JP7449091B2 - 合成化合物 - Google Patents
合成化合物 Download PDFInfo
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- JP7449091B2 JP7449091B2 JP2019514855A JP2019514855A JP7449091B2 JP 7449091 B2 JP7449091 B2 JP 7449091B2 JP 2019514855 A JP2019514855 A JP 2019514855A JP 2019514855 A JP2019514855 A JP 2019514855A JP 7449091 B2 JP7449091 B2 JP 7449091B2
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- 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
- C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
- C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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Description
・直接、及び/又は
・リンカーを介して、接続されていることが好ましい。
(i)Y形状構造の基部に位置するエフェクター部分と、
(ii)任意で、エフェクター部分に付着した1つ又は2つのリンカーと、
(iii)1つ又は2つのリンカーの末端に付着し、Y形状構造を形成する2つのバインダー分子と、を含む。
・少なくとも1つのフェニルアラニン残基と、少なくとも1つのロイシン残基と、又は
・少なくとも1つのフェニルアラニン残基と、少なくとも1つのロイシン残基と、スレオニン残基及び/又はバリン残基から選択される少なくとも1つと、を
含むことが好ましい。
・1つ又は2つのイソロイシン残基を含む第1ブロックと、
・互いに任意の順番でフェニルアラニン残基及びロイシンを含む第2ブロックと、が続く。
ここで、2つのブロックを、互いに任意の順番で位置決めすることができ、2つのブロックは、直接、又は、最大2つのアミノ酸残基を含むペプチド配列により結合する。
以下から成る群から選択される少なくとも1つの配列モチーフを含む。
・IFL
・LFII
・IVTLF
・LFIIK、及び/又は、
・IFTLF
・ペプチド又はペプチド模倣物
・抗体、又は、そのフラグメント若しくは誘導体
・受容体分子、又は、そのフラグメント若しくは誘導体
・抗体模倣物、又は、そのフラグメント若しくは誘導体
・アプタマー
・CDR (complementarity determining region:相補性決定領域)
・超可変領域
・可変ドメイン(Fv)
・1本鎖可変フラグメント(a single chain variable fragment:scFv)
・IgG重鎖(VH、CH1、ヒンジ、CH2、及び、CH3領域からなる)
・IgG軽鎖(VL及びCL領域からなる)、及び/又は、
・Fab及び/又はF(ab)2
・[3 + 2]環化付加、例えば、ヒュスゲン(Huisgen) 1,3-双極性環化付加(アジド‐アルキン・ヒュスゲン環化付加(Azide-Alkyne Huisgen Cycloaddition)とも呼ばれる)
・チオール‐エンクリック反応
・ディールス‐アルダー反応及び逆電子要求ディールス‐アルダー反応
・イソニトリル(イソシアニド)とテトラジンとの間の[4 + 1]環化付加
・求核置換、特に、エポキシ及びアジリジン化合物のような小さなひずみ連鎖への置換
・ウレアーゼのカルボニル化学反応形成、低熱力学的駆動力のためアルドール型の反応ではない
・チオール‐イン反応におけるジヒドロキシル化又はアルキンのようなカーボン‐カーボン二重結合に対する付加反応
・腫瘍性疾患
・自己免疫疾患
・神経病理学的疾患
・代謝性疾患、及び/又は、
・感染性疾患
本発明の更なる詳細、特徴、性質、及び、効果は、従属項に開示されている。各図及び実施例に関する以下の説明は、本発明の好ましい実施形態を示す。しかしながら、これらの図は、本発明の範囲を限定するものではない。
1.抱合反応/クリックケミストリー
1つのアジド部分を有するバインダーペプチドと、2つのアルキン基を有するエフェクターペプチドとの銅触媒アジド‐アルキン環化付加のプロトコル。
1当量のアルキン
2,5当量のアジド
1-6当量のCuSO4(ddH2O中の100-200mM溶剤)
8-50当量のアスコルビン酸ナトリウム(ddH2O中の500-1500mM溶剤)
1,2-6,5当量のTBTA(無水DMF中の100mM溶剤)
好中球の酸化的バーストは、細胞宿主防御の一部を形成し、例えば、N-ホルミルペプチドfMLPにより誘発され得る(Kim他 (2003))。従って、酸化アッセイは、ホルミルペプチドの効能を決定するための有用なツールである。エフェクターペプチド又はペプチド模倣物との培養により引き起こされた好中球の酸化バースト活量は、フローサイトメトリーにより測定され、ローダミンへのジヒドロローダミン123(DHR)の細胞内変換を定量化する。要約すると、ヒト又はマウスの白血球(1,25 * 106細胞/ml)を、10mM Hepesを含むハンクス緩衝食塩水(Hanks' Buffered Saline Solution:HBSS、Ca2+、Mg2+を含まない)中のカタラーゼ、サイトカラシンB(シグマ)及びDHRと共に、pH7,4、5mM EDTA及び0.3%BSA中で37℃で10分間培養した。その後、異なるエフェクターペプチド又はペプチド模倣物と共に、異なる濃度で37℃で15分間培養した。PMAは陽性対照として使用された。
フローサイトメトリーを用いて、特定の標的を示す異なる細胞株に対する本発明の合成化合物のペプチド又はペプチド模倣物の結合能力を調査した。分離細胞は、氷の上で少なくとも30分間、ブロッキング緩衝剤においてビオチン化ペプチド/ペプチド模倣物、又は、ビオチン化合成化合物と共に培養した。細胞を洗浄緩衝剤で2回洗浄した。その後、氷の上で15分間、ペリジニン-クロロフィルタンパク質PerCP-Cy5.5(BD Biosciences)で標識したストレプトアビジンと共に培養した。1回の追加の洗浄ステップ後、FASC Canto(1サンプル当たり少なくとも10000細胞が数えられた)を用いて、サンプルを、ビオチン化試薬とストレプトアビジン- PerCP-Cy5.5とを結合した細胞について分析した。ペプチド又は対照ペプチドと培養した細胞のオーバーレイヒストグラムを作成し、各サンプルの幾何学平均蛍光をFloJoで決定した。グラフプリズム(Graph Prism)ソフトウェアを用いて、EC50測定を計算した。
エフェクターペプチド又はペプチド模倣物の走化性効果をテストするために、10*10 6 細胞/mlで10mMのHepes pH7.4及び0.3%BSAによるハンクス緩衝食塩水(Hanks' Buffered Saline Solution:HBSS、Ca2+、Mg2+を含まない)中に、ヒト白血球を再懸濁した。20分間37℃で細胞を予備加熱した。24ウェルプレートのウェル(800 μl/ウェル)に、上記緩衝剤のエフェクター希釈液を添加した後、孔径5μmのミリセル(Millicell)カルチャープレートインサートを各ウェルに配置した。その後、直ぐに、200 μl(200万)の白血球を添加した。45分間37℃でプレートを培養した。下部チャンバーに遊走した白血球の総数を、ノイバウア(Neubauer)チャンバーを用いて決定した、又は、遊出した単球、好中球、及び、リンパ球の数を、フローサイトメトリーにより決定した(FCS/SSCプロットにおける細部集団を区別する)。
別のアッセイでは、白血球の呼吸バーストを刺激するために、N-ホルミルメチオニンペプチドを含む異なるイソロイシンの効力をテストした。
健康なボランティアのヘパリン添加血液から白血球を単離した。デキストラン500000を1%まで添加し、37℃で30分間培養することにより、赤血球は沈殿した。白血球を含有する上層を2回の低張溶解し、残留赤血球を排除した。室温で遠心分離後、PBSに細胞ペレットを再懸濁し、10倍量の滅菌蒸留水を添加し、室温で20秒間培養後、元容量の10 x PBSを添加した。細胞を再ペレット化し、白色ペレットが観察されるまで、この溶解工程を繰り返した。
C57BL/6(ブラック6)マウスから大腿骨を解剖した。PBS及び26ゲージの針を用いて骨髄を洗い流した。BD Pharm lyse(Becton Dickinson)緩衝剤を用いて製造者の指示に従い赤血球を溶解した。
細胞ベースのジヒドロローダミン(DHR123、分子プローブ(Molecular Probes))酸化アッセイを用いて、酸化バースト(NADPHオキシダーゼ活性)の活性化を測定した。新たに単離したヒト又はマウスの白血球のサンプル(サンプル当たり2,5×105細胞/ml、ハンクス平衡塩溶液(Hank’s balanced salt solution:HBSS)+ 10mMのHepes、pH7.3、0.3%BSA及び5mM EDTA)に、DHR123(0,1 mM)、カタラーセ(1 U/ml、Sigma-Aldrich)及びサイトカラシンB(21μM、Sigma-Aldrich)を添加し、エッペンドルフ管(Eppendorf tube)に分注した。37℃で10分間細胞をプレインキュベートした後、同じ緩衝剤で調製した0.25容量のエフェクターペプチド希釈物(意図濃度の5倍)を添加した。以下のN-ホルミルメチオニンエフェクターペプチドをテストした。
・Frokjaer & Hovgaard, Pharmaceutical Formulation Development of Peptides and Proteins, Taylor & Francis Ltd (2000)
・Ishida & Inoue, Reviews on Heteroatom Chemistry, 19, 79-142 (1999)
・O'Donnell et al., Tetrahedron Lett., 38, 7163-7166 (1997)
・Scott et al., Tetrahedron Lett., 38, 3695-3698 (1997)
・Zhang & Tam, J.P., J. Amer. Chem. Soc., 119, 2363-2370 (1997)
・Koppitz et al., Helv. Chim. Acta, 80, 1280-1300 (1997)
・Gobbo et al., Int. J. Peptide Prot. Res., 50, 336-341 (1997)
・Tam & Lu, Protein Sci., 7, 1583-1592 (1998)
・James et al. (1993) Science 260: 1937- 1942
・O'Donnell et al., J. Am. Chem. Soc. 118, 6070 (1996)
・Kim et al . J. Immunol. 171:4425-4430 (2003)
・TBTA トリス[(1‐ベンジル‐1H‐1,2,3‐トリアゾール‐4‐イル)メチル]アミン:Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
・DMF N、N-ジメチルホルムアミド:N,N-Dimethylformamide
・ACN アセトニトリル:Acetonitrile
・HPLC 高速液体クロマトグラフィー:High Performance Liquid Chromatography
・ESI-MS エレクトロスプレーイオン化質量分析:Electrospray Ionization Mass Spectrometry
・FACS 蛍光活性化セルソーティング:Fluorescence-activated cell sorting
・RP-HPLC 逆相高速液体クロマトグラフィー:Reverse-phase High Performance Liquid Chromatography
・PEG ポリエチレングリコール:Polyethylene glycol
SEQUENCE LISTING
<110> Syntab GmbH
<120> Novel Synthetic Antibodies
<130> SD 43742
<160> 7
<170> PatentIn version 3.5
<210> 1
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> SYN-B9; binder to alpha 3 Integrin
<220>
<221> misc_feature
<222> (1)..(2)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa can be any naturally occurring amino acid
<400> 1
Xaa Xaa Gly Xaa Gly Xaa Asn Xaa
1 5
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> SYN-B13; binder to alpha v beta 6 Integrin (beta chain)
<400> 2
Arg Gly Asp Leu Ala Thr Leu Arg Gln Leu
1 5 10
<210> 3
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> SYN-F2 effector peptide
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa is formyl methionine
<400> 3
Xaa Ile Phe Leu
1
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> SYN-F4 effector peptide
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa is formyl methionine
<400> 4
Xaa Leu Phe Ile Ile
1 5
<210> 5
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> SYN-F5 effector peptide
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa is formyl methionine
<400> 5
Xaa Ile Val Thr Leu Phe
1 5
<210> 6
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> SYN-F14・effector peptide
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa is formyl methionine
<400> 6
Xaa Leu Phe Ile Ile Lys
1 5
<210> 7
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> SYN-FX・effector peptide
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<400> 7
Xaa Ile Phe Thr Leu Phe
1 5
Claims (8)
- 少なくとも1つのエフェクター部分と、
少なくとも1つのバインダー部分と、を含み、
前記エフェクター部分は、直接、及び/又は、リンカーを介して、前記バインダー部分に接続され、
前記少なくとも1つのエフェクター部分は、fMIFL(配列番号3)、fMLFII(配列番号4)、fMIVTLF(配列番号5)、fMLFIIK(配列番号6)及びfMIFTLF(配列番号7)から選択される少なくとも1つのペプチド配列を含み、
前記少なくとも1つのバインダー部分は、ペプチド又はペプチド模倣物からなり、
前記ペプチド又はペプチド摸倣物は、dCys-dAsp-Gly-NitroTyr-Gly-4HydroxiPro-Asn-dCys(配列番号1)又はRGDLATLRQL(配列番号2)を含む、合成化合物。 - 請求項1に記載の合成化合物であって、
前記バインダー部分は、α3インテグリン若しくはαvβ6インテグリンを標的とする、合成化合物。 - 請求項1又は2に記載の合成化合物であって、
前記リンカーは、ポリエチレングリコールを含む、合成化合物。 - 請求項3に記載の合成化合物であって、
前記リンカーは、長さが≦40及び≧15モノマーの間の1つ以上のポリエチレングリコール分子を含む、合成化合物。 - 請求項3又は4に記載の合成化合物であって、
前記ポリエチレングリコールリンカーは、1つ以上アミノ酸側鎖群により、前記エフェクター部分に結合している、合成化合物。 - 請求項1~5のいずれかに記載の合成化合物であって、
エフェクター部分、バインダー部分、及び、リンカーから選択される少なくとも2つの部分は、クリックケミストリーにより互いに結合している、合成化合物。 - 請求項1~6のいずれかの合成化合物と、生理学的に許容される賦形剤と、を含む医薬製剤。
- 腫瘍性疾患、自己免疫疾患、神経病理学的疾患、代謝性疾患、及び/又は、感染性疾患、からなる群から選択される少なくとも1つの疾患の治療に使用される請求項7に記載の製剤、又は、請求項1~6のいずれかに記載の合成化合物。
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GBGB1609083.9A GB201609083D0 (en) | 2016-05-24 | 2016-05-24 | Synthetic compound |
GB1609083.9 | 2016-05-24 | ||
PCT/EP2017/062576 WO2017202933A1 (en) | 2016-05-24 | 2017-05-24 | Synthetic compound |
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EP (1) | EP3464334A1 (ja) |
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JP2009541398A (ja) | 2006-06-30 | 2009-11-26 | アンドレ コルターマン, | 医薬目的のための新規な多官能性化合物 |
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CN1849141A (zh) | 2003-05-12 | 2006-10-18 | 阿费麦克斯公司 | 用于聚(乙二醇)修饰的肽的间隔臂部分 |
US20120010153A1 (en) * | 2009-01-14 | 2012-01-12 | Andre Koltermann | Novel tumor-targeting compounds |
WO2012040513A1 (en) * | 2010-09-22 | 2012-03-29 | The Board Of Regents Of The University Of Texas System | Compositions and methods for the delivery of beta lapachone |
US20130078646A1 (en) | 2011-09-26 | 2013-03-28 | Nour Heart, Inc. | Antibodies, compositions, and assays for detection of cardiac disease |
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2016
- 2016-05-24 GB GBGB1609083.9A patent/GB201609083D0/en not_active Ceased
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2017
- 2017-05-24 WO PCT/EP2017/062576 patent/WO2017202933A1/en unknown
- 2017-05-24 CN CN201780042728.2A patent/CN109641943A/zh active Pending
- 2017-05-24 JP JP2019514855A patent/JP7449091B2/ja active Active
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- 2017-05-24 US US16/304,121 patent/US11318208B2/en active Active
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Patent Citations (1)
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JP2009541398A (ja) | 2006-06-30 | 2009-11-26 | アンドレ コルターマン, | 医薬目的のための新規な多官能性化合物 |
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US11318208B2 (en) | 2022-05-03 |
US20190201539A1 (en) | 2019-07-04 |
EP3464334A1 (en) | 2019-04-10 |
US20220226486A1 (en) | 2022-07-21 |
GB201609083D0 (en) | 2016-07-06 |
WO2017202933A1 (en) | 2017-11-30 |
CN109641943A (zh) | 2019-04-16 |
JP2019523782A (ja) | 2019-08-29 |
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