JP6240600B2 - ヒト化免疫モノクローナル抗体の変異体 - Google Patents
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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Description
表1 既知のhBAT−1軽鎖及び重鎖の可変領域及び定常領域
(i)配列番号1〜4のアミノ酸配列を有する軽鎖可変領域の、Thr5、Thr20、Cys71、Asn75、Ser76、Phe93及びPhe97
(ii)配列番号5〜9のアミノ酸配列を有する重鎖可変領域の、Asp54、Ser55及びTrp107
(iii)配列番号10のアミノ酸配列を有する軽鎖定常領域の、Asn51、Ser52、Asp63及びSer64
(iv)配列番号12のアミノ酸配列を有する重鎖定常領域の、Thr3、Ser7、Asn42、Ser43、Asn86、His87、Asp104、Lys105、Thr108、Met135、Asp153、Pro154、Asp163、Gly164、Asn180、Ser181、Asn198、Gly199、Asn267、Gly268、Asp282、Ser283、Asp284、Ser285、Asn317、His318、Lys330及びMet311
表2 F93、F97又はW107アミノ酸置換を含む、hBAT−1変異した軽鎖及び重鎖の例示的な可変領域
定義
1)アラニン(Ala、A)、セリン(Ser、S)、スレオニン(Thr、T)
2)アスパラギン酸(Asp、D)、グルタミン酸(Glu、E)
4)アルギニン(Arg、R)、ヒスチジン(His、H)、リシン(Lys、K)
5)イソロイシン(Ile、I)、ロイシン(Leu、L)、メチオニン(Met、M)、バリン(Val、V)
6)フェニルアラニン(Phe、F)、チロシン(Tyr、Y)、トリプトファン(Trp、W)
ガン免疫療法は、腫瘍細胞の死滅及び腫瘍の成長の制御を誘導又は強化するための、免疫系の応答を調節することにより向けられ、それを大きな目的としている。このアプローチは、選択的にT細胞上の特異的決定基に結合し、それによって、活性化経路を開始するか又は阻害作用を誘発するかのいずれかである、モノクローナル抗体を含む様々な免疫調節剤の使用を利用する。
本発明の特定の態様によると、少なくとも一つの抗腫瘍化学療法剤と組み合わせた、改質されたアミノ酸を含む免疫刺激性ヒト化抗体の投与は、化学療法剤の抗腫瘍効果を増強及びその逆を行うように作用する。好ましい実施形態において、少なくとも一つの化学療法剤と免疫刺激抗体との組み合わせは、単独の治療法のそれぞれに対して有意の臨床成果を改善する。好ましい実施形態において、腫瘍を、少なくとも一つの化学療法剤と併せて、必要に応じて更に放射線と組み合わせて、本発明のヒト化抗体を用いて処理した場合、相乗効果がある。
各種実施形態によれば、方法は更に、放射線を用いて対象を治療することを含む。各種実施形態によれば、方法は、本発明の抗体を投与すること、少なくとも一つの化学療法剤を投与すること、及び、放射線を用いて治療することの全てを含む。一部の実施形態によれば、抗体、少なくとも一つの化学療法剤及び放射線治療を、実質的に同時に、並行して、交互に、連続して又は、重複するスケジュールに従って投与する。
本明細書において使用されるように、用語「BAT」及び「BAT抗体」は、広い意味で使用され、具体的には、mBAT−1又はその抗原結合断片として知られている、マウスモノクローナル抗体と一致する又は基づく抗体を含む。モノクローナル抗体mBAT−1は、米国特許第5,897,862号に開示されるように、寄託番号1−1397の下で、Collection Nationale de Cultures de Microorganismes (CNCM)に寄託された、ハイブリドーマ細胞株によって、分泌される。更に「BAT」及び「BAT抗体」は、米国特許出願第2003/0026800に記載されているように、例えばキメラ抗体などのmBAT−1として同じ抗原エピトープを認識する抗体を指し得る。BAT抗体はまた、ヒト化抗体を含み、それらの様々な例は、国際公開03/099196号及び米国特許出願第2008/0025980に開示され、区別なく「CT−011」、「hBAT」及び「hBAT−1」と表記されている。
FRL1−CDRL1−FRL2−CDRL2−FRL3−CDRL3−FRL4
式中、各FRは独立して、ヒト化抗体のフレームワーク領域であり、各CDRは独立して、モノクローナルmBAT−1抗体の相補性決定領域である。
FRH1−CDRH1−FRH2−CDRH2−FRH3−CDRH3−FRH4
式中、各FRは独立して、ヒト抗体のフレームワーク領域であり、各CDRは独立して、モノクローナルmBAT−1抗体の相補性決定領域である。
本発明の方法における使用のために、ヒト化抗体を、特にタンパク質の活性剤に関して、番技術分野で知られているような医薬組成物を形成するために、一つ以上の薬学的に許容される担体、安定化剤又は賦形剤(ビヒクル)を用いて、従来の方法で製剤化することができる。担体(単数又は複数)は、組成物の他の成分と適合し、その受容者に有害ではないという意味で「許容可能」である。適切な担体は、典型的には、生理食塩水又はグリセロール又はプロピングレコールなどのエタノールポリオールを含む。
CT−011二重変異体を用いたインキュベーション後の、CD4+Tリンパ球生存率
マウス腫瘍モデルにおける改質されたhBAT―1のin vivoでの効果
改質されたhBAT−1による、SCIDマウス中のヒトメラノーマ(SK−28)の阻害
ヌードマウスにおける改質したhBAT−1mAbによる、ヒト結腸直腸ガン肝転移の免疫療法
CD4及びCD8を用いて改質したhBATの共局在化
Bリンパ球への改質されたhBAT−1の結合
改質されたhBAT−1の安定性
配列番号1〜4のアミノ酸配列を有する軽鎖可変領域からのThr5、Thr20、Cys71、Asn75、Ser76、Phe93及びPhe97;配列番号5〜9のアミノ酸配列を有する重鎖可変領域のAsp54、Ser55及びTrp107;配列番号10のアミノ酸配列を有する軽鎖定常領域のAsn51、Ser52、Asp63及びSer64;又は、配列番号12のアミノ酸配列を有する重鎖定常領域のThr3、Ser7、Asn42、Ser43、Asn86、His87、Asp104、Lys105、Thr108、Met135、Asp153、Pro154、Asp163、Gly164、Asn180、Ser181、Asn198、Gly199、Asn267、Gly268、Asp282、Ser283、Asp284、Ser285、Asn317、His318、Lys330及びMet311から選択される位置に、少なくとも一つのアミノ酸改質を含むCT−001mAbを、当該技術分野で知られているように形成する。
Claims (16)
- Phe97がAlaに置換されている、配列番号1、2、3及び4から成る群から選択される軽鎖可変領域、並びに、Trp107がAlaに置換されている、配列番号5、6、7、8及び9から成る群から選択される重鎖可変領域を含む、ヒト化BAT−1抗体又はその抗原結合断片。
- 重鎖可変領域及び軽鎖可変領域の組み合わせを含み、前記組み合わせが、配列番号5/配列番号1、配列番号6/配列番号2、配列番号7/配列番号2、配列番号7/配列番号3、配列番号8/配列番号3、及び、配列番号7/配列番号1から成る群から選択される、請求項1に記載の抗体又はその抗原結合断片。
- 配列番号5/配列番号1に対応する可変領域を含む、請求項1に記載の抗体又はその抗原結合断片。
- 元の未置換であるhBAT−1よりも大きい抗腫瘍活性を有する、請求項1に記載の抗体又はその抗原結合断片。
- 前記ヒト化抗体の前記断片が、Fv、Fv(ab’)、F(ab’)2及び単鎖抗体から成る群から選択される、請求項1に記載の抗体又はその抗原結合断片。
- 請求項1〜3のいずれか一項に記載の前記抗体又はその断片をコードするポリヌクレオチド。
- 請求項6の前記ポリヌクレオチドを含むベクター。
- 請求項6の前記ポリヌクレオチドを含むベクターを含む宿主細胞。
- 活性成分として、請求項1〜3のいずれか一項の前記抗体、又はその抗原結合断片、及び、薬学的に許容可能な担体、希釈剤、或いは安定剤を含む、医薬組成物。
- 必要とする対象においてガン治療又は免疫不全疾患の治療における使用のために有効量を投与するための、請求項9に記載の医薬組成物。
- 前記対象が、固体腫瘍又は非固体腫瘍から選択される腫瘍を有する、請求項10に記載の医薬組成物。
- 前記対象が、非固体腫瘍を有する、請求項10に記載の医薬組成物。
- 前記対象が、血液悪性腫瘍を有する、請求項12に記載の医薬組成物。
- 前記ガンが、結腸直腸ガン、非小細胞肺ガン(NSCLC)、小細胞肺ガン(SCLC)、乳ガン、黒色腫、卵巣ガン、子宮頚ガン、膵臓ガン、頭部及び頸部ガン、消化器ガン、食道腫瘍、肝細胞ガン、多発性骨髄腫、腎細胞ガン、前立腺腫瘍、非ホジキンリンパ腫、ホジキン病、マントル細胞リンパ腫、カポジ肉腫、扁平上皮ガン、基底細胞ガン、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、並びに、慢性リンパ性白血病(CLL)から成る群から選択される、請求項10に記載の医薬組成物。
- 前記ガンが、結腸直腸ガン、黒色腫、膵臓ガン、頭部及び頸部ガン、食道腫瘍、多発性骨髄腫、腎細胞ガン、非ホジキンリンパ腫並びにホジキン病から成る群から選択される、請求項14に記載の医薬組成物。
- Phe97がAlaに置換されている、配列番号1〜4から選択される軽鎖可変領域、及び、Trp107がAlaに置換されている、配列番号5〜9から選択される重鎖可変領域を含むヒト化BAT−1抗体又はその抗原結合断片の、医薬組成物を形成するための使用。
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US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
IL108501A (en) | 1994-01-31 | 1998-10-30 | Mor Research Applic Ltd | Antibodies and pharmaceutical compositions containing them |
US6417337B1 (en) * | 1996-10-31 | 2002-07-09 | The Dow Chemical Company | High affinity humanized anti-CEA monoclonal antibodies |
US6884879B1 (en) * | 1997-04-07 | 2005-04-26 | Genentech, Inc. | Anti-VEGF antibodies |
IL129299A0 (en) | 1999-03-31 | 2000-02-17 | Mor Research Applic Ltd | Monoclonal antibodies antigens and diagnosis of malignant diseases |
AU2002317333C1 (en) | 2001-08-01 | 2009-06-25 | University Of Bristol | VEGF isoform |
IL149820A0 (en) | 2002-05-23 | 2002-11-10 | Curetech Ltd | Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency |
US7322582B2 (en) * | 2003-07-17 | 2008-01-29 | Mind Wurx, Llc | Enhanced shopping cart with lowered center of gravity and frame therefor |
FI20050753A (fi) * | 2004-09-03 | 2006-03-04 | Licentia Oy | Uudet peptidit |
RU2531758C2 (ru) * | 2008-02-11 | 2014-10-27 | Куретек Лтд. | Моноклональные антитела для лечения опухолей |
CA2840018C (en) * | 2011-07-24 | 2019-07-16 | Curetech Ltd. | Variants of humanized immunomodulatory monoclonal antibodies |
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