JP2013529190A - ヘテロ多量体タンパク質の産生 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C—CHEMISTRY; METALLURGY
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Abstract
Description
本出願は、2010年4月23日に提出された「ヘテロ多量体タンパク質の産生」と題された米国仮特許出願番号61/327302に優先権を主張し、その内容全体が参照により本明細書に組み込まれる。
(a)ヒンジ含有ポリペプチドが発現される条件下で第一のヒンジ含有ポリペプチドをコードする第一の核酸を含む第一の宿主細胞を培養し;
(b)ヒンジ含有ポリペプチドが発現される条件下で第二のヒンジ含有ポリペプチドをコードする核酸を含む第二の宿主細胞を培養し;
(c)第一のヒンジ含有ポリペプチド及び第二のヒンジ含有ポリペプチドが細胞外環境に放出されるように、細胞膜を破壊し、ここで第一の宿主細胞及び第二の宿主細胞が単一の懸濁液中で一緒に組合わされ;
(d)ヘテロ多量体タンパク質を回収する
工程を含み、
ここで、前記方法は還元剤の添加を必要としない。
(a)第一のヘテロ二量体化ドメインを有する精製された第一のヒンジ含有ポリペプチドを提供し;
(b)第二のヘテロ二量体化ドメインを有する精製された第二のヒンジ含有ポリペプチドを提供し;
(c)第一のヒンジ含有ポリペプチドと第二のヒンジ含有ポリペプチドを組合わせ、
(d)第一のヒンジ含有ポリペプチドを第二のヒンジ含有ポリペプチドとともにリフォールディングし、
(d)ヘテロ多量体タンパク質複合体を回収する
工程を含む。
(a)第一の宿主細胞と、少なくとも2つの更なる宿主細胞を培養し、
a. 第一の宿主細胞は、第一のヘテロ二量体化ドメイン含有ポリペプチドをコードする第一の核酸を含み;及び
b. 前記更なる宿主細胞は、第二のヘテロ二量体化ドメイン含有ポリペプチドをコードする核酸を含み、
(b)第一の宿主細胞及び少なくとも2つの更なる宿主細胞を組合わせ;
(c)第一及び第二のヘテロ二量体ドメイン含有ポリペプチドが細胞外環境に放出されるように細胞を処置し、
(d)ヘテロ多量体タンパク質を回収する
工程を含み、
ここで、前記方法は還元剤の添加を必要としない。
ADCC=抗体依存性細胞傷害
API=抗病原体イムノアドヘシン
BPI=殺菌性/透過性増加タンパク質
C1q=補体因子1q
CD=分化のクラスター
CDC=補体依存性細胞傷害
CH1又はCH1=重鎖第一定常ドメイン
CH2又はCH2=重鎖第二定常ドメイン
CH3又はCH3=重鎖第三定常ドメイン
CH4又はCH4=重鎖第四定常ドメイン
CL又はCL=軽鎖定常ドメイン
CLTA=細胞傷害性Tリンパ球関連分子
Fc=結晶化可能断片
FcγR=IgGのFcタンパク質のレセプターガンマ
HIV=ヒト免疫不全ウイルス
ICAM=細胞間接着分子
BsAb=二重特異性抗体
BsDb=二重特異性ダイアボディー
dsFv=ジスルフィド安定化Fv
Fc=抗体の定常ドメイン
Fd=抗体のVH+CH1
FcR=Fcレセプター
Fv=抗体の可変ドメイン
IgG=免疫グロブリンG
mAb=モノクローナル抗体
PBL=末梢血リンパ球
scDB=単鎖ダイアボディ
scFv=単鎖Fv
(scFv)2=scFv−scFvタンデム型
Tandab=タンデムダイアボディ
VH又はVH=抗体の重鎖の可変ドメイン
VL又はVL=抗体の軽鎖の可変ドメイン
本発明は、以下の定義及び実施例を使用する参照によってのみ詳細に説明される。本明細書で言及されるような特許及び刊行物は、そのような特許及び刊行物に開示すべての配列を含み、参照により明示的に援用される。
「ヘテロ多量体」、「ヘテロ多量体複合体」、又は「ヘテロ多量体タンパク質」とは、少なくとも第一のヒンジ含有ポリペプチド及び第二のヒンジ含有ポリペプチドを指し、ここで第二のヒンジ含有ポリペプチドがアミノ酸配列において、第一のヒンジ含有ポリペプチドと少なくとも一つのアミノ酸残基だけ異なる。ヘテロ多量体は、第一及び第二のヒンジ含有ポリペプチドで形成される「ヘテロダイマー」を含むことができ、又は第一及び第二のヒンジ含有ポリペプチドに加えてポリペプチドが存在している高次立体構造を形成することができる。ヘテロ多量体のポリペプチドは、非ペプチド性、共有結合(例えば、ジスルフィド結合)及び/又は非共有結合性相互作用(例えば、水素結合、イオン結合、ファンデルワールス力、及び/又は疎水性相互作用)により相互作用し得る。
[146] 「変異体Fc領域」は、少なくとも1のアミノ酸修飾、好ましくは1以上のアミノ酸置換によって天然配列Fc領域のものとは異なるアミノ酸配列を含む。好ましくは、変異体Fc領域は、天然配列Fc領域と又は親ポリペプチドのFc領域と比較して少なくとも1のアミノ酸置換、例えば、天然配列Fc領域に又は親ポリペプチドのFc領域に約1から約10のアミノ酸置換、および好ましくは約1から約5のアミノ酸置換を有する。本明細書での変異体Fc領域は、好ましくは、天然配列Fc領域との及び/又は親ポリペプチドのFc領域との少なくとも約80%の相同性、ならびに最も好ましくはそれらとの少なくとも約90%の相同性、より好ましくはそれらとの少なくとも約95%、少なくとも約96%、少なくとも約97%、少なくとも約98%、又は少なくとも約99%の相同性を有する。
筋又は他の組織の再灌流損傷、急性炎症性成分を有する皮膚病、急性化膿性髄膜炎又は他の中枢神経系炎症性疾患、眼性及び眼窩の炎症性疾患、顆粒球輸血関連症候群、サイトカイン誘発性毒性、急性重症炎症、慢性難治性炎症、腎盂炎、肺線維症、糖尿病性網膜症、糖尿病性大動脈疾患、動脈内過形成、消化性潰瘍、弁膜炎、及び子宮内膜症などがある。
「副腎皮質ステロイド」は、天然に生じる副腎皮質ステロイドの効果を模倣するかあるいは増大するステロイドの一般的な化学構造を有するいくつかの合成又は天然に生じる物質の何れか一つを指す。合成副腎皮質ステロイドの例として、プレドニゾン、プレドニゾロン(メチルプレドニゾロンを含む)、デキサメサゾン、トリアムシノロン及びベタメサゾンが含まれる。
一般的に、本明細書に記載されるヘテロ多量体タンパク質は、抗体のFc領域の大部分を含む。しかし、他の態様では、重鎖はCH1, CH2ドメイン及び/又はCH3ドメインの部分のみを含む。
ヘテロ多量体タンパク質は、ヘテロ多量体化ドメインを含む。ヘテロ二量体分子の実質的に均一な集団を生成するため、ヘテロ二量体化ドメインは、ホモ二量体よりもヘテロ二量体を形成について強い優先度を持っている必要がある。本明細書に例示されるヘテロ多量体タンパク質は、ヘテロ二量体化を容易にするためノブ・イントゥー・ホール(knob−into−hole)技術を用いるが、当業者は、本発明において有用な他のヘテロ二量体化ドメインを認識するであろう。
多選択性抗体を産生する方法としてのノブ・イントゥー・ホールの使用は当技術分野でよく知られている。Genentechに割り当てられ、1998年3月24日に付与された米国特許第5731168号、Amgenに割り当てられ、2009年7月16日に付与されたPCT公開国際公開第2009089004号、及びNovo Nordisk A/Sに割り当てられ、2009年7月16日に公開された米国特許出願公開第20090182127号を参照。また、Marvin and Zhu, Acta Pharmacologica Sincia (2005) 26(6):649-658及びKontermann (2005) Acta Pharacol. Sin., 26:1-9を参照。簡潔な議論がここに提供される。
本発明のヘテロ多量体タンパク質(例えば、抗体)の組み換え生成のために、コードする核酸を単離して、更なるクローニング(DNAの増幅)又は発現のために複製ベクターに挿入する。抗体をコードするDNAは従来の手順で簡単に単離し、配列決定される(例えば、抗体の重鎖及び軽鎖をコードする遺伝子に特異的に結合することができるオリゴヌクレオチドプローブを用いて)。多くのベクターが利用可能である。用いる宿主細胞にある程度依存してベクターを選択する。一般的に、好適な宿主細胞は原核生物又は真核生物(一般的に哺乳動物であるが、菌類(例えば酵母)、昆虫、植物、および他の多細胞微生物の有核細胞)由来の細胞である。IgG、IgM、IgA、IgD及びIgE定常領域を含め、任意のアイソタイプの定常領域がこの目的のために使われてもよく、このような定常領域はヒト又は動物種の何れかから得られうることは理解されるであろう。
i.ベクター構築
本発明のヘテロ多量体タンパク質(例えば、抗体)のポリペプチド成分をコードしているポリヌクレオチド配列は標準的な組換え技術を使用して得ることができる。所望のポリヌクレオチド配列は、例えば、ハイブリドーマ細胞のような抗体産生細胞から単離し配列決定することができる。あるいは、ポリヌクレオチドはヌクレオチド合成機又はPCR法を使用して合成することができる。ひとたび得られると、ポリペプチドをコードしている配列は原核生物宿主中で異種ポリヌクレオチドを複製し、発現することが可能な組換えベクター中に挿入される。当該分野において入手でき知られている多くのベクターを本発明の目的のために使用することができる。適切なベクターの選択は、主として、ベクターに挿入される核酸のサイズとベクターで形質転換される特定の宿主に依存する。各ベクターは、機能(異種性ポリヌクレオチドの増幅又は発現ないしその両方)及び属する特定の宿主細胞への適合性に応じて、様々な成分を含む。一般的に、限定するものではないが、ベクター成分には複製起源、選択マーカー遺伝子、プロモータ、リボゾーム結合部位(RBS)、シグナル配列、異種性核酸挿入及び転写終末配列が含まれる。
上述した発現ベクターで宿主細胞を形質転換又は形質移入し、プロモーターを誘導し、形質転換体を選択し、又は所望の配列をコードする遺伝子を増幅するのに適するように修飾された通常の栄養培地中で培養する。
一実施態様において、本明細書生産ヘテロ多量体タンパク質は、更なるアッセイ及び用途について、実質的に均質である調製を得るために更に精製される。当分野で公知の標準的なタンパク質精製方法を用いることができる。以下の方法は好適な精製手順の例である:免疫親和性又はイオン交換カラムによる分画化、エタノール沈降法、逆相HPLC、シリカ又はDEAEなどの陽性交換樹脂によるクロマトグラフィ、クロマトフォーカシング、SDS−PAGE、硫酸アンモニウム沈降法及び、例えばSephadex G−75を用いたゲルろ過法。
一般的に、ベクターは、限定するものではないが、以下の一以上を含む:シグナル配列、複製起点、一以上のマーカ遺伝子、エンハンサー因子、プロモータ及び転写終末因子。
真核生物の宿主細胞に用いるベクターはまた、シグナル配列あるいは成熟タンパク質あるいは対象とするポリペプチドのN末端に特異的切断部位を有する他のポリペプチドを含んでいてもよい。好ましく選択された異種シグナル配列は宿主細胞によって認識され加工される(すなわち、シグナルペプチダーゼによって切断される)ものである。哺乳動物細胞での発現においては、哺乳動物のシグナル配列並びにウイルス分泌リーダー、例えば単純ヘルペスgDシグナルが利用できる。このような前駆体領域のDNAは、所望のヘテロ多量体タンパク質(例えば抗体)をコードするDNAに読み取り枠を一致させて結合される。
一般には、哺乳動物の発現ベクターには複製開始点成分は不要である。例えば、SV40開始点は典型的にはただ初期プロモーターを有しているために用いられる。
発現及びクローニングベクターは、選択可能マーカーとも称される選択遺伝子を含む。典型的な選択遺伝子は、(a)アンピシリン、ネオマイシン、メトトレキセートあるいはテトラサイクリンのような抗生物質あるいは他の毒素に耐性を与え、(b)必要があれば栄養要求性欠陥を補い、又は(c)複合培地から得られない重要な栄養素を供給するタンパク質をコードする。
発現及びクローニングベクターは通常は宿主生物体によって認識され、所望のヒンジ含有ポリペプチド(例えば、抗体)核酸に作用可能に結合しているプロモーターを含む。真核生物のプロモーター配列が知られている。実質的に全ての真核生物の遺伝子が、転写開始部位からおよそ25ないし30塩基上流に見出されるATリッチ領域を有している。多数の遺伝子の転写開始位置から70ないし80塩基上流に見出される他の配列は、Nが任意のヌクレオチドであるCNCAAT領域である。大部分の真核生物遺伝子の3'末端には、コード配列の3'末端へのポリA尾部の付加に対するシグナルであるAATAAA配列がある。これらの配列は全て真核生物の発現ベクターに適切に挿入される。
より高等の真核生物による所望のヒンジ含有ポリペプチド(例えば、抗体)をコードしているDNAの転写は、ベクター中にエンハンサー配列を挿入することによってしばしば増強されうる。哺乳動物遺伝子由来の多くのエンハンサー配列が現在知られている(例えばグロビン、エラスターゼ、アルブミン、α-フェトプロテイン及びインスリン遺伝子)。また、真核細胞ウィルス由来のエンハンサーが用いられてよい。例としては、複製起点の後期側のSV40エンハンサー(100−270塩基対)、サイトメガロウィルス初期プロモーターエンハンサー、複製起点の後期側のポリオーマエンハンサー及びアデノウィルスエンハンサーが含まれる。真核生物プロモーターの活性化を亢進するのための因子の記載については、Yaniv, Nature, 297:17-18 (1982)もまた参照のこと。エンハンサーは、抗体ポリペプチドコード配列の5'又は3'位でベクター中にスプライシングされうるが、亢進されるのであれば、一般にプロモーターから5'位に位置している。
また、真核生物宿主細胞に用いられる発現ベクターは、典型的には、転写の終結及びmRNAの安定化に必要な配列を含む。このような配列は、真核生物又はウィルスのDNA又はcDNAの5'、時には3'の非翻訳領域から一般に取得できる。これらの領域は、抗体をコードしているmRNAの非翻訳部分にポリアデニル化断片として転写されるヌクレオチドセグメントを含む。一つの有用な転写終結成分はウシ成長ホルモンポリアデニル化領域である。国際公開第94/11026号とそこに開示された発現ベクターを参照のこと。
ここに記載のベクター中のDNAをクローニングあるいは発現させるために適切な宿主細胞は、脊椎動物の宿主細胞を含む本明細書中に記載の高等真核生物細胞を含む。培養(組織培養)中での脊椎動物細胞の増殖は常套的な手順になっている。有用な哺乳動物宿主株化細胞の例は、SV40によって形質転換されたサル腎臓CV1株 (COS-7, ATCC CRL1651);ヒト胚腎臓株(293又は懸濁培養での増殖のためにサブクローン化された293細胞、Graham等, J. Gen Virol., 36:59 (1977));ハムスター乳児腎細胞(BHK, ATCC CCL10);チャイニーズハムスター卵巣細胞/-DHFR(CHO, Urlaub等, Proc. Natl. Acad. Sci. USA, 77:4216 (1980));マウスのセルトリ細胞(TM4, Mather, Biol. Reprod., 23:243-251 (1980));サルの腎細胞 (CV1 ATCC CCL70); アフリカミドリザルの腎細胞(VERO-76, ATCC CRL-1587);ヒト子宮頸癌細胞 (HELA, ATCC CCL2);イヌ腎細胞 (MDCK, ATCC CCL34);バッファローラット肝細胞 (BRL3A, ATCC CRL1442);ヒト肺細胞 (W138, ATCC CCL75);ヒト肝細胞 (Hep G2, HB8065);マウス乳房腫瘍細胞 (MMT060562, ATCC CCL51);TRI細胞(Mather等, Annals N.Y. Acad. Sci., 383:44-68 (1982));MRC5細胞;FS4細胞;及びヒト肝癌株(HepG2)である。
本発明の所望のヒンジ含有ポリペプチド(例えば、抗体)を産生するために用いられる宿主細胞は種々の培地において培養することができる。市販培地の例としては、ハム(Ham)のF10(シグマ)、最小必須培地((MEM),(シグマ)、RPMI-1640(シグマ)及びダルベッコの改良イーグル培地((DMEM),シグマ)が宿主細胞の培養に好適である。また、Ham等, Meth. Enz. 58:44 (1979), Barnes等, Anal. Biochem. 102:255 (1980), 米国特許第4767704号;同4657866号;同4927762号;同4560655号;又は同5122469号;国際公開第90/03430号;国際公開第87/00195号;又は米国再発行特許第30985号に記載された何れの培地も宿主細胞に対する培地として使用できる。これらの培地には何れもホルモン及び/又は他の成長因子(例えばインシュリン、トランスフェリン、又は表皮成長因子)、塩類(例えば、塩化ナトリウム、カルシウム、マグネシウム及びリン酸塩)、バッファー(例えばHEPES)、ヌクレオチド(例えばアデノシン及びチミジン)、抗生物質(例えば、GENTAMYCINTM薬)、微量元素(最終濃度がマイクロモル範囲で通常存在する無機化合物として定義される)及びグルコース又は等価なエネルギー源を必要に応じて補充することができる。任意の他の必要な補充物質もまた当業者に知られている適当な濃度で含むことができる。培養条件、例えば温度、pH等々は、発現のために選ばれた宿主細胞について過去に用いられているものであり、当業者には明らかであろう。
組換え技術を用いる場合、ヒンジ含有ポリペプチドは細胞内で生成され、又は培地内に直接分泌される。ヒンジ含有ポリペプチドが細胞内に生成された場合、第1の工程として、宿主細胞か溶解された断片の何れにしても、粒子状の細片が、例えば遠心分離又は限外ろ過によって除去される。ヒンジ含有ポリペプチドが培地に分泌された場合は、そのような発現系からの上清を、一般的には先ず市販のタンパク質濃縮フィルター、例えばAmicon又はPelliconの限外ろ過装置を用いて濃縮する。PMSFなどのプロテアーゼ阻害剤を上記の任意の工程に含めて、タンパク質分解を阻害してもよく、また抗生物質を含めて外来性の汚染物の成長を防止してもよい。
組み換えバキュロウイルスは、スポドプテラ・フルギペルダ細胞(例えばSf9細胞;ATCC CRL1711)またはキイロショウジョウバエS2細胞のような昆虫細胞に抗体ないし抗体断片とBaculoGoldTMウイルスDNA(Pharmingen)をコードするプラスミドを、例えばリポフェクチン(GIBCO−BRLから市販されている)を使用して同時形質移入することによって作製されうる。具体的な例では、抗体配列は、バキュロウイルス発現ベクター内に含有されるエピトープ標識の上流で融合する。このようなエピトープ標識はポリ−Hisタグを含む。pVL1393(Novagen)又はpAcGP67B(Pharmingen)といった市販のプラスミド由来のプラスミドを含め、様々なプラスミドが使用されてよい。簡単に言うと、抗体ないしその断片をコードする配列は、5’および3’領域に相補的なプライマーによるPCRによって増幅されうる。5’プライマーは、隣接(選択した)制限酵素部位を組み込んでよい。次いで、生成物を選択した制限酵素にて消化し、発現ベクターにサブクローニングしてよい。
完全なヘテロ多量体タンパク質の形成は、本発明において再フォールディングと呼ばれている、ジスルフィド結合の形成により第一のヒンジ含有ポリペプチド及び第二のヒンジ含有ポリペプチドの再構築が含まれる。再フォールディングは、第一のヒンジ含有ポリペプチドの第二のヒンジ含有ポリペプチドとの会合、及び鎖間ジスルフィド結合の形成を含む。再フォールディングはまた、再生とも呼ばれ、本発明においては還元剤を添加せずにインビトロで行われる。
本発明のヘテロ多量体タンパク質によって標的化されうる分子の例には、限定するものではないが、可溶性血清タンパク質およびそのレセプターおよび他の膜結合タンパク質(例えばアドヘシン)が含まれる。
本発明のヘテロ多量体タンパク質は、当該分野で公知の種々のアッセイにより、それらの物理的/化学的性質及び生物学的機能について特徴づけることができる。
また、本発明は、本明細書中に記載のヘテロ多量体タンパク質(例えば本明細書において記述される方法に従って作製される抗体)の何れかを含む、コンジュゲート抗体又はイムノコンジュゲート(例えば「抗体-薬剤コンジュゲート」又は「ADC)といったコンジュゲートされたタンパク質であって、このとき軽鎖または重鎖の定常領域のうちの一つが、色素又は細胞障害性剤、例えば化学療法剤、薬剤、増殖阻害性剤、毒素(例えば細菌、真菌、植物又は動物の起源の酵素的に活性な毒素ないしその断片)又は放射性同位体(すなわち放射性コンジュゲート)のような化学的分子にコンジュゲートしている、コンジュゲートされたタンパク質を提供する。特に、本明細書に記述されるように、ヘテロ多量体化ドメインの使用により2の異なる重鎖(HC1およびHC2)並びに2の異なる軽鎖(LC1およびLC2)を含有する抗体の構築が可能となる。本明細書に記述される方法を用いて構築されるイムノコンジュゲートは、重鎖のうちの一つ(HC1又はHC2)又は軽鎖のうちの一つ(LC1又はLC2)の定常領域にコンジュゲートした細胞障害性剤を含有してよい。また、イムノコンジュゲートがただ一つの重鎖または軽鎖に接着した細胞障害性剤を有しうるので、被検体に投与される細胞障害性剤の量は、重鎖と軽鎖の両方に接着した細胞障害性剤を有する抗体の投与と比較して低い。被検体に投与される細胞障害性剤の量を減らすことは、細胞障害性剤と関係する副作用を制限する。
いくつかの実施態様では、イムノコンジュゲートは一又は複数のメイタンシノイド分子と結合している本発明の抗体(完全長又は断片)を含んでなる。
いくつかの実施態様では、イムノコンジュゲートは、ドラスタチン又はドロスタチンペプチジル類似体及び誘導体、アウリスタチン(auristatin)(米国特許第5635483号;同第5780588号)にコンジュゲートした本発明の抗体を含んでなる。ドラスタチン及びアウリスタチンは、微小管動態、GTP加水分解及び核と細胞の分割を妨げ(Woyke 等 (2001) Antimicrob. Agents and Chemother. 45(12): 3580-3584)、抗癌活性(米国特許第5663149号)及び抗真菌性活性(Pettit 等 (1998) Antimicrob. Agents Chemother. 42:2961-2965)を有することが示されている。ドラスタチン又はアウリスタチン薬剤成分は、ペプチジル薬剤分子のN(アミノ)末端又はC(カルボキシル)末端により抗体に接着しうる(国際公開公報02/088172)。
他の実施態様では、イムノコンジュゲートは、一又は複数のカリケアマイシン分子と結合した本発明の抗体を含んでなる。抗生物質のカリケアマイシンファミリーはサブ-ピコモルの濃度で二重鎖DNA破壊を生じることができる。カリケアマイシンファミリーのコンジュゲートの調製については、米国特許第5712374号、同5714586号、同5739116号、同5767285号、同5770701号、同5770710号、同5773001号、同5877296号(全て、American Cyanamid Company)を参照のこと。使用可能なカリケアマイシンの構造類似体には、限定するものではないが、γ1 I、α2 I、α3 I、N-アセチル-γ1 I、PSAG及びθI 1(Hinman等, Cancer Research, 53:3336-3342(1993)、Lode等 Cancer Research, 58:2925-2928(1998)及び上述したAmerican Cyanamidの米国特許)が含まれる。抗体が結合可能な他の抗腫瘍剤は、葉酸代謝拮抗薬であるQFAである。カリケアマイシン及びQFAは双方共、細胞内に作用部位を有し、原形質膜を容易に通過しない。よって抗体媒介性インターナリゼーションによるこれらの薬剤の細胞への取込により、細胞障害効果が大きく向上する。
本発明の抗体またはここに記載の方法に従って作製された抗体と結合可能な他の抗腫瘍剤には、BCNU、ストレプトゾイシン、ビンクリスチン及び5−フルオロウラシル、米国特許第5053394号、同5770710号に記載されており、集合的にLL−E33288複合体として公知の薬剤のファミリー、並びにエスペラマイシン(esperamicine)(米国特許第5877296号)が含まれる。
本発明のコンジュゲート抗体において、抗体を、場合によってリンカーを介して、一つ以上の薬剤部分(例えば薬剤部分)、例えば抗体につき約1〜約20の部分にコンジュゲートする。コンジュゲート抗体はいくつかの手段、当業者に公知の有機化学反応、状態及び試薬を用いて調製されうる:(1)共有結合による二価のリンカー試薬と抗体の求核基との反応の後に対象の部分と反応;及び(2)共有結合による二価のリンカー試薬と部分の求核基との反応の後に抗体の求核基との反応、が含まれる。コンジュゲート抗体を調製するための更なる方法は本願明細書中に記載される。
本明細書にて与えられる本方法は、ヘテロ多量体タンパク質の生産において産業上の利用可能性を見いだしている。本発明の方法は、2つの別々な発酵において固有の技術的な難しさがあるため、2つの別々な発酵と単離に必要な作業の量を減らす。更に、従来の方法の手順のアニーリング(annealment)と酸化還元工程の排除は、収量を上げ、処理の複雑さとコストを削減することができる。
本明細書に記載の抗体又は抗体断片などのヘテロ多量体タンパク質(例えば本明細書に記述される方法に従って作製される抗体及び/又はその断片)は、治療上の適用のために使われてよい。例えば、このようなヘテロ多量体タンパク質は、前癌性、非転移性、転移性および癌性の腫瘍(例えば初期癌)を含む腫瘍の治療のため、アレルギー性または炎症性の疾患の治療のため、または自己免疫性疾患の治療のため、または、癌(例えば乳癌、結腸直腸癌、肺癌、腎臓細胞カルチノーマ、膠腫又は卵巣癌)、アレルギー性または炎症性の疾患又は自己免疫性疾患を発症するリスクがある被検体の治療のために使われてよい。
灌流損傷、急性炎症性成分を有する皮膚病、急性化膿性髄膜炎又は他の中枢神経系炎症性疾患、眼性及び眼窩の炎症性疾患、顆粒球輸血関連症候群、サイトカイン誘発性毒性、急性重症炎症、慢性難治性炎症、腎盂炎、肺線維症、糖尿病性網膜症、糖尿病性大動脈疾患、動脈内過形成、消化性潰瘍、弁膜炎、及び子宮内膜症などがある。
本発明のタンパク質は、良好な医療行為に一致した形で処方され、投与量が決められ、投与される。この場合に考慮される因子には、治療されている特定の疾患、治療されている特定の哺乳動物、個々の被検体の臨床症状、疾患の原因、薬剤の送達部位、投与方法、投与スケジュール、及び医師に知られている他のファクターが含まれる。投与されるタンパク質の「治療上有効量」は、このような考慮によって調整され、特定の疾患(例えば癌、アレルギーないし炎症性疾患または自己免疫性疾患)を予防するか、改善するかまたは治療するために必要な最小限量である。タンパク質は、必ずしもそうする必要はないが、場合によっては、疾患の予防又は治療のために現在使用されている一又は複数の薬剤と共に処方される。かかる他の薬剤の有効量は、製剤中に存在するタンパク質の量、疾患又は治療のタイプ、及び上で検討した他の因子に依存する。これらは、一般に、これまで使用されたものと同じ用量及び投与経路で、あるいはこれまで用いられた投薬量の約1から99%で使用される。一般に、癌の寛解又は治療は、癌と関係する一又は複数の症状又は医学的な問題を少なくすることを伴う。治療上有効な量の薬剤によって、以下の何れか又はいくつかが達成される。癌細胞数の(少なくとも10%、20%、30%、40%、50%、60%、70%、80%、90%又は100%以上の)減少;腫瘍サイズ又は腫瘍負担の低減又は阻害;周辺臓器への癌細胞の浸潤の阻害(すなわちある程度の減少及び/又は停止);腺腫の場合のホルモン分泌の低減;血管密度の低減;腫瘍転移の阻害;腫瘍増殖の低減又は阻害;及び/又は、癌関連の一又は複数の症状のある程度の軽減。ある実施態様では、タンパク質を用いて、被検体の癌又は自己免疫性疾患の発症又は再発を防ぐ。
本発明の他の実施態様は、本明細書中に記載の一又は複数のタンパク質複合体と疾患(例えば自己免疫性疾患または癌)の治療または診断に有用な材料を具備する製造品である。製造品は、容器と容器上ないしは容器に付随するラベルないしはパッケージ挿入物を具備する。適切な容器には、例えば瓶、バイアル、注射器などが含まれる。容器は、ガラス又はプラスチックのような様々な材料から形成されてよい。容器は、症状の治療に有効である組成物を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針により貫通可能なストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも一つの活性薬剤は本発明のヘテロ多量体タンパク質(例えば、抗体又は抗体断片)である。ラベル又はパッケージ挿入物は、組成物が特定の疾患の治療に用いられることを示す。ラベル又はパッケージ挿入物は更に、ヘテロ多量体タンパク質の組成物を被検体に投与するための指示を含む。また、本明細書中に記載の併用用治療を含む製造品及びキットも考慮される。
実施例1:
発現ベクターの構築
別々の細胞培養を用いるヘテロ多量体タンパク質の生産
以下の例では、単量体成分を発現する細胞を別々の培養において増殖させるヘテロ多量体タンパク質の産生を示す。この方法では、別々の培養において半抗体を発現するように細胞を増殖し、誘導する。一つの方法では、宿主細胞培養液は、タンパク質精製の前に組み合わせることができる。別の方法では、その成分を最初に精製し、その後ヘテロ多量体タンパク質を形成するために組み合わせ得る。
方法1−インタクトなBsAbを形成するための、半抗体の別々の培養、別々の精製、混合及び酸化還元による、ノブ半抗体及びホール半抗体の独立した産生。
単一混合細胞培養を用いたヘテロ多量体タンパク質の生産
この例では、2つの宿主細胞の集団を含む培養物からのヘテロ多量体タンパク質の形成を示し、ここで該プロセスにおいて還元は添加しない。
ヘテロ多量体タンパク質ライブラリー
この例では、ヘテロ多量体タンパク質ライブラリーの構成を示している。
いくつかのケースでは二重特異性抗体の選択は知られていないが、多くの異なる半抗体の組み合わせの結果であるかもしれない。あるいは、特定の標的の組み合わせ、例えば、抗IL−4/抗IL−13が望まれるが、中から選択される数多くの候補の半抗体が存在する。最良の結合又は効果をもたらす特定の半抗体の組み合わせを見つけることは、マトリックス形式で半抗体を組み合わせることによって達成することができ、多くの二重特異性抗体変異体を迅速に生成することができる。この実験では、抗CD3などの抗体は、スクリーニングのために必要な抗体の量の約10倍(またはそれ以上)過剰で産生することができる。この分子は、その後アニールし、例1に記載された手順を用いて酸化することができる。第一の抗体の総量の約10分の1は、図10に図解したように、異なる抗原(例えば、抗CD19、抗CD20、等)を標的とする約10の半抗体の等しい量と組合わせるために使用できる。更なる一次半抗体が、第二の半抗体レパートリーと組み合わせるために必要とされる場合に、これは、一組のスクリーニング分子を生成するために行うことができる。
一次半抗体は、半抗体が結合した他の抗体のすべてを結合するのに十分な量で、この半抗体を産生することからなる方法で半抗体と提携する代替の宿主と組み合わせることができる。バルクアニーリングは、一次半抗体が重鎖のノブ型またはホール型のいずれかであって、二次標的半抗体の組が相補的変異体であるように、単一の反応で実行できる。ここでは、抗体の複合体混合物を、組合わせとして疾患を治療することに有用であり得るように産生することができる。
インビトロでの活性
この例では本明細書に記載の二重特異性抗体はインビトロ系での活性を有する。二つの細胞株はが、この実施例5および以下の実施例6で用いられた。これらの実験では、KP4、膵管癌細胞株、及びA431、表皮癌細胞株は、それぞれ強くMetまたはEGFRによって駆動され、従って、これらは、各標的に対して独立してbsAbの有効性を探るために良好な細胞株及び腫瘍異種移植片である。
インビボでの活性
この例では、本明細書に記載の二重特異性抗体はインビボモデルでの活性を有することを示す。
腫瘍サイズ(mm3)=(長い測定×短い測定2)×0.5
グループパーセントの体重変化=(新しい重量−初期重量)/初期重量)×100
%TGI=100x(1−AUC用量/AUCビヒクル)
CHO細胞培養を用いたヘテロ多量体タンパク質の生産
この例では、2つの宿主CHO細胞集団を含む培養液からのヘテロ多量体タンパク質の形成を示す。
多重特異性抗体を産生する方法としてのノブ・イントゥー・ホールの使用は当技術分野でよく知られている。Genentechに割り当てられ、1998年3月24日に付与された米国特許第5731168号、Amgenに割り当てられ、2009年7月16日に付与されたPCT公開国際公開第2009089004号、及びNovo Nordisk A/Sに割り当てられ、2009年7月16日に公開された米国特許出願公開第20090182127号を参照。また、Marvin and Zhu, Acta Pharmacologica Sincia (2005) 26(6):649-658及びKontermann (2005) Acta Pharmacol. Sin., 26:1-9を参照。簡潔な議論がここに提供される。
Claims (89)
- 第一のヘテロ二量体化ドメインを有する第一のヒンジ含有ポリペプチド、及び第二のヘテロ二量体化ドメインを有する第二のヒンジ含有ポリペプチドを含むヘテロ多量体タンパク質を調製する方法であって、第二のヘテロ二量体化ドメインが第一のヘテロ二量体化ドメインと相互作用し、及び第一及び第二のヒンジ含有ポリペプチドが少なくとも一の鎖間ジスルフィド結合により連結されており、該方法が、
(a)ヒンジ含有ポリペプチドが発現される条件下で第一のヒンジ含有ポリペプチドをコードする第一の核酸を含む第一の宿主細胞を培養し;
(b)ヒンジ含有ポリペプチドが発現される条件下で第二のヒンジ含有ポリペプチドをコードする核酸を含む第二の宿主細胞を培養し;
(c)第一及び第二の宿主細胞の細胞膜を破壊し、第一及び第二の宿主細胞が単一の懸濁液中で一緒に混合され、及び
(d)ヘテロ多量体タンパク質を回収する
工程を含み、
前記方法は還元剤の添加を必要としない方法。 - 第一のヘテロ二量体化ドメインを有する第一のヒンジ含有ポリペプチド、及び第二のヘテロ二量体化ドメインを有する第二のヒンジ含有ポリペプチドを含むヘテロ多量体タンパク質を含むヘテロ多量体タンパク質を調製する方法であって、第二のヘテロ二量体化ドメインが第一のヘテロ二量体化ドメインと相互作用し、及び第一及び第二のヒンジ含有ポリペプチドが少なくとも一の鎖間ジスルフィド結合により連結されており、該方法が、
(a)第一のヘテロ二量体化ドメインを有する精製された第一のヒンジ含有ポリペプチドを提供し;
(b)第二のヘテロ二量体化ドメインを有する精製された第二のヒンジ含有ポリペプチドを提供し;
(c)第一のヒンジ含有ポリペプチドと第二のヒンジ含有ポリペプチドを組合わせ、
(d)単離されたポリペプチドの多量体化を可能にする条件下で、第一のヒンジ含有ポリペプチドを第二のヒンジ含有ポリペプチドとともにインビトロでリフォールディングし、
(e)ヘテロ多量体タンパク質複合体を回収する
工程を含む方法。 - 第一のヘテロ二量体化ドメインと第二のヘテロ二量体化ドメインが界面で接触し、及び第二のヘテロ二量体化ドメインのインターフェイシング部分が、第一のヘテロ二量体化ドメインのインターフェイシング部分の空洞内に配置可能である突起を含む、請求項1又は2に記載の方法。
- 第二のヘテロ二量体化ドメインが突起を含むFcポリペプチドであるか、又は第一のヘテロ二量体化ドメインが空洞を含むFcポリペプチドであるか、又はその両方である、請求項1又は2に記載の方法。
- 第一のFcポリペプチドと第二のFcポリペプチドが界面で接触し、第二のFc融合ポリペプチドの界面が、第一のFcポリペプチドの界面にある空洞内に配置可能である突起を含み、及び空洞又は突起又はその両方がそれぞれ、第一及び第二のFcポリペプチドの界面中に導入されている、請求項1又は2に記載の方法。
- 第一のヘテロ二量体化ドメイン及び第二のヘテロ二量体化ドメインがロイシンジッパーを含む、請求項1又は2に記載の方法。
- 第一のヘテロ二量体化ドメイン及び第二のヘテロ二量体化ドメインがコイルドコイルを含む、請求項1又は2に記載の方法。
- 鎖間ジスルフィド結合が、抗体のヒンジ領域にある、請求項1又は2に記載の方法。
- 前記鎖間ジスルフィド結合が、ヒンジ領域間である、請求項1又は2に記載の方法。
- 前記ジスルフィド結合が、分子間である、請求項1又は2に記載の方法。
- 前記分子間ジスルフィド結合が、2つの免疫グロブリンのヒンジ含有ポリペプチド鎖のシステイン間である、請求項1又は2に記載の方法。
- ヒンジ含有ポリペプチドが、CHドメイン又はその変異体を含む、請求項1又は2に記載の方法。
- ヒンジ含有ポリペプチドが、Fc領域又はその変異体を含む、請求項1又は2に記載の方法。
- 第一のヒンジ含有ポリペプチドが抗体の重鎖である、請求項1又は2に記載の方法。
- 第二のヒンジ含有ポリペプチドが抗体の重鎖である、請求項1又は2に記載の方法。
- 第一のヒンジ含有ポリペプチドが抗体の軽鎖と対合した抗体の重鎖である、請求項1又は2に記載の方法。
- 第二のヒンジ含有ポリペプチドが抗体の軽鎖と対合した抗体の重鎖である、請求項1又は2に記載の方法。
- ヒンジ含有ポリペプチドが抗体の軽鎖ポリペプチドと対合して標的結合アームを形成する、請求項16又は17に記載の方法。
- ヒンジ含有ポリペプチドがヒトCH2及び/又はCH3ドメインの少なくとも一部分を含む、請求項1又は2に記載の方法。
- ヒンジ含有ポリペプチドと軽鎖ポリペプチドの片方対又は両方の対がヒト化されている、請求項1又は2に記載の方法。
- ヒンジ含有ポリペプチドと軽鎖ポリペプチドが、別個の発現プラスミド上にコードされている、請求項1に記載の方法。
- ヒンジ含有ポリペプチドと軽鎖ポリペプチドが、同じ発現プラスミド上にコードされている、請求項1に記載の方法。
- 宿主細胞が、原核細胞、真核細胞、哺乳動物細胞、植物細胞からなる群から選択される、請求項1に記載の方法。
- 宿主細胞が原核細胞である、請求項1に記載の方法。
- 前記原核細胞が大腸菌細胞である、請求項24に記載の方法。
- 前記大腸菌細胞がlpp欠損である、請求項25に記載の方法。
- 宿主細胞が哺乳動物細胞である、請求項1に記載の方法。
- 前記哺乳動物細胞がCHO細胞である、請求項27に記載の方法。
- 第一の宿主細胞と第二の宿主細胞は別の細胞培養にある、請求項1に記載の方法。
- 工程(a)及び(b)の細胞が両方の宿主細胞を含む混合培養にある、請求項1に記載の方法。
- 工程(a)及び(b)の細胞が組合わされ、遠心分離され、細胞膜を破壊する前に緩衝液に再懸濁される、請求項29に記載の方法。
- 工程(a)及び(b)の細胞が遠心分離され、細胞膜を破壊する前に組合わされる、請求項29に記載の方法。
- 細胞膜を破壊することが、細胞膜を透過処理すること及び細胞膜の崩壊からなる群から選択される、請求項1に記載の方法。
- 細胞膜を破壊することが、細胞溶解、超音波処理、浸透圧ショック、マイクロフルイダイザーの通過、EDTAの添加、種々の界面活性剤、溶媒(例えば、トルエン、ジメチルスルホキシド等)、界面活性剤(例えば、トリトン−X100、Tween 20等)、低張緩衝液、凍結/解凍技術の使用、エレクトロポレーション、ステンレス鋼のボールホモジナイザーの通過からなる群から選択される、請求項1に記載の方法。
- 回収工程が、少なくとも一つの精製工程を更に含む、請求項1又は2に記載の方法。
- (a)プロテインAを含むカラム上で前記抗体を捕獲し、
(b)前記抗体を前記カラムから溶出し、及び
(c)前記溶出された抗体をカオトロピック剤又は中性界面活性剤を含有する溶液に希釈する
工程を更に含む、請求項1又は2に記載の方法。 - ヘテロ多量体タンパク質が、抗体、二重特異性抗体、多選択性抗体、ワンアームド抗体、多選択性一価抗体、二重特異性マキシボディ、モノボディ、イムノアドヘシン、ペプチボディ、二重特異性ペプチボディ、一価ペプチボディ、及び抗体からなる群から選択される、請求項1又は2に記載の方法。
- ヘテロ多量体タンパク質が抗体である、請求項37に記載の方法。
- ヘテロ多量体タンパク質が二重特異性抗体である、請求項37に記載の方法。
- ヘテロ多量体タンパク質が多選択性抗体である、請求項37に記載の方法。
- ヘテロ多量体タンパク質がワンアームド抗体である、請求項37に記載の方法。
- 前記抗体が、重鎖定常ドメイン及び軽鎖定常ドメインを含む、請求項37に記載の方法。
- 前記抗体がヒト化されている、請求項37に記載の方法。
- 抗体が全長抗体である、請求項37に記載の方法。
- 前記全長抗体が、重鎖及び軽鎖を含む、請求項44に記載の方法。
- 重鎖ポリペプチドと軽鎖ポリペプチドの片方又は両方の対がヒト型である、請求項16又は17に記載の方法。
- 前記抗体がヒト型である、請求項37に記載の方法。
- 前記抗体が、ヒトCH2及び/又はCH3ドメインの少なくとも一部分を含む抗体断片である、請求項37に記載の方法。
- 前記抗体断片がFc融合ポリペプチドである、請求項48に記載の方法。
- 抗体が、IgG、IgA及びIgDからなる群から選択される、請求項37に記載の方法。
- 抗体がIgGである、請求項50に記載の方法。
- 抗体がIgG1である、請求項51に記載の方法。
- 抗体がIgG2である、請求項51に記載の方法。
- 抗体が治療用抗体である、請求項37に記載の方法。
- 抗体がアゴニスト抗体である、請求項37に記載の方法。
- 抗体がアンタゴニスト抗体である、請求項37に記載の方法。
- 抗体が診断用抗体である、請求項37に記載の方法。
- 抗体が遮断抗体である、請求項37に記載の方法。
- 抗体が中和抗体である、請求項37に記載の方法。
- 抗体が腫瘍抗原に結合することができる、請求項37に記載の方法。
- 腫瘍抗原が細胞表面分子でない、請求項60に記載の方法。
- 腫瘍抗原がクラスター分化因子でない、請求項60に記載の方法。
- 抗体がクラスター分化因子に結合することができる、請求項37に記載の方法。
- 抗体が細胞生存調節因子に結合することができる、請求項37に記載の方法。
- 抗体が細胞増殖調節因子に特異的に結合することができる、請求項37に記載の方法。
- 抗体が組織発達又は分化に関連する分子に結合することができる、請求項37に記載の方法。
- 抗体が細胞表面分子に結合することができる、請求項37に記載の方法。
- 抗体がリンホカインに結合することができる、請求項37に記載の方法。
- 第一の対及び第二の対の軽鎖が異なる可変ドメイン配列を含む、請求項37に記載の方法。
- 少なくとも45%のポリペプチドが前記二重特異性抗体を形成する、請求項37に記載の方法。
- 前記二重特異性抗体が2つの標的分子に特異的に結合することができる、請求項39に記載の方法。
- 第一のアームが第一の標的分子に特異的に結合し、及び第二のアームが第二の標的分子に特異的に結合する、請求項71に記載の方法。
- 少なくとも45%のポリペプチドが、第一のヒンジ含有ポリペプチド及び軽鎖対及び第二のヒンジ含有ポリペプチド及び軽鎖対を含む複合体の状態である、請求項1又は2に記載の方法。
- 抗体を精製する工程の前に、わずか10の単離されたポリペプチドが単量体又はホモ二量体として存在する、請求項1又は2に記載の方法。
- 第一の対及び第二の対の軽鎖が異なる可変ドメイン配列を含む、請求項71に記載の方法。
- 第一及び第二の重鎖の対の各々が、お互いにジスルフィド結合した重鎖及び軽鎖を含む、請求項71に記載の方法。
- 第一の対及び第二の対の間のpI値の違いが少なくとも0.5である、請求項71に記載の方法。
- 請求項1−2の何れか一項により産生されたヘテロ多量体タンパク質。
- ヘテロ多量体タンパク質が多選択性抗体である、請求項78に記載の方法。
- ヘテロ多量体タンパク質が少なくとも2つの標的分子に結合することができる、請求項78に記載のヘテロ多量体タンパク質。
- ヘテロ多量体タンパク質が同じ抗原上の少なくとも2つのエピトープに結合することができる抗体である、請求項78に記載のヘテロ多量体タンパク質。
- 請求項1又は2の方法に従って産生された二重特異性抗体。
- 重鎖ポリペプチドと軽鎖ポリペプチドの第一の対、及び重鎖ポリペプチドと軽鎖ポリペプチドの第二の対を含む二重特異性抗体であって、軽鎖ポリペプチドが異なる可変ドメイン配列を含む、二重特異性抗体。
- 請求項78に記載のヘテロ多量体タンパク質及び担体を含む組成物。
- 請求項78に記載のヘテロ多量体タンパク質を少なくとも10%含む組成物。
- 請求項78に記載のヘテロ多量体タンパク質を含む薬学的組成物。
- 第一のヘテロ二量体化ドメインを有する第一のヒンジ含有ポリペプチド、及び第二のヘテロ二量体化ドメインを有する第二のヒンジ含有ポリペプチドを含み、第二のヘテロ二量体化ドメインが第一のヘテロ二量体化ドメインと相互作用し、及び第一及び第二のヒンジ含有ポリペプチドが少なくとも一の鎖間ジスルフィド結合により連結されているコンビナトリアルヘテロ多量体タンパク質ライブラリを産生する方法であって、該方法が、
(a)第一の宿主細胞と、少なくとも2つの更なる宿主細胞を培養し、
i.第一の宿主細胞は、第一のヘテロ二量体化ドメイン含有ポリペプチドをコードする第一の核酸を含み;及び
ii.前記更なる宿主細胞は、第二のヘテロ二量体化ドメイン含有ポリペプチドをコードする核酸を含み、
(b)第一及び第二のヘテロ二量体ドメイン含有ポリペプチドが細胞外環境に放出されるように、第一の宿主細胞及び少なくとも2つの更なる宿主細胞の細胞膜を破壊し、第一の宿主細胞及び第二の宿主細胞が単一の懸濁液中で一緒に組合わされ、及び
(c)ヘテロ多量体タンパク質複合体を回収する
工程を含み、
前記方法が還元剤の添加を必要としない方法。 - 第一のヒンジ含有ポリペプチドが抗体の軽鎖ポリペプチドと対合し、第一の標的結合アームを形成し、第二のヒンジ含有ポリペプチドが抗体の軽鎖ポリペプチドと対合し、第二の標的結合アームを形成する、請求項1又は2に記載の方法。
- 結合アームの各々又は両方が一以上の標的に結合することができる、請求項88に記載の方法。
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