JP2006513203A - 非コンジュゲートおよびコンジュゲート抗体、抗体の組合せおよび融合タンパク質を用いるb細胞悪性腫瘍および自己免疫疾患の免疫療法 - Google Patents
非コンジュゲートおよびコンジュゲート抗体、抗体の組合せおよび融合タンパク質を用いるb細胞悪性腫瘍および自己免疫疾患の免疫療法 Download PDFInfo
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Abstract
Description
(a)少なくとも一つの標的抗原と結合する多重特異性多価抗体、フラグメントまたは融合タンパク質を含んでなる組成物を哺乳類に投与すること;
(b)場合により、その組成物に非局在抗体を循環から排除させるためのクリアリング剤;および
(c)該多重特異性多価抗体、フラグメントまたは融合タンパク質と結合する、薬学上有効な量の治療複合体を該哺乳類に投与すること
を含んでなり、非放射性標識抗体の前投与を行わない。
本発明の他の目的、特徴および利点は以下の詳細な説明および添付の特許請求の範囲から明らかになる。
以下の説明では多数の専門用語が使用されているが、以下、本発明の理解を容易にするために定義を示す。
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集団であり、その抗体はただ一種の抗原結合部位を含んでなり、抗原決定基上のただ一つのエピトープに結合する。特定の抗原に対する齧歯類モノクローナル抗体は、当業者に公知の方法により得ることができる。例えば、Kohler and Milstein, Nature 256:495(1975)、およびColigan et al.(eds.), CURRENT PROTOCOLS IN IMMUNOLOGY, VOL. 1, pages 2.5.1-2.6.7(John Wiley & Sons 1991)[以下「Coligan」]を参照することができる。要するに、マウスに抗原を含む組成物を注射し、血清サンプルを採取して抗体産生を確認し、脾臓を摘出してBリンパ球を採取し、そのBリンパ球と骨髄腫細胞を融合させてハイブリドーマを作製し、そのハイブリドーマをクローニングし、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て、その抗体をハイブリドーマ培養物から単離することによりモノクローナル抗体を得ることができる。
特定のエピトープを認識する抗体フラグメントは、公知の技術により作製し得る。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、限定されるものではないが、抗体分子のペプシン消化により作製できる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結合を還元することにより作製できるFab'フラグメントが挙げられる。あるいは、所望の特異性を有するモノクローナルFab’フラグメントの迅速で容易な同定を可能にするには、Fab’発現ライブラリーを構築することができる(Huse et al., 1989, Science, 246:1274-1281)。本発明は抗体および抗体フラグメントを包含する。
本明細書に記載の併用療法に用いられる、同じ特異性を有する抗体も異なる特異性を有する抗体も多重特異性抗体(CD20エピトープまたは抗原に対する少なくとも一つの結合部位とCD20または他の抗原上の別のエピトープに対する少なくとも一つの結合部位を含む)および多価抗体(同じエピトープまたは抗原に対して複数の結合部位を含む)
として作製することができる。
本発明では多価抗体も意図される。この多価標的結合タンパク質は、第一および第二のポリペプチドの結合により構築される。第一のポリペプチドは、好ましくは免疫グロブリン軽鎖可変領域ドメインである第一の免疫グロブリン様ドメインに共有結合された第一の単鎖Fv分子を含んでなる。第二のポリペプチドは、好ましくは免疫グロブリン重鎖可変領域ドメインである第二の免疫グロブリン様ドメインに共有結合された第二の単鎖Fv分子を含んでなる。第一および第二の単鎖Fv分子は各々、標的結合部位を形成し、第一および第二の免疫グロブリン様ドメインは結合して第三の標的結合部位を形成する。
本発明の抗体はまた、ダイアボディーとも呼ばれる、機能的二重特異性単鎖抗体(bscAb)の調製に使用でき、組換え法により哺乳類細胞において生産させることができる。例えば、引用することにより本明細書の一部とされる、Mack et al., Proc. Natl. Acad. Sci., 92:7021-7025,1995を参照することができる。例えば、bscAbは組換え法によりグリシン−セリンリンカーを介して二つの単鎖Fvフラグメントを結合することで作製する。問題の二つの抗体のV軽鎖(VL)およびV重鎖(VH)ドメインは、標準的PCR法により単離される。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のcDNAは二段階の融合PCRにおいて結合されて単鎖フラグメントを形成する。第一のPCR工程では(Gly4−Ser1)3リンカーを導入し、第二の工程ではVLおよびVHアンプリコンを結合させる。次いでそれぞれの単鎖分子を細菌発現ベクターへクローニングする。増幅後に単鎖分子の一つを切り出して問題の第二の単鎖分子を含む他のベクターへサブクローニングする。得られたbscAbフラグメントを真核細胞発現ベクターへサブクローニングする。機能性タンパク質の発現は、そのベクターをチャイニーズハムスター卵巣細胞へトランスフェクトすることにより得られる。二重特異性融合タンパク質も同様の方法で調製される。二重特異性単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実施形態は、コンジュゲート多価抗体である。第一または第二のポリペプチドのN末端またはC末端のいずれかに、さらなるアミノ酸残基を付加してもよい。このさらなるアミノ酸残基は、ペプチドタグ、シグナルペプチド、サイトカイン、酵素(例えば、プロドラッグ活性化酵素)、ホルモン、シュードモナス外毒素のようなペプチド毒素、ペプチド薬、細胞傷害性タンパク質または他の機能性タンパク質を含んでよい。本明細書において機能性タンパク質とは、生物学的機能を有するタンパク質である。
本発明に従う類人霊長類化、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CD20 MAbおよびその他のMAbは治療法および診断法で用いるのに好適である。従って本発明は、本発明の類人霊長類化、ヒト化、キメラおよびヒト抗体の裸の抗体としての単独投与、または多様式療法として、治療薬とは結合させないが、投与計画に従った一時的投与を意図する。裸の抗CD20 MAbの効力は、一以上の他の裸の抗体、すなわちCD4、CD5、CD8、CD14、CD15、CD19、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、B7、Ia、HM1.24、テネイシン、MUC1、またはHLA−DR等の特異抗原に対するMAb、ならびに一以上の抗CD20の免疫複合体を含む抗血管形成抗体(例えば、VEGFおよびPlGF抗体)を含む裸の抗体、あるいは薬物、毒素、免疫調節剤、ホルモン、治療用放射性核種などをはじめとする治療薬と結合され、同時または逐次または指示された投与計画に従って投与される薬物、毒素、免疫調節剤、ホルモン、治療用放射性核種などをはじめとする一以上の治療薬を含むこれら挙げられた抗原に対する抗体であって、MAbを含むものを補足することにより増強させることができる。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抗原と同等なものが挙げられる。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)抗原と同等なものが挙げられる。HLA−DR抗原と同等なものは、B細胞およびT細胞性疾患の双方の治療に使用できる。特に好ましいB細胞抗原はヒトCD19、CD22、CD21、CD23、CD74、CD80およびHLA−DR抗原と同等なものである。特に好ましいT細胞抗原は、ヒトCD4、CD8およびCD25抗原と同等なものである。CD46は癌細胞表面上の抗原であり、補体依存性溶解(CDC)を阻害する。
多種多様な治療薬が、本発明の抗体と有利に結合できる。本明細書に列挙された治療薬は、上記のように裸の抗体とは別に投与しても有用である薬剤である。治療薬としては、例えば、ビンカアルカロイド、アントラサイクリン、エピトフィロトキシン、タキサン、抗代謝剤、アルキル化剤、抗生物質、Cox−2阻害剤、抗有糸分裂剤、抗血管形成剤およびアポトーシス剤、特にドキソルビシン、メトトレキサート、タキソール、CPT−11、カンプトテカン、およびこれらまたは他の種類の抗癌剤由来の他のものなどの化学療法薬が挙げられる。免疫複合体および抗体融合タンパク質の調製に有用な他の癌化学療法薬としては、ナイトロジェンマスタード、アルキルスルホネート、ニトロソウレア、トリアゼン、葉酸類似体、COX−2阻害剤、ピリミジン類似体、プリン類似体、プラチナ錯体(オキサリプラチンを含む)、ホルモンなどが挙げられる。好適な化学療法薬はREMINGTON'S PHARMACEUTICAL SCIENCES,19th Ed.(Mack Publishing Co., 1995)およびGOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th Ed. (MacMillan Publishing Co., 1985)、ならびにこれらの刊行物の改訂版に記載されている。実験薬のような他の好適な化学療法薬も、当業者に公知である。
本発明のいずれの抗体または抗体融合タンパク質も、一種以上の治療薬と結合させることができる。一般に、一種の治療薬を各々抗体または抗体フラグメントに結合させるが、二種以上の治療薬を同じ抗体または抗体フラグメントに結合させることもできる。本発明の抗体融合タンパク質は二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各々が治療薬を含み得る。また、一以上の抗体融合タンパク質の抗体には、二種以上の治療薬を結合させることができる。さらに、この治療薬は同じである必要はなく、異なる治療薬であってもよい。例えば、同じ融合タンパク質に薬物と放射性同位元素を結合させることができる。特に、IgGは131Iで放射性標識し、薬物に結合させることができる。この131Iは、IgGのチロシンに組み込むことができ、薬物はIgGリジンのεアミノ酸に結合させることができる。治療薬は、還元SH基および炭化水素側鎖に結合させることもできる。
被検体に送達される類人霊長類化、ヒト化、キメラまたはヒト放射性標識抗体は、mAb単独、免疫複合体、融合タンパク質から構成されるか、または一以上の薬学上好適なビヒクル、一以上の付加的成分またはこれらのある組合せを含み得る。
本発明の免疫複合体抗体は、薬学上有用な組成物を調製するための公知の方法に従って調剤され、この免疫複合体または裸の抗体は混合物中で薬学上好適なビヒクルと結合する。滅菌リン酸緩衝生理食塩水は薬学上好適なビヒクルの一例である。他の好適なビヒクルも当業者に周知である。例えば、Ansel et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5th Edition (Lea & Febiger 1990)、およびGennaro(ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (Mack Publishing Company 1990)およびそれらの改訂版を参照することができる。
本発明はB細胞関連悪性腫瘍、T細胞関連悪性腫瘍または他種のリンパ腫などの疾病の治療のための基本組成物としての本発明の抗体の使用を意図する。さらに、本発明はまた、自己免疫疾患の治療にも有用である。特に、本明細書に記載の組成物は、種々の自己免疫疾患、ならびに緩徐進行型B細胞リンパ腫、急速進行型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、およびワルデンストロームマクログロブリン血症、多発性骨髄腫の治療に特に有用である。また、T細胞白血病または菌状息肉腫などのT細胞疾患も治療できる。例えば、ヒト化抗CD22抗体成分および免疫複合体は緩徐進行型と急速進行型の双方の非ホジキンリンパ腫の治療に使用できる。自己免疫疾患は、急性特発性血小板減少性紫斑病、慢性特発性血小板減少性紫斑病、皮膚筋炎、シドナム舞踏病、重症筋無力症、全身性紅斑性狼瘡、ループス腎炎、リウマチ熱、多腺性症候群、水疱性類天疱瘡、真性糖尿病、ヘノッホ−シェンライン紫斑病、溶連菌感染後腎炎、結節性紅斑、高安動脈炎、アジソン病、慢性関節リウマチ、多発性硬化症、サルコイドーシス、潰瘍性大腸炎、多形性紅斑、IgA腎症、結節性多発性動脈炎、強直性脊椎炎、グッドパスチャー症候群、閉塞性血栓性血管炎、シェーグレン症候群、原発性胆汁性肝硬変、橋本甲状腺炎、甲状腺中毒症、硬皮症、慢性活動性肝炎、多発性筋炎/皮膚筋炎、多発性軟骨炎、尋常性天疱瘡、ウェゲナー肉芽腫、膜性腎症、筋萎縮性側索硬化症、脊髄ろう、巨細胞性動脈炎/多発性筋痛、悪性貧血、急速進行性糸球体腎炎、乾癬、および繊維性肺胞炎からなる群から選択される。
本発明の実施形態を、本発明の態様を詳しく示す実施例によりさらに説明する。これらの実施例は本発明の特定の構成要素を示すものであり、その範囲を限定するものではない。
エプラツズマブはヒト化LL2抗体であり、Immunomedics Inc., Morris Plains, NJが開発したものである。ヒト化のプロセスでは、ネズミIg配列の約95%がヒトIgG1配列に置き換わる。エプラツズマブは、三番目のIgドメイン(Kehrl, J. H. B6 CD22 Workshop Panel Report, in Leukocyte Typing V. White Cell Differentiation Antigens., S. F. Schlossman (ed.), Oxford University Press, p. 523-5, 1995)に相当するCD22抗原のBエピトープ(Stein, R. et al., Cancer Immunol. Immunother. 37 (5): 293-8, 1993)にひと度結合するとインターナライズされる。イン・ビトロインターナリゼーションが5分後に見られ、5時間後に50%といった量の抗原の再発現が起こることが報告されている(Shih, L. B. et al.Int J Cancer 56(4):538-45, 1994)。
66歳の男性、第IV病期びまん性大細胞NHL患者は2年前に3コースの化学療法を受けた後に再発していた。この患者は1週間あけて、7.5mCi/m2の90Yを含む90Y−DOTA−エプラツズマブ(Govinden,同書に従って標識)の二回注射量を施し、これは各回全用量30mgの抗体タンパク質を静脈点滴することで投与した。6週間後、患者の頸部リンパ節および巨脾腫に顕著な退縮があったことが明らかになり、この患者は症状改善を見せ、フルタイムの仕事に復帰した。この患者は完全緩解には至らなかったので、1週間おきに計4回の点滴で投与するエプラツズマブ(360mg/m2)およびhA20(250mg/m2)の組合せを含む継続治療を設定し、次に、組合せ抗体療法コースをその後12週間繰り返した。裸のCD22およびCD20抗体の組合せによる二回目の治療コースが完了してから3ヶ月後、放射線走査または骨髄生検によって患者に疾病の証拠はなかったことから、完全緩解であるとみなされた。次の評価時である3ヶ月後においても、患者はまだ疾病の完全緩解の状態にあった。
従来の化学療法に不応の、進行したT細胞白血病患者に、20mCi90Y−DOTAと結合させた50mg抗CD25ヒト化Mabの点滴を行った後、1週間後に200mg/m2用量のCD25Mab(抗TACヒト化抗体)の点滴を行った。4週間後、この患者の血球計数および骨髄生検を行ったところ、疾病の部分緩解が示された。
多くの関節、特に膝を侵す進行した重度の慢性関節リウマチを示し、その時点で化学療法に不応の患者を、線量10mCi/m2の90Yで標識したCD4およびCD20ヒト化Mab混合物、計50mgの一回点滴で治療した。2週間後、この患者に100mgCD4および250mgCD20抗体からなる裸のヒト化抗体を投与し、2週間後にこれをもう一度繰り返した。患者は4週間後、特に膝において関節炎の軽減を感じ、歩行が楽になり、階段を登ることさえもできるようになり、主治医が診たところ関節の炎症もほとんどなかった。3ヶ月後、この放射性標識抗体混合物の点滴一回、その後、裸のCD4およびCD20抗体の二回の点滴を含む治療コースを繰り返し、6週間後に患者を再評価した。医師は著しい改善を認め、患者は関節に最小の痛みしかなく、手足の動きが相当よくなったとうったえた。
本明細書に引用されている刊行物ならびに特許出願および特許は総て、引用することによりその全開示内容が本明細書の一部とされる。
Claims (56)
- 哺乳類の疾病の治療に用いるための薬剤の製造における、薬学上許容されるビヒクルと少なくとも一種のコンジュゲート抗体もしくはそのフラグメント、またはコンジュゲート抗体融合タンパク質もしくはそのフラグメントとを含んでなる治療組成物の使用であって、非放射性標識抗体の前投与が行われず、該治療組成物が該哺乳類に同時または逐次投与される、使用。
- 増殖腫瘍または自己免疫疾患細胞が標的逸出しないようにするための維持療法として、前記コンジュゲート抗体もしくはそのフラグメントまたは前記コンジュゲート抗体融合タンパク質もしくはそのフラグメントに加え、場合により、非コンジュゲート抗体もしくはフラグメントまたは非コンジュゲート抗体融合タンパク質もしくはそのフラグメントが加えられる、請求項1に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質、またはそのフラグメントが、CD3、CD4、CD5、CD8、CD11c、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、D38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、MUC1、テネイシン、Ia、HMI.24、HLA−DR、および腫瘍関連抗原からなる群から選択される抗原に向けられたものである、請求項1または2に記載の使用。
- 前記腫瘍関連抗原が血管内皮抗原である、請求項3に記載の使用。
- 前記哺乳類がヒトおよび家畜または伴侶動物からなる群から選択される、請求項3に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質、またはそのフラグメントが、ヒト、ネズミ、キメラ、霊長類化またはヒト化抗体である、請求項3に記載の方法。
- 前記抗体、抗体融合タンパク質、またはそのフラグメントが、薬物、毒素、免疫調節剤、キレート剤、ホウ素化合物、光活性剤、および放射性核種からなる群から選択される治療薬と結合されてなるものである、請求項3に記載の使用。
- 薬学上許容されるビヒクルと少なくとも一種の抗体、抗体融合タンパク質またはそのフラグメントとを含んでなる治療組成物を、前記哺乳類に同時または逐次投与することをさらに含み、前記抗体、抗体融合タンパク質またはそのフラグメントが少なくとも一種の治療薬と結合されてなるものである、請求項3に記載の使用。
- 増殖腫瘍または自己免疫疾患細胞が標的逸出しないようにするための維持療法として、前記コンジュゲート抗体、抗体融合タンパク質またはそのフラグメントに加え、場合により、非コンジュゲート抗体、抗体融合タンパク質またはそのフラグメントが加えられる、請求項8に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質、またはそのフラグメントが、CD3、CD4、CD5、CD8、CD11c、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、D38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、MUC1、テネイシン、Ia、HMI.24、HLA−DR、および腫瘍関連抗原からなる群から選択される抗原に向けられたものである、請求項8または9に記載の使用。
- 前記腫瘍関連抗原が血管内皮抗原である、請求項10に記載の使用。
- 前記哺乳類がヒトおよび家畜または伴侶動物からなる群から選択される、請求項10に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質、またはそのフラグメントが、ヒト、ネズミ、キメラ、霊長類化またはヒト化抗体である、請求項10に記載の方法。
- 前記抗体、抗体融合タンパク質、またはそのフラグメントが薬物、毒素、免疫調節剤、キレート剤、ホウ素化合物、光活性剤、および放射性核種からなる群から選択される治療薬と結合されてなるものである、請求項10に記載の使用。
- 薬学上許容されるビヒクルと、少なくとも二種の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またはそのフラグメントとを含んでなる治療組成物を前記哺乳類に同時または逐次投与することをさらに含む、請求項1に記載の使用。
- 増殖腫瘍またはその他の罹患細胞が標的逸出しないようにするための維持療法として、前記抗体融合タンパク質またはそのフラグメントに加え、場合により、非コンジュゲート抗体が加えられる、請求項15に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体が、CD3、CD4、CD5、CD8、CD11c、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、D38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、MUC1、テネイシン、Ia、HMI.24、HLA−DR、および腫瘍関連抗原からなる群から選択される抗原に向けられたものである、請求項15または16に記載の使用。
- 前記腫瘍関連抗原が血管内皮抗原である、請求項17に記載の使用。
- 前記哺乳類がヒトおよび家畜または伴侶動物からなる群から選択される、請求項17に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体がヒト、ネズミ、キメラ、霊長類化またはヒト化抗体である、請求項17に記載の方法。
- 前記抗体が薬物、毒素、免疫調節剤、キレート剤、ホウ素化合物、光活性剤、および放射性核種からなる群から選択される治療薬と結合されてなるものである、請求項17に記載の使用。
- 前記薬物が抗有糸分裂薬、アルキル化薬、代謝拮抗薬、抗脈管形成薬、アポトーシス薬、アルカロイド薬、および抗生物質、ならびにそれらの組合せからなる群から選択される薬理特性を有する、請求項7に記載の使用。
- 前記薬物がナイトロジェンマスタード、エチレンイミン誘導体、スルホン酸アルキル、ニトロソ尿素、トリアゼン、葉酸類似体、アントラサイクリン、タキサン、COX−2阻害剤、ピリミジン類似体、プリン類似体、抗生物質、酵素、エピポドフィロトキシン、プラチナ錯体、ビンカアルカロイド、置換尿素、メチルヒドラジン誘導体、副腎皮質抑制剤、アンタゴニスト、エンドスタチン、タキソール、カンプトテシン、ドキソルビシンおよびそれらの類似体、ならびにそれらの組合せからなる群から選択される、請求項7に記載の使用。
- 前記薬物がシクロホスファミド、エトポシド、ビンクリスチン、プロカルバジン、プレドニゾン、カルムスチン、ドキソルビシン、メトトレキサート、ブレオマイシン、デキサメタゾン、酪酸フェニル、ブリオスタチン−1、およびロイコボリンからなる群から選択される、請求項7に記載の使用。
- 前記毒素がリシン、アブリン、アルファトキシン、サポリン、リボヌクレアーゼ(RNアーゼ)、DNアーゼI、ブドウ球菌腸毒素−A、アメリカヤマゴボウ抗ウイルスタンパク質、ゲロニン、ジフテリア毒、シュードモナス外毒素、およびシュードモナス内毒素からなる群から選択される、請求項7に記載の使用。
- 前記免疫調節剤がサイトカイン、幹細胞増殖因子、リンホトキシン、造血系増殖因子、コロニー刺激因子(CSF)、インターフェロン(IFN)、エリスロポエチン、トロンボポエチンおよびそれらの組合せからなる群から選択される、請求項7に記載の使用。
- 前記免疫調節剤が本質的にIL−1、IL−2、IL−3、IL−6、IL−10、IL−12、IL−18、G−CSF、GM−CSF、インターフェロン−γ、−α、−βまたは−γ、TNF−α、および「S1因子」からなる、請求項7に記載の使用。
- 前記キレート剤がDTPA、DOTA、TETA、NOTAおよび検出可能な標識または細胞傷害性薬剤が結合可能な好適なペプチドからなる群から選択される、請求項7に記載の使用。
- 前記検出可能な標識が蛍光分子であり、かつ、前記細胞傷害性薬剤が重金属または放射性核種である、請求項28に記載の使用。
- 前記リンホトキシンが腫瘍壊死因子、造血系増殖因子、コロニー刺激因子、インターフェロン、幹細胞増殖因子からなる群から選択される、請求項26に記載の使用。
- 前記光活性剤が色素原または色素である、請求項7に記載の使用。
- (A)前記放射性核種が実質的にβ粒子の放出により崩壊し、P−32、P−33、Sc−47、Fe−59、Cu−64、Cu−67、Se−75、As−77、Sr−89、Y−90、Mo−99、Rh−105、Pd−109、Ag−111、I−125、I−131、Pr−142、Pr−143、Pm−149、Sm−153、Tb−161、Ho−166、Er−169、Lu−177、Re−186、Re−188、Re−189、Ir−194、Au−198、Au−199、Pb−211、Pb−212、およびBi−213からなる群から選択されるか;
(B)前記放射性核種が実質的にオージェ粒子の放出により崩壊し、Co−58、Ga−67、Br−80m、Tc−99m、Rh−103m、Pt−109、In−111、Sb−119、I−125、Ho−161、Os−189mおよびIr−192からなる群から選択されるか;または
(C)前記放射性核種が実質的にα粒子の放出により崩壊し、Ac−225、Dy−152、At−211、Bi−212、Ra−223、Rn−219、Po−215、Bi−211、Ac−225、Fr−221、At−217、Bi−213およびFm−255からなる群から選択される、
請求項7に記載の使用。 - 前記治療薬が光線力学療法および中性子捕捉法で用いられる、請求項7に記載の使用。
- 前記光線力学療法が金属錯体を用い、かつ、前記金属錯体が亜鉛、アルミニウム、ガリウム、ルテチウムおよびパラジウムからなる群から選択される、請求項33に記載の使用。
- 前記中性子捕捉法がB−10、Gd−157およびU−235からなる群から選択される放射性核種を用いる、請求項33に記載の使用。
- 前記疾病がB細胞関連疾患、T細胞関連疾患または自己免疫疾患である、請求項1に記載の使用。
- 前記B細胞関連疾患が緩徐進行型B細胞リンパ腫、急速進行型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、ワルデンストロームマクログロブリン血症、または多発性骨髄腫である、請求項37に記載の使用。
- 前記B細胞関連疾患がヒトまたは家畜疾患である、請求項37に記載の使用。
- 前記B細胞リンパ腫が非ホジキンリンパ腫である、請求項37に記載の使用。
- 前記T細胞関連疾患がヒトまた家畜T細胞白血病または菌状息肉腫である、請求項37に記載の使用。
- 前記自己免疫疾患が急性特発性血小板減少性紫斑病、慢性特発性血小板減少性紫斑病、皮膚筋炎、シドナム舞踏病、重症筋無力症、全身性紅斑性狼瘡、ループス腎炎、リウマチ熱、多腺性症候群、水疱性類天疱瘡、真性糖尿病、ヘノッホ−シェンライン紫斑病、溶連菌感染後腎炎、結節性紅斑、高安動脈炎、アジソン病、慢性関節リウマチ、多発性硬化症、サルコイドーシス、潰瘍性大腸炎、多形性紅斑、IgA腎症、結節性多発性動脈炎、強直性脊椎炎、グッドパスチャー症候群、閉塞性血栓性血管炎、シェーグレン症候群、原発性胆汁性肝硬変、橋本甲状腺炎、甲状腺中毒症、硬皮症、慢性活動性肝炎、多発性筋炎/皮膚筋炎、多発性軟骨炎、尋常性天疱瘡、ウェゲナー肉芽腫、膜性腎症、筋萎縮性側索硬化症、脊髄ろう、巨細胞性動脈炎/多発性筋痛、悪性貧血、急速進行性糸球体腎炎、乾癬、および繊維性肺胞炎からなる群から選択される、請求項37に記載の使用。
- 罹患組織上の標的抗原の比率が正常組織上の標的抗原の比率を、1.6:1の比率より超える、請求項1に記載の使用。
- 罹患組織上の標的抗原の比率が正常組織上の標的抗原の比率を、5:1の比率より超える、請求項1に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質またはそのフラグメントが同じ、または異なる標的に向けられている、請求項1に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体、抗体融合タンパク質、またはそのフラグメントが完全IgG、F(ab’)2、F(ab)2、Fab’、Fab、scFv、ダイアボディー、トリアボディーまたはテトラボディーからなる群から選択される、請求項1に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体が抗CD22モノクローナル抗体である、請求項1に記載の使用。
- 前記コンジュゲートおよび非コンジュゲート抗体がヒト化LL2モノクローナル抗体である、請求項1に記載の使用。
- 前記ヒト化LL2抗体がイットリウム−90で放射性標識されている、請求項47に記載の使用。
- 前記抗CD22モノクローナル抗体がヒト抗体である、請求項46に記載の使用。
- 前記コンジュゲート抗体が1回当たり20〜600ミリグラムタンパク質の用量で非経口投与される、請求項44に記載の使用。
- 前記コンジュゲート抗体が1回当たり20〜150ミリグラムタンパク質の用量で非経口投与される、請求項44に記載の使用。
- 前記コンジュゲート抗体が1回当たり20〜100ミリグラムタンパク質の用量で非経口投与される、請求項44に記載の使用。
- 前記哺乳類が前記抗CD22モノクローナル抗体を1回当たり20〜150ミリグラムタンパク質の反復非経口用量として受容する、請求項46に記載の使用。
- 前記哺乳類が前記抗CD22モノクローナル抗体を1回当たり20〜100ミリグラムタンパク質の反復非経口用量として受容する、請求項46に記載の使用。
- 哺乳類の疾病の治療に用いるための薬剤の製造における、薬学上許容されるビヒクルと、少なくとも一つの標的抗原および治療薬と結合する多重特異性多価抗体、フラグメントまたは融合タンパク質複合体を含んでなる治療組成物の使用であって、非放射性標識抗体の前投与が行われず、該治療組成物が該哺乳類に同時または逐次投与される、使用。
- 哺乳類の疾病の治療に用いるための薬剤の製造における、
(A)少なくとも一つの標的抗原と結合する多重特異性多価抗体、フラグメントまたは融合タンパク質;
(B)場合により、その組成物に非局在抗体を循環から排除させるためのクリアリング剤;および
(C)該多重特異性多価抗体、フラグメントまたは融合タンパク質と結合する、薬学上有効な量の治療複合体
を含んでなる治療組成物の使用であって、非放射性標識抗体の前投与が行われず、該治療組成物が該哺乳類に同時または逐次投与される、使用。
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PCT/GB2003/005700 WO2004058298A1 (en) | 2002-12-31 | 2003-12-31 | Immunotherapy of b cell malignancies and autoimmune disease using unconjugated antibodies and conjugated antibodies, antibody combinations and fusion proteins |
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- 2003-12-31 AU AU2003295166A patent/AU2003295166B2/en not_active Expired
- 2003-12-31 EP EP16000173.1A patent/EP3031473A1/en not_active Withdrawn
- 2003-12-31 RU RU2005124281/15A patent/RU2335297C2/ru not_active IP Right Cessation
- 2003-12-31 PL PL378636A patent/PL216208B1/pl unknown
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US9446146B2 (en) | 2007-12-26 | 2016-09-20 | Biotest Ag | Methods and agents for improving targeting of CD138 expressing tumor cells |
JP2011508738A (ja) * | 2007-12-26 | 2011-03-17 | バイオテスト・アクチエンゲゼルシヤフト | Cd138発現腫瘍細胞のターゲティングを向上させる方法及び剤 |
US11466095B2 (en) | 2010-03-12 | 2022-10-11 | Debiopharm International S.A. | CD37-binding molecules and immunoconjugates thereof |
JP2013544493A (ja) * | 2010-09-03 | 2013-12-19 | ステム セントリックス, インコーポレイテッド | 新規モジュレータ及びその使用法 |
JP2018115162A (ja) * | 2010-09-03 | 2018-07-26 | アッヴィ・ステムセントルクス・エル・エル・シー | 新規モジュレータ及びその使用法 |
JP2018520207A (ja) * | 2015-05-21 | 2018-07-26 | アクティニウム ファーマシューティカルズ インコーポレイテッド | 結合型モノクローナル抗体の注入投与 |
US11395796B2 (en) | 2015-06-08 | 2022-07-26 | Debiopharm International, S.A. | Anti-CD37 immunoconjugate and anti-CD20 antibody combinations |
JP2018517714A (ja) * | 2015-06-08 | 2018-07-05 | デビオファーム インターナショナル, エス. アー. | 抗cd37イムノコンジュゲートおよび抗cd20抗体の組み合わせ |
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JP2019534844A (ja) * | 2016-09-08 | 2019-12-05 | ウリィ・テクノロジーズ・コーポレーション | clec14aに特異的に結合する脱糖化抗体及びその用途 |
US11278629B2 (en) | 2016-11-02 | 2022-03-22 | Debiopharm International, S.A. | Methods for improving anti-CD37 immunoconjugate therapy |
JP2020529416A (ja) * | 2017-07-31 | 2020-10-08 | アクティニウム ファーマシューティカルズ インコーポレイテッド | 血液悪性腫瘍の治療 |
JP7370958B2 (ja) | 2017-07-31 | 2023-10-30 | アクティニウム ファーマシューティカルズ インコーポレイテッド | 血液悪性腫瘍の治療 |
Also Published As
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RU2005124281A (ru) | 2006-01-27 |
EP1578440A1 (en) | 2005-09-28 |
PL216208B1 (pl) | 2014-03-31 |
US7534427B2 (en) | 2009-05-19 |
CN1756561A (zh) | 2006-04-05 |
MXPA05007245A (es) | 2005-09-12 |
CZ2005487A3 (cs) | 2005-12-14 |
PL378636A1 (pl) | 2006-05-15 |
AU2009222547B2 (en) | 2012-04-26 |
US20140147382A1 (en) | 2014-05-29 |
AU2003295166A1 (en) | 2004-07-22 |
AU2003295166B2 (en) | 2009-07-16 |
EP3031473A1 (en) | 2016-06-15 |
JP2010189413A (ja) | 2010-09-02 |
IL169313A0 (en) | 2007-07-04 |
KR20050100366A (ko) | 2005-10-18 |
WO2004058298A1 (en) | 2004-07-15 |
AU2009222547A1 (en) | 2009-10-22 |
EP2301570B8 (en) | 2017-01-25 |
EP2301570B1 (en) | 2016-01-27 |
CA2512188C (en) | 2013-11-19 |
US20090285752A1 (en) | 2009-11-19 |
CN102133410A (zh) | 2011-07-27 |
EP2301570A1 (en) | 2011-03-30 |
JP5085005B2 (ja) | 2012-11-28 |
US20040219156A1 (en) | 2004-11-04 |
CA2512188A1 (en) | 2004-07-15 |
RU2335297C2 (ru) | 2008-10-10 |
BR0317898A (pt) | 2005-12-06 |
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