JP6535668B2 - B細胞受容体複合体膜結合IgMを標的とする抗体およびその使用 - Google Patents
B細胞受容体複合体膜結合IgMを標的とする抗体およびその使用 Download PDFInfo
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Description
本発明の一部は、米国国立衛生研究所により授与されたSBIR認可番号第1R43AI081332−01A1号による政府支援に基づいて行われた。政府は、本発明に対し一定の権利を有する。
本出願は、ASCIIフォーマットで電子的に提出された配列表を含み、参照によりその全体が本明細書に援用される。2014年12月1日に作成された上記ASCIIコピーは、10199−003571−WO0_SL.txtと命名され、7,207バイトのサイズである。
本発明はB細胞リンパ腫および白血病において認められるB細胞受容体複合体の膜結合IgM(mIgM)を標的とする抗体およびその使用に関する。
詳細な説明および実施例の全体を通して、次の略語が使用される:
ADCC 抗体依存性細胞傷害
ATCC アメリカ合衆国培養細胞系統保存機関
BCL2またはBcl−2 B細胞リンパ腫2
BCR B細胞受容体
BCRC B細胞受容体複合体
BTK チロシンプロテインキナーゼBTK
CDC 補体依存性細胞傷害
CDR Kabatナンバリングシステムを使って決定される、免疫グロブリン可変領域中の相補性決定領域
CHO チャイニーズハムスター卵巣
CLL 慢性リンパ性白血病
ELISA 酵素結合免疫吸着測定法
FM 蛍光顕微鏡
FR 抗体フレームワーク領域:CDR領域を除く免疫グロブリン可変領域
HRP 西洋ワサビペルオキシダーゼ
IFN インターフェロン
IC50 50%阻害を生じる濃度
Ig 免疫グロブリン
IgA 免疫グロブリンA
IgD 免疫グロブリンD
IgE 免疫グロブリンE
IgG 免疫グロブリンG
IgM 免疫グロブリンM
Kabat Elvin A.Kabatにより開拓された免疫グロブリン整列化およびナンバリングシステム((1991)Sequences of Proteins of Immunological Interest,5th Ed. Public Health Service,National Institutes of Health,Bethesda,Md.)。
mAb、Mab、またはMAb モノクローナル抗体
mAb 1またはmAb1 モノクローナル抗体mAb1−1
mAb 2またはmAb2 モノクローナル抗体mAb2−2b
mAb 3またはmAb3 モノクローナル抗体mAb3−2b
mAb 4またはmAb4 モノクローナル抗体mAb4−2b
mIg 細胞表面膜結合免疫グロブリン
mIgA 細胞表面膜結合免疫グロブリンA
mIgD 細胞表面膜結合免疫グロブリンD
mIgE 細胞表面膜結合免疫グロブリンD
mIgG 細胞表面膜結合免疫グロブリンG
mIgM 細胞表面膜結合免疫グロブリンM
PCR ポリメラーゼ連鎖反応
PD 近位ドメイン
PI3K フォスフォイノシチド3キナーゼ
PK 薬物動態学
SEM 走査型免疫電子顕微鏡
V領域 異なる抗体間の配列で可変であるIgG鎖のセグメント。V領域は、軽鎖のKabat残基109および重鎖の113まで伸びている。
VH 免疫グロブリン重鎖可変領域
VK 免疫グロブリンカッパ軽鎖可変領域
VL 免疫グロブリン軽鎖可変領域
本出願を通して使用される用語は、当業者にとって通常の典型的な意味を有するものと解釈されるべきである。しかし、出願者らは次の用語が以降で定義される特定の定義を与えられるべきであることを要求する。
以降で示すように、本発明の詳細説明および実施例の全体を通して、以下の11種のヒトB細胞系列細胞株および1種のマウス細胞株が参照される:
1.CRL1432−Namalwa mIgM−L バーキットリンパ腫
2.CRL1596−Ramos sIgM mIgM−L バーキットリンパ腫
3.CRL1647−ST486 sIgM mIgM−K バーキットリンパ腫
4.CRL1648−CA46 mIgM−K バーキットリンパ腫
5.CRL1649−MC116 mIgM−L 未分化リンパ腫
6.CRL2260−HT mIgM−K びまん性混合型B細胞リンパ腫
7.CRL2289−DB mIgG−L 大細胞型B細胞型リンパ腫
8.CRL2568−H2.8 マウス IgG1−K 骨髄腫
9.CRL2632−びまん性大細胞型リンパ腫 IgGk
10.CRL2958−SU−DHL−5 びまん性大細胞型リンパ腫 mIgM
11.CRL3006−JeKo−1−L マントル細胞リンパ腫 mIgM
12.SK007−リンパ腫 mIgE
本発明の抗体は、当該技術分野において既知の任意の好適な方法によって生成できる。本発明の抗体はポリクローナル抗体を含んでもよい。ポリクローナル抗体の作製方法は当業者に既知である(Harlow,et al.,Antibodies:a Laboratory Manual,Cold spring Harbor Laboratory Press,2nd ed.(1988)、この文献は参照によりその全体が本明細書に援用される)。
本発明は、本発明の抗体およびその断片をコードするヌクレオチド配列を含むポリヌクレオチドまたは核酸、例えば、DNAをさらに提供する。代表的ポリヌクレオチドとしては、配列表(例えば、配列番号1および3)に記載の1種または複数種のアミノ酸配列を含む抗体鎖をコードするものが含まれる。本発明はまた、ストリンジェントな条件下、またはより低い厳密度のハイブリダイゼーション条件下で、本発明の抗体をコードするポリヌクレオチドにハイブリダイズするポリヌクレオチドを包含する。
別の態様では、本発明は本明細書で開示の抗体をコードする単離核酸配列、本発明の抗体をコードするヌクレオチド配列を含むベクター構築物、このようなベクターを含む宿主細胞、および抗体の作製のための組換え技術を提供する。
多くのベクターが利用可能である。ベクター構成要素は、通常、下記の内の1つまたは複数を含むが、これらに限定されない:シグナル配列、複製起点、1個または複数個のマーカー遺伝子、エンハンサー配列、プロモータ、および転写終止配列。本発明の抗体をコードするヌクレオチド配列を含む組換え体発現ベクターはよく知られた技術を使って調製できる。発現ベクターは、哺乳動物、微生物、ウイルス、または昆虫遺伝子由来のものなど適切な転写または翻訳調節ヌクレオチド配列に機能的に連結されるヌクレオチド配列を含んでよい。調節配列の例には、転写プロモータ、オペレータ、エンハンサー、mRNAリボソーム結合部位、ならびに/または転写および翻訳反応の開始および終止を制御する他の適切な配列が含まれる。調節配列が適切なポリペプチドのヌクレオチド配列に機能的に関連する場合、ヌクレオチド配列は「機能的に連結」されている。したがって、プロモータヌクレオチド配列が適切なヌクレオチド配列の転写を制御する場合、プロモータヌクレオチド配列は、例えば、抗体重鎖配列に、機能的に連結されている。本発明の抗体を発現するための有用な発現ベクターの例は、国際公開第WO04/070011号に見出される。この特許は参照により本明細書に援用される。
本発明において有用な宿主細胞は、原核、酵母、または高等真核細胞であり、抗体コード配列を含む組換え型バクテリオファージDNA、プラスミドDNAまたはコスミドDNA発現ベクターで形質転換された細菌(例えば、大腸菌、枯草菌)などの微生物;抗体コード配列を含む組換え型酵母発現ベクターで形質転換された酵母(例えば、サッカロマイセス、ピキア);抗体コード配列を含む組換え型ウイルス発現ベクター(例えば、バキュロウイルス)で感染された昆虫細胞系;抗体コード配列を含む組換え型ウイルス発現ベクター(例えば、カリフラワーモザイクウイルス、CaMV;タバコモザイクウイルス、TMV)で感染されたまたは組換えプラスミド発現ベクター(例えば、Tiプラスミド)で形質転換された植物細胞系;または哺乳動物細胞のゲノム由来のプロモータ(例えば、メタロチオネインプロモータ)または哺乳動物ウイルス由来のプロモータ(例えば、アデノウイルス後期プロモータ;ワクシニアウイルス7.5Kプロモータ)を含む組換え体発現構築物を含む哺乳動物細胞(例えば、COS、CHO、BHK、293、3T3細胞)が挙げられるが、これらに限定されない。
本発明の抗体は、抗体の合成のために当該技術分野において既知のいずれかの方法、特に、化学合成または好ましくは、組換え体発現技術により作製できる。
組換え技術を使う場合、抗体は、細胞内で産生され、細胞周辺腔中で産生され、または媒質中に直接分泌され得る。抗体が細胞内で産生される場合、第一ステップとして、粒子状壊死組織片、宿主細胞または溶解断片を、例えば、遠心分離または限外濾過により除去できる。Carterら、Bio/Technology 10:163(1992)は、大腸菌の細胞周辺腔に分泌される抗体を単離する方法を記載する。簡単に説明すると、細胞ペーストを酢酸ナトリウム(pH3.5)、EDTA、およびフッ化フェニルメチルスルホニル(PMSF)の存在下で約30分にわたり解凍する。細胞壊死組織片を遠心分離により除去できる。抗体が媒質中に分泌される場合は、通常最初に、このような発現系由来の上清を、市販のタンパク質濃縮フィルター、例えば、AmiconまたはMillipore Pellicon限外濾過ユニットを使って濃縮する。PMSFなどのプロテアーゼ阻害剤を前述のステップのいずれかで加えてタンパク質分解を抑制し、抗生物質を加えて外来性混入物の増殖を防ぐことができる。
本発明は、B細胞受容体複合体(BCRC)の膜結合IgM(mIgM)成分を特異的に標的とする抗体に関する。大部分のB細胞リンパ腫および白血病はそれらの細胞表面上にmIgMを発現しているので、これらの抗体をこの分子の研究およびmIgM随伴疾患の診断と処置に使用できる。
1.収集した初期のクローンは、抗原標的のユニークな配列にもかかわらず低親和性であった。免疫したBalb/cマウスのスクリーニングは、血清応答が不良であることを示した。種々のアジュバントを検討したが、測定できるほどの血清試料の力価または親和性の増加は得られなかった。その後、種々の株のマウスを試験し、CD−1マウスのみが高親和性抗体の生成に適する宿主であることが分かった。
2.標的ポリペプチドは少なくとも、3種の異性体型として存在する。臨床的に適切なmAb試薬を生成するために、標的PDのすべての異性体型を認識するmAbについてmAbをスクリーニングした。
3.マウス抗体免疫応答の親和性を高めるために、および追加のエピトープの探索を広げるために、細胞抽出物(mAb1−1免疫アフィニティカラムから取得)由来の精製mIgM調製物を免疫原中に組み込んだ(mIgM PD−ペプチド−MAP免疫原との同時投与により)。
4.抗体mAb1は、mIgM−PDペプチド−MAP免疫原のみを含む融合体から得て、一方、全ての他の抗体(mAb2、mAb3およびmAb4)は、mIgM−PDペプチド−MAP免疫原に加えて精製mIgMを使って生成した。これらのmAbが異なる免疫原を使った融合体由来であることを示すために、接尾辞1をmAb1に加え(mAb1−1)、その他の抗体に接尾辞2を加えた(mAb2−2、mAb3−2およびmAb2−4)。さらに、抗体mAb2、mAb3およびmAb4の生成に使用した精製mIgMは、細胞株b(CA46、CRL1648)抽出物から得られるので、接尾辞2に文字bを付加した(mAb2−2b、mAb3−2bおよびmAb4−2b)。
5.精製mIgMによる免疫中に、血清IgM上では検出されないmIgMの第4定常領域を共有するエピトープに対してmAbが生成された。これは、血清IgM mRNAスプライスバリアントに比較して、膜IgM中の遠位の20アミノ酸の末端欠失に起因して生成された新抗原の結果である。mAb4−2bは、mIgMの第4定常領域中の構造変化がIgMドメインμC4中でユニークな高次構造エピトープを誘導したことを立証する。
1.ハイブリドーマパネルの生成と選択
2.生存標的細胞および細胞抽出物に対する特異性の調査(表4)
3.標的ペプチド、異性体および細胞抽出物に対する特異性の調査(表5、6)
4.免疫アフィニティーmIgMまたはPerfect−FOCUS(商標)抽出物に対する直接結合の抑制の分子特異性調査(表7、8)
5.競合的mAb結合および6マー抑制による分子エピトープマッピング(表9、10)
6.走査電子顕微鏡結合調査(表11〜18、図1〜5)
7.mAb結合媒介BCRC内部移行(表19、図2)
8.mAb4−2b媒介増殖抑制、抗クローン原性活性およびアポトーシス(表20〜24および図6〜7)
抗ECPDハイブリドーマパネルの生成
標的ペプチドと反応性のモノクローナル抗体を単離するために、IgM−EGEVSADEEGFEN(配列番号11)およびIgG−ELQLEESCAEAQDGELDG(配列番号12)、免疫原を有するこれらのペプチドを生成(グルタチオン−S−トランスフェラーゼ(GST))または購入した(多抗原ペプチド(MAP(Bio−Synthesis,Lewisville,TX)およびKLHペプチド(Bio−Synthesis,Lewisville,TX))。GST、MAPおよびKLH構築物を免疫原性キャリアタンパク質として使用し、複数組のマウスを標的ペプチド保持タンパク質の1つまたは組み合わせで免疫した。Balb/cマウスを宿主として使用した最初の実験で、これらのペプチドは市販のアジュバント調製物を加えても免疫原性がないことがすぐに明らかになった。低免疫原性は、前に行った抗mIgMおよびmIgG PD mAb作製の試みと一致するが、対照的に、mIgEを作製する試みにより、いくつかの機能上異なるタイプが得られた(Poggianella M,et al.,J Immunol 177:3597−3605(2006);Feichter S,et al.,J of Immunol 180:5499−5505(2008))。Balb/cマウスから生成された11個のモノクローナル抗体の第一のパネルは、反応性が弱すぎて臨床的価値がないと思われた。
抗体精製
pH8.6のトリス溶液中のそれぞれのハイブリドーマ株由来の上清を適用するプロテインAセファロースカラム(Pierce Inc.,Rockford,IL,USA)を使用して、抗体精製を行った。さらなる洗浄をpH7.0のPBSで行った後、pH4.0でmIgMを溶出した。無菌濾過したモノクローナル抗体を、アジド含有/不含の無菌PBS中に500マイクログラム/mlで4℃にて貯蔵した。ADCC、補体溶解、増殖抑制アッセイおよび生物学的アッセイ用の抗体調製物は、1000マイクログラム/mlにてアジド不含PBS中で無菌濾過した。
mIgMの抗体免疫アフィニティー精製
mAb1−1、またはmAb2−2bおよびmAb3−2bを含むmAb1−1共有結合免疫アフィニティービーズ(Pierce Inc.,Rockford,IL,USA)を使い、CRL−1648 NP−40抽出物を適用し、その後ビーズをpH8.6のトリス溶液で洗浄して、mIgMの抗体精製を行った。さらなる洗浄をpH7.0のPBSで行った後、pH4.0でmIgMを溶出した。無菌濾過したmIgMバッチを、アジド含有/不含の無菌PBS中に500マイクログラム/mlで4℃にて貯蔵した。
特異性分析
抗体の上皮細胞株バンクに対するパネルの赤血球吸着試験を行い、非特異的交差反応性を有するクローンを除去した(Rettig WJ,et al.,Int J Cancer 58:385−392(1994);Kitamura K,et al.,Proc Natl Acad Sci USA 91:12957− 12961(1994);Garin−Chesa P,et al.,Int J Oncol 9:465−471(1996);Rader C,et al.,J Biol Chem 275;13668−13676(2000))。真の陰性細胞を確定するために、これらの上皮細胞株のサブセットをPD配列に対するRT−PCRで試験したが、しかし、これまでmIgMがB細胞系列のもの以外の悪性細胞により発現されるという報告はなく、本明細書での調査は、パネル中のいずれの細胞株においてもこれらの配列を示さなかった。PD13マーmIgMおよび18マーmIgGに対する黒色腫および肉腫のパネルのRT−PCRによりこの観察は拡大され、これらの非B細胞系列細胞においてこのペプチドの発現を示すシグナルは認められなかった。したがって、いずれの結合も交差反応性を示し、BCRC抗原検出を示さないであろう。抗体の腫瘍細胞の細胞表面への結合は、抗マウスIg抗体またはプロテインAでコートされた赤血球の吸着により顕微鏡的に検出された。力価は、最大ロゼッティングを与える試薬の最大希釈として定義される(Rettig WJ,et al.,Int J Cancer 58:385−392(1994);Kitamura K,et al.,Proc Natl Acad Sci USA 91:12957−12961(1994);Garin−Chesa P,et al.,Int J Oncol 9:465−471(1996);Rader C,et al.,J Biol Chem 275:13668−13676(2000))。出願人および共同研究者により以前に開発された、mAb A33、mAb 3S193、mAb G250およびmAb F19を含む抗体パネル中に、陽性対照抗体を含めた(Rettig WJ,et al.,Int J Cancer 58:385−392(1994);Kitamura K,et al.,Proc Natl Acad Sci USA 91:12957−12961(1994);Garin−Chesa P,et al.,Int J Oncol 9:465−471(1996);Rader C,et al.,J Biol Chem 275:13668−13676(2000))。ヒト上皮細胞株のパネル:乳癌(9)、肺癌(9)、結腸癌(12)、腎臓癌(6)、前立腺癌(3)、卵巣癌(3)、黒色腫(6)および肉腫(2)に対する結合アッセイにおける、モノクローナル抗体mAb1−1、mAb2−2b、mAb3−2bおよびmAb4−2bの広範囲にわたる選別は、全て陰性であった。
生存細胞株とのmAbの特異的反応性およびNP−40ライセートアッセイ
プロテインGコートhuRBCを用いる赤血球吸着アッセイ(HA)では、位相差顕微鏡(100x)を使って、陰性(neg)、+、++、または+++としてスコア化した。細胞株パネルは、(1)mIgMラムダ、CRL1432、CRL1596、CRL1649、CRL3006、CRL2958、(2)mIgMカッパ、CRL1647、CRL1648、CRL2260、(3)mIgGラムダ2289、(4)mIgG、CRL2632、および(5)SK007から構成した。上皮癌および黒色腫細胞株を、アイソタイプ対応対照mAbとの反応性のために選択した。マウスIg予備吸着キャプチャーヤギ抗ヒトIgM定常領域血清を使ってCLのESA(細胞ライセートのELISAサンドイッチ法)を行い、ヒトIg予備吸着ヤギ抗マウスIg−HRPで検出した。留意すべきは、全てのリンパ腫株は、血清IgMと類似の細胞質IgMを有することである。したがって、このアッセイは、mIgMと血清または細胞質IgMとの間の反応性を区別するmAbの特異性を確認または評価しない。下表4に結果を示す。
(1)結腸癌:T84、SW1222、Colo 205、Lim 1215、HT−29、DLD−1、SW1116、SW 620、SW 480、LoVo、HCT−15、HCT−116
(2)乳癌:BT 474、SK BR7、CaMa−1、BT−20、MCF−7、SK Br−3、MDA−MB453、MDA− MB436、MDA−MB468
(3)肺癌:H64、SW1271、DMS78、SK−LU−9、NCI H596、A549、NCI H1105、NCI H69、DMS53。
(4)黒色腫:SK MEL−29、MeWo
相対的結合調査
上述のようにELISAを使って、精製モノクローナル抗体mAb1−1、mAb2−2b、mAb3−2b、mAb4−2b、およびmAb11−1を1:4に系列希釈した後、添加して、キャプチャー抗ヒトIgMにより結合されるヒトmIgMに結合させた。その後、結合されたマウスmAbをHRP標識特異的ヤギ抗マウスIg試薬で検出した。同じアイソタイプのモノクローナル抗体は相互に比較することが可能である。下表5〜8で特定された他の陽性標的を使って類似のアッセイを行った。
ペプチド抑制による結合調査およびエピトープマッピング
最初の放射標識調査では、IgG2bモノクローナル抗体は、放射免疫反応性アッセイにより良好に標識されなかった(Barendswaard EC,et al.,Int J Oncol 12:45−53(1998);Barendswaard E,et al.,J Nucl Med 42:1251−1256(2001);スキャッチャードプロット www.curvefit.com/scatchard_plots.htm#transforming_data_to_create_a_scatchard)。固相ラベリング技術でHRP用タンパク質ラベリングキット(Sigma−Aldrich,St Louis,MO,USA;Pierce Chemicals,Rockford,IL,USA)を使った。標識抗体結合をブロックする過剰の非標識抗体を使って、次の群のクローンに分類した:1.標識抗体をブロックするもの(同じエピトープ)、2.エピトープをブロックしないもの(異なるエピトープ)および3.部分的にブロックするもの(近いエピトープまたは弱い結合剤)。全てのクローンのエピトープが分類されるまでこのプロセスを繰り返した。抑制アッセイにより追加の情報が得られ、mAbは6マーによりブロックされ、このデータは確証された。結合調査の結果は、下表9および10に示す。
走査型免疫電子顕微鏡による結合調査
細胞株CA46(CRL1648)は、フローサイトメトリー分析による「DIM」軽鎖反応性に基づくと、慢性リンパ性白血病(CLL)細胞に類似の、比較的低いmIgM発現を有するB細胞株であり、走査型免疫電子顕微鏡(SEM)によるモノクローナル抗体の結合を調査するために使用された。SEM結果を下表11〜18に示す。図1Aの顕微鏡写真は、対照−IgG2bアイソタイプ対応対照抗体+2次ヤギ抗マウスIg−goldを示す。図1Bおよび1Cの顕微鏡写真は、写真中でmAb4と表示される、CA46(CRL1648)の2つの異なる細胞に結合したモノクローナル抗体m−Ab4−2bを、図1Aの対照抗体と同じ倍率で示す。図1Dの顕微鏡写真は、第3のCA46(CRL1648)細胞に結合した、写真中でmAb4と表示されるモノクローナル抗体m−Ab4−2bを、図1Aの対照抗体に比較して高倍率で示す。明るい白色スポットは、細胞表面のmAb4モノクローナル抗体と反応する免疫金粒子ヤギ抗マウスIgを表す。バックグラウンドのヤギ抗マウスIg反応性は図1Aの対照抗体では認められず、ヒトmIgMとの交差反応性のないこと、およびB細胞上のFc受容体による非特異的結合がないことを示している。これらの顕微鏡写真から、mIgMは細胞当たり5,000〜10,000分子で存在していると推定された。これらのSEM顕微鏡写真は、細胞表面上でmAb4−2bがmIgMに結合することを示す。
mAb結合がBCRC内部移行を媒介する
走査型免疫電子顕微鏡(SEM)を行って、モノクローナル抗体mAb4の細胞株CRL1648の細胞への結合を検出した。図2Aは、グルタルアルデヒド固定CRL1648細胞に結合するモノクローナル抗体mAb4を示す。図2Bは、BCRCのマイクロクラスタに結合するmAb4を示す。CRL1648細胞をmAb4と37℃で30分間インキュベートし、固定してヤギ抗マウスIgで染色した場合、図2Aで認められるmAb4結合とは対照的に、図2Cで示すように、検出可能なモノクローナル抗体mAb4は存在しなかった。膜上の検出可能なmAb4の欠如は、BCRC内部移行が原因であった。図2Dでは、CRL1648細胞をmAb4と37℃で15分間インキュベートし、固定してヤギ抗マウスIgで染色した場合、内部移行が不完全で、残留結合モノクローナル抗体mAb4が認められる(図2D)。CRL1648細胞をmAb4と37℃で30分間インキュベートし、固定してヤギ抗−hu−IgMで染色した場合、BCRCが検出されなかった。これは図2Eに示される。
酸洗浄ありまたはなしの場合の前処理細胞株によるmAb4結合の抑制
mAbが誘導するmIgMの内部移行の評価
各種条件下の相対的細胞表面mIgMレベルを測定するために、B細胞株をグルタルアルデヒド固定細胞に暴露し(表19の行1および2)(下記のSEMプロトコルにより)または生存細胞を使用した。細胞をmAb4、10mcg/mlに4℃で0分間(表19の行3および4)、および37℃で5分間(表19の行5および6)、15分間(表19の行7および8)、または30分間(表19の行9および10)暴露した。次に、mAb4−HRP結合抑制アッセイに使用する前に、細胞をpH7.0のPBSまたはpH4.0の0.5M酢酸塩緩衝液0.15NのNaClで洗浄した。行1を各細胞株の100%結合として設定し、行2は、細胞結合mAb4を取り除き細胞によりmAb4−HRPを吸着させて結合アッセイに利用可能なmAb4−HRPを減らす、酸洗浄能力を示した。類似の結果は、氷上でインキュベートした細胞にも認められ、グルタルアルデヒド固定および低温の両方がmIgMのmAb媒介内部移行を減らすことを示す。時間を限定した実験は、37℃で30分までに、細胞抑制は低減され、PBS洗浄と酢酸塩洗浄との間の差異はないことを示し、mIgMのほとんどが内部移行されたことを示唆している。結果を下表19に示す。
生物活性
mAb4−2bは増殖抑制、抗クローン原性活性およびアポトーシスを媒介する
mIgM PD中の配列の特異性および膜貫通細胞シグナル伝達がCD79αβに送られるという証拠から、CA46(CRL1648)細胞の増殖曲線(MTT)およびクローン原性の試験を行って、このプロセスの調節があるか否かを判定した(Kikushige Y,et al.,Cancer Cell 20(2):246−59(2011);Martinez−Climent JA,Haematol 95(2):293−302(2010);Franken NP,et al.,Nature Protocols 1:2315−2319(2006))。96ウエルプレートにおける限界希釈での単一クローン生存の最初の試験は、3つのモノクローナル抗体がある程度の活性を有することを示した。最大の活性は、PDおよびドメイン4の両方で結合し、および立体構造的エピトープ領域に結合する、モノクローナル抗体mAb4−2bが有していた。モノクローナル抗体mAb4−2bは、ある程度界面活性剤感受性で、パラホルムアルデヒドおよび還元抵抗性のエピトープに結合する。その他の3つのmAbは、PD中のより近位のエピトープに結合する。これらの細胞増殖抑制効果が、直接的にシグナルを伝達するエピトープのブロッキングに関連するのか、またはmAbの大きなサイズおよび/またはマイクロクラスタ化による立体構造に関連するのかは、明らかでない。
細胞を24ウエルプレートに播種し、下表20〜23に示すように、1:2系列希釈を使って96ウエルプレートに移した。MTTアッセイを実施する。各値は8ウエルの平均/希釈点である。ng=増殖なし、生存細胞なし。
限界希釈アッセイおよび細胞密度実験
1マイクログラムのmAb4を含むまたは含まない限界希釈アッセイは、10日までに、顕著な細胞生存および増殖特性を示した。結果を下表24に示す。値は、(mAb4処理の場合の%生存細胞)/(対照mAb処理の場合の%生存細胞)として示した。48と24培養プレートとの間の培地体積の倍増の間の細胞増殖における、大きな差異に留意されたい。細胞を、96ウエルプレート中の100マイクロリットル、48ウエルプレート中の250マイクロリットル、および24ウエルプレート中の500マイクロリットルで播種した。500〜1000播種細胞まで、顕著な増殖抑制が観察された。これは、mAb4により死滅させられる、幹細胞により産生されるパラクリン増殖因子に対する効果を示していると考えられる。これらの実験はまた、異なる細胞密度で細胞増殖を救済できるいくつかの異なる幹細胞集団が異なる頻度で存在することを示唆している。
補体溶解およびADCC
目的は、これらのモノクローナル抗体の、ヒト補体(C’)(IgG2、IgG3およびIgM)およびヒトエフェクター細胞媒介抗体依存性細胞介在性細胞傷害(ADCC)(IgG2およびIgG3)に関する免疫細胞傷害能力を評価することであった(Paneerselvam M,et al.,J Immunol 136:2534−2541(1986);Welt S,et al.,Clin Immunol Immunopathol 45:214−229(1987))。これらのモノクローナル抗体はマウスモノクローナル抗体であるので、この分析は、部分的には、C’またはADCCがこれらのマウス抗体で陽性であるかどうか、およびしたがって、ヒト化抗体の臨床製品開発で保持すべき重要な因子であるかどうかを判定するのを支援するためにのみ用いられた。マウスIgG1モノクローナル抗体はそれらのIgサブクラスのために、エフェクター機能の能力を持たない可能性があるが、狙いは、何れかの個別のクローンが優れた活性を有するかどうかを判定することである。
ポリペプチドまたは抗体の治療製剤は、所望の純度を有するポリペプチドを、当該技術分野で通常用いられる任意選択の「薬学的に許容される」キャリア、賦形剤または安定剤(これらはすべて「賦形剤」と呼ばれる)、すなわち、緩衝剤、安定剤、保存剤、等張化剤、非イオン性界面活性剤、抗酸化剤およびその他の種々の添加剤と混合することにより、凍結乾燥製剤あるいは水溶液として保管用に調製できる。Remington’s Pharmaceutical Sciences,16th edition,Osol,Ed.(1980)を参照されたい。このような添加剤は、用いられる服用量および濃度においてレシピエントに無毒である必要がある。
本発明の抗体は、修飾、すなわち、共有結合がB細胞mIgMに対する結合を妨害しないように、抗体への任意のタイプの分子の共有結合により修飾されている誘導体を含む。例えば、限定するものではないが、抗体誘導体は、例えば、ビオチン化、HRP、または何れか他の検出可能成分により修飾されている抗体を含む。
本発明の抗体は哺乳動物を処置するために使用されることが意図されている。一実施形態では、抗体は、例えば、前臨床のデータを得るために非ヒト哺乳動物に投与される。治療される代表的な非ヒト哺乳動物には、非ヒト霊長類、イヌ、ネコ、げっ歯類および前臨床調査が行われるその他の哺乳動物が含まれる。このような哺乳動物は、抗体で処置される疾患用の樹立動物モデルであってもよく、または対象抗体の毒性試験に使用されてもよい。これらの実施形態のそれぞれでは、用量漸増調査は哺乳動物で行われる。
Claims (25)
- B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体またはその抗原結合断片であって、重鎖可変領域および軽鎖可変領域を含み、
(a)前記重鎖可変領域(VH)は、配列番号1の核酸配列によってコードされ;
(b)前記軽鎖可変領域(VL)は、配列番号3の核酸配列によってコードされる、
単離された抗体またはその抗原結合断片。 - B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体またはその抗原結合断片であって、重鎖可変領域および軽鎖可変領域を含み、
(a)前記重鎖可変領域は、配列番号2(重鎖)のアミノ酸配列を含み;
(b)前記軽鎖可変領域は、配列番号4(軽鎖)のアミノ酸配列を含む、
単離された抗体またはその抗原結合断片。 - B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体またはその抗原結合断片であって、重鎖可変領域および軽鎖可変領域を含み、
(a)配列番号5のアミノ酸配列を含む重鎖可変領域CDR1と、
(b)配列番号6のアミノ酸配列を含む重鎖可変領域CDR2と、
(c)配列番号7のアミノ酸配列を含む重鎖可変領域CDR3と、
(d)配列番号8のアミノ酸配列を含む軽鎖可変領域CDR1と、
(e)配列番号9のアミノ酸配列を含む軽鎖可変領域CDR2と、
(f)配列番号10のアミノ酸配列を含む軽鎖可変領域CDR3と、
を含み、
B細胞受容体複合体の膜結合IgMに特異的に結合する、
単離された抗体またはその抗原結合断片。 - 前記抗原結合断片は、Fab、Fab’、F(ab’)2、Fd、単鎖Fv、単鎖抗体、ジスルフィド結合Fv、単一ドメイン抗体、抗原結合断片、ダイアボディ、トリアボディ、またはミニボディである、請求項1、2または3の単離された抗体またはその抗原結合断片。
- 標識、細胞毒素、放射性同位元素または免疫毒素をさらに含む、請求項1、2、3または4の単離された抗体またはその抗原結合断片。
- 請求項1、2、3または4の抗体またはその抗原結合断片と、生理学的に許容可能なキャリア、希釈剤、賦形剤または安定剤の内の少なくとも1種と、を含む組成物。
- 配列番号1および配列番号3の核酸配列を含む、抗体をコードする単離された核酸であって、配列番号1の核酸配列は重鎖可変領域(VH)をコードし、配列番号3の核酸配列は軽鎖可変領域(VL)をコードする、核酸。
- 配列番号2のアミノ酸配列を含む重鎖可変領域(VH)をコードし、および配列番号4のアミノ酸配列を含む軽鎖可変領域(VL)をコードする、単離された核酸。
- 請求項7または8の単離された核酸を含む発現ベクター。
- 発現ベクターを含む宿主細胞であって、前記発現ベクターが請求項7または8の単離された核酸を含む、宿主細胞。
- 抗体またはその抗原結合断片を産生する方法であって、
a.請求項7または8の核酸を含む発現ベクターを含む宿主細胞を培地中で培養することであって、前記核酸配列が発現されることにより軽鎖可変領域および/または重鎖可変領域を含むポリペプチドが産生される条件下で培養することと、
b.前記ポリペプチドを前記宿主細胞または培地から回収することと、
を含む方法。 - B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体であって、
アメリカ培養細胞系統保存機関(ATCC)に寄託されたハイブリドーマ細胞株(ATCC寄託番号PTA−121716)により産生されるmAb4−2bと命名されたモノクローナル抗体である、抗体。 - B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体であって、
アメリカ培養細胞系統保存機関(ATCC)に寄託されたハイブリドーマ細胞株(ATCC寄託番号PTA−121717)により産生されるmAb2−2bと命名されたモノクローナル抗体である、抗体。 - B細胞受容体複合体の膜結合IgMの第4の定常領域に位置するエピトープに特異的に結合する、単離された抗体であって、
アメリカ培養細胞系統保存機関(ATCC)に寄託されたハイブリドーマ細胞株(ATCC寄託番号PTA−121718)により産生されるmAb3−2bと命名されたモノクローナル抗体である、抗体。 - B細胞受容体複合体の膜結合IgMに特異的に結合する、単離された抗体であって、
アメリカ培養細胞系統保存機関(ATCC)に寄託されたハイブリドーマ細胞株(ATCC寄託番号PTA−121719)により産生されるmAb1−1と命名されたモノクローナル抗体である、抗体。 - 請求項12に記載のモノクローナル抗体を産生するための、ATCC PTA−121716と命名されたハイブリドーマ細胞株。
- 請求項13に記載のモノクローナル抗体を産生するための、ATCC PTA−121717と命名されたハイブリドーマ細胞株。
- 請求項14に記載のモノクローナル抗体を産生するための、ATCC PTA−121718と命名されたハイブリドーマ細胞株。
- 請求項15に記載のモノクローナル抗体を産生するための、ATCC PTA−121719と命名されたハイブリドーマ細胞株。
- 抗体を産生する方法であって、前記抗体の産生に適する条件下で請求項16、17、18または19に記載のハイブリドーマ細胞株を培養することと、前記抗体の単離と、を含む方法。
- 試料中のB細胞mIgMの検出のための方法であって、前記試料を請求項1、2、3、4または12に記載の抗体と接触させることを含む、方法。
- B細胞受容体を精製するための方法であって、請求項1、2、3、4または12に記載の抗体を使用する、方法。
- 1つの容器に所定量で請求項1、2、3、4または12に記載の抗体を含み、および別の容器に緩衝液を含む、キット。
- 1つの容器に所定量で請求項6に記載の組成物を含み、および別の容器に緩衝液を含む、キット。
- 対象におけるB細胞リンパ腫および白血病の処置のための医薬の製造における請求項1、2、3、4または12に記載の単離された抗体または抗原結合断片の使用。
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