JP2021525724A - プロドラッグおよび複合体に使用する修飾自己切断部分ならびにその使用方法および製造方法 - Google Patents
プロドラッグおよび複合体に使用する修飾自己切断部分ならびにその使用方法および製造方法 Download PDFInfo
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- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
Description
本出願は、2018年5月29日出願の米国仮出願番号第62/677307号に対する優先権を米国特許法第119条(e)の下に主張するものであって、該開示は引用により本明細書に組み込まれる。
R1は、C1-C5アルキル、N3、OH、SH、ONH2、NH2、CO2H
R2は、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、およびバリンからなる群から選択される側鎖のアミノ酸残基であり;
nは、2、3、4、または5であり;
R3は、O、NH、
R4は、マウス血清中の
Lは、式L-R3Hの生物活性分子の残渣であり;および
Xは、スペーサー基である]
で示される化合物を提供する。
Abは、抗体であり;
R2は、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、およびバリンからなる群から選択される側鎖のアミノ酸残基であり;
nは、2、3、4、または5であり;
R3は、O、NH、
R4は、マウス血清中の
R5は、
Lは、式L-R3Hの生物活性分子の残渣であり;および
Xは、スペーサー基である]
で示される複合体を提供する。
「抗体」は、全抗体およびいずれかの抗原結合フラグメント(すなわち「抗原結合部位」)またはその一本鎖バリアントを意味する。全抗体は、少なくとも2つの重鎖(H)および2つの軽鎖(L)がジスルフィド結合で相互接続したタンパク質である。各重鎖は、重鎖可変領域(VH)および3つのドメイン、CH1、CH2およびCH3を有する重鎖定常領域を包含する。各軽鎖は、軽鎖可変領域(VLまたはVk)および単一のドメイン、CLを有する軽鎖定常領域を包含する。VHおよびVL領域は、より変異の少ないフレームワーク領域(FR)が散在している、相補性決定領域(CDR)と呼ばれる超可変領域にさらに細分割され得る。各VHおよびVLは、3つのCDRおよび4つのFRを包含し、アミノ末端からカルボキシ末端が次の順序で配列されている:FR1、CDR1、FR2、CDR2、FR3、CDR3、およびFR4。可変領域は、抗原と相互作用する結合ドメインを有する。定常領域は、ホスト組織または因子(免疫系の様々な細胞(例えばエフェクター細胞)および古典的補体システムの最初の成分(C1q)など)への抗体の結合を仲介し得る。抗体が、KDが5 x 10-8M以下、より好ましくは1 x 10-8M以下、より好ましくは6 x 10-9M以下、より好ましくは3 x 10-9M以下、さらにより好ましくは2 x 10-9M以下で抗原Xに結合する場合、その抗体は抗原Xに「特異的に結合する」と言われる。該抗体は、キメラ抗体、ヒト化抗体、または好ましくはヒト抗体であり得る。重鎖定常領域は、グリコシル化のタイプまたは度合に作用するように、抗体半減期を延長するように、エフェクター細胞または補体システムとの相互作用を強める、または弱めるように、もしくはいくつかの他の性質を調節するように改変され得る。この改変は、1つ以上のアミノ酸を置換、付加、ならびに欠失すること、またはドメインを別の免疫グロブリン型のドメインと置換すること、もしくは前述の組み合わせにより行われ得る。
我々は、PABC部分のベンジルオキシカルボニル基に対してオルト位に置換基R4を配置することで、マウス血清中のペプチド
このタイプの分子は、Toll様受容体7(TLR7)のアゴニストである。それらによるTLR7の活性化は、ワクチンおよび免疫療法剤に対するアジュバント効果を発揮し得る。
式(II)の複合体は、R1基の特性により、抗体および式(I)の化合物から多数の方法で製造され得る。
本発明の実践は、次の実施例を参照することによりさらに理解され得る。該実施例は、説明の手段として提供するものであり、限定を意図するものではない。
次の工程は、マウス、ラット、またはヒト血清においてリンカーの血清安定性を試験するために用いられた。
次の工程は、リンカーのカテプシンB切断を試験するために用いられた。
次の工程は、アミンドナーとして機能し得るアミン基を有するリンカーである、リンカー化合物(例えば、化合物Ia-02からIa-12およびIb-01からIb-04)のトランスグルタミナーゼ媒介複合体に用いられ得る。該抗体は、トランスグルタミナーゼ反応性グルタミンを有する抗体(例えばN297AまたはN297Q置換のもの)であり得る。複合化は、抗体:酵素のモル比率が5:1で、組み換え細菌トランスグルタミナーゼにより行われる。その複合化は、50mMトリス緩衝液(pH=8.0)中で標準プロトコルを用いて行われ、37℃で一夜インキュベートした。得られた複合体は、50mMトリス(pH=8.0)で予め平衡化したタンパク質Aカラムで精製される。複合体を0.1Mクエン酸ナトリウム緩衝液(pH=3.5)で溶出する。溶出したフラクションを1Mトリス(pH=9.0)で中和する。該複合体は、20mg/mLソルビトール、10mg/mLグリシン(pH=5.0)中で製剤化され得る。
図1より、CD70ではなくメソテリンを発現するH226がん細胞(中皮腫)を用いるマウスモデルにおいて、本明細書に開示の修飾したSI部分と共に製造したADCが抗がん治療に有効であることが確認される。このグラフは、コントロール(製剤緩衝液、または化合物(Ia-03)と共に製造したADCおよび抗CD70モノクローナル抗体(Terrett et al., US 8,124,738 B2(2012))のいずれかを含むもの)と比較して、化合物(Ia-03)と共に製造したADCおよび抗メソテリンモノクローナル抗体(Terrett et al., US 8,268,970 B2(2012))が、35日後の腫瘍体積を減少させたことを示す。抗CD70 ADCのコントロールにおいて、H226細胞によるCD70抗原の発現の欠損は、抗CD70抗体がADCに対して有効な標的薬剤となることを防いでいる。(抗メソテリンおよび抗CD70の両抗体は、それらがトランスグルタミナーゼ介在複合体に対して適切なアミンアクセプターとなるようにN297A置換で修飾されている)
この基本的な工程は、リシンε-アミノ基と2-イミノチオランとの反応、続いてマレイミドを含むリンカー部分との反応による、抗体への遊離チオール基の導入に基づいている(例えば化合物Ia-01およびIb-05)。初めに、抗体の緩衝液を、50mM NaClおよび2mM DTPAを含む0.1Mホスフェート緩衝液(pH=8.0)に交換し、5〜10mg/mLに濃縮する。抗体に2-イミノ-チオランを加えることでチオール化を行う。加える2-イミノチオランの量は予備実験により決定され得て、それは抗体によって異なる。予備実験において、2-イミノチオランを滴定して抗体に加え、続いて1時間室温で抗体と共にインキュベートした。抗体をSEPHADEXTMG-25カラムを用いて脱塩し、50mM HEPES、5mMグリシン、2mM DTPA、pH=5.5中に加え、導入されたチオール基の数をDTDPとの反応により速やかに決定した。チオール基とDTDPとの反応により、324nmのスペクトルでモニターされ得る、チオピリジンの遊離を生じた。タンパク質濃度0.5〜1.0mg/mLのサンプルが一般に用いられる。280nmでの吸光度は、サンプル中のタンパク質濃度を正確に決定するために用いられ得り、次いで各サンプルの一部(0.9mL)を0.1mLのDTDP(エタノールのストック溶液(5mM))と共に10分間室温でインキュベートする。緩衝液とDTDPのみのブランクサンプルも並行してインキュベートする。10分後、324nmの吸光度を測定し、チオピリジン19,800M-1の吸光係数を用いてチオール基の数を定量する。
一般にチオール化は、抗体あたり約2〜3個のチオール基が導入される程度に達する。これは例えば、いくつかの抗体において、15倍モル過剰の2-イミノチオランを加え、続いて室温で1時間インキュベートすることにより達成され得る。次いで抗体を2-イミノチオランと共に所望のモル率でインキュベートし、次いで脱塩し、コンジュゲーション緩衝液(50mM HEPES、5mMグリシン、2mM DTPA、pH=5.5))に加える。導入したチオール数を上記に記載の通りに定量化する間、チオール化した物質を氷上に静置する。
導入されたチオール数を検証後、ドラッグ-リンカー部分がチオールに対して2.5倍モル過剰で加えられる。複合化反応は、コンジュゲーション緩衝液(最終濃度25%プロピレングリコールおよび5%トレハロース含有)中で進められる。一般に、リンカーストック溶液を100%DMSOに溶解する。ストック溶液を直接チオール化抗体に加える。
この複合化反応混合物を、ゆっくり撹拌しながら室温で2時間インキュベートする。10倍モル過剰のN-エチルマレイミド(DMSO中100mMでストック)を次いで複合体混合物に加え、さらにl時間撹拌し、未反応のチオールをいずれも阻害する。次いでこのサンプルを0.2μフィルターで濾過し、緩衝液をTFF VivaFlow 50 Sartorius 30 MWCO PES膜を用いて10mg/mLグリシン、20mg/mLソルビトール、15%アセトニトリル、pH=5.0(5X TFF緩衝液交換体積)に交換し、あらゆる未反応の薬剤を除去する。最終の製剤は、TFFにより20mg/mLソルビトール、10mg/mLグリシン、pH=5.0中で行う。
次の工程は、図1で説明したタイプのマウスモデル試験に用いられ得る。
本実施例および図1A-1Bは、本明細書に開示の化合物の合成、特に化合物Ia-03に言及する、スキームAに関する。
6-アミノイソベンゾフラン-1(3H)-オン1(1.0g、6.70mmol)およびメタンアミン(MeOH中2M、16.76mL、33.5mmol)/DCM(5mL)の混合物を3日間撹拌した。LCMSで開環生成物の存在が示された(M+H-H2O=163.0)。溶媒を濃縮し、化合物2を無色のペーストとして得た(定量的収量)。
(S)-2-((S)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)-アミノ)-3-メチルブタンアミド)-5-ウレイドペンタン酸(Fmoc-Val-Cit、1.681g、3.39mmol)および化合物2(1.22g、6.77mmol)のTHF(5mL)溶液に、EEDQ(1.674g、6.77mmol)を加えた。反応混合物を室温で一夜撹拌した。LCMSで生成物の形成が示された(M+H-H2O=659.3)。反応液はシリカゲル(40g)を用いてCOMBIFLASHTMカラムで直接精製し、0〜100%のMeOH/DCMで溶出し、化合物3を得た(53%収率)。
化合物3(206mg、0.313mmol)/DMF(1mL)の溶液に、ビス(4-ニトロフェニル)カルボネート(190mg、0.625mmol)、続いてDIEA(0.164mL、0.938mmol)を加えた。反応液を室温で3時間撹拌後、LCMSで生成物の形成が示された(M+H=824.3)。これをCOMBIFLASHTMカラム(シリカゲル40g)に直接注入し、0〜100%のMeOH/DCMで溶出し、化合物4を白色固体として得た(50%収率)。
化合物5(26mg、0.054mmol)/DMF(0.5mL)の溶液に、化合物4(66.6mg、0.081mmol)、続いて2,6-ルチジン(0.013mL、0.108mmol)を加えた。反応液を室温で3時間撹拌後、LCMSで中間体付加化合物が形成し、反応の完了が示された(M+H=1167.3)。反応液を飽和NaHCO3水溶液/EtOAcでワークアップし、付加物を精製せずに次のステップに用いた。
付加物(63.0mg、0.054mmol)/DMF(0.5mL)の溶液に、DEA(0.056mL、0.540mmol)を加えた。30分後、LCMSで反応の完了が示された(M+H=945.4)。反応混合物をDMSO(0.5mL)で希釈し、XBridge Prep C18カラム(5μm、OBD、10 x 150mm)を取り付けたLC-20AP分取HPLC(Shimadzu)で精製し、0〜95%のH2O/アセトニトリル(0.05%ギ酸含有)で溶出した。得られた生成物を含む11分でのフラクションを凍結乾燥し、化合物6を紫色固体として得た。
(S)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-5-(アリルオキシ)-5-オキソペンタン酸(FmocNH-O-alloc-Glu、38.1mg、0.093mmol)および化合物6(88mg、0.093mmol)の混合物を2,6-ルチジン(0.033mL、0.279mmol)およびHATU(70.8mg、0.186mmol)で処理し、1時間撹拌した。LCMSで付加化合物の形成が示された(M+H=1279.6)。反応液をEtOAc/飽和NaHCO3水溶液でワークアップし、付加物を精製せずに次のステップに用いた。
上記のステップから得た付加物に、モルホリン(0.016mL、0.186mmol)、続いてテトラキスパラジウム(10.76mg、9.31μmol)を加え、30分間撹拌した。LCMSでalloc基の除去が示された(M+H=1240.0)。この混合物に、DEA(0.049mL、0.466mmol)を加えて30分間撹拌後、LCMSで反応の完了が示された(M+H=1017.6)。反応液を逆相COMBIFLASHTMカラム(40g、c-18)で精製し、0〜100%の水/アセトニトリル(0.05%ギ酸含有)で溶出し、化合物7を紫色固体として得た。
化合物7(10.2mg、9.50μmol)および2,5-ジオキソピロリジン-1-イル1-(9H-フルオレン-9-イル)-3-オキソ-2,7,10,13,16-ペンタオキサ-4-アザノナデカン-19-オエート(FmocNH-PEG4-OSuc、5.55mg、9.50μmol)/DMF(0.5mL)の溶液を2,6-ルチジン(3.32μL、0.028mmol)で処理し、3時間撹拌した。LCMSで反応の完了が示された(M+H=1357.5)。この反応液に、DEA(0.020mL、0.190mmol)を加え、続いて30分間撹拌後、LCMSで反応の完了が示された(M+H=1135.4)。反応混合物をDMSO(0.5mL)で希釈し、XBridge Prep C18カラム(5mm、OBD、10 x 150mm)を取り付けたLC-20AP分取HPLC(Shimadzu)で精製し、0〜95%のH2O/アセトニトリル(0.05%ギ酸含有)で溶出した。得られた生成物を含む11.5分でのフラクションを凍結乾燥し、化合物Ia-03を紫色固体として得た。
本実施例および図3A-3Cは、本明細書に開示の化合物の合成、特に化合物Ia-06およびIa-09に言及する、スキームBに関する。
6-アミノイソベンゾフラン-1(3H)-オン1(1g、6.70mmol)/メタノール(1mL)の溶液に、エタン-1,2-ジアミン(2.246mL、33.5mmol)を加えた。反応混合物を室温で3時間撹拌した。LCMSで出発物質が消失し、生成物の出現が示された(M+H-H2O=192.2)。溶媒および過剰な試薬を蒸発により除去し、得られた粗製物質8を次のステップに用いた。
化合物8(1402mg、6.70mmol)のDMF(5mL)溶液に、0℃でアリルクロロホルメート(0.715mL、6.70mmol)のTHF(1mL)溶液を加えた。反応液を1時間撹拌後、LCMSで生成物の形成が示された(M+H-H2O=276.2)。反応液に飽和NaHCO3水溶液を添加してクエンチし、EtOAcで抽出した。得られた粗製生成物を、シリカゲルカラム(40g)で精製し、0〜100%のMeOH/DCMで溶出し、化合物9を白色固体として得た。
(S)-2-((S)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-3-メチルブタンアミド)-5-ウレイドペンタン酸(Fmoc-Val-Cit、242mg、0.488mmol)および化合物9(286mg、0.975mmol)のMeOH(2mL)溶液に、EEDQ(241mg、0.975mmol)を加えた。反応混合物を室温で一夜撹拌した。LCMSで新たなピークが示された(M+H=772.5)。反応液は、シリカゲル(40g)を用いて直接COMBIFLASHTMカラムで精製し、0〜100%のMeOH/DCMで溶出し、化合物10を得た。
化合物10(102mg、0.132mmol)のDMF(1mL)溶液に、ビス(4-ニトロフェニル)カルボネート(121mg、0.396mmol)およびDIPEA(0.046mL、0.264mmol)を加えた。反応液を室温で3時間撹拌後、LCMSで反応の完了が示された(M+H=937.3)。シリカゲルカラム(40g)を用いて直接COMBIFLASHTMユニットで精製し、0〜50%のMeOH/DCMで溶出し、化合物11を白色固体として得た。
化合物11および化合物5(53.0mg、0.110mmol)の混合物を一夜撹拌した。LCMSで反応の完了が示され(M+H=1110.4)、これを飽和水溶液NaHCO3/EtOAcでワークアップし、乾燥させた。この粗製混合物/DMF(5mL)に、DEA(0.057mL、0.550mmol)を加え、続いて30分間撹拌した。LCMSで反応の完了が示された(M+H=888.1)。得られた生成物を、逆相COMBIFLASHTMカラム(150g C-18)に直接注入し、0〜50%の水/アセトニトリル(0.05%ギ酸含有)で溶出し、化合物12を紫色固体として得た。
化合物12(150mg、0.142mmol)および2,5-ジオキソピロリジン-1-イル1-(9H-フルオレン-9-イル)-3-オキソ-2,7,10,13,16-ペンタオキサ-4-アザノナデカン-19-オエート(FmocNH-PEG4-OSu、83mg、0.142mmol)のDMF(0.5mL)溶液に、2,6-ルチジン(0.050mL、0.425mmol)を加えた。反応混合物を2時間撹拌し、LCMSで新たなピークが示された(M+H=1528.7)。得られた粗製生成物を、逆相COMBIFLASHで精製し、0〜100%のアセトニトリル/水(0.05%ギ酸含有)で溶出し、所望の生成物を紫色固体として得た。
前述のステップから得られた生成物(5mg、0.037μmol)をDMF(0.5mL)に溶解し、フェニルシラン(0.775μL、6.28μmol)、続いてテトラキスパラジウム(1.815mg、1.571μmol)で処理した。LCMSでalloc基の除去が示された(M+H=1444.4)。反応液はシリンジフィルターを介して濾過し、溶媒を濃縮し、化合物13を得た。
8(4.8mg、3.14μmol)の溶液をDMF(0.5mL)に溶解し、2,5,8,11,14,17,20,23-オクタオキサヘキサコサン-26-酸(6.75mg、0.016mmol)、HATU(6.22mg、0.016mmol)および2,6-ルチジン(4μL、0.033mmol)で処理し、1時間撹拌後、アミンがアシル化した。粗製反応液を次いでDEA(3.28μL、0.031mmol)で処理した。LCMSでFmoc基の脱保護が示された(M+H=1616.5)。得られた粗製生成物を、XBridge Prep C18カラム(5μm、19 x 150mm)を取り付けた分取HPLC(Shimadzu)に直接注入し、0〜95%のMeCN/H2O(0.1%FA含有)で溶出し、生成物を含むフラクションを凍結乾燥し、化合物Ia-09(1.3mg、0.833μmol、26.5%収率)を紫色固体として得た。
化合物12/DMF(0.5mL)の溶液を2,6-ルチジン(10.24μL、0.088mmol)、続いて無水酢酸(2.76μL、0.029mmol)で処理した。5分後、LCMSでアセチル化の完了が示された(M+H=1100.3)。この混合物に、モルホリン(5.10μL、0.059mmol)、続いてテトラキスパラジウム(6.77mg、5.86μmol)を加え、1時間撹拌した。LCMSで反応の完了が示された(M+H=1016.3)。反応液は、C18カラム(50g)を用いて逆相COMBIFLASHTMユニットで直接精製し、0〜50%の水/アセトニトリル(0.05%ギ酸含有)で溶出し、化合物14を紫色固体として得た。
化合物14(22mg、0.022mmol)/DMF(0.5mL)の溶液に、2,5-ジオキソピロリジン-1-イル1-(9H-フルオレン-9-イル)-3-オキソ-2,7,10,13,16-ペンタオキサ-4-アザノナデカン-19-オエート(12.66mg、0.022mmol)および2,6-ルチジン(7.57μL、0.065mmol)を加えた。反応液を1時間撹拌後、LCMSで反応の完了が示された。ジエチルアミン(0.011mL、0.108mmol)を加え、反応混合物を30分間撹拌後、LCMSで生成物の形成が示された(M+H=1363.3)。反応液をDMSO(0.5mL)で希釈し、XBridge Prep C18カラム(5μm、OBD、10 x 150mm)を取り付けたLC-20AP分取HPLC(Shimadzu)で精製し、0〜95%のH2O/アセトニトリル(0.05%ギ酸含有)で溶出した。得られた生成物を含むフラクションを凍結乾燥し、化合物Ia-06を紫色固体として得た。
本実施例および図4は、本明細書に開示の化合物の合成、特に化合物Ib-05に言及する、スキームCに関する。
化合物15(124mg、0.312mmol)および化合物16(310mg、0.312mmol)/DMF(2mL)およびDMSO(2mL)の混合物に、DIPEA(0.164mL、0.937mmol)を加えた。反応混合物を50℃で2時間加熱し、LCMSで反応の完了が示された(M+H=1251.2)。塩基を蒸発させ、得られた粗製生成物を、COMBIFLASHTMカラム(80gシリカゲル)で精製し、0〜50%のMeOH/DCMで溶出し、化合物17を白色固体として得た。
化合物17(52mg、0.042mmol)/DMF(0.5mL)の溶液をモルホリン(7.23μL、0.083mmol)、続いてテトラキスパラジウム(9.60mg、8.30μmol)で処理した。1時間後、LCMSでalloc基の除去が示された。この溶液をDEA(0.043mL、0.415mmol)で処理した。30分後、LCMSで反応の完了が示された(M+H/2=495.9)。得られた粗製生成物を、XBridge Prep C18カラム(5mm、19 x 150mm)を取り付けた分取HPLC(Shimadzu)に直接注入し、0〜95%のアセトニトリル/H2O(0.1%ギ酸含有)で溶出した。得られた生成物を含むフラクションを凍結乾燥し、化合物18を白色固体として得た。
化合物18(17mg、0.017mmol)および2,5-ジオキソピロリジン-1-イル6-(2,5-ジオキソ-2,5-ジヒドロ-1H-ピロール-1-イル)ヘキサノエート(MC-OSuc、5.29mg、0.017mmol)/DMF(0.5mL)およびDMSO(0.5mL)の溶液を2,6-ルチジン(6.00μL、0.052mmol)で処理し、40℃で1時間加熱した。LCMSで反応の完了が示された(M+H=1183.3)。得られた粗製生成物を、XBridge Prep C18カラム(5mm、19 x 150mm)を取り付けた分取HPLC(Shimadzu)に直接注入し、0〜95%のアセトニトリル/H2O(0.1%ギ酸含有)で溶出した。得られた生成物を含むフラクションを凍結乾燥し、化合物Ib-05を白色固体として得た(15mg)。
本実施例および図5は、本明細書に開示の化合物の合成、特に化合物Ib-01に言及する、スキームDに関する。
化合物20(575mg、0.604mmol)および化合物19(240mg、0.604mmol)のDMF(1mL)溶液を、DIPEA(0.316mL、1.811mmol)で処理した。室温で3時間撹拌後、LCMSで反応の完了が示された(M+H=1211.0)。塩基を濃縮し、得られた粗製生成物を、シリカゲル(80g)を用いてCOMBIFLASHTMカラムで精製し、0〜50%のMeOH/DCMで溶出し、化合物21を淡黄色固体として得た。
化合物21(0.206g、0.170mmol)/DMF(1mL)溶液をDEA(1mL)で処理し、1時間撹拌した。過剰の塩基を蒸発させ、溶液をHATU(0.071g、0.187mmol)および1-(9H-フルオレン-9-イル)-3-オキソ-2,7,10,13,16-ペンタオキサ-4-アザノナデカン-19-酸(0.083g、0.170mmol)、および2,6-ルチジン(0.059mL、0.510mmol)の溶液で処理した。30分間撹拌後、LCMSで反応の完了が示された(M+H=1458.4)。反応液は、カラム(50g)を用いて逆相COMBIFLASHTMユニットで精製し、0〜100%のアセトニトリル/H2O(0.05%ギ酸含有)で溶出し、化合物22を得た。
化合物22(0.249g)の溶液をTFA(1mL)で処理し、1時間撹拌後、LCMSでBoc保護基の除去が示された(M+H=1358.1)。TFAをV-10エバポレーターで濃縮した。
この溶液をDEA(0.357mL、3.41mmol)で処理した。30分後、LCMSで化合物Ib-01の形成が示された(M+H=1529.3)。塩基をV-10エバポレーターで蒸発させ、得られた粗製生成物を、C-18カラム(50g)を用いて逆相COMBIFLASHTMユニットで精製し、0〜95%のアセトニトリル/H2O(0.1%ギ酸含有)で溶出し、生成物を含むフラクションを凍結乾燥し、化合物Ib-01を得た(122mg、0.073mmol、43.0%収率)。
本明細書において、第一著者(または発明者)および先の日付により省略形で示した次の文献の完全な引用を下記に示す。各引用文献は参照により本明細書に援用される。
Alouane et al., Ang. Chem. Int. Ed. 2015, 54, 7492, "Self-Immolative spacers: Kinetic Aspects, Structure-Property Relationships, and Application."
Boyd et al., US 7,691,962 B2 (2010).
Burke et al., US 2017/0247412 A1 (2017).
Carl et al., J. Med. Chem. 1981, 24(5), 479, "A Novel Connector Linkage Applicable in Prodrug Design." [1981a]
Carl et al., WO 81/01145 A1 (1981). [1981b]
Doronina et al., Bioconjugate Chem. 2008, 19, 1960, "Novel Peptide Linkers for Highly Potent Antibody-Auristatin Conjugate."
Dorywalska et al., Mol. Cancer Ther. 2016, 15(5), 958, "Molecular Basis of Valine-citrulline-PABC Linker Instability in Site-specific ADCs and its Mitigation by Linker Design."
Dubowchik et al., Biorg. Med. Chem. Lett. 1998, 8, 3341, "Cathepsin B-Sensitive Dipeptide Prodrugs. 1. A Model Study of Structural Requirements for Efficient Release of Doxorubicin." [1998a].
Dubowchik et al., Bioorg. Med. Chem. Lett. 1998, 8, 3347, "Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Paclitaxel (Taxol(登録商標)), Mitomycin C and Doxorubicin." [1998b].
Dubowchik et al., Bioconjugate Chem. 2002, 13, 855, "Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates: Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity."
Feng, US 7,375,078 B2 (2008).
Feng, US 7,989,434 B2 (2011).
Firestone et al., US 6,214,345 B1 (2001).
Gerber et al., Nat. Prod. Rep. 2013, 30, 625, "The antibody-drug conjugate: an enabling modality for natural product based cancer therapies."
Jeffrey, US 8,039,273 (2011).
Jeffrey et al., Bioconjugate Chem. 2006, 17, 831, "Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody-Drug Conjugates."
Lin et al., US 9,089,614 B2 (2015).
Kim et al., US 2016/0184451 A1 (2016).
Kim et al., US 2017/0095576 A1 (2017).
Machida et al., Angew. Chem. Int. Ed. 2016, 55, 8595, "Allosterically Regulated Phosphatase Activity from Peptide-PNA Conjugates Folded Through Hybridization."
Major et al., Chem. Commun. 2011, 47, 7968, "Investigation of Self-Immolative Linkers in the Design of Hydrogen Peroxide Activated Metalloprotein Inhibitors."
McDonagh et al., WO 2007/103288 A2 (2007).
Senter et al., US 7,091,186 B2 (2006).
Szczepanik et al., US 8,828,678 B2 (2014).
Zhang et al., Chem. Commun. 2015, 51, 7031, "An Enzyme Activatable Probe with a Self-immolative Linker for Rapid and Sensitive Alkaline Phosphatase Detection and Cell Imaging through a Cascade Reaction."
Claims (20)
- 式(I)
R1は、C1-C5アルキル、N3、OH、SH、ONH2、NH2、CO2H、
R2は、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、およびバリンからなる群から選択される側鎖のアミノ酸残基であり;
nは、2、3、4、または5であり;
R3は、O、NH、
R4は、マウス血清中の
Lは、式L-R3Hの生物活性分子の残渣であり;および
Xは、スペーサー基である]
で示される化合物。 - 式(II)
Abは、抗体であり;
R2は、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、およびバリンからなる群から選択される側鎖のアミノ酸残基であり;
nは、2、3、4、または5であり;
R3は、O、NH、
R4は、マウス血清中の
R5は、
Lは、式L-R3Hの生物活性分子の残渣であり;および
Xは、スペーサー基である]
で示される複合体。 - 式(II)
Abは、抗体であり;
R1は、C1-C5アルキル、N3、OH、SH、ONH2、NH2、CO2H、
R2は、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、およびバリンからなる群から選択される側鎖のアミノ酸残基であり;
nは、2、3、4、または5であり;
R3は、O、NH、
R4は、マウス血清中の
R5は、
Lは、式L-R3Hの生物活性分子の残渣であり;および
Xは、スペーサー基である]
の化合物と結合することを含む、方法。 - R1が、NH2である、請求項16に記載の方法。
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EA202092747A1 (ru) * | 2018-05-29 | 2021-03-16 | Бристол-Маерс Сквибб Компани | Модифицированные саморазрушающиеся фрагменты для применения в пролекарствах и конъюгатах и способы применения и изготовления |
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007103288A2 (en) * | 2006-03-02 | 2007-09-13 | Seattle Genetics, Inc. | Engineered antibody drug conjugates |
WO2008067495A2 (en) * | 2006-11-29 | 2008-06-05 | Rutgers, The State University Of New Jersey | Chemotherapeutic conjugates and methods of use |
JP2014507439A (ja) * | 2011-02-25 | 2014-03-27 | ロンザ リミテッド | タンパク質薬剤接合体のための分枝リンカー |
CN104587487A (zh) * | 2015-01-06 | 2015-05-06 | 华东师范大学 | 一种应用于靶向给药系统的新的支链连接体 |
WO2017214339A1 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
WO2017214458A2 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-cd98 antibodies and antibody drug conjugates |
WO2017214335A1 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
WO2017214462A2 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-cd98 antibodies and antibody drug conjugates |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US828678A (en) | 1902-09-05 | 1906-08-14 | Roberto Taeggi Piscicelli | Electric telpher postal system. |
CA104587A (en) | 1906-12-24 | 1907-04-09 | Thomas Henry Cole | Apparatus for generating and storing products of combustion under pressure |
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
NZ517202A (en) | 1999-08-24 | 2004-05-28 | Medarex Inc | Human CTLA-4 antibodies and their uses |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
CN1638800B (zh) | 2002-01-09 | 2014-07-16 | 梅达雷克斯有限责任公司 | 抗cd30的人类单克隆抗体 |
GB0220319D0 (en) * | 2002-09-02 | 2002-10-09 | Cancer Res Campaign Tech | Enzyme activated self-immolative nitrogen mustard drugs |
CN1826138B (zh) | 2003-07-22 | 2012-05-23 | 舍林股份公司 | Rg1抗体及其用途 |
SI2383295T1 (sl) | 2003-12-10 | 2015-07-31 | E.R. Squibb & Sons, L.L.C. | Protitelesa IP-10 in njihova uporaba |
JP5064037B2 (ja) | 2004-02-23 | 2012-10-31 | ジェネンテック, インコーポレイテッド | 複素環式自壊的リンカーおよび結合体 |
AU2005227326B2 (en) | 2004-03-24 | 2009-12-03 | Xencor, Inc. | Immunoglobulin variants outside the Fc region |
US7691962B2 (en) | 2004-05-19 | 2010-04-06 | Medarex, Inc. | Chemical linkers and conjugates thereof |
MX2007009935A (es) | 2005-02-18 | 2007-10-10 | Medarex Inc | Anticuerpos monoclonales que carecen de residuos fucosilo contra antigeno membranal especifico de prostata (psma). |
US20090297438A1 (en) | 2005-02-18 | 2009-12-03 | Haichun Huang | Human Monoclonal Antibodies to Prostate Specific Membrane Antigen (PSMA) |
RU2406760C3 (ru) | 2005-05-09 | 2017-11-28 | Оно Фармасьютикал Ко., Лтд. | Моноклональные антитела человека к белку программируемой смерти 1 (pd-1) и способы лечения рака с использованием анти-pd-1-антител самостоятельно или в комбинации с другими иммунотерапевтическими средствами |
JP5215180B2 (ja) | 2005-06-20 | 2013-06-19 | メダレックス インコーポレーティッド | Cd19抗体およびその使用法 |
CN101248089A (zh) | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1(pd-l1)的人单克隆抗体 |
CA2616005C (en) | 2005-07-18 | 2015-09-22 | Seattle Genetics, Inc. | Beta-glucuronide-linker drug conjugates |
KR20080056167A (ko) | 2005-09-26 | 2008-06-20 | 메다렉스, 인코포레이티드 | 씨디70에 대한 인간 모노크로날 항체 |
PL1960434T3 (pl) | 2005-12-08 | 2012-12-31 | Squibb & Sons Llc | Ludzkie przeciwciała monoklonalne przeciw fozylowi-gm1 i sposoby zastosowania antyfukozylu-gm1 |
SG177194A1 (en) | 2005-12-08 | 2012-01-30 | Medarex Inc | Human monoclonal antibodies to protein tyrosine kinase 7 (ptk7) and methods for using anti-ptk7 antibodies |
WO2007067991A2 (en) | 2005-12-08 | 2007-06-14 | Medarex, Inc. | Human monoclonal antibodies to o8e |
EP2035554B1 (en) | 2006-06-29 | 2013-04-24 | The Board of Trustees of The Leland Stanford Junior University | Cell-free synthesis of proteins containing unnatural amino acids |
CN101506233A (zh) | 2006-08-18 | 2009-08-12 | 诺沃-诺迪斯克保健股份有限公司 | 具有提高的特异性的转谷氨酰胺酶变异体 |
CN101528914B (zh) | 2006-09-08 | 2014-12-03 | Ambrx公司 | 通过脊椎动物细胞位点特异性并入非天然氨基酸 |
BRPI0718197A2 (pt) | 2006-10-02 | 2014-09-30 | Medarex Inc | Anticorpo monoclonal isolado, ou uma porção de ligação ao antígeno do mesmo, composição, imunoconjugado, molécula de ácido nucleico isolada, vetor de expressão, célula hospedeira, e, métodos para preparar um anticorpo anti-cxcr4, para modular a atividade do cxcr4 em uma célula, e para estimular a mobilização de células tronco cd34+ da medula óssea para o sangue periférico em um indivíduo. |
BRPI0717902A2 (pt) | 2006-12-01 | 2013-10-29 | Medarex Inc | "anticorpo monoclonal humano isolado, composição, conjugado anticorpo-molécula parceria, imunoconjugado, molécula de ácido nucléico isolada, vetor de expressão, célula hospedeira, método para prepar um anticorpo anti-cd22, método para inibir o desenvolvimento de uma célula tumoral que expressa cd22 e método para tratar uma doença inflamatória ou autoimuneem um indivíduo" |
UY30776A1 (es) | 2006-12-21 | 2008-07-03 | Medarex Inc | Anticuerpos cd44 |
WO2008102007A1 (en) | 2007-02-22 | 2008-08-28 | Novo Nordisk Health Care Ag | Transglutaminase variants with improved specificity |
ES2562790T3 (es) | 2007-07-17 | 2016-03-08 | E. R. Squibb & Sons, L.L.C. | Anticuerpos monoclonales contra Glipicano-3 |
KR101554848B1 (ko) | 2007-10-01 | 2015-09-21 | 브리스톨-마이어스 스큅 컴퍼니 | 메소텔린에 결합하는 인간 항체 및 이의 용도 |
US8394922B2 (en) | 2009-08-03 | 2013-03-12 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
WO2012059882A2 (en) | 2010-11-05 | 2012-05-10 | Rinat Neuroscience Corporation | Engineered polypeptide conjugates and methods for making thereof using transglutaminase |
US8828678B2 (en) | 2010-11-16 | 2014-09-09 | Enzo Life Sciences, Inc. | Self-immolative probes for enzyme activity detection |
RU2015129800A (ru) | 2012-12-21 | 2017-01-30 | Биоэллаенс К. В. | Гидрофильные саморазрушающиеся линкеры и их конъюгаты |
WO2014126836A1 (en) | 2013-02-14 | 2014-08-21 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
JP6474404B2 (ja) | 2013-08-14 | 2019-02-27 | ウィリアム マーシュ ライス ユニバーシティWilliam Marsh Rice University | ウンシアラマイシン誘導体、合成方法、および抗腫瘍薬としてのそれらの使用 |
KR101628872B1 (ko) | 2014-05-28 | 2016-06-09 | 주식회사 레고켐 바이오사이언스 | 자가-희생 기를 포함하는 화합물 |
SG11201701311YA (en) * | 2014-09-11 | 2017-03-30 | Seattle Genetics Inc | Targeted delivery of tertiary amine-containing drug substances |
CN107406496A (zh) | 2015-03-10 | 2017-11-28 | 百时美施贵宝公司 | 可通过转谷氨酰胺酶缀合的抗体和由其制备的缀合物 |
KR20180055889A (ko) | 2015-10-02 | 2018-05-25 | 브리스톨-마이어스 스큅 컴퍼니 | 항체를 접합시키기 위한 트랜스글루타미나제 변이체 |
EA202092747A1 (ru) * | 2018-05-29 | 2021-03-16 | Бристол-Маерс Сквибб Компани | Модифицированные саморазрушающиеся фрагменты для применения в пролекарствах и конъюгатах и способы применения и изготовления |
-
2019
- 2019-05-28 EA EA202092747A patent/EA202092747A1/ru unknown
- 2019-05-28 IL IL278938A patent/IL278938B1/en unknown
- 2019-05-28 KR KR1020207037582A patent/KR20210015923A/ko unknown
- 2019-05-28 BR BR112020024022-2A patent/BR112020024022A2/pt unknown
- 2019-05-28 CN CN201980035056.1A patent/CN112188902A/zh active Pending
- 2019-05-28 CA CA3101601A patent/CA3101601A1/en active Pending
- 2019-05-28 MX MX2020012674A patent/MX2020012674A/es unknown
- 2019-05-28 WO PCT/US2019/034114 patent/WO2019231879A1/en unknown
- 2019-05-28 SG SG11202011739SA patent/SG11202011739SA/en unknown
- 2019-05-28 EP EP19731428.9A patent/EP3801629A1/en active Pending
- 2019-05-28 JP JP2020566576A patent/JP7458997B2/ja active Active
- 2019-05-28 AU AU2019277094A patent/AU2019277094A1/en active Pending
- 2019-05-29 US US16/425,596 patent/US10898578B2/en active Active
-
2020
- 2020-12-18 US US17/126,555 patent/US11911483B2/en active Active
-
2024
- 2024-01-16 US US18/413,928 patent/US20240165249A1/en active Pending
- 2024-01-26 JP JP2024009895A patent/JP2024045327A/ja active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007103288A2 (en) * | 2006-03-02 | 2007-09-13 | Seattle Genetics, Inc. | Engineered antibody drug conjugates |
WO2008067495A2 (en) * | 2006-11-29 | 2008-06-05 | Rutgers, The State University Of New Jersey | Chemotherapeutic conjugates and methods of use |
JP2014507439A (ja) * | 2011-02-25 | 2014-03-27 | ロンザ リミテッド | タンパク質薬剤接合体のための分枝リンカー |
JP2014169298A (ja) * | 2011-02-25 | 2014-09-18 | Lonza Ag | タンパク質薬剤接合体のための分枝リンカー |
CN104587487A (zh) * | 2015-01-06 | 2015-05-06 | 华东师范大学 | 一种应用于靶向给药系统的新的支链连接体 |
WO2017214339A1 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
WO2017214458A2 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-cd98 antibodies and antibody drug conjugates |
WO2017214335A1 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
WO2017214462A2 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-cd98 antibodies and antibody drug conjugates |
Non-Patent Citations (1)
Title |
---|
XUAN ZHANG ET AL., BIOCONJUGATE CHEM, vol. 27, JPN6023022765, 2016, pages 1267 - 1275, ISSN: 0005077002 * |
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MX2020012674A (es) | 2021-02-09 |
US20240165249A1 (en) | 2024-05-23 |
CN112188902A (zh) | 2021-01-05 |
EA202092747A1 (ru) | 2021-03-16 |
WO2019231879A1 (en) | 2019-12-05 |
AU2019277094A1 (en) | 2021-01-21 |
IL278938B1 (en) | 2024-05-01 |
JP7458997B2 (ja) | 2024-04-01 |
US20190365915A1 (en) | 2019-12-05 |
JP2024045327A (ja) | 2024-04-02 |
BR112020024022A2 (pt) | 2021-02-23 |
CA3101601A1 (en) | 2019-12-05 |
US10898578B2 (en) | 2021-01-26 |
SG11202011739SA (en) | 2020-12-30 |
IL278938A (en) | 2021-01-31 |
EP3801629A1 (en) | 2021-04-14 |
KR20210015923A (ko) | 2021-02-10 |
US20210113706A1 (en) | 2021-04-22 |
US11911483B2 (en) | 2024-02-27 |
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