JP2021510375A - 抗体protacコンジュゲート - Google Patents
抗体protacコンジュゲート Download PDFInfo
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- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
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- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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Abstract
Description
1.抗体の結合が、PROTAC部分のいずれかの末端(AまたはB)ではなく、PROTAC部分内のリンカー(L1)に対するものであるため、AおよびBの結合親和性が変化しないように、PROTAC部分内の標的リガンド(A)およびE3リガーゼリガンド(B)の元の構造を維持すること。
2.リンカーに対する、基の結合のための構造修飾は、リガンド(AまたはB)に対する修飾よりもはるかに容易であり、2つのリンカー部分(L1およびL2)間の結合は柔軟性が高い。
3.リンカーに対する修飾は、ほとんどのAPCに適している。したがって、異なる抗体部分が同じPROTACに容易に結合され得るか、同じ抗体が異なるPROTACに容易に結合され得るように、共通のカップリング官能基を使用するようにリンカーを設計することが可能である。
(a)Abは、抗体またはその結合フラグメントであり、
(b)L1およびL2は、独立してリンカーであり、L1は、PROTAC部分内のリンカー(すなわち、PROTAC=A−L1−B)であり、L2は、PROTACのリンカー部分(L1)を介して抗体をPROTACに結合するリンカーであり、
(c)Aは、標的リガンド/バインダーであり(すなわち、キナーゼ、Gタンパク質共役受容体、転写因子、ホスファターゼ、RASスーパーファミリーメンバーなどであり得る標的タンパク質に対するバインダー)、
(d)Bは、ユビキチンリガーゼリガンド/バインダーであり、ユビキチンリガーゼは、E2ユビキチンリガーゼまたはE3ユビキチンリガーゼであり得、
(e)nおよびmは、独立して1〜8の整数である。
実施例1 トラスツズマブ−BRD4−PROTAC−1の調製
化合物2の合成
化合物4の合成
化合物5の合成
化合物7の合成
トラスツズマブ−BRD4−PROTAC 1のコンジュゲーション
実施例2 トラスツズマブ−BRD4−PROTAC−2の調製
化合物8の合成
化合物9の合成
トラスツズマブ−BRD4−PROTAC 2のコンジュゲーション
実施例3 直鎖形態を有するBRD4−PROTACの合成(17)
実施例4 生物活性
BRD4タンパク質分解に対する式(I)の化合物の細胞効力を評価する。ブロモドメインタンパク質4(BRD4)は、BET(ブロモドメインおよびエクストラターミナル)ファミリータンパク質の1つであり、血液悪性腫瘍および固形腫瘍の腫瘍形成に関与する。BRD4は、アセチル化ヒストンを認識し、それに結合し、細胞分裂および転写調節を介したエピジェネティックメモリーの伝達に重要な役割を果たす。BRD4を標的とする強力な阻害剤は、抗腫瘍活性を示し、様々な癌細胞の増殖および形質転換を抑制する。これにより、BRD4は癌治療の有望な治療標的とされた。BRD4タンパク質分解誘導キメラ分子(PROTAC)は、BRD4タンパク質分解を誘導することにより抗癌活性を有することが示されている。ただし、抗癌作用に加えて、正常な細胞もこれらの薬剤の影響を受ける。これは、自閉症様症候群(autism−like syndrome)、および記憶形成の障害など、BET阻害の厄介な有害作用をもたらす。
上記のように、本発明のAPCは、特異的な抗原を有する疾患または障害を治療するために使用され得る。疾患は、癌、自己免疫疾患、感染症または血管増殖性障害であり得る。癌は、肺癌、結腸癌、結腸直腸癌、乳癌、前立腺癌、肝癌、膵癌、膀胱癌、胃癌、腎癌、唾液腺癌、卵巣癌、子宮体癌、子宮頸癌、口腔癌、皮膚癌、脳癌、リンパ腫または白血病であり得る。CellTiter(商標)−96アッセイを使用して、本発明のAPCによる細胞増殖の阻害を測定した。様々なHER2発現表現型を有する乳癌細胞株を対象に、APCの細胞傷害性を評価した。結果は、本発明のAPCがHER2陽性乳癌細胞に対してのみ毒性であることを示し、BRD4タンパク質、SrcキナーゼまたはRASタンパク質は、トラスツズマブに結合した適切なPROTACを使用することにより、プロテアソーム分解のために特異的に標的化され得る。
Claims (13)
- 前記標的タンパク質が、キナーゼ、Gタンパク質共役受容体、転写因子、ホスファターゼおよびRASスーパーファミリーメンバーからなる群から選択される
請求項1に記載のイムノコンジュゲート。 - Aが、熱ショックタンパク質90(HSP90)阻害剤、キナーゼ阻害剤またはホスファターゼ阻害剤、MDM2阻害剤、HDAC阻害剤、ヒトリジンメチルトランスフェラーゼ阻害剤、血管新生阻害剤、免疫抑制化合物、ならびにヒトBETブロモドメイン含有タンパク質、アリール炭化水素受容体(AHR)、REF受容体キナーゼ、FKBP、アンドロゲン受容体(AR)、エストロゲン受容体(ER)、甲状腺ホルモン受容体、HIVプロテアーゼ、HIVインテグラーゼ、HCVプロテアーゼまたはアシルタンパク質チオエステラーゼ1および2(APT1およびAPT2)を標的とする化合物からなる群から選択される
請求項1に記載のコンジュゲート。 - Bが、XIAP、VHL、セレブロンおよびMDM2からなる群から選択されるE3リガーゼに結合する基である
請求項1に記載のイムノコンジュゲート。 - Abが、モノクローナル抗体またはその変異体である
請求項1に記載のイムノコンジュゲート。 - Abが、DLL3、EDAR、CLL1;BMPR1B;E16;STEAP1;0772P;MPF;NaPi2b;Sema 5b;PSCA hlg;ETBR;MSG783;STEAP2;TrpM4;CRIPTO;CD21;CD79b;FcRH2;B7−H4;HER2;NCA;MDP;IL20Rct;ブレビカン;EphB2R;ASLG659;PSCA;GEDA;BAFF−R;CD22;CD79a;CXCRS;HLA−DOB;P2X5;CD72;LY64;FcRH1;IRTA2;TENB2;PMEL17;TMEFF1;GDNF−Ra1;Ly6E;TMEM46;Ly6G6D;LGR5;RET;LY6K;GPR19;GPR54;ASPHD1;チロシナーゼ;TMEM118;GPR172A;MUC16およびCD33からなる群から選択されるポリペプチドのうちの1つ以上に結合する
請求項1に記載のイムノコンジュゲート。 - Abが、トラスツズマブ、セツキシマブ、リツキシマブ、ブレンツキシマブ、ゲムツズマブ、イノツズマブ、サシツズマブ、アレムツズマブまたはニモツズマブである
請求項5に記載のイムノコンジュゲート。 - 請求項1に記載のイムノコンジュゲートおよび1つ以上の薬学的に許容される賦形剤を含む
医薬組成物。 - 疾患を治療するための医薬組成物であって、
請求項1に記載のイムノコンジュゲートまたは請求項8に記載の組成物の有効量を含む
医薬組成物。 - 前記疾患が癌である
請求項9に記載の医薬組成物。 - 前記癌が乳癌または胃癌であり、前記Abがトラスツズマブである
請求項10に記載の医薬組成物。 - 前記癌が結腸癌または扁平上皮癌であり、前記Abがセツキシマブである
請求項10に記載の医薬組成物。 - 前記疾患が白血病であり、前記Abが、リツキシマブ、ブレンツキシマブ、ゲムツズマブ、イノツズマブまたはアレムツズマブである
請求項10に記載の医薬組成物。
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JP2023188179A JP2024012491A (ja) | 2018-01-10 | 2023-11-02 | 抗体protacコンジュゲート |
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US201862615955P | 2018-01-10 | 2018-01-10 | |
US62/615,955 | 2018-01-10 | ||
PCT/US2019/012931 WO2019140003A1 (en) | 2018-01-10 | 2019-01-09 | Antibody protac conjugates |
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WO2018067702A1 (en) | 2016-10-04 | 2018-04-12 | Massachusetts Institute Of Technology | Bottlebrush copolymers and uses thereof |
TW202342454A (zh) * | 2018-04-20 | 2023-11-01 | 大陸商四川科倫博泰生物醫藥股份有限公司 | 一種多功能化合物、其製備方法及其在醫藥上的應用 |
US11639354B2 (en) | 2018-07-31 | 2023-05-02 | Fimecs, Inc. | Heterocyclic compound |
CN111018857B (zh) * | 2018-10-09 | 2023-06-02 | 嘉兴优博生物技术有限公司 | 靶向蛋白酶降解平台(ted) |
AU2019365238A1 (en) * | 2018-10-24 | 2021-05-13 | F. Hoffmann-La Roche Ag | Conjugated chemical inducers of degradation and methods of use |
PT116050B (pt) * | 2020-01-09 | 2022-06-15 | Hovione Farm S A | Conjugados fármaco-ligando e inibidores das proteínas da família bromodomínio e domínio extraterminal -(bet) modificados |
US20210220391A1 (en) * | 2020-01-10 | 2021-07-22 | Massachusetts Institute Of Technology | Proteolysis targeting chimeric molecules (protacs) with functional handles and uses thereof |
CN111217804A (zh) * | 2020-02-21 | 2020-06-02 | 四川大学华西医院 | 一种靶向降解ido1的protac化合物及其制备方法和应用 |
GB202007106D0 (en) | 2020-05-14 | 2020-07-01 | Ucl Business Plc | Cyclosporine analogues |
WO2022093809A1 (en) * | 2020-10-26 | 2022-05-05 | Trustees Of Tufts College | Enhanced hyt-induced protein degradation using lipid nanoparticle delivery |
CN117279664A (zh) | 2021-04-10 | 2023-12-22 | 普方生物制药美国公司 | Folr1结合剂、其偶联物及其使用方法 |
CN117203238A (zh) | 2021-04-23 | 2023-12-08 | 普方生物制药美国公司 | Cd70结合剂、其偶联物及其使用方法 |
CN117500821A (zh) * | 2021-06-11 | 2024-02-02 | 纳米智能生物医学工程有限公司 | 具有细胞内递送功能的Bio PROTAC蛋白和包含该蛋白的药物组合物 |
KR20240029062A (ko) | 2021-07-02 | 2024-03-05 | 메르크 파텐트 게엠베하 | 항-protac 항체 및 복합체 |
TW202320857A (zh) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | 連接子、藥物連接子及其結合物及其使用方法 |
CN115109047B (zh) * | 2021-09-08 | 2024-02-20 | 中国科学院化学研究所 | 一种基于protac设计的铁死亡诱导剂 |
WO2023056069A1 (en) * | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
CN114288422B (zh) * | 2022-01-21 | 2023-04-28 | 陕西科技大学 | 一种化学靶向降解目标蛋白的脂质体及其制备方法 |
CN114560908A (zh) * | 2022-03-11 | 2022-05-31 | 国家纳米科学中心 | 一种多肽protac分子及其制备方法和应用 |
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