JP2022502367A - HPTP−β(VE−PTP)およびVEGFを標的にする多特異性抗体 - Google Patents
HPTP−β(VE−PTP)およびVEGFを標的にする多特異性抗体 Download PDFInfo
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Images
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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
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- C07—ORGANIC CHEMISTRY
- 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
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Abstract
Description
本出願は、2018年9月24日に出願された米国仮特許出願第62/735,331号および2019年4月11日に出願された米国仮特許出願第62/832,461号の利益を主張し、これらのそれぞれは、その全体が、参照によって本明細書に組み込まれる。
参照による組込み
HPTP−β/VE−PTP、Tie2および血管安定性
VEGFおよび血管安定性
受容体チロシンキナーゼ(RTK)および受容体チロシンキナーゼアゴニスト
抗体および抗原結合性化合物
抗原結合性化合物は、多価および/または多特異性の化合物を生じさせるために組み合わせることができる。このような多価および/または多特異性の化合物は、個々に投与される親化合物に優る利点を有し得る。これらの利点としては、例えば、より簡単な投薬レジメン、対象内でのより長い半減期、および近傍の標的抗原に結合する能力が挙げられ得る。
阻害剤、活性化剤、モジュレーターおよび結合剤
方法
配列
重鎖シグナルペプチド(配列番号11):MGWTLVFLFLLSVTAGVHS
軽鎖シグナルペプチド(配列番号12):MVSSAQFLGLLLLCFQGTRC
CDR
医薬組成物
医薬組成物の投与
投薬
併用療法
a)例えば、HPTP−β(VE−PTP)およびVEGFを標的にする、治療有効量の多特異性化合物または抗体、ならびに
b)治療有効量の追加の抗VEGF剤
を投与することを含み、
多特異性化合物または抗体および追加の抗VEGF剤の投与は、本明細書に記載の通り、実施することができる。
a)例えば、HPTP−β(VE−PTP)およびVEGFを標的にする、治療有効量の多特異性化合物または抗体、ならびに
b)治療有効量の追加の抗HPTP−β(VE−PTP)剤
を投与することを含み、
多特異性化合物または抗体および追加の抗HPTP−β(VE−PTP)剤の投与は、本明細書に記載の通り、実施することができる。
a)例えば、HPTP−β(VE−PTP)およびVEGFを標的にする、治療有効量の多特異性化合物または抗体、ならびに
b)治療有効量のTie2活性化剤
を投与することを含み、
多特異性化合物または抗体および追加のTie2受容体活性化化合物の投与は、本明細書に記載の通り、実施することができる。
マウスモデル
酸素誘発虚血性網膜症モデル
Rho/VEGFマウスモデル
Tet/オプシン/VEGFマウスモデル
Tet/オプシン/Ang2マウスモデル
レーザー誘発脈絡膜新血管形成モデル
新血管形成の評価
網膜の血管漏出の評価
血管漏出のためのマイルスアッセイ
がんモデル
例示的なCDRの組合せ
抗体HC2:LC1およびアフリベルセプト由来配列を含む四価二特異性抗体
抗体HC2:LC1の重鎖がアフリベルセプト由来VEGF結合性ドメインと融合された四価二特異性抗体を生じさせるために、以下に添付のN末端からC末端のアミノ酸配列を含むアミノ酸配列を生じさせた:
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号22(アフリベルセプト由来配列)。
抗体HC2:LC1およびブロルシズマブ由来配列を含む四価二特異性抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
抗体HC2:LC1およびラニビズマブ由来配列を含む四価二特異性抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号28(ラニビズマブ由来配列)。
二特異性化合物の特性評価
(実施例5)
抗体HC2:LC1およびアビシパル由来配列を含む四価二特異性抗体
1)配列番号14の残基1〜467(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号244(アビシパル由来配列)。
抗体HC2:LC1およびブロルシズマブ由来配列を含む六価二特異性抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
抗体HC2:LC1およびアフリベルセプト由来配列を含む六価二特異性抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号22(アフリベルセプト由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号22(アフリベルセプト由来配列)。
抗体HC2:LC1およびラニビズマブ由来配列を含む六価二特異性抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号28(ラニビズマブ由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号28(ラニビズマブ由来配列)。
抗体HC2:LC1およびアビシパル由来配列を含む六価二特異性抗体
1)配列番号14の残基1〜467(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号244(アビシパル由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号244(アビシパル由来配列)。
抗体HC2:LC1およびブロルシズマブ由来配列を含む四価二特異性抗体
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
抗体HC2:LC1およびアフリベルセプト由来配列を含む四価二特異性抗体
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号22(アフリベルセプト由来配列)。
抗体HC2:LC1およびラニビズマブ由来配列を含む四価二特異性抗体
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号28(ラニビズマブ由来配列)。
抗体HC2:LC1およびアビシパル由来配列を含む四価二特異性抗体
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号244(アビシパル由来配列)。
Tie2を活性化する二特異性抗体
(実施例15)
二特異性抗体はAng1媒介Tie2活性化を増強し、VEGF媒介VEGFR2活性化をブロックする
VEGFおよびAng1での処理は、VEGFR2およびTie2の増加されたリン酸化をもたらした(図20)。HPTP−βに対して特異的なHC2:LC1抗体での処理は、Ang1およびVEGFで処理された細胞において、Ang1媒介Tie2活性化を増強した。二特異性抗体での処理は、Ang1およびVEGFで処理された細胞において、Ang1媒介Tie2活性化を増強し、VEGF媒介VEGFR2活性化をブロックした。上パネルは、それぞれ、リン酸化Tie2およびリン酸化VEGFR2(上半分)、ならびに総Tie2およびVEGFR2(下半分)の検出を通して示されるように、Tie2活性化およびVEGFR2活性化を示すウエスタンブロットを提供する。下側パネルは、リン酸化されたTie2の総Tie2に対する濃度測定比およびリン酸化されたVEGFR2の総VEGFR2に対する濃度測定比を提供する。
(実施例16)
二特異性抗体はAng1媒介Tie2活性化を増強し、VEGF媒介VEGFR2活性化をブロックする(免疫沈降およびウエスタンブロットアッセイ)
(実施例17)
二特異性抗体はAng1媒介Tie2活性化を増強し、VEGF媒介VEGFR2活性化をブロックする(電気化学発光アッセイ)
(実施例18)
多特異性抗体高は親和性でHPTP−βおよびVEGFに結合する(biacore表面プラズモン共鳴アッセイ)
(実施例19)
抗体HC2:LC1、アビシパル由来配列およびブロルシズマブ由来配列を含む六価抗体
1)配列番号14の残基1〜467(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号244(アビシパル由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
抗体HC2:LC1、アフリベルセプト由来配列およびブロルシズマブ由来配列を含む六価抗体
1)配列番号14(抗体HC2:LC1の重鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号23(ブロルシズマブ由来配列)。
1)配列番号17(抗体HC2:LC1の軽鎖);
2)配列番号31(リンカーペプチド、下線);および
3)配列番号22(アフリベルセプト由来配列)。
以下の非限定的な実施形態は、本開示の実例を提供するが、本開示の範囲を限定するものではない。
Claims (98)
- (a)ホスファターゼをモジュレートする第1のドメインであって、前記ホスファターゼが、Tie2をモジュレートする、第1のドメイン;および
(b)受容体チロシンキナーゼアゴニストと特異的に結合する第2のドメイン
を含む化合物。 - 抗体である、請求項1に記載の化合物。
- 多特異性抗体である、請求項1に記載の化合物。
- 四価抗体である、請求項1に記載の化合物。
- 六価抗体である、請求項1に記載の化合物。
- 二特異性抗体である、請求項1に記載の化合物。
- 四価二特異性抗体である、請求項1に記載の化合物。
- 六価二特異性抗体である、請求項1に記載の化合物。
- Tie2をモジュレートする前記ホスファターゼを阻害する、請求項1に記載の化合物。
- HPTP−βを阻害する、請求項1に記載の化合物。
- VE−PTPを阻害する、請求項1に記載の化合物。
- Tie2を活性化する、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストを阻害する、請求項1に記載の化合物。
- VEGF受容体シグナル伝達を阻害する、請求項1に記載の化合物。
- VEGFを阻害する、請求項1に記載の化合物。
- VEGF−Aを阻害する、請求項1に記載の化合物。
- Tie2をモジュレートする前記ホスファターゼを阻害し、かつ前記受容体チロシンキナーゼアゴニストを阻害する、請求項1に記載の化合物。
- 前記ホスファターゼが、HPTP−βであり、前記受容体チロシンキナーゼアゴニストが、VEGFである、請求項1に記載の化合物。
- 前記ホスファターゼが、HPTP−βであり、前記受容体チロシンキナーゼアゴニストが、VEGF−Aである、請求項1に記載の化合物。
- Tie2を活性化し、前記受容体チロシンキナーゼアゴニストが、VEGFである、請求項1に記載の化合物。
- Tie2を活性化し、前記受容体チロシンキナーゼアゴニストが、VEGF−Aである、請求項1に記載の化合物。
- Tie2シグナル伝達をモジュレートする前記ホスファターゼが、タンパク質チロシンホスファターゼである、請求項1に記載の化合物。
- Tie2シグナル伝達をモジュレートする前記ホスファターゼが、受容体様タンパク質チロシンホスファターゼである、請求項1に記載の化合物。
- Tie2シグナル伝達をモジュレートする前記ホスファターゼが、HPTP−βである、請求項1に記載の化合物。
- Tie2シグナル伝達をモジュレートする前記ホスファターゼが、VE−PTPである、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、増殖因子である、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、システインノット増殖因子スーパーファミリーメンバーである、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、PDGFファミリーメンバーである、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、血管新生促進因子である、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、VEGF受容体アゴニストである、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、VEGFである、請求項1に記載の化合物。
- 前記受容体チロシンキナーゼアゴニストが、VEGF−Aである、請求項1に記載の化合物。
- 前記第1のドメインが、HPTP−βに結合する、請求項1に記載の化合物。
- 前記第1のドメインが、VE−PTPに結合する、請求項1に記載の化合物。
- 前記第1のドメインが、HPTP−βの細胞外ドメインに結合する、請求項1に記載の化合物。
- 前記第1のドメインが、HPTP−βの細胞外ドメインの第1のFN3リピートに結合する、請求項1に記載の化合物。
- 前記第2のドメインが、VEGFに結合する、請求項1に記載の化合物。
- 前記第2のドメインが、VEGF−Aに結合する、請求項1に記載の化合物。
- 前記第1のドメインが、HPTP−βに結合し、前記受容体チロシンキナーゼアゴニストが、VEGFである、請求項1に記載の化合物。
- 前記第1のドメインが、HPTP−βに結合し、前記受容体チロシンキナーゼアゴニストが、VEGF−Aである、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号76〜98のいずれか1つと少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号76、配列番号77、配列番号78、配列番号79または配列番号80と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号81、配列番号82、配列番号83、配列番号84、配列番号85、配列番号86または配列番号87と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号88、配列番号89または配列番号90と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号91、配列番号92または配列番号93と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号94、配列番号95または配列番号96と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、配列番号97または配列番号98と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第1のドメインが、
(a)配列番号76、配列番号77、配列番号78、配列番号79または配列番号80と少なくとも80%同一である配列;
(b)配列番号81、配列番号82、配列番号83、配列番号84、配列番号85、配列番号86または配列番号87と少なくとも80%同一である配列;
(c)配列番号88、配列番号89または配列番号90と少なくとも80%同一である配列;
(d)配列番号91、配列番号92または配列番号93と少なくとも80%同一である配列;
(e)配列番号94、配列番号95または配列番号96と少なくとも80%同一である配列;および
(f)配列番号97または配列番号98と少なくとも80%同一である配列
を含む、請求項1に記載の化合物。 - 前記第2のドメインが、配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号99〜146のいずれか1つと少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号99、配列番号100、配列番号101、配列番号102、配列番号103、配列番号104、配列番号105、配列番号106、配列番号107、配列番号108、配列番号109、配列番号110、配列番号111、配列番号112または配列番号113と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号114、配列番号115、配列番号116、配列番号117、配列番号118、配列番号119、配列番号120、配列番号121、配列番号122または配列番号123と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号124、配列番号125、配列番号126、配列番号127、配列番号128、配列番号129、配列番号130または配列番号131と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号132、配列番号133、配列番号134、配列番号135、配列番号136または配列番号137と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号138、配列番号139、配列番号140、配列番号141、配列番号142または配列番号143と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、配列番号144、配列番号145または配列番号146と少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- 前記第2のドメインが、
(a)配列番号99、配列番号100、配列番号101、配列番号102、配列番号103、配列番号104、配列番号105、配列番号106、配列番号107、配列番号108、配列番号109、配列番号110、配列番号111、配列番号112または配列番号113と少なくとも80%同一である配列;
(b)配列番号114、配列番号115、配列番号116、配列番号117、配列番号118、配列番号119、配列番号120、配列番号121、配列番号122または配列番号123と少なくとも80%同一である配列;
(c)配列番号124、配列番号125、配列番号126、配列番号127、配列番号128、配列番号129、配列番号130または配列番号131と少なくとも80%同一である配列;
(d)配列番号132、配列番号133、配列番号134、配列番号135、配列番号136または配列番号137と少なくとも80%同一である配列;
(e)配列番号138、配列番号139、配列番号140、配列番号141、配列番号142または配列番号143と少なくとも80%同一である配列;および
(f)配列番号144、配列番号145または配列番号146と少なくとも80%同一である配列
を含む、請求項1に記載の化合物。 - 前記第2のドメインが、配列番号147、配列番号148、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、請求項1に記載の化合物。
- (a)前記第1のドメインが、配列番号76〜98のいずれか1つと少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号99〜148のいずれか1つまたは配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、
(i)配列番号76、配列番号77、配列番号78、配列番号79または配列番号80と少なくとも80%同一である配列;
(ii)配列番号81、配列番号82、配列番号83、配列番号84、配列番号85、配列番号86または配列番号87と少なくとも80%同一である配列;
(iii)配列番号88、配列番号89または配列番号90と少なくとも80%同一である配列;
(iv)配列番号91、配列番号92または配列番号93と少なくとも80%同一である配列;
(v)配列番号94、配列番号95または配列番号96と少なくとも80%同一である配列;および
(vi)配列番号97または配列番号98と少なくとも80%同一である配列
を含み;
(b)前記第2のドメインが、
(i)配列番号99、配列番号100、配列番号101、配列番号102、配列番号103、配列番号104、配列番号105、配列番号106、配列番号107、配列番号108、配列番号109、配列番号110、配列番号111、配列番号112または配列番号113と少なくとも80%同一である配列;
(ii)配列番号114、配列番号115、配列番号116、配列番号117、配列番号118、配列番号119、配列番号120、配列番号121、配列番号122または配列番号123と少なくとも80%同一である配列;
(iii)配列番号124、配列番号125、配列番号126、配列番号127、配列番号128、配列番号129、配列番号130または配列番号131と少なくとも80%同一である配列;
(iv)配列番号132、配列番号133、配列番号134、配列番号135、配列番号136または配列番号137と少なくとも80%同一である配列;
(v)配列番号138、配列番号139、配列番号140、配列番号141、配列番号142または配列番号143と少なくとも80%同一である配列;および
(vi)配列番号144、配列番号145または配列番号146と少なくとも80%同一である配列
を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号76、配列番号77、配列番号78、配列番号79または配列番号80と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号81、配列番号82、配列番号83、配列番号84、配列番号85、配列番号86または配列番号87と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号88、配列番号89または配列番号90と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号91、配列番号92または配列番号93と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号94、配列番号95または配列番号96と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、配列番号97または配列番号98と少なくとも80%同一である配列を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)前記第1のドメインが、
(i)配列番号76、配列番号77、配列番号78、配列番号79または配列番号80と少なくとも80%同一である配列;
(ii)配列番号81、配列番号82、配列番号83、配列番号84、配列番号85、配列番号86または配列番号87と少なくとも80%同一である配列;
(iii)配列番号88、配列番号89または配列番号90と少なくとも80%同一である配列;
(iv)配列番号91、配列番号92または配列番号93と少なくとも80%同一である配列;
(v)配列番号94、配列番号95または配列番号96と少なくとも80%同一である配列;および
(vi)配列番号97または配列番号98と少なくとも80%同一である配列
を含み;
(b)前記第2のドメインが、配列番号22、配列番号147、配列番号148、配列番号244、または配列番号233〜242のいずれか1つと少なくとも80%同一である配列を含む、
請求項1に記載の化合物。 - (a)配列番号254、配列番号255、配列番号256または配列番号257と少なくとも80%同一である重鎖配列;および
(b)配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である軽鎖配列
を含む、請求項1に記載の化合物。 - (a)配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列;
(b)配列番号246、配列番号247、配列番号248または配列番号249と少なくとも80%同一である配列;
(c)配列番号31〜75のいずれか1つと少なくとも80%同一である配列;および
(d)配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である配列
を含む四価二特異性抗体である、請求項1に記載の化合物。 - (a)リンカーを含む第1の鎖であって、前記リンカーが、配列番号31〜75のいずれか1つと少なくとも80%同一である配列を含み、前記リンカーが、N末端およびC末端を含み、前記リンカーの前記N末端が、配列番号246、配列番号247、配列番号248または配列番号249と少なくとも80%同一である配列のC末端に結合されており、前記リンカーの前記C末端が、配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列のN末端に結合されている、第1の鎖;および
(b)配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である配列を含む第2の鎖
を含む四価二特異性抗体である、請求項1に記載の化合物。 - (a)配列番号246、配列番号247、配列番号248または配列番号249と少なくとも80%同一である配列を含む第1の鎖;および
(b)リンカーを含む第2の鎖であって、前記リンカーが、配列番号31〜75のいずれか1つと少なくとも80%同一である配列を含み、前記リンカーが、N末端およびC末端を含み、前記リンカーの前記N末端が、配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である配列のC末端に結合されており、前記リンカーの前記C末端が、配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列のN末端に結合されている、第2の鎖
を含む四価二特異性抗体である、請求項1に記載の化合物。 - (a)配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列;
(b)配列番号246、配列番号247、配列番号248または配列番号249と少なくとも80%同一である配列;
(c)配列番号31〜75のいずれか1つと少なくとも80%同一である配列;および
(d)配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である配列
を含む六価二特異性抗体である、請求項1に記載の化合物。 - (a)リンカーを含む第1の鎖であって、前記リンカーが、配列番号31〜75のいずれか1つと少なくとも80%同一である配列を含み、前記リンカーが、N末端およびC末端を含み、前記リンカーの前記N末端が、配列番号246、配列番号247、配列番号248または配列番号249と少なくとも80%同一である配列のC末端に結合されており、前記リンカーの前記C末端が、配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列のN末端に結合されている、第1の鎖;および
(b)リンカーを含む第2の鎖であって、前記リンカーが、配列番号31〜75のいずれか1つと少なくとも80%同一である配列を含み、前記リンカーが、N末端およびC末端を含み、前記リンカーの前記N末端が、配列番号250、配列番号251、配列番号252または配列番号253と少なくとも80%同一である配列のC末端に結合されており、前記リンカーの前記C末端が、配列番号22、配列番号23、配列番号28または配列番号244と少なくとも80%同一である配列のN末端に結合されている、第2の鎖
を含む六価二特異性抗体である、請求項1に記載の化合物。 - (a)配列番号262、または配列番号246〜249のいずれか1つと少なくとも80%同一である重鎖配列;および
(b)配列番号258、配列番号259、配列番号261または配列番号260と少なくとも80%同一である軽鎖配列
を含む、請求項1に記載の化合物。 - (a)配列番号254、配列番号255、配列番号256または配列番号257と少なくとも80%同一である重鎖配列;および
(b)配列番号258、配列番号259、配列番号261または配列番号260と少なくとも80%同一である軽鎖配列
を含む、請求項1に記載の化合物。 - 前記化合物のHPTP−βに対する結合親和性(KD)が、約30fM〜約70nMである、請求項40に記載の化合物。
- 前記化合物の前記VEGFに対する結合親和性(KD)が、約30fM〜約70nMである、請求項40に記載の化合物。
- 前記化合物のHPTP−βに対する結合親和性(KD)が、約30fM〜約70nMであり、前記化合物のVEGFに対する結合親和性(KD)が、約30fM〜約70nMである、請求項40に記載の化合物。
- それを必要とする対象における状態を処置する方法であって、治療有効量の請求項1〜78のいずれか一項に記載の化合物を前記対象に投与することを含む、方法。
- 前記状態が、眼の状態である、請求項79に記載の方法。
- 前記状態が、糖尿病性網膜症である、請求項79に記載の方法。
- 前記状態が、新血管形成である、請求項79に記載の方法。
- 前記状態が、血管漏出である、請求項79に記載の方法。
- 前記状態が、増加した眼圧である、請求項79に記載の方法。
- 前記状態が、眼球浮腫である、請求項79に記載の方法。
- 前記状態が、糖尿病性黄斑浮腫である、請求項79に記載の方法。
- 前記状態が、高眼圧症である、請求項79に記載の方法。
- 前記状態が、眼の炎症である、請求項79に記載の方法。
- 前記状態が、緑内障である、請求項79に記載の方法。
- 前記投与が、前記対象の目に対してである、請求項79に記載の方法。
- 前記投与が、硝子体内である、請求項79に記載の方法。
- 前記投与が、皮下である、請求項79に記載の方法。
- 前記投与が、局所である、請求項79に記載の方法。
- 前記対象が、ヒトである、請求項79に記載の方法。
- 前記治療有効量が、約0.25mg〜約200mgである、請求項79に記載の方法。
- 前記治療有効量が、約1mg/kg〜約10mg/kgである、請求項79に記載の方法。
- 前記治療有効量が、約1mg〜約50mgである、請求項79に記載の方法。
- 前記治療有効量が、約50mg〜約200mgである、請求項79に記載の方法。
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US10894824B2 (en) | 2021-01-19 |
EP3856245A1 (en) | 2021-08-04 |
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