JP4486494B2 - 生物学的製剤 - Google Patents
生物学的製剤 Download PDFInfo
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- JP4486494B2 JP4486494B2 JP2004501459A JP2004501459A JP4486494B2 JP 4486494 B2 JP4486494 B2 JP 4486494B2 JP 2004501459 A JP2004501459 A JP 2004501459A JP 2004501459 A JP2004501459 A JP 2004501459A JP 4486494 B2 JP4486494 B2 JP 4486494B2
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Description
CD22はほとんどのB細胞白血病とリンパ腫[NHL、急性リンパ性白血病(B−ALL)、慢性リンパ性白血病(B−CLL)、および特に急性非リンパ性白血病(ANLL)を含む]で発現される。
実施例1:候補抗体の生成
以下の選択基準を利用して、CD22に対する抗体の一団をハイブリドーマから選択した:ダウディ(Daudi)細胞への結合、ダウディ細胞でのインターナリゼーション、末梢血単核細胞(PBMC)への結合、PBMCでのインターナリゼーション、親和性(10-9Mを超える)、マウスγ1および産生速度。5/44を好ましい抗体として選択した。
5/44ハイブリドーマ細胞の調製およびそこからのRNA調製
5/44抗CD22モノクローナル抗体を用いる染色の出現率と分布を調べるために免疫組織化学試験に着手した。腫瘍のB細胞領域を確認するために、試験には対照の抗CD20および抗CD79a抗体を含めた。
・ 4個 B−CLL/小リンパ球性リンパ腫(低/A)
・ 3個 リンパ形質細胞様/免疫細胞腫(低/A)
・ 1個 外套細胞(中/F)
・ 14個 濾胞性リンパ腫(低〜中/D)
・ 13個 びまん性大細胞型リンパ腫(中〜高/G、H)
・ 6個 分類不能(K)
・ 2個 T細胞リンパ腫
5/44重鎖と軽鎖の可変ドメインをコードするcDNA配列は、逆転写酵素を用いて全RNA中に存在するmRNAの1本鎖cDNAコピーを生成させることにより合成した。次にこれを、ポリメラーゼ連鎖反応(Polymerase Chain Reaction)(PCR)による特異的なオリゴヌクレオチドプライマーを用いてマウスV領域配列の増幅のための鋳型として使用した。
cDNAは、以下の試薬:50mMトリス−HCl(pH8.3)、75mM KCl、10mMジチオスレイトール、3mM MgCl2、0.5mMの各デオキシリボヌクレオシド三リン酸、20単位のRNAsin、75ngランダムヘキサヌクレオチドプライマー、2μgの5/44RNAおよび200単位のマウスモロニー白血病ウイルス逆転写酵素を含む20μlの反応容量中で合成した。42℃で60分間インキュベート後、95℃で5分間加熱して、反応を停止させた。
cDNAのアリコートを、重鎖と軽鎖に特異的なプライマーの組合せを用いるPCRにかけた。シグナルペプチドの保存配列とアニーリングするために設計された変性したプライマープールを前進プライマーとして使用した。これらの配列は全て、順に、5’末端から7ヌクレオチドで開始する制限部位(VLSFuI;VHHindIII)、生じたmRNAの最適な翻訳を可能にする配列:GCCGCCACC(配列番号50)、開始コドン、および既知のマウス抗体のリーダーペプチド配列に基づく20〜30ヌクレオチドを含む(カバト(Kabat)ら、「免疫学的関心のあるタンパク質の配列(Sequences of Proteins of Immunological Interest)」、第5版、1991年、米国保健社会福祉省(U.S. Department of Health and Human Services)、公衆衛生局(Public Health Service)、国立衛生研究所(National Institutes of Health))。
次にマウスV領域配列を、発現ベクターpMRR10.1およびpMRR14中にクローン化した(図7)。これらは、ヒトカッパ軽鎖とヒトガンマ−4重鎖の定常領域をコードするDNAを含む、それぞれ軽鎖と重鎖の発現用のベクターである。VL領域は、SfuIとBsiWI制限部位を用いて、配列決定ベクターからの制限消化と連結により、発現ベクター中にサブクローン化して、プラスミドpMRR10(544cL)を作成した。重鎖DNAは、5’プライマーを用いてPCRにより増幅することによりシグナルペプチドを導入したが、これは、異なる社内のハイブリドーマ(162と呼ばれる)からのマウス重鎖抗体リーダーを使用したクローニング方策では得られなかったためである。5’プライマーは、以下の配列を有する:
可能なN結合グリコシル化部位配列は、アミノ酸配列N−Y−Tを有するCDR−H2に観察された(図3)。5/44およびその断片(Fabを含む)のゲルの、SDS−PAGE、ウェスタンブロッティングおよび炭水化物染色は、この部位が実際にグリコシル化されていることを示している(図示せず)。さらにリジン残基は、CDR−H2内の露出位置に観察されたが、これは、抗体が結合体形成しうる物質との結合体形成のための追加の部位を提供することにより、抗体の結合親和性を低下させる潜在力を有する。
キメラ遺伝子の活性は、CHO細胞への一過性トランスフェクションにより評価した。
グリコシル化部位または反応性リジンを除去したキメラ5/44またはその変種の親和性は、CD22−mFc構築体への結合についてBIA法を用いて調査した。結果を図8に示す。全ての結合測定は、BIAコア(BIAcore)(登録商標)2000機器(ファルマシア・バイオセンサー(Pharmacia Biosensor AB)、ウプサラ、スウェーデン)で実施した。このアッセイは、固定化抗マウスFcを介したCD22mFcの捕捉により実施した。抗体は可溶性相に入れた。試料、標準物質、および対照(50ul)を固定化抗マウスFcに注入し、続いて可溶性相の抗体を加えた。各サイクル後に、表面を50ulの40mM HClで30ul/分で再生した。反応速度分析は、BIA評価3.1ソフトウェア(ファルマシア(Pharmacia))を用いて実施した。
5/44抗体の重鎖と軽鎖の可変領域の遺伝子の分子クローニング、およびキメラ(マウス/ヒト)5/44抗体を産生するためのその使用を上記した。マウス5/44のVLおよびVHドメインのヌクレオチドおよびアミノ酸配列は、それぞれ図2と3に示される(配列番号7と8)。この実施例は、アデア(Adair)ら(WO91/09967)の方法による、ヒトにおける潜在的な免疫原性を低下させるためのヒトフレームワークへの5/44抗体のCDR移植を説明する。
ヒトサブグループIカッパ軽鎖V領域からのコンセンサス配列とのタンパク質配列の整列は、64%の配列同一性を示した。その結果、CDR移植軽鎖を作成するために選択したアクセプターフレームワーク領域は、ヒトVKサブグループI生殖細胞系O12、DPK9配列のものに対応した。フレームワーク4のアクセプター配列は、ヒトJ領域生殖細胞系配列JK1から誘導した。
5/44重鎖のCDR移植は、軽鎖に関して記述されたものと同じ方策を用いて行った。5/44重鎖のVドメインは、サブグループIに属するヒト重鎖と相同である(70%の配列同一性)ことが見い出されたため、ヒトサブグループI生殖細胞系フレームワークVH1−3、DP7の配列をアクセプターフレームワークとして使用した。フレームワーク4アクセプター配列は、ヒトJ領域生殖細胞系配列JH4から誘導した。
遺伝子は、移植配列gH1とgL1をコードするように設計し、一連の重複オリゴヌクレオチドを設計し構築した(図9)。PCR組立法を利用することにより、CDR移植V領域遺伝子を作成した。10mMトリス−HCl(pH8.3)、1.5mM MgCl2、50mM KCl、0.001%ゼラチン、0.25mM各デオキシリボヌクレオシド三リン酸、1pmol各「内部」プライマー(T1、T2、T3、B1、B2、B3)、10pmol各「外部」プライマー(F1、R1)、および1単位のTaqポリメラーゼ(アンプリTaq(AmpliTaq)、アプライド・バイオシステムズ(Applied BioSystems)、カタログ番号N808−0171)を含む、100ulの反応容量を設定した。PCRサイクルパラメータは、94℃で1分、55℃で1分、72℃で1分を30サイクルであった。次に反応産物を1.5%アガロースゲルに流して、切り出し、キアゲン(QIAGEN)スピンカラム(QIAクイック(QIAquick)ゲル抽出キット、カタログ番号28706)を用いて回収した。DNAを30μlの容量で溶出した。次にgH1とgL1 DNAのアリコート(1μl)を、インビトロジェン(InVitrogen)TOPO TAクローニングベクターpCR2.1 TOPO(カタログ番号K4500−01)中に製造業者の説明書によってクローン化した。この非発現ベクターは、多数のクローンの配列決定を促進するためのクローニング中間体の役目を果たした。ベクター特異的プライマーを用いるDNA配列決定を使用することにより、gH1とgL1を含む誤りのないクローンを同定して、プラスミドpCR2.1(544gH1)とpCR2.1(544gL1)を作成した(図10)。
移植変種をコードするベクターを、元々のキメラ抗体鎖と一緒に種々の組合せでCHO細胞中に同時トランスフェクトした。結合活性は、元々のマウス5/44抗体の結合をラモス(Ramos)細胞(ATCCから入手;表面CD22を発現するバーキット(Burkitt's)リンパ腫リンパ芽球ヒト細胞株)への結合に関して競合させて、競合アッセイで比較した。このアッセイは、移植片をその細胞表面CD22に結合する能力において比較するための最良の方法と考えられた。結果を図8に示す。明らかなように、移植片のいずれの間にもほとんど差がなく、全てがマウスの親に対する競合でキメラより有効に奏効する。CDR−H3(gH5とgH7)の末端に3個の追加のヒト残基を導入しても、結合に影響はないようである。
Claims (29)
- ヒトCD22に対する特異性を有する抗体分子であって、重鎖として、可変ドメインが、CDR−H1について配列番号1に示す配列、CDR−H2について配列番号2に示す配列もしくは配列番号13に示す配列もしくは配列番号15に示す配列もしくは配列番号16に示す配列もしくは図6のgH7における配列GINPGNNYATYRRKFQG、およびCDR−H3について配列番号3に示す配列を含むものを、ならびに、軽鎖として、可変ドメインが、CDR−L1について配列番号4に示す配列、CDR−L2について配列番号5に示す配列、およびCDR−L3について配列番号6に示す配列を含むものを、含む、キメラ抗体分子またはCDR移植抗体分子である、抗体分子。
- CDR−H2について図6のgH7における配列GINPGNNYATYRRKFQGを含む、請求項1の抗体分子。
- 可変ドメインは、ヒトアクセプターフレームワーク領域と非ヒトドナーCDRとを含む、請求項1の抗体分子。
- 重鎖の可変ドメインのヒトアクセプターフレームワーク領域は、配列番号21および22に基づき、配列番号8の1、28、48、72および97位の残基にそれぞれ対応する、Kabatによる番号付けで1、28、48、71および93位のドナー残基を含む、請求項3の抗体分子。
- 配列番号8の68および70位の残基にそれぞれ対応する、Kabatによる番号付けで67と69位のドナー残基をさらに含む、請求項4の抗体分子。
- 軽鎖の可変ドメインのヒトアクセプターフレームワーク領域は、配列番号17および18に基づき、配列番号7の2、4、42、43、50および65位の残基にそれぞれ対応する、Kabatによる番号付けで2、4、37、38、45および60位のドナー残基を含む、請求項3〜5のいずれか1項の抗体分子。
- 配列番号7の3位の残基に対応する、Kabatによる番号付けで3位のドナー残基をさらに含む、請求項6の抗体分子。
- 請求項4または請求項5の重鎖と、請求項7または請求項8の軽鎖とを含む、ヒトCD22に対する特異性を有する抗体分子。
- 軽鎖可変領域5/44−gL1(配列番号19)と重鎖可変領域5/44−gH7(配列番号27)とを含む、請求項1〜8のいずれか1項の抗体分子。
- 配列番号28に示す配列を含むことを特徴とする軽鎖と、配列番号30に示す配列を含むことを特徴とする重鎖とを有する、ヒトCD22に対する特異性を有する抗体分子。
- 配列番号28に示す配列からなることを特徴とする軽鎖と、配列番号30に示す配列からなることを特徴とする重鎖とを有する、ヒトCD22に対する特異性を有する抗体分子。
- 請求項1〜11のいずれか1項の抗体分子の重鎖および/または軽鎖をコードするDNA。
- 請求項12のDNAを含むクローニングベクターまたは発現ベクター。
- 請求項13のクローニングベクターまたは発現ベクターを含む宿主細胞。
- 治療で使用される請求項1〜11のいずれか1項の抗体分子。
- ヒトCD22に対する特異性を有する請求項1〜11のいずれか1項または請求項15の抗体分子。
- 悪性リンパ腫を治療するのに使用される請求項1〜11のいずれか1項の抗体分子。
- 悪性リンパ腫は非ホジキンリンパ腫である、請求項17の抗体分子。
- 治療で使用される請求項12のDNA。
- CD22を発現する細胞により仲介される病態を治療するのに使用される請求項12のDNA。
- 悪性リンパ腫を治療するのに使用される請求項12のDNA。
- 悪性リンパ腫は非ホジキンリンパ腫である、請求項21のDNA。
- CD22を発現する細胞により仲介される病態の治療のための、ヒトCD22に対する特異性を有する請求項1〜11のいずれか1項の抗体分子、または請求項12のDNAを含む、医薬組成物。
- 病態は悪性リンパ腫である、請求項23の医薬組成物。
- 病態は非ホジキンリンパ腫である、請求項24の医薬組成物。
- 請求項1〜11のいずれか1項の抗体分子または請求項12のDNAを含む診断用組成物。
- 薬剤学的に許容される賦形剤、希釈剤または担体を含む、請求項24または25の医薬組成物。
- 抗T細胞、抗IFNγ、または抗LPS抗体、またはキサンチンのような非抗体成分をさらに含む、請求項24または請求項25の医薬組成物。
- 請求項1〜11のいずれか1項の抗体分子の製造方法であって、該抗体分子をコードするDNAからのタンパク質の発現に適した条件下で請求項14の宿主細胞を培養し、該抗体分子を単離することを特徴とする、上記方法。
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