JP2022023156A - 糖尿病黄斑浮腫の治療のための組成物および方法 - Google Patents
糖尿病黄斑浮腫の治療のための組成物および方法 Download PDFInfo
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Abstract
Description
本願は、米国特許法第119条(e)の下、2014年3月27日に出願の米国特許仮出願番号第61/971,170号の利益を主張するものであり、この文献全体は本明細書中参照として援用されている。
本開示は、活性PKal、たとえばPKalの触媒ドメインに特異的に結合する単離抗体を提供する。一部の実施形態では、本明細書中記載される抗体は、プレカリクレイン(たとえばヒトのプレカリクレイン)に結合しない。
(数2)
[Bound]=[N][Free]/(Kd+[Free])
により、遊離の標的タンパク質濃度([Free])および標的上の結合タンパク質の結合部位の濃度に関連しており、式中の(N)は、標的分子あたりの結合部位の数である。
www.bioinf.org.uk/abs/
一部の実施形態では、活性PKalに特異的に結合する抗体は、V410、L412、T413、A414、Q415、R416、L418、C419、H434、C435、F436、D437、G438、L439、W445、Y475、K476、V477、S478、E479、G480、D483、F524、E527、K528、Y552、D554、Y555、A564、D572、A573、C574、K575、G576、S578、T596、S597、W598、G599、E600、G601、C602、A603、R604、Q607、P608、G609、V610、および/またはY611を含む、ヒトのPKalの触媒ドメインにおける、1つまたは複数の残基(たとえば少なくとも3、5、8、10、15、20、25、30、35、40、または45個)と相互作用する(完全長のプレカリクレインアミノ酸配列に基づく数)。これら残基の位置を、図4に示す(太字および下線)。これらの残基は、以下の実施例2に記載される結晶構造に従って、DX-2930の1つまたは複数の残基と相互作用すると同定されている。
一部の実施形態では、本明細書中に記載される抗PKal抗体は、VHおよびVLを含み、そのそれぞれが、フレームワーク領域に隣接した3つのCDRを含む(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4;図3参照)。重鎖のCDR3は、モチーフ:X99R100X101G102X103P104R105X106X107X108X109X110X111であって、X99がRまたはQであり、X101がT、I、R、S、またはPであり、X103がV、I、またはLであり、X106がRまたはWであり、X107がDまたはNであり、X108がA、S、D、E、またはVであり、X109がFまたはLであり、X110がD、E、またはNであり、およびX111がI、N、M、またはS(SEQ ID NO:15)である、モチーフを含むことができる。一部の例では、X99がQであり、かつX101がI、R、S、またはPである。あるいはまたはさらに、X106がWであり、かつX111がN、M、またはSである。他の例では、X101がIであり、X108がEであり、かつX103がIまたはLであり;またはX101がIであり、かつX103がIまたはLである。さらなる他の例では、X103がIまたはLであり、かつX110がD、E、またはNである。
本開示の態様は、たとえばDME、AMD、RVO、ぶどう膜炎、眼内炎、またはPCVといった網膜疾患を有する、有する疑いのある、または有するリスクのある対象の治療に関する。一部の実施形態では、このような対象を治療する方法であって、本明細書中に記載される活性PKalに特異的に結合する抗体の有効量を含む組成物を適切な経路を介して上記対象に投与する、方法が提供される。
本明細書中に記載されるPKalに結合できる抗体は、当該分野で知られたいずれかの方法により作製することができる。たとえば、Harlow and Lane, (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New Yorkを参照されたい。
上述の抗PKal抗体のうちの1つまたは複数を、DMEの緩和に使用するための医薬組成物を形成するため、緩衝剤を含む薬学的に許容可能な担体(賦形剤)と混合することができる。「許容可能な」は、担体が組成物の活性成分に適合することができ(および好ましくは活性成分を安定化させることができ)なければならず、処置される対象に有害であってはならないことを意味する。薬学的に許容可能な賦形剤(担体)は、緩衝剤を含み、当該分野でよく知られている。たとえばRemington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover.を参照されたい。一例では、本明細書中に記載される医薬組成物は、活性PKalの異なるエピトープ/残基を認識する1つより多くの抗PKal抗体を含む。
また、本開示は、DME、AMD、RVO、ぶどう膜炎、眼内炎、またはPCVなどの網膜疾患の治療に使用するためのキットをも提供する。このようなキットは、たとえば本明細書中に記載されるいずれか、たとえばDX-2930といった抗PKal抗体を含む1つまたは複数の容器を含むことができる。
本発明の実務は、特段他の記載がない限り、分子生物学(組み換え技術を含む)、微生物学、細胞生物学、生化学、および免疫学の従来技術を用いており、これらは従来技術の範囲内にある。このような技術は、Molecular Cloning: A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel, et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis, et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995)などの文献に十分に説明されている。
実施例1:レーザー誘発脈絡膜血管新生(レーザCNV)疾患モデルにおけるDX-2944の効果
DX―2944は、大腸菌発現系から発現させて精製したDX-2930の組み換えFab型である。レーザーCNVモデルは、加齢黄斑変性(AMD)、網膜静脈閉塞症、および黄斑浮腫などのヒトの網膜疾患に関連する合併症に関する確立されたげっ歯類モデルである。この試験のために使用した実験計画を、以下に概説する。
実験計画
1日目:眼あたり3つの病変を作製するために両側のレーザー処置
3日目:試験薬剤、ビヒクル、または陽性対照(抗VEGF Ab)の両側の硝子体内注射
22日目:in vivoでのフルオレセイン眼底血管造影
図1A~1Bおよび図2A~2Bにおける結果は、DX-2944が、観察されたCNVを、陽性対照(抗VEGF抗体)とほぼ同程度に低減させることを示す。抗VEGF処置群のフルオレセイン眼底血管造影シグナルの平均値は7023蛍光単位であったが、これは、DX-2944処置群で観察された7071蛍光単位と類似する。
His-タグと融合した、ヒト血漿カリクレインの触媒ドメインを、昆虫細胞で発現させ、まずニッケル親和性カラムにより精製した。トリプシン消化を介して、His-タグを血漿カリクレインから除去し、遊離した血漿カリクレインを、ベンズアミジン親和性カラム、次にSECカラムにより精製した、精製した生成物をPAGEゲル上で試験した。この結果は、ヒトの血漿カリクレインの触媒ドメインが適切に発現されて精製されたことを示した。
抗体M0162-A04の重鎖可変領域、特にHC CDR3領域を、親和性成熟に供した。HC CDR3領域における1つまたは複数の位置でアミノ酸変異を有する様々な変異体を作製し、そのKi,appを、定例的な方法に従って決定した。
様々なPKal変異体に対する変異体X115-F02の阻害活性を調べた。
本明細書中に記載されるDX-2944を、大腸菌発現系から発現させて精製した。この試験で使用したレーザーCNVモデルは、加齢黄斑変性(AMD)、網膜静脈閉塞症、および黄斑浮腫などのヒトの網膜疾患に関連する合併症の、確立されたげっ歯類モデルである。行われた実験計画を以下に概説する。
実験計画:ラットにおけるレーザー誘発脈絡膜血管新生(CNV)
1日目:眼あたり3つの病変を生成するために両側のレーザー処置
3日目:試験薬剤、ビヒクル、および陽性対照の両側の硝子体内注射
10日目:試験薬剤、ビヒクル、および陽性対照の両側の硝子体内注射
15日目:in vivoでのフルオレセイン眼底血管造影
22日目:in vivoでのフルオレセイン眼底血管造影
本明細書に開示される特徴のすべては、何等かの組み合わせで組み合わせてもよい。本明細書に開示される各特徴は、同じ、均等、または類似の目的を果たす代替的な特徴と置換してもよい。よって、特段他の記載が明確に記載されていない限り、開示される特徴は、それぞれ、一般的な一連の均等なまたは類似の特徴の単なる一例である。
いくつかの発明の実施形態が本明細書中に記載され、例示されているが、当業者は、本明細書中に記載される機能を実施するための、および/もしくは本明細書中に記載される結果および/または利点の1つまたは複数を得るための、様々な他の手段および/または構造を容易に想定するものであり、このような変更および/または修正は、それぞれ、本明細書に記載される本発明の実施形態の範囲内にあるとされる。より一般的には、当業者は、本明細書中に記載されるすべてのパラメータ、次元、材料、および構成が例示的であることを意味し、実際のパラメータ、次元、材料および/または構成が、本発明の技術が使用される特定の用途に依存することを容易に理解するものである。当業者は、単なる定例的な実験を使用して、本明細書中に記載される特定の発明の実施形態の多くの均等物を認識し、または確認することができる。よって、上記の実施形態が、単なる例として提示されており、添付される特許請求の範囲およびその均等物の中で、発明の実施形態を、具体的に記載され、主張されるものとは異なるように実施してもよいと理解される。本開示の発明の実施形態は、本明細書中に記載されるそれぞれ個々の特徴、システム、物品、材料、キット、および/または方法を目的としている。さらに、このような特徴、システム、物品、材料、キット、および/または方法が相互に矛盾しない場合に、このような特徴、システム、物品、材料、キット、および/または方法の2つ以上の任意の組み合わせが、本開示の発明の範囲内に含まれる。
特許請求の範囲で使用する場合「~から本質的になる」は、特許法の分野で使用される通常の意味を有する。
Claims (1)
- 対象の網膜疾患を治療する方法であって、
活性血漿カリクレイン(PKal)に特異的に結合する抗体を含む組成物の有効量を、その必要がある対象に投与すること
を含む、方法。
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