記載される方法は、2つ以上の抗フェロポーチン抗体の投与を含む。いくつかの実施形態において、本明細書に記載される方法は、1つ以上の抗フェロポーチン抗体の投与、および任意に、1つ以上の抗ヘプシジン抗体の投与を含む。抗ヘプシジンモノクローナル抗体は、2007年2月2日に出願された米国暫定公開第60/888,059号および2007年12月19日に出願された第61/015,138号にそれぞれ記載されており、これらの開示は、参照することによりそれらの全体が本明細書に組み込まれる。
いくつかの実施形態において、本明細書に記載される方法の施行に使用されるフェロポーチン抗体は、所望の送達方法に好適な担体を含む医薬組成物に製剤化され得る。好適な担体には、フェロポーチン抗体と組み合わせる際、フェロポーチンの高親和性結合を保持し、対象の免疫系と反応しない、任意の材料が含まれる。例には、滅菌リン酸緩衝生理食塩水、静菌水等の多くの標準医薬担体のいずれかが挙げられるが、これらに限定されない。種々の水溶性担体は、例えば、水、緩衝用水、0.4%生理食塩水、0.3%グリシン等が使用され得、かつ低刺激の化学修飾等に供されるアルブミン、リポタンパク質、グロブリン等の強化された安定性のために他のタンパク質を含み得る。
便宜上、本明細書に開示される抗体または特異的結合剤は、キット、即ち、診断または検出圧制を実施するための説明書とともに、パッケージ化された既定の量の試薬の組み合わせに提供される。抗体が酵素で標識化される場合、キットは、酵素によって必要とされる基質および補因子(例えば、検出可能な発色団またはフルオロフォアを提供する、基質の前駆物質)を含む。さらに、安定剤、緩衝剤(例えば、ブロック緩衝剤または溶解緩衝剤)等の、他の添加剤も含まれ得る。種々の試薬の相対量は、アッセイの感度を実質的に最適化する試薬の溶液中の濃度を提供するように、広範に変動し得る。特に、試薬は、溶解の際、適切な濃度を有する試薬溶液を提供する賦形剤を含む、通常、凍結乾燥された、乾燥粉末として提供され得る。
本明細書に開示される抗体は、標的抗原のための親和性精製剤として、または、例えば、特定の細胞(例えば、血球)もしくは組織において、その発現を検出する、標的抗原のための診断アッセイにおいて使用され得る。該抗体は、生体内診断アッセイのためも使用され得る。一般的に、これらの目的上、該抗体は、免疫シンチオグラフィーを使用して、部位を局所化することができるように、放射性核種(111In、99Tc、14C、131I、125I、3H、32Pまたは35S等)で標識化される。
実施例1−遺伝子免疫法による抗フェロポーチンモノクローナル抗体の産生
ヒトフェロポーチン(hFpn)の発現のためのウイルスベクターを、その終止コドンを欠失した後、ヒトフェロポーチンcDNA(配列番号15)の3’末端までのフレームで、PADREペプチドであるAKFVAAWTLKAAA(配列番号24)をコードするDNAを融合することによって、構築した。hFpn−PADRE融合をコードする得られたDNAを、LR再結合反応によって、pAd/CMV/V5−DESTゲートウェイアデノウイルスベクター(Invitrogen V493−20,Carlsbad,CA)に挿入した。アデノウイルスベクターは、293T細胞中で増幅され、CsCl勾配遠心分離によって精製され、Adeno−X Rapid Titer Kit(Cat No 631028,BD Biosciences,CA)によって力価測定された。
追加の抗フェロポーチン抗体は、以下のように生成した。Xenomouse(商標)IgG2κλおよびIgG4κλマウスを、フェロポーチン発現細胞、またはフェロポーチン発現細胞からの膜のいずれかで免疫付与した。簡潔に述べると、IgG4κλおよびIgG2κλマウスは、フェロポーチンを一時的に発現する293T細胞、またはフェロポーチンを発現する293E6細胞からの膜調製物で免疫付与した。抗原を、皮下または腹腔を介して送達した。マウスは、抗フェロポーチン抗体が血清において検出可能となるまで、一定分量の初期抗原を使用して、追加免疫した。最高の抗フェロポーチン力価を有するマウスから細胞採取し、ハイブリドーマを、最初にフェロポーチン発現細胞(実施例4)を使用して、フェロポーチン結合に関し、次いで、鉄反応アッセイ(実施例5)を使用して、機能(フェロポーチン鉄排出活性の持続)に関してスクリーニングした。
フェロポーチンに対する31A5の特異性を確認するために、フェロポーチン発現細胞からの膜調製物を使用して、ウェスタン分析を実施した。
以下の実施例は、ヒト抗体37A2、37B9、37C8、37G8、38A4、38C8、38D2、38E3および38G6についての、エピトープマッピングを説明する。
このアッセイは、フェリチン鉄反応要素に融合したベータラクタマーゼレポータ遺伝子の活性を監視することにより、細胞内鉄レベルの検出を可能にする。フェロポーチン発現細胞における低レベルの細胞内鉄は、活性フェロポーチンを示す一方、高レベルの細胞内鉄は、フェロポーチン活性の低減を示す。ヘプシジンは、フェロポーチンを内在化させ、細胞表面から除去し、したがって、鉄の放出を阻害し、細胞内鉄濃度を上昇させる。この鉄隔離に対する抗ヒトフェロポーチン抗体の効果は、生体外で評価した。
V5エピトープタグをコードするC末端配列を有する、ドキシサイクリン誘導性フェロポーチン(Fpn)発現構築物を含有する293細胞株を構築した。70〜80%コンフルエントな培養物から採ったこれらの293/Fpn−V5細胞を、Poly−Dリジン被覆プレート(Becton−Dickinson Cat#35−6640)内の、DMEM(Invitrogen Cat#11965)、10% FBS(Invitrogen Cat#10099−141)、PSQ(Invitrogen Cat#10378−016)、100μg/mLドキシサイクリン、2.5μg/mLクエン酸酸化鉄、100μL/ウェル(50,000細胞)に、5.0×105細胞/mLでプレートし、終夜もしくは少なくとも20時間、37℃で5% CO2とともに温置した。翌日、媒体をウェルから除去し、DMEM、10% FBS、PSQ、2.5μg/mLクエン酸酸化鉄、37nM組換えヒトヘプシジン、ならびに抗体(2.7、31A5、37A2、37B9、37C8、37G8、38A4、38C8、38D2、および38G6、ならびにmIgG2対照抗体)の段階希釈物(すべて、アッセイプレートへの添加直前に、96ウェルポリプロピレンディープウェルブロックプレートで調製)の予め作製された混合物で置き換えた。混合物を100μL/ウェルで添加し、細胞培養物インキュベータで37℃、5% CO2で終夜温置した。
哺乳類フェロポーチン発現は、十二指腸細胞の側底膜上、および細網内皮系のマクロファージ内で検出されている(Canonne−Hergaux,et al.,Am J Physiol Gastrointest Liver Physiol.,290(1):p.G156−63,2006、Donovan,A.,et al.,Cell Metab,1(3):p.191−200,2005)。31A5を使用して、この発現プロファイルは、IHCによってヒト組織内で確認された(図5Aおよび5B)。
Claims (71)
- フェロポーチン(配列番号16)の細胞外ドメインに結合し、ヘプシジンの存在下でフェロポーチン活性を持続する単離されたモノクローナル抗体であって、フェロポーチンの細胞外ドメインが、配列番号16のアミノ酸394−449および393−449からなる群から選択されるアミノ酸配列を含む、モノクローナル抗体。
- 配列番号5〜10を含むCDR、配列番号29〜34を含むCDR、配列番号69〜74を含むCDRおよび配列番号109〜114を含むCDRからなる群から選択されるCDRを含む、請求項1に記載の単離されたモノクローナル抗体。
- 配列番号2または4と少なくとも90%同一であるアミノ酸配列を含み、前記アミノ酸配列は、配列番号5〜10を含むCDRを含む、請求項1または2に記載のモノクローナル抗体。
- 配列番号26または28と少なくとも90%同一であるアミノ酸配列を含み、前記アミノ酸配列は、配列番号29〜34を含むCDRを含む、請求項1または2に記載のモノクローナル抗体。
- 配列番号66または68と少なくとも90%同一であるアミノ酸配列を含み、前記アミノ酸配列は、配列番号69〜74を含むCDRを含む、請求項1または2に記載のモノクローナル抗体。
- 配列番号106または108と少なくとも90%同一であるアミノ酸配列を含み、前記アミノ酸配列は、配列番号109〜114を含むCDRを含む、請求項1または2に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号4と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号2と少なくとも90%同一であるアミノ酸配列を含む、請求項3に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号28と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号26と少なくとも90%同一であるアミノ酸配列を含む、請求項4に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号68と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号66と少なくとも90%同一であるアミノ酸配列を含む、請求項5に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号108と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号106と90%同一であるアミノ酸配列を含む、請求項6に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号4と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号2と少なくとも90%同一であるアミノ酸配列を含み、CDRが配列番号5〜10のアミノ酸配列を含む、請求項3に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号28と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号26と少なくとも90%同一であるアミノ酸配列を含み、CDRが配列番号29〜34のアミノ酸配列を含む、請求項4に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号68と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号66と少なくとも90%同一であるアミノ酸配列を含み、CDRが配列番号69〜74のアミノ酸配列を含む、請求項5に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号108と少なくとも90%同一であるアミノ酸配列を含み、軽鎖可変領域が配列番号106と90%同一であるアミノ酸配列を含み、CDRが配列番号109〜114のアミノ酸配列を含む、請求項6に記載のモノクローナル抗体。
- 重鎖および軽鎖を含む単離されたモノクローナル抗体であって、前記重鎖が、配列番号14のアミノ酸18〜466を含み、前記軽鎖が、配列番号12のアミノ酸21〜239を含む、抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号4に記載のアミノ酸配列を含み、軽鎖可変領域が配列番号2に記載のアミノ酸配列を含む、請求項3に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号28に記載のアミノ酸配列を含み、軽鎖可変領域が配列番号26に記載のアミノ酸配列を含む、請求項4に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号68に記載のアミノ酸配列を含み、軽鎖可変領域が配列番号66に記載のアミノ酸配列を含む、請求項5に記載のモノクローナル抗体。
- 抗体が、重鎖可変領域および軽鎖可変領域を含み、重鎖可変領域が配列番号108のアミノ酸配列を含み、軽鎖可変領域が配列番号106に記載のアミノ酸配列を含む、請求項6に記載のモノクローナル抗体。
- 配列番号16のアミノ酸393〜449内に位置するヒトフェロポーチンのフラグメントに結合するか、ヒトフェロポーチンのエピトープに結合する、請求項1から19のうちの一項に記載の単離されたモノクローナル抗体。
- 請求項1から20のうちのいずれか一項に記載の単離されたモノクローナル抗体であって、アミノ酸SITPTKIPEI(配列番号16のアミノ酸417〜426)、アミノ酸ITTEIYMSNGSNS(配列番号16のアミノ酸426〜438)およびアミノ酸TEIYMSNGSNSA(配列番号16のアミノ酸428〜439)からなる群から選択される前記ヒトフェロポーチンのフラグメントに結合する単離されたモノクローナル抗体。
- キメラ化、ヒト化、または完全なヒト抗体である、請求項1から21のうちのいずれか一項に記載の単離された抗体。
- キメラ化抗体である、請求項22の単離された抗体。
- ヒト化抗体である、請求項22の単離された抗体。
- 単鎖Fv抗体フラグメントである、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- Fabフラグメント、F(ab’)2フラグメント、Fd、ドメイン抗体(dAb)、ダイアボディ(diabody)、マキシボディ(maxibody)またはナノボディ(nanobody)である、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- 完全なヒト抗体である、請求項22の単離されたモノクローナル抗体。
- ヒトコンセンサス抗体配列、ヒト生殖細胞系抗体配列、またはヒト生殖細胞系コンセンサス抗体配列である、フレームワークアミノ酸配列を含む、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- IgA、IgG、IgE、IgDまたはIgMアイソタイプのものである、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- IgG1、IgG2、IgG3またはIgG4アイソタイプのものである、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- IgG抗体である、請求項1から21のうちのいずれか一項に記載の単離されたモノクローナル抗体。
- 2本の重鎖および2本の軽鎖を含む、請求項31の単離されたモノクローナル抗体。
- 請求項1から21のうちのいずれか一項に記載の抗体をコードする核酸。
- 請求項33の核酸を含むベクター。
- 請求項34のベクターまたは請求項33の核酸を含む宿主細胞。
- 請求項1から21のうちのいずれか一項に記載の抗体を産生する方法であって、(a)非ヒト哺乳動物に、フェロポーチン(配列番号16)をコードする核酸を投与するステップ、任意に(b)前記哺乳動物に、フェロポーチン(配列番号16)をコードする同一または異なる核酸を投与するステップ、任意に(c)前記哺乳動物に、フェロポーチンを発現する細胞膜を含む組成物を投与するステップ、および(d)前記哺乳動物から、抗体を発現する細胞を獲得するステップを含む、方法。
- 核酸を発現させて、抗体を産生するように、請求項35の宿主細胞を培養するステップを含む、請求項1から21のうちのいずれか一項に記載の抗体を産生する方法。
- 宿主細胞培養物から抗体を回収するステップをさらに含む、請求項37の方法。
- 請求項1から21のうちのいずれか一項に記載の抗体、および薬学的に許容可能な担体、賦形剤または希釈剤を含む医薬組成物。
- 生体試料において、フェロポーチンの存在を検出するための方法であって、請求項1から21のうちのいずれか一項に記載のモノクローナル抗体のうちの少なくとも1つとともに、フェロポーチンに前記モノクローナル抗体を結合させることが可能な条件下で、前記生体試料を温置するステップ、および前記結合モノクローナル抗体または前記結合フェロポーチンを検出するステップを含む、方法。
- モノクローナル抗体が、抗体31A5、37A2,38A4または38G6と同一のエピトープに結合する、または、フェロポーチンへの結合に対して、抗体31A5、37A2,38A4または38G6と75%競合する、請求項40の方法。
- フェロポーチンに結合するポリクローナル抗体とともに、前記試料を温置するステップをさらに含む、請求項40の方法。
- モノクローナル抗体が、固体支持体上に固定化される、請求項42の方法。
- ポリクローナル抗体が標識化される、請求項42の方法。
- ポリクローナル抗体が、固体支持体上に固定化される、請求項42の方法。
- モノクローナル抗体が標識化される、請求項43の方法。
- 抗体が、固体支持体上に固定化され、ならびに請求項1から21のうちのいずれか一項に記載の第2の抗体と、フェロポーチンを接触させるステップをさらに含む、請求項40の方法。
- 生体試料がヒトから単離される、請求項40の方法。
- 生体試料が、組織、および血球からなる群から選択される、請求項48の方法。
- 第2の抗体が、固体支持体上に固定化される抗体によって認識されるものとは異なるエピトープを認識する、請求項47の方法。
- 第2の抗体が、標識化される、請求項47の方法。
- 抗体とともに、既知量の精製されたフェロポーチン標準物質を温置するステップを含む、請求項47の方法。
- 鉄ホメオスタシスの障害に罹患する対象を治療するための、請求項1から21のいずれか一項に記載のモノクローナル抗体を含む医薬組成物。
- 鉄ホメオスタシスの障害が、貧血、敗血症、炎症性貧血、癌性貧血、化学療法誘導貧血、慢性炎症性貧血、うっ血性心不全、末期腎疾患、慢性腎臓病(ステージI、II、III、IVまたはV)、鉄欠乏性貧血、フェロポーチン病、ヘモクロマトーシス、糖尿病、炎症、関節リウマチ、動脈硬化症、腫瘍、血管炎、全身性エリテマトーデス、異常血色素症、および赤血球障害からなる群から選択される、請求項53に記載の医薬組成物。
- 前記対象に、赤血球生成刺激剤をさらに含む、請求項53に記載の医薬組成物。
- 赤血球生成刺激剤が、エリスロポエチン、エリスロポエチンの変異体およびエリスロポエチンに結合する抗体からなる群から選択される、請求項55に記載の医薬組成物。
- 鉄ホメオスタシスの障害の治療のための併用療法のための、請求項1から21のうちのいずれか一項に記載の抗体および赤血球生成刺激剤を含む医薬組成物。
- 抗体および赤血球生成刺激剤が、1つの組成物に製剤化される、請求項57に記載の医薬組成物。
- 抗体および赤血球生成刺激剤が、別個の組成物に製剤化される、請求項57に記載の医薬組成物。
- 鉄ホメオスタシスの障害の治療のための併用療法のための、請求項1から21のうちのいずれか一項に記載の抗体および抗ヘプシジン抗体を含む医薬組成物。
- 抗体および抗ヘプシジン抗体が、1つの組成物に製剤化される、請求項60に記載の医薬組成物。
- 抗体および抗ヘプシジン抗体が、別個の組成物に製剤化される、請求項60に記載の医薬組成物。
- エリスロポエチン刺激剤による療法に対して低応答性である対象を治療するための、請求項1から21のうちのいずれか一項に記載の抗体を含む医薬組成物。
- 赤血球生成刺激剤をさらに含む、請求項63に記載の医薬組成物。
- 対象が、貧血、敗血症、炎症性貧血、癌性貧血、化学療法誘導貧血、慢性炎症性貧血、うっ血性心不全、末期腎疾患、慢性腎臓病(ステージI、II、III、IVまたはV)、鉄欠乏性貧血、フェロポーチン病、ヘモクロマトーシス、糖尿病、炎症、関節リウマチ、動脈硬化症、腫瘍、血管炎、全身性エリテマトーデス、異常血色素症、赤血球障害および腎不全からなる群から選択される病態に罹患している、請求項63に記載の医薬組成物。
- 対象が貧血に罹患している、請求項63に記載の医薬組成物。
- 対象がヒトである、請求項63に記載の医薬組成物。
- 赤血球生成刺激剤が、配列番号21のヒトエリスロポエチンである、請求項64に記載の医薬組成物。
- 赤血球生成刺激剤が、配列番号22のダルベポエチンアルファである、請求項64に記載の医薬組成物。
- 静脈切開と併用される、請求項64に記載の医薬組成物。
- 鉄過剰の治療のための併用療法のための医薬組成物であって、請求項1から21のうちのいずれか一項に記載の抗体および鉄キレート剤を含む医薬組成物。
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