JP2014530599A - Vegf/dll4結合剤およびその使用 - Google Patents
Vegf/dll4結合剤およびその使用 Download PDFInfo
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- JP2014530599A JP2014530599A JP2014532067A JP2014532067A JP2014530599A JP 2014530599 A JP2014530599 A JP 2014530599A JP 2014532067 A JP2014532067 A JP 2014532067A JP 2014532067 A JP2014532067 A JP 2014532067A JP 2014530599 A JP2014530599 A JP 2014530599A
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- 229960000575 trastuzumab Drugs 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 210000005102 tumor initiating cell Anatomy 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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- 108020001612 μ-opioid receptors Proteins 0.000 description 1
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Abstract
Description
本発明は広くは、VEGF、DLL4またはVEGFとDLL4の両方を結合する抗体および他の薬剤、特に抗VEGF/抗DLL4二重特異性抗体に関し、ならびにがんのような疾患の処置のために抗体または他の薬剤を使用する方法に関する。
血管新生は、固形腫瘍および転移を含む、いくつかの障害の病因において重要な役割を果たす。新しい血管の生成は、腫瘍の成長および拡大のために酸素および栄養素を供給するのに不可欠であり、それゆえ、血管新生はがん治療法に適した標的になる。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む抗体である。
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む、ヒトVEGFを特異的に結合する第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。いくつかの態様において、二重特異性抗体は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む、ヒトVEGFを特異的に結合する第1の抗原結合部位を含む。
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む、ヒトDLL4を特異的に結合する第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む、ヒトDLL4を特異的に結合する第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。いくつかの態様において、二重特異性抗体は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む、ヒトDLL4を特異的に結合する第1の抗原結合部位を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、a) ヒトVEGFを特異的に結合する第1の抗原結合部位、およびb) ヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、a) ヒトVEGFを特異的に結合する第1の抗原結合部位、およびb) ヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、a) ヒトVEGFを特異的に結合する第1の抗原結合部位、およびb) ヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、a) ヒトVEGFを特異的に結合する第1の抗原結合部位、およびb) ヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
本発明は、VEGFおよび/またはDLL4を結合する、抗体のようなポリペプチドを含むがこれに限定されない、新規の結合剤(例えば、VEGF/DLL4結合剤)を提供する。関連したポリペプチドおよびポリヌクレオチド、VEGF/DLL4結合剤を含む組成物、ならびにVEGF/DLL4結合剤を作出する方法も提供される。腫瘍成長を阻害する方法、がんを処置する方法、腫瘍の腫瘍形成性を低減する方法、腫瘍内のがん幹細胞の頻度を低減する方法、および/または血管新生を調節する方法のような、新規のVEGF/DLL4結合剤を使用する方法がさらに提供される。
本発明の理解を容易にするために、いくつかの用語および語句を以下に定義する。
本発明は、ヒトVEGFタンパク質および/またはヒトDLL4タンパク質を特異的に結合する薬剤を提供する。これらの薬剤は、本明細書において「VEGF/DLL4結合剤」といわれる。「VEGF/DLL4結合剤」という語句は、VEGFだけを結合する薬剤、DLL4だけを結合する薬剤、ならびにVEGFおよびDLL4の両方を結合する二重特異性薬剤を包含する。ある種の態様において、VEGFおよび/またはDLL4を特異的に結合することに加えて、VEGF/DLL4結合剤はさらに、少なくとも1つのさらなる標的または抗原を特異的に結合する。いくつかの態様において、VEGF/DLL4結合剤は抗体である。いくつかの態様において、VEGF/DLL4結合剤はポリペプチドである。ある種の態様において、VEGF/DLL4結合剤はヒトVEGFを特異的に結合する。ある種の態様において、VEGF/DLL4結合剤はヒトDLL4を特異的に結合する。ある種の態様において、VEGF/DLL4結合剤は二重特異性抗体である。ある種の態様において、VEGF/DLL4結合剤は、ヒトVEGFおよびヒトDLL4を特異的に結合する二重特異性抗体である。ヒトVEGF (VEGF-A)およびヒトDLL4に対する全長アミノ酸(aa)配列は、当技術分野において公知であり、本明細書においてSEQ ID NO:27 (VEGF)およびSEQ ID NO:23 (DLL4)として提供されている。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、VEGF結合剤は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。ある種の態様において、VEGF結合剤は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (b)
を含んだ重鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (c)
を含んだ重鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (d)
を含んだ軽鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (e)
を含んだ軽鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; および(f)
を含んだ軽鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種を含む。ある種の態様において、アミノ酸置換は保存的置換である。
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、DLL4結合剤は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。ある種の態様において、DLL4結合剤は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (b)
を含んだ重鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (c)
を含んだ重鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (d)
を含んだ軽鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (e)
を含んだ軽鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; および(f)
を含んだ軽鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種を含む。ある種の態様において、アミノ酸置換は保存的置換である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、DLL4結合剤は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。ある種の態様において、DLL4結合剤は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (b)
を含んだ重鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (c)
を含んだ重鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (d)
を含んだ軽鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (e)
を含んだ軽鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; および(f)
を含んだ軽鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種を含む。ある種の態様において、アミノ酸置換は保存的置換である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、DLL4結合剤は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。ある種の態様において、DLL4結合剤は、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (b)
を含んだ重鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (c)
を含んだ重鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (d)
を含んだ軽鎖CDR1、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; (e)
を含んだ軽鎖CDR2、または1、2、3もしくは4個のアミノ酸置換を含んだその変種; および(f)
を含んだ軽鎖CDR3、または1、2、3もしくは4個のアミノ酸置換を含んだその変種を含む。ある種の態様において、アミノ酸置換は保存的置換である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。いくつかの態様において、VEGF/DLL4結合剤は、ヒトVEGFを特異的に結合する第1の抗原結合部位を含んだ二重特異性抗体であり、第1の抗原結合部位が、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、VEGF/DLL4結合剤は、ヒトDLL4を特異的に結合する第1の抗原結合部位を含んだ二重特異性抗体であり、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含む第1の抗原結合部位を含む。いくつかの態様において、二重特異性抗体は、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3をさらに含む。いくつかの態様において、VEGF/DLL4結合剤は、ヒトDLL4を特異的に結合する第1の抗原結合部位を含んだ二重特異性抗体であり、第1の抗原結合部位が、(a)
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3、ならびに(b)
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; 第2の抗原結合部位が、
を含んだ重鎖CDR1、配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3; ならびに
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、ヒトVEGFを特異的に結合する第1の抗原結合部位、およびヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、219R45-MB-21R79である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、219R45-MB-21M18である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、219R45-MB-21R75である。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、219R45-MB-21R83である。
ある種の態様において、本発明は、VEGF、DLL4、VEGFおよびDLL4の両方を特異的に結合するポリペプチド(またはポリペプチドの断片)をコードするポリヌクレオチドを含んだポリヌクレオチドを包含する。「ポリペプチドをコードするポリヌクレオチド」という用語は、ポリペプチドのコード配列だけを含むポリヌクレオチド、ならびにさらなるコード配列および/または非コード配列を含むポリヌクレオチドを包含する。例えば、いくつかの態様において、本発明は、ヒトVEGFに対する抗体をコードする、またはこのような抗体の断片(例えば、抗原結合部位を含んだ断片)をコードするポリヌクレオチド配列を含んだポリヌクレオチドを提供する。いくつかの態様において、本発明は、ヒトDLL4に対する抗体をコードする、またはこのような抗体の断片(例えば、抗原結合部位を含んだ断片)をコードするポリヌクレオチド配列を含んだポリヌクレオチドを提供する。本発明のポリヌクレオチドはRNAの形態であってもよく、DNAの形態であってもよい。DNAは、cDNA、ゲノムDNA、および合成DNAを含み、二本鎖または一本鎖でもよく、一本鎖ならコード鎖または非コード(アンチセンス)鎖でもよい。
のペプチドであり、これを他のアフィニティータグとともに用いてもよい。
VEGFおよび/またはDLL4を結合する(例えば、特異的に結合する)本発明の(ポリペプチドおよび抗体を含む)結合剤は、がんの処置のような、治療的処置方法を含むが、これに限定されない、さまざまな用途において有用である。ある種の態様において、この薬剤は、VEGF活性を阻害するのに、DLL4誘導性のNotchシグナル伝達を阻害するのに、腫瘍成長を阻害するのに、腫瘍容積を低減するのに、腫瘍内のがん幹細胞の頻度を低減するのに、腫瘍の腫瘍形成性を低減するのに、血管新生を調節するのに、および/または血管新生を阻害するのに有用である。使用方法は、インビトロ、エクスビボ、またはインビボのものであってよい。ある種の態様において、VEGF/DLL4結合剤は、ヒトVEGFのアンタゴニストである。ある種の態様において、VEGF/DLL4結合剤は、ヒトDLL4のアンタゴニストである。ある種の態様において、VEGF/DLL4結合剤は、VEGFおよびDLL4の両方のアンタゴニストである。
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、ヒトVEGFを特異的に結合する第1の抗原結合部位、およびヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、ヒトVEGFを特異的に結合する第1の抗原結合部位、およびヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、ヒトVEGFを特異的に結合する第1の抗原結合部位、およびヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。いくつかの態様において、二重特異性抗体は、ヒトVEGFを特異的に結合する第1の抗原結合部位、およびヒトDLL4を特異的に結合する第2の抗原結合部位を含み、第1の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み、ならびに第2の抗原結合部位が、
を含んだ重鎖CDR1、
を含んだ重鎖CDR2、および
を含んだ重鎖CDR3を含み; かつ第1および第2の抗原結合部位の両方が、
を含んだ軽鎖CDR1、
を含んだ軽鎖CDR2、および
を含んだ軽鎖CDR3を含む。
本発明は、本明細書において記述されるVEGF/DLL4結合剤(例えば、抗体)を含み、かつ本明細書において記述される方法を実施するのに使用可能な、キットを提供する。ある種の態様において、キットは、1つまたは複数の容器に入れられた、VEGFおよび/またはDLL4に対する少なくとも1種類の精製された抗体を含む。いくつかの態様において、キットは、全ての対照を含む、検出アッセイ法を行うのに必要および/または十分な成分の全て、アッセイ法を行うための説明書、ならびに分析および結果の表示に必要な任意のソフトウェアを含む。当業者であれば、本発明の開示されたVEGF/DLL4結合剤を、当技術分野において周知の確立されたキット形式の1つに容易に組み込むことができることを容易に認識するであろう。
親抗体である抗VEGF 219R45 (IgG形式)抗体、抗DLL4 21R79 (IgG形式)抗体、抗DLL4 21M18 (IgG形式)抗体、ならびに二重特異性抗体219R45-MB-21M18および219R45-MB-21R79のKDを、Biacore LifeSciences (GE Healthcare)のBiacore 2000システムを用いて決定した。組み換えヒトDLL4-FcまたはマウスDLL4-Fcタンパク質を、標準的なアミンに基づく化学(NHS/EDC)を用いてCM5カルボキシルチップ上に固定化し、エタノールアミンでブロッキングした。組み換えヒトVEGF165またはマウスVEGF165をビオチン化し、ストレプトアビジンチップ上に固定化した。抗体をHBS-P (0.01 M HEPES pH 7.4、0.15 M NaCl、0.005% v/v Polysorbate 20)中に100 nMから0.78 nMまで連続的に2倍希釈した。抗体ごとに、全8種の希釈液を特定のチップに連続注入した。動的データを経時的に集め、同時全体適合式を用いて適合させ、各二重特異性抗体の親和性定数(KD値)を得た。
VEGFおよびDLL4の両方に対する特定の抗体および/または抗体混合物の結合能を特徴付けるため、均一時間分解蛍光(HTRF)アッセイ法を行った。試験した抗体は、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18および219R45-MB-21R79、親抗体219R45 (抗VEGF)、21M18 (抗DLL4)、21R79 (抗DLL4)、219R45および21M18の組み合わせ、または219R45および21R79の組み合わせであった。抗体または抗体混合物を結合用緩衝液(1×PBS、0.1%ゼラチン、0.1% Polysorbate 20、400 mMフッ化カリウム)中に3000 nMから2.9 nMまで連続的に2倍希釈し、白色の96ウェルプレート中に入れた。4 μg/mlのd2標識hDLL4-Fcおよび21.4 ng/mlのユウロピウムクリプテート標識hVEGF165を含有する等容量の溶液を、終容量100 μlとなるように各ウェルに加えた(アクセプターおよびドナー・フルオロフォアの終濃度は、それぞれ、2 μg/mlおよび10.7 ng/mlであった)。アッセイプレートを2時間〜終夜インキュベートし、SpectraMax M5eマイクロプレートリーダー(Molecular Devices, Sunnyvale CA)にて励起波長314 nmで読み取った。
HUVEC細胞は、Lonza (Walkersville MD)から入手し、成長培地(M199、10%熱不活化FBS (HI-FBS)、50 μg/ml EGS、1×ヘパリン、1 mM L-グルタミン)中で培養した。HUVEC増殖アッセイ法のため、96ウェルプレートを10 μg/mlのラット尾部コラーゲンI型溶液(0.02 N酢酸中のコラーゲンI) 50 μlで予めコーティングし、4℃で終夜インキュベートした。インキュベーション後、プレートを十分に吸引して、未結合のコラーゲンI溶液を除去し、DPBS 200 μlで1回洗浄した。内皮細胞サブクローン試薬を用いて成長用フラスコの表面からHUVEC細胞を除去し、これを4℃で5分間1200 rpmで遠心分離した。細胞を、細胞105個/mlの密度で飢餓/アッセイ培地(M199および2% HI-FBS、1×ヘパリン、5 U/mlヘパリン-グルタミン)に再懸濁した。細胞を、コラーゲンでコーティングしたアッセイプレートの中に、細胞5000個/ウェル、50 ul/ウェルで播種した。細胞を37℃で3時間インキュベートし、1回洗浄し、アッセイ培地100 ulを再供給し、37℃で終夜インキュベートした。翌日、二重特異性抗体219R45-MB-21M18、219R45-MB-21R79、親抗体219R45または対照抗体LZ1をヒトVEGF (R&D Biosystems, Minneapolis MN)との混合物として調製した。抗体をhVEGF (終濃度5 ng/ml)と組み合わせてアッセイ用緩衝液中に20 μMから0.25 nMまで連続的に5倍希釈した。混合物を2時間37℃でプレインキュベートした。培地をアッセイプレートから除去し、抗体/hVEGF混合物100 μlを各ウェルに加えた。3〜4日のインキュベーション後、培地を除去し、抗体/hVEGF混合物の新鮮なアリコットを各ウェルに加え、さらに4日間インキュベートさせた。7日目に、アラマーブルー(Alamar Blue)試薬(Invitrogen, Carlsbad, CA) 20 μlを各ウェルに加え、5〜6時間37℃でインキュベートした。プレートをSpectraMax M5eマイクロプレートリーダー(Molecular Devices, Sunnyvale CA)で、励起波長539 nmおよび放出波長590 nmを用いて読み取った。
完全長ヒトNotch2受容体をコードする発現ベクター、およびNotchシグナル伝達に応答するホタル・ルシフェラーゼレポーターベクター(8×CBFルシフェラーゼレポーター)をヒトPC3細胞にトランスフェクションした。また、トランスフェクション効率の内部対照としてウミシイタケ・ルシフェラーゼレポーター(Promega, Madison WI)を細胞にトランスフェクションした。96ウェルプレートに精製ヒトDLL4タンパク質を100 ng/ウェルでコーティングし、ウェルにNotch2発現PC3-luc細胞を加えた。抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18、219R45-MB-21R79、親抗DLL4抗体21M18、21R79または対照抗体LZ1を20 ug/mlから0.064 ug/mlまで連続的に5倍希釈し、適切なウェルに加え、終夜インキュベートした。デュアル・ルシフェラーゼアッセイキット(Promega, Madison, WI)を用い、ホタル・ルシフェラーゼ活性をウミシイタケ・ルシフェラーゼ活性に対し規準化して、ルシフェラーゼ活性を決定した。
ヒト皮膚移植片およびヒト腫瘍細胞を含むヒト皮膚移植片モデルが報告されている。ヒト皮膚移植片を樹立し、その後、ヒト腫瘍細胞を皮膚移植片へ移植し、ヒト間質および脈管構造を有する環境中で腫瘍細胞を成長させる(Tahtis et al., 2003, Mol. Cancer Ther. 2:229-737)。ヒト皮膚サンプルを新生児包皮組織から得て、NOD-SCIDマウスの側腹部に移植した。皮膚移植片の樹立後、ルシフェラーゼ標識OMP-C8結腸腫瘍細胞(細胞20,000個)をヒト皮膚に皮内注射した。IVIS画像システム(Caliper Life Sciences, Mountain View, CA)を用いて生物発光画像法により腫瘍成長をモニターした。腫瘍を、光子1.2×106個/秒に達するまで、成長させた。腫瘍担持マウス(n = 6マウス/群)を無作為に選び、対照Ab、抗hDLL4抗体21M18、抗VEGF抗体ベバシズマブ、または抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18で処置した。動物を週1回処置し、抗体を25 mg/kgの用量で腹腔内に投与した。表示した日に生物発光画像法により腫瘍成長をモニターした。
OMP-PN8膵臓腫瘍を担持するマウスを対照抗体(15 mg/kg)、抗hDLL4抗体21M18 (15 mg/kg)、抗VEGF抗体ベバシズマブ(15 mg/kg)、または抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18もしくは219R45-MB-21R79 (30 mg/kg)により、ゲムシタビン(70 mg/kg)ありまたはなしで処置した。4週の処置後、腫瘍を収集し、単個細胞浮遊液へ処理し、ヒト腫瘍細胞をマウス細胞の免疫磁性枯渇によって精製した。各処置群由来のヒト腫瘍細胞90個を新しいコホートのマウス(n = 10マウス/群)へ移入した。腫瘍を、いずれの処置もなしに、55日間成長させ、腫瘍容積を電子キャリパで測定した。
VEGF (ATGEN, South Korea)を2 ug/ml (100 μl/ウェル)でNunc maxisorbプレート上にコーティングし、2〜8℃で終夜インキュベートした。二重特異性抗体219R45-MB-21M18、219R45-MB-21R79、219R45-MB-21R75および219R45-MB-21R83を、2 μg/mlのビオチン-DLL4-hFcを含有するブロッキング用緩衝液(1×PBS、0.1%ゼラチン、0.1% Polysorbate-20, pH 7.4)中に希釈した。抗体を500 ng/mlから0.008 ng/mlまで連続的に3倍希釈した。抗体サンプルを、ビオチン-DLL4-hFcを含有するブロッキング用緩衝液中で2時間インキュベートした。インキュベーション後、抗体サンプルを、VEGFでコーティングしたアッセイプレート(100 ul/ウェル)へ移入し、2時間インキュベートした。ストレプトアビジン-HRP (Jackson ImmunoResearch, West Grove, PA)を各ウェルに加え、1時間インキュベートした。TMB基質をウェルに加え、10分発色させ、反応を2 M硫酸で停止させた。吸光度を450〜650 nmで読み取り、Softmax Pro分析プログラム(Molecular Devices, Sunnyvale, CA)内の4-パラメータフィットを用いてデータを分析した。
二重特異性抗体は、GS-CHO細胞株を用いて産生された。選択可能なマーカーとしてグルタミン合成酵素(GS)とカップリングされた関心対象の遺伝子をエレクトロポレーションによってCHOK1SV細胞(Lonza Biologics)にトランスフェクションした。トランスフェクタントおよびサブクローンを抗体産生性についてスクリーニングし、高産生株を大規模産生のために選択した。流加培養過程および流加培養バイオリアクタを用いて細胞を増殖させた。クロマトグラフィー技法を用いて、収集細胞培養液(HCCF)中に貯留した抗体を単離および精製した。
OMP-C8結腸腫瘍異種移植片の単個細胞浮遊液(細胞20,000個)を6〜8週齢のNOD/SCIDマウスの側腹部に皮下注射した。腫瘍を、240 mm3の平均容積に達するまで33日間成長させた。マウス(1群あたりn = 10)を無作為に選び、抗hDLL4抗体21M18、抗VEGF抗体ベバシズマブ、抗体21M18およびベバシズマブの組み合わせ、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21R79、または対照抗体により、全てイリノテカンとの組み合わせで処置した。抗体およびイリノテカンを、腹腔内への注射により毎週投薬した。抗体21M18およびベバシズマブは7.5 mg/kgで投薬し、二重特異性抗体219R45-MB-21M18および219R45-MB-21R79は15 mg/kgで投薬し、イリノテカンは45 mg/kgで投薬した。イリノテカンは4週間投薬し、その時点で、それを中断し、抗体の投与を継続した。腫瘍成長をモニターし、表示した時点で電子キャリパにより腫瘍容積を測定した。データは平均±S.E.Mとして表されている。
OMP-C8結腸腫瘍異種移植片の単個細胞浮遊液(細胞20,000個)を6〜8週齢のNOD/SCIDマウスの側腹部に皮下注射した。腫瘍を、300 mm3の平均容積に達するまで33日間成長させた。マウス(1群あたりn = 5)を無作為に選び、抗DLL4抗体21M18、抗VEGF抗体ベバシズマブ、抗体21M18およびベバシズマブの組み合わせ、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21R79、または対照抗体により、イリノテカンとの組み合わせでまたはイリノテカンなしで処置した。抗体およびイリノテカンを、腹腔内への注射により毎週投薬した。抗体21M18およびベバシズマブは7.5 mg/kgで投薬し、二重特異性抗体219R45-MB-21M18および219R45-MB-21R79は15 mg/kgで投薬し、イリノテカンは45 mg/kgで投薬した。腫瘍を4週後に収集し、単個細胞浮遊液へ処理し、ヒト腫瘍細胞を単離した。各実験群由来の腫瘍細胞150個を新しいコホートのマウス(n = 10マウス/群)へ皮下注射し、腫瘍を処置なしに成長させた。腫瘍成長をモニターし、腫瘍容積を電子キャリパで測定した。
OMP-C8結腸腫瘍異種移植片の単個細胞浮遊液(細胞50,000個)を6〜8週齢のNOD/SCIDマウスの側腹部に皮下注射した。腫瘍を、80 mm3の平均容積に達するまで21日間成長させた。マウス(1群あたりn = 8)を無作為に選び、抗DLL4抗体21M18、抗VEGF抗体ベバシズマブ、抗VEGF/抗DLL4二重特異性抗体219R45-MB-21M18、219R45-MB-21R75、219R45-MB-21R79、219R45-MB-21R83、または対照抗体により、単独でまたはイリノテカンとの組み合わせで処置した。抗体およびイリノテカンを、腹腔内への注射により毎週投薬した。ベバシズマブ、ならびに二重特異性抗体219R45-MB-21M18、219R45-MB-21R75、219R45-MB-21R79および219R45-MB-21R83は15 mg/kgで投薬し、イリノテカンは7.5 mg/kgで投薬した。腫瘍成長をモニターし、表示した時点で電子キャリパにより腫瘍容積を測定した。データは平均±S.E.Mとして表されている。
二重特異性抗体のいくつかの毒性プロファイルを評価および比較するために、カニクイザルにおける非GLP毒性試験を開始した。動物に、静注によって2週間ごとに抗DLL4/抗VEGF二重特異性抗体(219R45-MB-21M18、219R45-MB-21R83または219R45-MB-21R79) 0 mg/kg (対照)、5 mg/kg (低用量)または30 mg/kg (高用量)を投薬した。各群において雄3匹および雌3匹に投薬した。15週後、平均体重は、高用量の219R45-MB-21R18または219R45-MB-21R83のいずれかを投与された動物におけるよりも高用量の219R45-MB-21R79を投与されていた動物において低かった。さらに、平均血清アルブミンレベルは、219R45-MB-21R18または219R45-MB-21R83のいずれかを投与された動物におけるよりも219R45-MB-21R79を投与された動物において低かった。事実上、予備的ではあるが、これらの初期データから、219R45-MB-21R18および219R45-MB-21R83が219R45-MB-21R79と比べて優れた毒性プロファイルを持ちうることが示唆される。
シグナル配列(下線)を有する21M18重鎖(SEQ ID NO:1)
シグナル配列(下線)を有する21R79重鎖(SEQ ID NO:2)
シグナル配列(下線)を有する219R45重鎖(SEQ ID NO:3)
シグナル配列(下線)を有する軽鎖(SEQ ID NO:4)
予測されるシグナル配列を有しない21M18重鎖(SEQ ID NO:5)
予測されるシグナル配列を有しない21R79重鎖(SEQ ID NO:6)
予測されるシグナル配列を有しない219R45重鎖(SEQ ID NO:7)
予測されるシグナル配列を有しない軽鎖(SEQ ID NO:8)
21M18重鎖可変領域(SEQ ID NO:9)
21R79重鎖可変領域(SEQ ID NO:10)
219R45重鎖可変領域(SEQ ID NO:11)
軽鎖可変領域(SEQ ID NO:12)
21R75、21R79、21R83および21M18重鎖CDR1 (SEQ ID NO:13)
TAYYIH
別の21R75、21R79、21R83および21M18重鎖CDR1 (SEQ ID NO:79)
AYYIH
21R79重鎖CDR2 (SEQ ID NO:14)
21M18重鎖CDR2 (SEQ ID NO:15)
21R75、21R79、21R83および21M18重鎖CDR3 (SEQ ID NO:16)
219R45重鎖CDR1 (SEQ ID NO:17)
NYWMH
219R45重鎖CDR2 (SEQ ID NO:18)
219R45重鎖CDR3 (SEQ ID NO:19)
軽鎖CDR1 (SEQ ID NO:20)
軽鎖CDR2 (SEQ ID NO:21)
軽鎖CDR3 (SEQ ID NO:22)
シグナル配列(下線)を有するヒトDLL4 (SEQ ID NO:23)
予測されるシグナル配列を有しないヒトDLL4 (SEQ ID NO:24)
ヒトDLL4 N末端領域(SEQ ID NO:25)
ヒトDLL4 DSLドメイン(SEQ ID NO:26)
シグナル配列(下線)を有するヒトVEGF-A (SEQ ID NO:27)
予測されるシグナル配列を有しないヒトVEGF-A (SEQ ID NO:28)
21M18重鎖ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:29)
21R79重鎖ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:30)
21R79重鎖ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:31)
219R45重鎖ヌクレオチド配列(13Aバージョン1) (SEQ ID NO:32)
219R45重鎖ヌクレオチド配列(13Aバージョン2) (SEQ ID NO:33)
軽鎖ヌクレオチド配列(SEQ ID NO:34)
21M18重鎖可変領域ヌクレオチド配列(SEQ ID NO:35)
21R79重鎖可変領域ヌクレオチド配列(13B) (SEQ ID NO:36)
21R79重鎖可変領域ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:37)
219R45重鎖可変領域ヌクレオチド配列(13Aバージョン1) (SEQ ID NO:38)
219R45重鎖可変領域ヌクレオチド配列(13Aバージョン2) (SEQ ID NO:39)
軽鎖可変領域ヌクレオチド配列(SEQ ID NO:40)
ヒトIgG1重鎖定常領域(SEQ ID NO:41)
ヒトIgG2重鎖定常領域(SEQ ID NO:42)
ヒトIgG3重鎖定常領域(SEQ ID NO:43)
ヒトIgG4重鎖定常領域(SEQ ID NO:44)
FLAGペプチド(SEQ ID NO:45)
DYKDDDDK
シグナル配列に下線を引いた親21R79重鎖 非修飾鎖(SEQ ID NO:46)
シグナル配列に下線を引いた親219R45重鎖(SEQ ID NO:47)
予測されるシグナル配列を有しない親21R79重鎖(SEQ ID NO:48)
シグナル配列を有しない親219R45重鎖(SEQ ID NO:49)
親21R79重鎖可変領域ヌクレオチド配列(SEQ ID NO:50)
親219R45重鎖可変領域ヌクレオチド配列(SEQ ID NO:51)
シグナル配列を有する親21R79重鎖ヌクレオチド配列(SEQ ID NO:52)
シグナル配列を有する親219R45重鎖ヌクレオチド配列(SEQ ID NO:53)
親21R79および219R45軽鎖可変領域ヌクレオチド配列(SEQ ID NO:54)
親21R79および219R45軽鎖ヌクレオチド配列(SEQ ID NO:55)
予測されるシグナル配列を有しない21R75重鎖(SEQ ID NO:56)
予測されるシグナル配列(下線)を有する21R75重鎖(SEQ ID NO:57)
21R75重鎖可変領域(SEQ ID NO:58)
21R75重鎖CDR2 (SEQ ID NO:59)
シグナル配列を有する21R75重鎖ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:60)
シグナル配列を有する21R75重鎖ヌクレオチド配列(13Bバージョン1T) (SEQ ID NO:77)
シグナル配列を有する21R75重鎖ヌクレオチド配列(13BバージョンS1-2) (SEQ ID NO:61)
予測されるシグナル配列を有しない21R83重鎖(SEQ ID NO:62)
予測されるシグナル配列(下線)を有する21R83重鎖(SEQ ID NO:63)
21R83重鎖可変領域(SEQ ID NO:64)
21R83重鎖CDR2 (SEQ ID NO:65)
シグナル配列に下線を引いた21R83重鎖ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:66)
シグナル配列に下線を引いた21R83重鎖ヌクレオチド配列(13Bバージョン1T) (SEQ ID NO:78)
シグナル配列に下線を引いた21R75重鎖ヌクレオチド配列(13BバージョンS1-2) (SEQ ID NO:67)
21R75重鎖可変領域ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:68)
21R75重鎖可変領域ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:69)
21R83重鎖可変領域ヌクレオチド配列(13Bバージョン1) (SEQ ID NO:70)
21R75重鎖可変領域ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:71)
シグナル配列に下線を引いた21R83重鎖ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:72)
21R83重鎖可変領域ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:73)
シグナル配列に下線を引いた21R75重鎖ヌクレオチド配列(13Bバージョン2) (SEQ ID NO:74)
21M18重鎖ヌクレオチド配列(バージョン2) (SEQ ID NO:75)
21M18重鎖可変領域(バージョン2) (SEQ ID NO:76)
抗DLL4重鎖CDR2コンセンサス配列(SEQ ID NO:80):
配列中でX1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である。
Claims (30)
- a) ヒト血管内皮成長因子(VEGF)を特異的に結合する第1の抗原結合部位、および
b) ヒトデルタ様4リガンド(DLL4)を特異的に結合する第2の抗原結合部位を含み、
第1の抗原結合部位が、
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3を含み;
第2の抗原結合部位が、
を含む重鎖CDR1、
を含む重鎖CDR2であって、X1がセリンまたはアラニンであり、X2がセリン、アスパラギンまたはグリシンであり、X3がアスパラギンまたはリジンであり、かつX4がグリシン、アルギニンまたはアスパラギン酸である、重鎖CDR2、および
を含む重鎖CDR3を含み; かつ
第1および第2の抗原結合部位の両方が、
を含む軽鎖CDR1、
を含む軽鎖CDR2、および
を含む軽鎖CDR3を含む、二重特異性抗体。 - (a) SEQ ID NO:11と少なくとも90%の配列同一性を有する第1の重鎖可変領域;
(b) SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:58またはSEQ ID NO:64と少なくとも90%の配列同一性を有する第2の重鎖可変領域; ならびに
(c) SEQ ID NO:12と少なくとも90%の配列同一性を有する第1および第2の軽鎖可変領域
を含む、請求項1または請求項2記載の二重特異性抗体。 - 各々がヘテロ多量体の形成を促進するように修飾されている第1のCH3ドメインおよび第2のCH3ドメインを含む、請求項1〜3のいずれか一項記載の二重特異性抗体。
- 第1および第2のCH3ドメインが静電効果に基づき修飾されている、請求項1〜4のいずれか一項記載の二重特異性抗体。
- モノクローナル抗体、組み換え抗体、キメラ抗体、ヒト化抗体、ヒト抗体、IgG1抗体またはIgG2抗体である、請求項1〜5のいずれか一項記載の二重特異性抗体。
- SEQ ID NO:42の位置249および288に対応する位置にアミノ酸置換を有する第1のヒトIgG2定常領域であって、アミノ酸がグルタメートまたはアスパルテートで置き換えられている、第1のヒトIgG2定常領域、ならびにSEQ ID NO:42の位置236および278に対応する位置にアミノ酸置換を有する第2のヒトIgG2定常領域であって、アミノ酸がリジンで置き換えられている、第2のヒトIgG2定常領域を含む、請求項1〜5のいずれか一項記載の二重特異性抗体。
- (i) VEGFと少なくとも1種のVEGF受容体との結合を阻害する;
(ii) DLL4と少なくとも1種のNotch受容体との結合を阻害する;
(iii) Notchシグナル伝達を阻害する; かつ/または
(iv) 血管新生を調節する、
請求項1〜7のいずれか一項記載の二重特異性抗体。 - (a) SEQ ID NO:7の重鎖;
(b) SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:56またはSEQ ID NO:62の重鎖; および
(c) SEQ ID NO:8の2つの軽鎖
を含む、ヒトVEGFおよびヒトDLL4を特異的に結合する二重特異性抗体。 - 219R45-MB-21M18、219R45-MB-21R79、219R45-MB-21R75および219R45-MB-21R83からなる群より選択される二重特異性抗体。
- (a) SEQ ID NO:11と少なくとも90%の配列同一性を有する重鎖可変領域; および
(b) SEQ ID NO:12と少なくとも90%の配列同一性を有する軽鎖可変領域
を含む、請求項11記載の抗体。 - (a) SEQ ID NO:49またはSEQ ID NO:7を含む重鎖、および
(b) SEQ ID NO:8を含む軽鎖
を含む、請求項11記載の抗体。 - VEGFと少なくとも1種のVEGF受容体との結合を阻害する、請求項11〜13のいずれか一項記載の抗体。
- (a) SEQ ID NO:10、SEQ ID NO:58またはSEQ ID NO:64を含む重鎖可変領域; および
(b) SEQ ID NO:12を含む軽鎖可変領域
を含む、請求項15または請求項16記載の抗体。 - モノクローナル抗体、組み換え抗体、キメラ抗体、ヒト化抗体、ヒト抗体、二重特異性抗体、IgG1抗体、IgG2抗体、または抗原結合部位を含む抗体断片である、請求項11〜17のいずれか一項記載の抗体。
- 請求項1〜18のいずれか一項記載の抗体および薬学的に許容される担体を含む薬学的組成物。
- 請求項1〜18のいずれか一項記載の抗体を含むかまたは産生する細胞。
- 請求項1〜18のいずれか一項記載の抗体をコードするポリヌクレオチドを含む単離ポリヌクレオチド分子。
- 請求項21記載のポリヌクレオチドを含むベクター。
- 請求項22記載のポリヌクレオチドを含む細胞。
- SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、SEQ ID NO:56、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:62、SEQ ID NO:63およびSEQ ID NO:64からなる群より選択される配列を含むポリペプチド。
- がんの処置のための医薬の製造における請求項1〜18のいずれか一項記載の抗体の使用。
- がんが、結腸直腸がん、結腸がん、卵巣がん、膵臓がん、肺がん、肝臓がん、乳がん、腎臓がん、前立腺がん、胃腸がん、黒色腫、子宮頚がん、膀胱がん、グリア芽細胞腫、頭頸部がん、リンパ腫および白血病からなる群より選択される、請求項25記載の抗体の使用。
- 腫瘍の成長を阻害するための医薬の製造における請求項1〜18のいずれか一項記載の抗体の使用。
- 腫瘍が、結腸直腸腫瘍、結腸腫瘍、卵巣腫瘍、膵臓腫瘍、肺腫瘍、肝臓腫瘍、乳腺腫瘍、腎臓腫瘍、前立腺腫瘍、胃腸腫瘍、黒色腫、子宮頚部腫瘍、膀胱腫瘍、グリア芽細胞腫および頭頸部腫瘍からなる群より選択される、請求項27記載の抗体の使用。
- 抗体および少なくとも1種のさらなる治療剤を含む、請求項25〜28のいずれか一項記載の抗体の使用。
- 細胞において少なくとも1種の請求項21記載のポリヌクレオチドを発現させる段階を含む、抗体の産生のための方法。
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