JP4733635B2 - 抗cd19抗体 - Google Patents
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- JP4733635B2 JP4733635B2 JP2006522093A JP2006522093A JP4733635B2 JP 4733635 B2 JP4733635 B2 JP 4733635B2 JP 2006522093 A JP2006522093 A JP 2006522093A JP 2006522093 A JP2006522093 A JP 2006522093A JP 4733635 B2 JP4733635 B2 JP 4733635B2
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Description
本発明は、抗CD19抗体、特にヒト化、キメラおよびヒト抗CD19抗体、特に裸であるかまたは少なくとも1つの治療および/または診断薬に接合したモノクローナル抗体(MAb)およびそのフラグメント、およびそれらの使用方法に関する。特に、本発明による抗CD19抗体は、例えば、悪性疾患および/または自己免疫疾患などの炎症性疾患または障害のようなB細胞疾患の治療に用いることができる。本発明の方法および組成物は、非ホジキンリンパ腫、慢性リンパ性白血病および急性リンパ芽球性白血病などのリンパ腫や白血病の治療に用いることもできる。好ましい態様では、腫瘍性疾患は、進行の遅い形態のB細胞リンパ腫、急速進行性形態のB細胞リンパ腫(非ホジキンリンパ腫)、慢性リンパ性白血病または急性リンパ性白血病のようなB細胞悪性疾患、または多発性骨髄腫である。
脊椎動物の免疫系は、外来抗原を正確に認識し、これらの外来抗原に特異的に結合して除去/破壊する目的で進化してきた多数の種類の臓器および細胞からなっている。リンパ球は、他の細胞型の中、免疫系にとって重要である。リンパ球は、2つの主要な下位個体群のT細胞とB細胞に分割される。それらは相互依存性であるが、T細胞は主として細胞性免疫に関与しており、B細胞は主として抗体産生(体液性免疫)に関与する。
1.大要
上記のように、治療用放射性核種と未接合であるかまたはで標識されている抗CD19抗体は、中または急速進行性B細胞リンパ腫の患者において客観的且つ継続的応答を高比率で提供することができなかった。本発明は、ヒトおよび家畜である哺乳類患者の治療に有用な、単独で、接合体として、または他の裸の抗体および抗体治療接合体などの他の治療薬と組み合わせて投与される、ヒト化、キメラおよびヒト抗CD19抗体、およびその抗体融合タンパク質を提供する。
(a)本明細書に記載の抗CD19 MAbまたはそのフラグメント、
(b)少なくとも2種類の抗CD19 MAbまたはそのフラグメントを含んでなる抗体融合タンパク質またはそのフラグメント、
(c)本明細書に記載の抗CD19 MAbまたはそのフラグメントを含んでなる少なくとも1つの第一のMAbまたはそのフラグメントと、抗CD19 MAbまたはそのフラグメント以外の少なくとも1つの第二のMAbまたはそのフラグメントとを含んでなる抗体融合タンパク質またはそのフラグメント、および
(d)抗CD19 MAbまたはそのフラグメントを含んでなる少なくとも1つの第一のMAbまたはそのフラグメントと、少なくとも1つの第二のMAbまたはそのフラグメントとを含んでなる抗体融合タンパク質またはそのフラグメントであって、第二のMAbが、CD4、CD5、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、CD138、B7、MUC−1、Ia、HM1.24、HLA−DR、テネイシン、ED−Bフィブロネクチン、IL−6、VEGF、PIGF、TRAIL−R1(DR4)およびTRAIL−R2(DR5)、またはそれらの組合せと反応性のMAbであるもの
からなる群から選択されるMAbまたはそのフラグメントをコードする核酸を含んでなるDNA配列にも関する。
下記の記載において、本発明の理解を容易にするために、多数の用語が用いられ、下記の定義が提供される。
モノクローナル抗体(MAb)は、特定の抗原に対する抗体の均質な個体群であり、この抗体は1種類のみの抗原結合部位を含んでなり、抗原決定基上の1つのエピトープのみに結合する。特異抗原に対する齧歯類のモノクローナル抗体は、当業者に知られている方法によって得ることができる。例えば、Kohler and Milstein, Nature 256:495 (1975)、およびColigan et al.(監修),「免疫学の最新のプロトコール 第1巻」,2.5.1−2.6.7頁(John Wiley & Sons 1991)[以下、「Coligan」と表す]を参照されたい。簡単に説明すれば、モノクローナル抗体は、マウスに抗原を含んでなる組成物を投与し、血清試料を採取することによって抗体産生の存在を明らかにし、脾臓を取り出してBリンパ球を得て、Bリンパ球を骨髄腫細胞と融合してハイブリドーマを産生し、抗原に対する抗体を産生する陽性クローンを選択し、抗原に対する抗体を産生するクローンを培養し、ハイブリドーマ培養物から抗体を単離することによって得ることができる。
特異的エピトープを認識する抗体フラグメントは、既知の手法によって生成させることができる。抗体フラグメントは、F(ab’)2、Fab’、Fab、Fv、sFvなどの抗体の抗原結合部分である。他の抗体フラグメントとしては、抗体分子のペプシン消化によって産生させることができるF(ab)’2フラグメント、およびF(ab)’2フラグメントのジスルフィド橋を換言することによって生成させることができるFab’フラグメントが挙げられるが、これらに限定されない。あるいは、Fab’発現ライブラリーを構築して(Huse et al., 1989, Science, 246:1274-1281)、所望な特異性を有するモノクローナルFab’フラグメントを迅速且つ容易に同定することができる。本発明は、抗体および抗体フラグメントを包含する。
抗CD19抗体、並びに本明細書に記載の併用療法に使用する異なる特異性を有する他の抗体を、多重特異性抗体(CD19エピトープまたは抗原に対して少なくとも1つの結合部位とCD19上の別のエピトープまたは別の抗原に対して少なくとも1つの結合部位を含んでなる)および多価抗体(同一のエピトープまたは抗原に対して複数の結合部位を含んでなる)とすることもできる。
様々な組換え法を用いて、上記のような二重特異性抗体および抗体フラグメントを産生することができる。
本発明の抗CD19抗体を用いて、ダイアボディーとも称される機能性の二重特異性一本鎖抗体(bscAb)を調製することもでき、組換え法を用いて哺乳類細胞で産生させることができる。例えば、Mack et al., Proc. Natl. Acad. Sci., 92:7021-7025, 1995を参照されたい。上記文献の全内容は、引用することにより本明細書の一部とされる。例えば、bscAbは、組換え法を用いるグリシン−セリンリンカーを介して2つの一本鎖Fvフラグメントを結合することによって産生される。目的とする2つの抗体のV軽鎖(VL)とV重鎖(VH)ドメインを、標準的PCR法を用いて単離する。次に、それぞれのハイブリドーマから得られたVLおよびVH cDNAを結合させて、二段階式PCRで一本鎖フラグメントを形成する。第一のPCR段階では、(Gly4−Ser1)3リンカーを導入し、第二の段階ではVLとVHアンプリコンを結合する。次に、それぞれの一本鎖分子を、細菌発現ベクター中でクローニングする。増幅の後、一本鎖分子の1つを切り出し、目的とする第二の一本鎖分子を含む他のベクター中にサブクローニングする。生成するbscAbフラグメントを、真核生物発現ベクター中にサブクローニングする。機能性タンパク質発現は、ベクターをチャイニーズハムスター卵巣細胞にトランスフェクションすることによって得ることができる。二重特異性融合タンパク質は、同様の方法で調製される。二重特異性一本鎖抗体および二重特異性融合タンパク質は、本発明の範囲内に含まれる。
本発明のもう一つの態様は、多価抗CD19抗体の接合体である。多価多重特異性薬剤の組成および方法は、Rossi et al.の2002年12月24日出願の米国特許出願出願番号第60/436,359号明細書、および2003年4月23日出願の米国特許出願出願番号第60/464,532号明細書に記載されており、上記特許明細書の全内容は、引用することにより本明細書の一部とされる。
本発明によるヒト化、キメラおよびヒトモノクローナル抗体、すなわち本明細書に記載の抗CD19 MAbおよび他のMAbは、治療方法および診断方法に用いるのに適している。従って、本発明では、単独で裸の抗体として投与されるかまたは多様療法として一時的に投薬法に準じて投与されるが、治療薬に接合していない本発明のヒト化、キメラおよびヒト抗体を意図する。裸の抗CD19 MAbの効力は、裸の抗体を1種類以上の他の裸の抗体と共にし、すなわち、CD4、CD5、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、CD138、B7、MUC−1、Ia、HM1.24、HLA−DR、テネイシン、VEGF、PIGF、ED−Bフィブロネクチン、癌遺伝子、癌遺伝子産物、NCA 66a−d、壊死抗原、Ii、IL−2、T101、TAC、IL−6、TRAIL−R1(DR4)およびTRAIL−R2(DR5)のような特異抗原に対するMAbを1種類以上の抗CD19 MAbの免疫接合体と共にし、または薬剤、毒素、免疫調節剤、ホルモン、酵素、オリゴヌクレオチド、治療用放射性核種などの治療薬を接合した上記抗原に対する抗体をMAbと同時にまたは逐次的にまたは指定投薬法に準じて投与される薬剤、毒素、酵素、オリゴヌクレオチド、免疫調節剤、ホルモン、治療用放射性核種などの1種類以上の治療薬と共に補足することによって高めることができる。好ましいB細胞抗原としては、ヒトCD19、CD20、CD21、CD22、CD23、CD46、CD52、CD74、CD80およびCD5抗原と同等のものが挙げられる。好ましいT細胞抗原としては、ヒトCD4、CD8およびCD25(IL−2受容体)抗原と同等のものが挙げられる。HLA−DR抗原に同等のものを、B細胞およびT細胞疾患の治療に用いることができる。特に好ましいB細胞抗原は、ヒトCD19、CD20、CD22、CD21、CD23、CD74、CD80およびHLA−DR抗原に同等のものである。特に好ましいT細胞は、ヒトCD4、CD8およびCD25抗原に同等のものである。CD46は、補体依存性リーシス(CDC)をブロックする癌細胞の表面上の抗原である。
本発明の抗体または抗体融合タンパク質のいずれを、1種類以上の治療または診断薬と接合させることもできる。一般に、1種類の治療または診断薬はそれぞれの抗体または抗体フラグメントに結合するが、2種類以上の治療薬または診断薬が同一の抗体または抗体フラグメントに結合することができる。本発明の抗体融合タンパク質は、2種類以上の抗体またはそのフラグメントを含んでなり、この融合タンパク質を含んでなる抗体のそれぞれが治療薬または診断薬を含むことができる。更に、抗体融合タンパク質の1つ以上の抗体は、2種類以上の治療または診断薬させることができる。更に、治療薬は同一である必要はなく、異なる治療薬であることができる。例えば、薬剤と放射性同位体を同一の融合タンパク質に結合することができる。特に、IgGを131Iで放射能標識して、薬剤に結合させることができる。131IはIgGのチロシンに取り込まれ、薬剤をIgGリシンのε−アミノ基に結合させることができる。治療および診断薬を両方とも、還元されたSH基および炭水化物側鎖に結合させることもできる。
患者に送達されるヒト化、キメラおよびヒト抗CD19 MAbは、MAb単独、免疫接合体、融合タンパク質からなることができ、または1種類以上の薬学上適当な賦形剤、1種類以上の追加成分、またはこれらのある種の組合せを含んでなることができる。
本発明は、本発明の裸の抗CD19抗体のB細胞疾患および他の疾患の治療用の主要な組成物としての使用を意図する。特に、本明細書に記載の組成物は、様々な自己免疫、並びに進行の遅い形態のB細胞リンパ腫、急速進行性形態のB細胞リンパ腫、慢性リンパ性白血病、急性リンパ性白血病、およびヴァルデンストレームマクログロブリン血症の治療に特に有用である。例えば、ヒト化抗CD19抗体成分および免疫接合体を用いて、進行の遅いおよび急速進行性形態の非ホジキンリンパ腫を治療することができる。
ヒト化、キメラまたはヒト抗CD19 MAbをコードするDNA配列を、核酸の複製を提供する様々な既知の宿主ベクター中で組換え処理を行うことができる。これらのベクターは、送達される細胞の核酸の転写、翻訳または両方を指定するのに必要な要素を含むように、既知の方法を用いてデザインすることができる。既知の方法を用いて、適当な転写/翻訳制御シグナルと操作可能に連結したタンパク質コード配列を有する発現構築物を生成することができる。これらの方法としては、イン・ビトロ組換えDNA法、および合成法が挙げられる。例えば、Sambrook et al.,1989,「分子クローニング: 実験室マニュアル」, Cold Spring Harbor Laboratory (ニューヨーク)、Ausubel et al., 1997,「分子生物学の最新の方法」,John Wiley & Sons (ニューヨーク)をを参照されたい。本発明では、ベクターと会合していないポリヌクレオチドの送達も提供する。
一般に、抗CD19 MAbについてのVk(可変軽鎖)およびVH(可変重鎖)配列は、RT−PCR、5’−RACE、およびcDNAライブラリースクリーニングのような様々な分子クローニング法によって得ることができる。具体的には、抗CD19 MAbのV遺伝子は、配列決定したネズミまたはキメラ抗CD19 MAbを発現する細胞からPCR増幅によってクローニングすることができる。それが正しいことを確認するため、クローニングしたVLおよびVH遺伝子を、Orlandi et al.によって報告されたキメラAbと同様に細胞培養物中で発現させることができ(Proc. Natl. Acad. Sci., USA, 86:3833 (1989))、この文献の全内容は、引用することにより本明細書の一部とされる。V遺伝子配列に基づいて、ヒト化抗CD19 MAbをLeung et al.によって報告された方法でデザインして構築することができ(Mol. Immunol., 32:1413 (1995))この文献の全内容は、引用することにより本明細書の一部とされる。cDNAは、一般的分子クローニングの手法によりネズミまたはキメラ抗CD19 MAbを産生する任意の既知ハイブリドーマ系またはトランスフェクション細胞系から調整することができる(Sambrook et al.,「分子クローニング、実験室マニュアル」第2版(1989))。MAbについてのVK配列はプライマーVK1BACKおよびVK1FOR(Orlandi et al., 1989)またはLeung et al.によって報告された伸長したプライマーセット(BioTechniques, 15:286 (1993))を用いて増幅することができ、上記文献の内容はその開示の一部として本明細書に引用され、一方、VH配列はプライマー対VH1BACK/VH1FOR(Orlandi et al., 1989 上記)、またはLeung et al.によって報告されたネズミIgGの定常領域にアニーリングするプライマーを用いて増幅することができ(Hybridoma, 13: 469(1994))、上記文献の全内容は、引用することにより本明細書の一部とされる。第一の鎖のcDNA産物10X1、PCR緩衝液[500mM KCI、100mM トリス−HCl(pH8.3)、15mM MgCl2および0.01%(w/v)ゼラチン](Perkin Elmer Cetus, ノーウォーク,コネティカット)10μl、それぞれのdNTP 250μM、プライマー200nM、およびTaq DNAポリメラーゼ(Perkin Elmer Cetus)5単位を含むPCR反応混合物に、PCRを30サイクル行うことができる。それぞれのPCRサイクルは、好ましくは、94℃で1分間の変性、50℃で1.5分間のアニーリング、および72℃で1.5分間の重合からなる。増幅したVkおよびVHフラグメントは、2%アガロース(BioRad,リッチモンド,カリフォルニア)上で精製することができる。同様に、ヒト化V遺伝子は、Leung et al.によって報告された長いオリゴヌクレオチド鋳型合成とPCR増幅との組合せによって構築することができる(Mol. Immunol., 32: 1413(1995))。ヒト化V遺伝子の構築に用いる自動RNA/DNA合成装置(Applied Biosystems, フォスターシティー,カリフォルニア)上でのオリゴAおよびオリゴBの製造方法については、実施例3をを参照されたい。
hA19VKA
5'-ATCACTTGTA AGGCCAGCCA AAGTGTTGAT TATGATGGTG ATAGTTATTT GAACTGGTAC CAGCAGATTC CAGGGAAAGC ACCTAAATTG TTGATCTACG ATGCTTCGAA TCTAGTTTCT GGTATC-3'
hA19VKB
5'-TGCTGACAGT GATATGTTGC AATGTCTTCT GGTTGAAGAG AGCTGATGGT GAAAGTGTAA TCTGTCCCAG ATCCGCTGCC AGAGAATCGA GGAGGGATAC CAGAAACTAG ATTCGAAGCA TCGTA-3'
hA19VKBack
5'-TCCGACATCC AGCTGACCCA GTCTCCATCA TCTCTGAGCG CATCTGTTGG AGATAGGGTC ACTATCACTT GTAAGGCCAG CCAAAG-3'
hA19VKFor
5'-GCTCCTTGAG ATCTGTAGCT TGGTCCCTCC ACCGAACGTC CACGGATCTT CAGTACTTTG CTGACAGTGA TATGTTGCAA T-3'
hA19VHA
5'-CTGGCTACGC TTTCAGTAGC TACTGGATGA ACTGGGTGAG GCAGAGGCCT GGACAGGGTC TTGAGTGGAT TGGACAGATT TGGCCTGGAG ATGGTGATAC TAACTACAAT GGAAAGTTCA AGGGGCGCGC CACTATT-3'
hAl9VHB
5'-CGTAGTCTCC CGTCTTGCAC AAGAATAGAA CGCTGTGTCC TCAGATCGTA GGCTGCTGAG TTCCATGTAG GCTGTATTAG TGGATTCGTC GGCAGTAATA GTGGCGCGCC CCTTGAACTT TCCATTGTA-3'
hA19VHBack
5'-CAGGTCCAAC TGCAGCAATC AGGGGCTGAA GTCAAGAAAC CTGGGTCATCG GTGAAGGTCTC CTGCAAGGCT TCTGGCTACG CTTTCAGTAG C-3'
hA19VHFor
5'-TGAGGAGACG GTGACCGTGG TCCCTTGGCC CCAGTAGTCC ATAGCATAGT AATAACGGCC TACCGTCGTA GTCTCCCGTCTTGCACAAG- 3'
キメラAl 9(cAl 9)抗体を構築して、Sp2/0細胞で発現させた。cA19のVkおよびVH配列を、図1に示す。cA19抗体は、ラージ、ダウディ、およびラモスのようなCD19+ヒトリンパ腫細胞系に結合されていることが示された。精製したcA19のAg結合特異性を、他の抗CD19抗体、例えばB4(Culter)およびBU12(Chembiochem)に対する細胞表面競合的結合測定法によって評価した。簡単に説明すれば、様々な濃度のcAl9を、ラージ細胞と共に一定量のI−125で放射能標識した抗CD19抗体の存在下にて1時間インキュベーションした。洗浄によって未結合抗体を除去した後、細胞表面に結合した放射能標識抗体をガンマーカウンターで細胞ペレットを計数することによって定量した。図2に示されるように、cAl9は細胞表面結合についてBU12(Chembiochem)と競合し、これらの抗体はCD19分子の同様なまたは重複エピトープを共有し手いることを示唆している。
CDR接合hA19VHおよびVk遺伝子を遺伝子工学処理するため、Leung et al.3によって記載された方法の変法を用いて、長いオリゴヌクレオチド合成とPCRの組合せを用いてhA19についてデザインされたVkおよびVH遺伝子を構築した。簡単に説明すれば、V配列の5’−(センス鎖、Aと称される)および3’−ハーフ(アンチセンス鎖、Bと称される)を表す2本の長い合成オリゴヌクレオチド(長さが約130マー)を、PCR反応の鋳型として用いる。長いオリゴヌクレオチドAおよびBの3’末端配列を、互いに重複し且つ相補性になるようにデザインする。PCRをAおよびBの3’末端をアニーリングして、長いオリゴヌクレオチドの残り(一本鎖)が隣接した短い二本鎖DNAを形成する。それぞれのアニーリング末端は一本鎖DNAの複製のプライマーとして働き、AおよびBを伸長して、二本鎖DNAを形成する。2本の短いオリゴヌクレオチドプライマーの存在下では、V遺伝子セグメントが二本鎖DNAのPCR増幅によって生成する。
hAl9 VHドメインを構築するため、長いオリゴヌクレオチドhAl9VHA(126マー)およびhA19VHB(128マー)を自動DNA合成装置(Applied Biosystem)上で合成した。hA19VHAはhA19 VHドメインのnt 74−126を表し、hA19VHBはnt 178−306に相補性のhA19VHドメインのマイナス鎖を表す。hA19VHAおよびVHBの3’末端配列(33nt残基)は、互いに相補性である。最小量のhA19VHAおよびVHB(経験的に決定)を、10xPCR緩衝液(500mM KCl,100mMトリス−HCl緩衝液,pH8.3、15mM MgCl2)、2μMのhA19VHBack(5'-CAGGTCCAAC TGCAGCAATC AGGGGCTGAA GTCAAGAAAC CTGGGTCATCG GTGAAGGTCTC CTGCAAGGCT TCTGGCTACG CTTTCAGTAG C-3')およびhA19VHFor (5'-TGAGGAGACG GTGACCGTGG TCCCTTGGCC CCAGTAGTCC ATAGCATAGT AATAACGGCC TACCGTCGTA GTCTCCCGTC TTGCACAAG-3')、および2.5単位のTaq DNAポリメラーゼ(Perkin Elmer Cetus, ノーウォーク,コネチカット)の存在下で増幅した。下線部分は、図4Bに示されるように、サブクローニングの制限部位である。この反応混合物に、94℃で1分間の変性、45℃で1分間のアニーリング、および72℃で1.5分間の重合からなるポリメラーゼ連鎖反応(PCR)を3サイクル行った。この処置に続いて、94℃で1分間の変性、55℃で1分間のアニーリング、および72℃で1分間の重合からなるPCR反応27サイクル行った。生成するDNAフラグメントは、アガロースゲル電気泳動で約350の予想した分子サイズを示した。hA19VHについての二本鎖PCR増幅産物をゲル精製し、PstIおよびBstEII制限酵素で制限消化し、重鎖ステージングベクターVHpBS2の相補性PstI/BstElI制限部位にクローニングし、VH配列は、翻訳開始コドンをコードするDNA配列と完全に組み立てられ、ぶんぴシグナルペプチドは5’末端でインフレーム連結し、イントロン配列は3’末端で連結した。VHpBS2はVHpBSの修飾したステージングベクターであり(Leung et al., Hybridoma, 13:469 (1994))、これの翻訳開始コドンの16塩基上流にXhoI制限部位を導入して、次のサブクローニング段階を促進した。組み立てられたVH遺伝子は、XhoI−BamHI制限フラグメントとして、IgHエンハンサーおよびMT1プロモーター、並びに選択および増幅のマーカーとしてのマウスdhfr遺伝子の制御下でヒトIgG重および軽鎖の両方についての発現カセットを含む発現ベクターpdHL2にサブクローニングした(図4B)。pdHL2の重鎖領域はBamHI制限部位を欠くので、この連結には、リンカーを用いて可変鎖のBamHI部位とpdHL2ベクターに存在するHindIII部位の間に橋を提供する必要がある。生成する発現ベクターは、hA19VHpdHL2と命名した。
hAl9についての発現ベクター約30gをSalIで消化することによって線形化し、電気穿孔(450Vおよび25μF)によってSp2/0−Agl4細胞にトランスフェクションした。トランスフェクション細胞を96穴プレートで2日間培養した後、MTX培地に0.075μMの最終濃度で添加することによって薬剤耐性について選択した。MTX耐性コロニーは、2−3週間でウェルに現れた。選択の後に残っているコロニーの上清を、ヒトAb分泌についてELISA分析法によってスクリーニングした。簡単に説明すれば、100μlの上清をF(ab’)2フラグメント特異AbであるGAH−IgGを予備コーティングしたマイクロタイタープレートのウェルに加え、室温で1時間インキュベーションした。未結合タンパク質を、洗浄緩衝液(0.05%ポリソルベート20を含むPBS)で3回洗浄することによって除去した。HRPと接合したGAH−IgGであるFcフラグメント特異Abを、ウェルに加えた。1時間インキュベーションの後、プレートを洗浄した。結合したHRP接合Abは、4mM OPDと0.04% H2O2を含む基質溶液を添加した後に、A490nmを読むことによって明らかになった。陽性細胞クローンを膨張させ、hB43をプロテインAカラム上でのアフィニティークロマトグラフィーによって細胞培養物上清から精製した。
プロテインAカラム上でのアフィニティークロマトグラフィーによって精製したcAl9およびhAl90のAg結合特異性を、細胞表面競合的結合測定法によって評価し、比較した。簡単に説明すれば、一定量(100,000cpm,約10μCi/μg)の125Iで標識したcA19またはhA19を、様々な濃度(0.2−700nM)のcAl9またはhAl9の存在下にてラージ細胞と共に4℃で1−2時間インキュベーションした。未結合Abは、細胞をPBSで洗浄することによって除去した。細胞に関する放射能を、洗浄後に測定した。図2に示されるように、精製したhA19は細胞表面結合について125I標識cAl9と競合し、その逆も成り立つことから、見かけの結合アビディティーはこれらの2種類のAbの間で類似していることを示している。
進行の遅い小胞細胞NHLの患者はデキサメタゾンを含む化学療法の後に再発し、胸部(大動脈傍リンパ節)、鬱血して入り組んだ脾臓、および鬱血した頸部リンパ節に疾病を有する。患者に、本発明のヒト化CD19 MAbに続いて同日にヒト化CD20 MAb (hA20)を組み合わせて静脈内輸液によりそれぞれ300mg/m2のコースを1週毎に4週間投与し、それぞれの投与時に、輸液に関連した反応を抑制するためにチレノール(Tylenol)(登録商標)とベナドリル(Benadryl)(登録商標)を標準的な公表された用量に従って前投与した。4週間後、患者に最初の追跡調査試験を行い、触診可能なリンパ節の幾つかが柔らかくなっている点のみを観察する。最初の治療サイクルに続いて3ヶ月後の再来時に、患者の胸部疾患はCTスキャン上では40%減少しており、脾臓は治療前の大きさのほぼ半分であり、頸部リンパ節はほとんどなくなっている。患者に、次に再治療サイクルを行い、更に3ヶ月後には、脾臓は正常な大きさとなっており、頸部リンパ節は蝕知不能かまたはCTスキャン上で測定不能であり、胸部の病巣は小さく1.5cmしかなかった。患者は更に4ヶ月間通院を続けたが、疾患はほぼなくなっていた。
Claims (9)
- ヒト化抗CD19モノクローナル抗体またはそのフラグメントであって、
前記ヒト化抗CD19モノクローナル抗体が、図4AのhA19Vk(配列番号7)、図4BのhA19V H (配列番号10)およびヒト抗体の定常領域を含んでなり、
前記フラグメントが、F(ab’) 2 、Fab’、Fab、FvおよびsFvからなる群から選択されるものである、ヒト化抗CD19モノクローナル抗体またはそのフラグメント。 - 少なくとも2つのモノクローナル抗体またはそのフラグメントを含んでなる抗体融合タンパク質であって、前記モノクローナル抗体またはそのフラグメントのそれぞれが独立して請求項1に記載の抗CD19モノクローナル抗体またはそのフラグメントである、抗体融合タンパク質。
- (a)請求項1に記載の少なくとも1つの第一の抗CD19モノクローナル抗体またはそのフラグメントと、(b)少なくとも1つの第二のモノクローナル抗体またはそのフラグメントとを含んでなり、前記第二のモノクローナル抗体またはそのフラグメントが抗CD19モノクローナル抗体またはそのフラグメント以外のものである、抗体融合タンパク質。
- 少なくとも1つのモノクローナル抗体またはそのフラグメントがターゲッティング可能な接合体と反応性であり、前記ターゲッティング可能な接合体が診断または治療薬を有するものである、請求項3に記載の抗体融合タンパク質。
- 前記第二のモノクローナル抗体またはそのフラグメントが、CD4、CD5、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、CD138、B7、MUC−1、Ia、HM1.24、HLA−DR、テネイシン、VEGF、PIGF、ED−Bフィブロネクチン、癌遺伝子、癌遺伝子産物、NCA 66a−d、壊死抗原、Ii、IL−2、T101、TAC、IL−6、TRAIL−R1(DR4)およびTRAIL−R2(DR5)、およびそれらの組合せからなる群から選択される抗原と反応性のモノクローナル抗体からなる群から選択されるものである、請求項4に記載の抗体融合タンパク質またはそのフラグメント。
- 少なくとも1つの診断薬または少なくとも1つの治療薬に結合した抗体成分を含んでなり、前記抗体成分が、請求項1に記載の抗CD19モノクローナル抗体またはそのフラグメント、または、請求項2または3に記載の抗体融合タンパク質を含んでなる、B細胞ターゲッティング診断または治療接合体。
- 前記抗体成分が、抗体融合タンパク質であり、前記モノクローナル抗体またはそのフラグメントのそれぞれが、少なくとも1つの治療薬に結合してなる、請求項6に記載の治療接合体。
- 前記治療薬が、放射性標識、免疫調節剤、酵素、ホルモン、オリゴヌクレオチド、光活性治療薬、細胞傷害剤およびそれらの組合せからなる群から選択されるものである、請求項6に記載の治療接合体。
- 前記細胞傷害剤が薬剤または毒素である、請求項8に記載の治療接合体。
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US7462352B2 (en) | 2008-12-09 |
WO2005012493A2 (en) | 2005-02-10 |
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CA2534639C (en) | 2013-07-30 |
US7109304B2 (en) | 2006-09-19 |
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JP2011144191A (ja) | 2011-07-28 |
WO2005012493A3 (en) | 2005-03-24 |
EP2216342A1 (en) | 2010-08-11 |
JP2007528209A (ja) | 2007-10-11 |
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EP2216342B1 (en) | 2015-04-22 |
US20060257398A1 (en) | 2006-11-16 |
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