JP2021523874A - 抗メソセリン抗体およびその抗体薬物コンジュゲート - Google Patents
抗メソセリン抗体およびその抗体薬物コンジュゲート Download PDFInfo
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Abstract
Description
本発明は、抗メソセリン抗体またはその機能的断片に関する。本発明はまた、抗メソセリン抗体および低分子薬物を含む抗体薬物コンジュゲートに関する。本発明はさらに、腫瘍の処置のための医薬品の製造における本発明の抗体およびコンジュゲートの使用に関する。
MSLN(メソセリン)は、中皮細胞、中皮腫および卵巣癌においてモノクローナル抗体CAK1によって認識される抗原である。多くの腫瘍組織で高発現している40kDaの細胞表面糖タンパク質なので、治療用抗体の非常に良好な標的マーカーである。
本発明は、抗メソセリン抗体またはその機能的断片、およびその抗体もしくはその機能的断片を含む抗体薬物コンジュゲートを提供する。特に、本発明の抗体薬物コンジュゲートは、安定性が高く、毒性のある副作用が少なく、および/またはメソセリンに対する親和性が高い。
一態様では、本発明は、以下の構造式を有する抗体薬物コンジュゲートであって、
Ab−(L−D)n
式中、AbはMSLNに特異的に結合する抗体またはその機能的断片であり、
Lは空であるか、または任意のリンカーであり、
Dは任意の治療剤であり、
nは1から8から選択される整数、例えば、1、2、3、4、5、6、7もしくは8であるかまたはそれらの任意の2つの間の間隔である、抗体薬物コンジュゲートを提供する。
(i)重鎖は少なくとも3つのCDR領域を含み、CDR領域の少なくとも1つのアミノ酸配列は配列番号1、2もしくは3に記載のアミノ酸配列を有するか、またはそれらと少なくとも80%(好ましくは、85%、90%、95%、98%もしくは99%)の配列同一性を有する配列を有し、および/または
(ii)軽鎖は少なくとも3つのCDR領域を含み、CDR領域の少なくとも1つのアミノ酸配列は配列番号4、5もしくは6に記載のアミノ酸配列を有するか、またはそれらと少なくとも80%(好ましくは、85%、90%、95%、98%もしくは99%)の配列同一性を有する配列を有する。
(i)重鎖可変領域は3つのCDR領域を含み、CDR領域は配列番号1、2もしくは3に記載のアミノ酸配列をそれぞれ有し、および/または
(ii)軽鎖可変領域は3つのCDR領域を含み、CDR領域は配列番号4、5もしくは6に記載のアミノ酸配列をそれぞれ有する。
(i)重鎖可変領域は配列番号7に記載のアミノ酸配列またはそれと少なくとも80%(好ましくは、85%、90%、95%、98%もしくは99%)の配列同一性を有する配列を含み、
(ii)軽鎖可変領域は配列番号8に記載のアミノ酸配列またはそれと少なくとも80%(好ましくは、85%、90%、95%、98%もしくは99%)の配列同一性を有する配列を含む。
(i)重鎖可変領域は配列番号7に記載のアミノ酸配列を含み、および/または
(ii)軽鎖可変領域は配列番号8に記載のアミノ酸配列を含む。
定義
特に定義しない限り、本明細書で使用した技術用語および科学用語は全て、当業者によって理解されているのと同じ意味を有する。当業界の特定の定義および専門用語については、従事者はCurrent Protocols in Molecular Biology (Ausubel)を参照することができる。アミノ酸残基の略語は、20個の一般的に使用されるL−アミノ酸の1つを意味する当業界で使用される標準的な3文字および/または1文字コードである。
本発明の抗体薬物コンジュゲートの抗体は、ヒトMSLNに特異的に結合することが特徴である。好ましくは、抗体は高い親和性で、例えば、1×10−7M以下のKDでMSLNに結合する。抗MSLN抗体は、好ましくは以下の特性の1つまたは複数を表す:
(a)ヒトMSLNに1×10−7M以下(例えば、5×10−8M以下、2×10−8M以下、5×10−9M以下、4×10−9M以下、3×10−9M以下、2×10−9M以下)のKDで結合する;
(b)MSLNを高発現するOval−Citar−3細胞に、例えば、2000ng/ml以下(例えば、1000ng/ml以下、500ng/ml以下、400ng/ml以下、300ng/ml以下、250ng/ml以下、200ng/ml以下、150ng/ml以下、100ng/ml以下、50ng/ml以下、40ng/ml以下、30ng/ml以下、20ng/ml以下、10ng/ml以下、5ng/ml以下)のEC50で結合し、好ましくは、EC50はフローサイトメトリー法またはELISA法を使用することによって決定される;および
(c)MSLNを発現する細胞のインビボにおける増殖を阻害する。
本発明の抗体薬物コンジュゲートで好ましく使用した抗体は、ヒトモノクローナル抗体RC88である。RC88のVHおよびVLのアミノ酸配列はそれぞれ、配列番号7および8で示される。
本発明の抗メソセリン抗体を生成するために、標準的方法を使用して免疫した動物を作製し、例えば、Kohler & Milstein、(1975)Nature 256巻:495〜497、Kozborら(1983)Immunol.Today 4巻:72、およびColeら、in MONOCLONAL ANTIBODIES AND CANCER THERAPY、Alan R.Liss、Inc.、1985、77〜96頁を参考にした。
実施例2a:リンカー−薬物コンジュゲートの調製
化合物Py−MAA(1,3,5−トリアクリロイルヘキサヒドロ−1,3,5−トリアジン−メルカプト酢酸、10.00g、29.3mmol)をDMF(200mL)に溶解し、HATU(16.73g、44.0mmol)、Val−Cit−PAB−OH(9.20g、23.4mmol)、DIPEA(15.32ml、87.9mmol)を添加し、室温で24時間撹拌し、反応の進行をTLCによってモニターした。反応が完了した後、溶媒を減圧下でロータリーエバポレーターによって蒸発させ、粗生成物を分取高速液体クロマトグラフィーによって精製し、得られた溶液を減圧下でロータリーエバポレーターによって蒸発させ、化合物1(6.67g、32.4%、白色固形粉末)を得た。
化合物1(7.02g、10.0mmol)をDMF(200mL)に溶解し、NPC(ジ(p−ニトロフェニル)カーボネート、4.56g、15.0mmol)およびDIPEA(2.09mL、12mmol)を添加し、反応は室温で5時間実施し、反応の進行をTLCによってモニターした。反応が完了した後、反応混合物を石油エーテル(1500mL)に注ぎ、撹拌し、濾過して、得られた濾過ケークを石油エーテル(150mL×3)で洗浄し、吸引によって乾燥し、灰白色の固形粉末(6.57g、75.7%)を得た。
化合物2(1.74g、2.2mmol)をDMF20mLに溶解し、MMAE(1.44g、2.0mmol)、HOBt(0.27g、2.0mmol)、DIPEA(0.70mL、4.0mmol)およびピリジン(4mL)を窒素ガスの保護下で添加した。室温で24時間撹拌しながら、反応の進行をTLCによってモニターした。反応が完了した後、精製は分取高速クロマトグラフィーによって実施し、得られた溶液を減圧下でロータリーエバポレーターによって蒸発させ、化合物3(白色固形粉末、1.35g、46.7%)を得た。LC−MS m/z(ES+)、1446.35(M+H)+、IR(3334.32cm−1、2965.9cm−1、1652.70cm−1、1538.92cm−1、1436.71cm−1)。
化合物2(0.87g、1.1mmol)をDMF10mLに溶解し、MMAD(0.77g、1.0mmol)、HOBt(0.14g、1.0mmol)、DIPEA(0.35mL、2.0mmol)およびピリジン(2mL)を窒素ガスの保護下で添加した。室温で24時間撹拌しながら、反応の進行をTLCによってモニターした。反応が完了した後、精製は分取高速クロマトグラフィーによって実施し、得られた溶液を減圧下でロータリーエバポレーターによって蒸発させ、化合物4(白色固形粉末、0.65g、43.5%)を得た。LC−MS m/z(ES+)、1499.76(M+H)+。
化合物5(Mc−Val−Cit−PAB、4.58g、8.0mmol)をDMF(100mL)に溶解し、NPC(ジ(p−ニトロフェニル)カーボネート、3.65g、12.0mmol)およびDIPEA(1.70mL、9.6mmol)を添加し、室温で5時間反応させ、反応の進行をTLCによってモニターした。反応が完了した後、反応混合物を石油エーテル(1000mL)に注ぎ、撹拌して濾過して、得られた濾過ケークを石油エーテル(60mL×3)で洗浄し、吸引によって乾燥し、灰白色の固形粉末(5.04g、85.2%)を得た。
化合物6(1.19g、1.6mmol)をDMF12mLに溶解し、MMAE(1.08g、1.5mmol)、HOBt(0.21g、1.5mmol)、DIPEA(0.55mL、3.0mmol)およびピリジン(2.5mL)を窒素ガスの保護下で添加した。室温で24時間撹拌しながら、反応の進行をTLCによってモニターした。反応が完了した後、精製は分取高速クロマトグラフィーによって実施し、得られた溶液を減圧下でロータリーエバポレーターによって蒸発させ、化合物7(白色固形粉末、0.891g、45.1%)を得た。LC−MS m/z(ES+)、1316.18(M+H)+。
化合物6(0.74g、1.1mmol)をDMF10mLに溶解し、MMAD(0.77g、1.0mmol)、HOBt(0.14g、1.0mmol)、DIPEA(0.35mL、2.0mmol)およびピリジン(2mL)を窒素ガスの保護下で添加した。室温で24時間撹拌しながら、反応の進行をTLCによってモニターした。反応が完了した後、精製は分取高速クロマトグラフィーによって実施し、得られた溶液を減圧下でロータリーエバポレーターによって蒸発させ、化合物8(白色固形粉末、0.59g、42.8%)を得た。LC−MS m/z(ES+)、1369.38(M+H)+。
良好に増殖したOval−Citar−3細胞(ATCC)を6ウェルプレートに3×105/ウェルで接種し、一晩接着させた後、元の培地を廃棄して、ポリブレン(sigma)10μg/mLを含有する新鮮な培地400μLを添加し、ヒトMSLNコーディング配列を含有するレンチウイルスベクター(pRRL−cmv)600μLを適切な濃度でその間に添加し、ウェルを混合した後、培養を24時間継続した。培養終了後、新鮮な培地との置換を実施し、培養の拡大を実施し、陽性細胞はフローサイトメーターを使用して選択した。選択した陽性細胞を培養拡大のために使用し、MSLNの発現はフローサイトメーターによって分析し、MSLNを最高に発現している細胞(以後、Oval−Citar−3−MSLNと称する)をその後の実験のために選択した。
良好な増殖状態のOval−Citar−3−MSLN細胞を96ウェル細胞培養プレート(5×104細胞/mL、100μL/ウェル)に添加し、CO2インキュベーター内で37℃で一晩インキュベートした。RC88抗体、RC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE、RC88−Py−MAA−Val−Cit−PAB−MMAD、RC88−Mc−Val−Cit−PAB−MMAE、RC88−Mc−Val−Cit−PAB−MMAD)および対応するリンカー−薬物コンジュゲート(Py−Val−Cit−PAB−MMAE、Py−Val−Cit−PAB−MMAD、Mc−Val−Cit−PAB−MMAE、Mc−Val−Cit−PAB−MMAD)、薬物(MMAE、MMAD)、PTX(パクリタキセル)を完全培地で以下の濃度に希釈した:RC88抗体、RC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE、RC88−Py−MAA−Val−Cit−PAB−MMAD、RC88−Mc−Val−Cit−PAB−MMAE、RC88−Mc−Val−Cit−PAB−MMAD)については、最終濃度は0.32、1.6、8、16、32、64、128、640、3200ng/mLであり、リンカー−薬物コンジュゲート(Py−Val−Cit−PAB−MMAE、Py−Val−Cit−PAB−MMAD、Mc−Val−Cit−PAB−MMAE、Mc−Val−Cit−PAB−MMAD)については、最終濃度は0.4、2、10、20、40、80、160、800、4000ng/mLであり、薬物(MMAE、MMAD)については、最終濃度は0.0016、0.008、0.04、0.2、0.4、0.8、1.6、8、40ng/mLであり、PTX(パクリタキセル)については、最終濃度は0.004、0.02、0.098、0.3、0.89、2.67、8、40、200ng/mLであった。希釈後、これらを96プレート(100μL/ウェル)に添加し、ブランク群(薬物を含まない同量の培地)および3つの対照群を設定し、インキュベーションはCO2恒温インキュベーター内で37℃で72時間実施した。100μL/ウェルの用量でCCK−8 10μLを含有する培地(FBSなし)を添加し、CO2インキュベーター内で37℃で2から4時間インキュベートし、450nmでのOD値をマイクロプレートリーダーで読み取った。阻害率は、以下の式:IR%=(ODブランク−OD薬物)×100/ODブランクによって計算した。Prismソフトウェアを使用して、阻害率をy値とし、薬物濃度をx値として使用し、4パラメータ曲線適合を実施し、最大阻害率と最小阻害率の間の値に対応する薬物濃度値を記録し(IC50値はソフトウェアによって初期設定した)、結果を図3および表4に示した。結果は、RC88−Py−MAA−Val−Cit−PAB−MMAD、RC88−Mc−Val−Cit−PAB−MMAD、RC88−Py−MAA−Val−Cit−PAB−MMAE、RC88−Mc−Val−Cit−PAB−MMAEはOval−Citar−3−MSLNの増殖の阻害に効果的であることを示した。
良好な増殖状態のOval−Citar−3−MSLN細胞(2×106)をヌードマウス(Changzhou Cavans Laboratory Animal Co.,Ltd.、証明書番号:201611240、登録番号:SCXK(Su)2011−0003)に皮下接種し、腫瘍体積が約100〜400mm3に増殖した後、動物を無作為化した。RC88抗体(2mg/kg)、RC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAD、RC88−Py−MAA−Val−Cit−PAB−MMAE、RC88−Mc−Val−Cit−PAB−MMAE、RC88−Mc−Val−Cit−PAB−MMAD、2mg/kg)およびMMAE(0.0716mg/kg)をそれぞれ、1週間に1回、全部で3回投与し、陰性対照群には同体積の生理食塩水を同時に投与した。結果を図4、5および6に示す。
正常な増殖状態のOval−Citar−3−MSLN細胞(2×106)をヌードマウス(Changzhou Cavans Laboratory Animal Co.,Ltd.、証明書番号:201611240、登録番号:SCXK(Su)2011−0003)に皮下接種し、腫瘍体積が約100〜400mm3に増殖した後、動物を無作為化した。RC88抗体(3mg/kg)、RC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE、3mg/kg、1.5mg/kg、0.75mg/kg)、MMAE(0.06mg/kg)、RC88抗体(3mg/kg)+MMAE(0.06mg/kg)、ヒト血清IgG−MMAE(3mg/kg)、PTX(パクリタキセル)(10mg/kg)をそれぞれ、週に1回、全部で3回(PTXは週に2回、全部で6回)投与し、陰性対照群には同量の生理食塩水を同時に投与した。結果を図7、8および9に示す。結果は、RC88抗体薬物コンジュゲートについては、3mg/kg群および1.5mg/kg群の腫瘍を有するマウスは最初の投与の7日後に腫瘍の著しい減少を示し、3mg/kg群では投与の10日後に肉眼で認められる腫瘍は示されず、1.5mg/kg群では投与の17日後に肉眼で認められる腫瘍は示されず、0.75mg/kg群では3回投与した後、腫瘍増殖は依然として比較的速いことが示され、対照(生理食塩水)群と比較して投与の21日後の腫瘍体積には統計学的差は認められず(P>0.05)、T/C>40%であったことを示した。パクリタキセル(PTX)群については、投与の21日後に2匹の腫瘍を有するマウスにおいて腫瘍は完全に排除され(CR)、腫瘍体積およびRTVは対照(生理食塩水)群とは統計学的に異なり(P<0.05)、T/C<40%であった。パクリタキセル(PTX)群とRC88抗体薬物コンジュゲート3mg/kg群および1.5mg/kg群の間には統計学的な差はなかった。RC88抗体群、MMAE群、RC88抗体+MMAE群、IgG−MMAE群および対照(生理食塩水)群の間には有意な差はなかった(P>0.05)。
MSLN陽性腫瘍細胞に対するRC88抗体およびRC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE)の親和性を検出するためにフローサイトメーターを使用した。対数増殖期のOval−Citar−3−MSLN細胞を1.5mL EP試験管(群当たり4×105)中で1500rpmで5分間遠心分離し、PBSで徹底的に洗浄し、上清画分を廃棄し、細胞をパラホルムアルデヒド(200μL、4%)中に再懸濁させ、25℃で15分間固定し、PBSで1回洗浄し、2500rpmで3分間遠心分離し、上清画分を廃棄し、RC88抗体およびRC88抗体薬物コンジュゲートを冷1%BSA−PBS(ウシ血清アルブミン−PBS)緩衝液で10000ng/mLから1.52ng/mLの3倍勾配に希釈し、各濃度の溶液200μLを使用して細胞を再懸濁した。ブランク対照群の細胞を直接冷1%BSA−PBSに再懸濁し、陰性対照群の細胞を1%BSAで調製したhIgG(Zhongke Chenyu)5μg/mLに再懸濁した。インキュベーションを4℃で30分間実施し、細胞を均一にインキュベートするために上下反転混合を10分毎に1回実施し、インキュベーション後、細胞を冷PBSで1回洗浄し、4℃で2500rpmで3分間遠心分離し、上清を廃棄し、冷PBSで1:200に希釈したFITC(フルオレセインイソチオシアネート)標識ヤギ抗ヒトIgG Fcγ(Jackson ImmunoResearch)200μLを各試験管に添加し、4℃で30分間インキュベートし、細胞を均一にインキュベートするために上下反転混合を10分毎に1回実施した。インキュベーション終了時、細胞を冷PBSで1回洗浄し、4℃で2500rpmで5分間遠心分離し、上清を廃棄し、細胞をPBS400μLに再懸濁し、検出のためにフローサイトメーター(BD Calibur)に移し、結果を図10に示した。結果は、RC88抗体およびRC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE)の両方がMSLN陽性腫瘍細胞に対して、それぞれEC50値153.5ng/mLおよび251.4ng/mLで強い結合親和性を有することを示した。
MSLN陽性腫瘍細胞へのRC88抗体およびRC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE)の結合活性をELISA法によって検出した。対数増殖期のOval−Citar−3−MSLN細胞を96ウェル細胞培養プレート(4×105細胞/mL、100μL/ウェル)に添加し、CO2インキュベーター内で37℃で一晩インキュベートし、上清画分を廃棄し、プレートを0.05%PBST緩衝液(250μL/ウェル)で3回洗浄し、4%パラホルムアルデヒド100μLをウェル毎に添加し、25℃で30分間固定し、プレートを0.05%PBST緩衝液(250μL/ウェル)で3回洗浄し、各ウェルに3%BAS−PBST(ウシ血清アルブミン−PBST)250μLを添加し、室温で2時間インキュベートした後、プレートを0.05%PBST緩衝液(250μL/ウェル)で3回洗浄し、試料を添加し、1)結合曲線:RC88抗体およびRC88抗体薬物コンジュゲートを1%BAS−PBST緩衝液で3000ng/mLから0.05ng/mLの3倍勾配に希釈し、次に96ウェルプレート(100μL/ウェル)に添加した、2)競合曲線:組換えヒトMSLNタンパク質(Yiqiao Shenzhou)を1%BAS−PBSTで10000ng/mLから0.51ng/mLに希釈し、RC88抗体およびRC88抗体薬物コンジュゲートを20ng/mLに希釈し、次に同体積のMSLNタンパク質希釈液と混合し、96ウェルプレートに100μL/ウェルで添加し、25℃で1時間インキュベートした後、プレートを3回洗浄し、各ウェルに1%BAS−PBSTで希釈したHRP(セイヨウワサビペルオキシダーゼ)標識ヤギ抗ヒトIgG Fc(Bethyl)(1:2000)を添加し、25℃で1時間インキュベートした後、プレートを3回洗浄し、暗所で5〜10分間発色させるためにTMB発色キット(Kangwei Century)を使用し、停止のために硫酸2Mを使用し、プレートをマイクロプレートリーダーを用いて読み取り、結果を図11に示した。結果は、RC88抗体およびRC88抗体薬物コンジュゲートの両方がMSLN陽性腫瘍細胞に強く結合し、RC88抗体薬物コンジュゲートがRC88抗体と比較してわずかに減少していることを示したが、有意な差はなく、それらのEC50値はそれぞれ11.0±0.81ng/mLおよび19.7±5.80ng/mLであることを示した。組換えヒトMSLNタンパク質の競合実験は、RC88抗体およびRC88抗体薬物コンジュゲートがOval−Citar−3−MSLN細胞の表面のMSLNに特異的に結合することを示した。
MSLNに対するRC88抗体およびRC88抗体薬物コンジュゲート(RC88−Py−MAA−Val−Cit−PAB−MMAE)およびCA125の競合結合能力をELISAによって決定した。ELISAプレートは、組換えタンパク質MSLN(Yiqiao Shenzhou、200ng/mL)でコーティングした。試料添加:RC88抗体およびRC88抗体薬物コンジュゲートは、20μg/mL(50μL/ウェル)から10点に達するまで、1%BAS−PBST(ウシ血清アルブミン−PBST)緩衝液で希釈し、組換えタンパク質CA125(hisタグ、R&D)は1%BAS−PBST緩衝液で200ng/mL(50μL/ウェル)まで希釈し、全反応系は100μL/ウェルで、2次抗体(マウス−抗hisモノクローナル抗体、R&D)は5000倍に希釈し、100μL/ウェル、TMB(3,3’,5,5’−テトラメチルベンジン)を5〜7分間発色のために使用し、次に、反応を硫酸2Mで停止させ、プレートをマイクロプレートリーダーを用いて450nmで読み取り、結果を図12に示した。結果は、組換えCA125タンパク質の組換えヒトMSLNタンパク質への結合はRC88抗体およびRC88抗体薬物コンジュゲートの濃度の増加につれて減少することを示し、RC88抗体およびRC88抗体薬物コンジュゲートは、組換えヒトCA125タンパク質の組換えヒトMSLNタンパク質への結合を遮断することができることを示唆している。
Claims (16)
- 式Ab−(L−D)nを有する抗体薬物コンジュゲートであって、式中、
(a)AbはMSLNに特異的に結合する抗体またはその機能的断片であり、
(b)Lはリンカーであるか、または存在せず、
(c)Dは治療剤であり、
(d)nは1、2、3、4、5、6、7または8である、抗体薬物コンジュゲート。 - MSLNに特異的に結合する前記抗体が重鎖および軽鎖を含み、
(i)前記重鎖が3つのCDR領域を含み、前記CDR領域の少なくとも1つのアミノ酸配列が配列番号1、2もしくは3に記載のアミノ酸配列またはそれらと少なくとも80%の配列同一性を有する配列を有し、
(ii)前記軽鎖が3つのCDR領域を含み、前記CDR領域の少なくとも1つのアミノ酸配列が配列番号4、5もしくは6に記載のアミノ酸配列またはそれらと少なくとも80%の配列同一性を有する配列を有する、請求項1に記載の抗体薬物コンジュゲート。 - MSLNに特異的に結合する前記抗体が重鎖可変領域および軽鎖可変領域を含み、
(i)前記重鎖可変領域が配列番号7に記載のアミノ酸配列またはそれと少なくとも80%の配列同一性を有する配列を含み、
(ii)前記軽鎖可変領域が配列番号8に記載のアミノ酸配列またはそれと少なくとも80%の配列同一性を有する配列を含む、請求項1または2に記載の抗体薬物コンジュゲート。 - 前記抗体がモノクローナル抗体、キメラ抗体、ヒト化抗体、1本鎖抗体(scFv)または2重特異性抗体である、請求項1〜3のいずれか一項に記載の抗体薬物コンジュゲート。
- 前記治療剤がドラスタチンペプチド、好ましくはMMAD、MMAEまたはMMAF、より好ましくはMMAEである、請求項1〜4のいずれか一項に記載の抗体薬物コンジュゲート。
- 前記リンカーおよび前記抗体が前記抗体のチオール基によって連結している、請求項1〜5のいずれか一項に記載の抗体薬物コンジュゲート。
- メソセリンに特異的に結合することができる抗体またはその機能的断片であって、
前記抗体が重鎖および軽鎖を含み、
(i)前記重鎖が3つのCDR領域を含み、前記CDR領域の少なくとも1つのアミノ酸配列が配列番号1、2もしくは3に記載のアミノ酸配列またはそれらと少なくとも80%の配列同一性を有する配列を有し、
(ii)前記軽鎖が3つのCDR領域を含み、前記CDR領域の少なくとも1つのアミノ酸配列が配列番号4、5もしくは6に記載のアミノ酸配列またはそれらと少なくとも80%の配列同一性を有する配列を有する、抗体またはその機能的断片。 - 前記抗体が重鎖可変領域および軽鎖可変領域を含み、
(i)前記重鎖可変領域が配列番号7に記載のアミノ酸配列またはそれと少なくとも80%の配列同一性を有する配列を含み、
(ii)前記軽鎖可変領域が配列番号8に記載のアミノ酸配列またはそれと少なくとも80%の配列同一性を有する配列を含む、請求項9に記載の抗体またはその機能的断片。 - 前記抗体がモノクローナル抗体、キメラ抗体、ヒト化抗体、1本鎖抗体(scFv)または2重特異性抗体である、請求項9または10に記載の抗体またはその機能的断片。
- 請求項9〜11のいずれか一項に記載の抗体またはその機能的断片をコードする、単離されたポリペプチド。
- 請求項9〜11のいずれか一項に記載の抗体またはその機能的断片の重鎖をコードするポリヌクレオチドおよび請求項9〜11のいずれか一項に記載の抗体またはその機能的断片の軽鎖をコードするポリヌクレオチドを含む、単離されたポリヌクレオチドの組み合わせ。
- 請求項12に記載のポリヌクレオチドまたは請求項13に記載のポリヌクレオチドの組み合わせを含み、前記ポリヌクレオチドが宿主細胞または無細胞発現系においてそれらによってコードされるポリペプチドの発現を可能にする制御配列に作動可能に連結している、発現ベクターまたは発現ベクターの組み合わせ。
- 請求項1〜8のいずれか一項に記載のコンジュゲートおよび/または請求項9〜11のいずれか一項に記載の抗体またはその機能的断片、および医薬的に許容できる担体を含む医薬組成物。
- 癌の処置または予防のための医薬品の製造における、請求項1〜8のいずれか一項に記載のコンジュゲート、請求項9〜11のいずれか一項に記載の抗体またはその機能的断片、請求項12に記載のポリヌクレオチド、請求項13に記載のポリヌクレオチドの組み合わせ、請求項14に記載の発現ベクターまたは請求項15に記載の医薬組成物の使用であって、好ましくは前記癌がメソセリン陽性癌である使用。
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WO2020233174A1 (zh) * | 2019-05-20 | 2020-11-26 | 烟台迈百瑞国际生物医药有限公司 | 一种抗体药物偶联物中间体的一锅法制备工艺 |
CN111560072B (zh) * | 2020-07-16 | 2020-12-11 | 上海恒润达生生物科技有限公司 | 抗人msln抗体以及靶向msln的免疫效应细胞 |
CN115297889A (zh) * | 2020-09-01 | 2022-11-04 | 荣昌生物制药(烟台)股份有限公司 | 抗c-Met抗体药物偶联物及其应用 |
JP2023169444A (ja) * | 2020-10-01 | 2023-11-30 | 株式会社Epsilon Molecular Engineering | 標的タンパク質と結合し得る架橋ペプチド、当該架橋ペプチドの作製方法、及び当該架橋ペプチドを有効成分とする医薬組成物 |
BR112023019048A2 (pt) * | 2021-03-31 | 2023-10-17 | Remegen Co Ltd | Método de preparação e purificação |
BR112023009912A2 (pt) | 2021-05-08 | 2023-11-28 | Remegen Co Ltd | Anticorpo anti-claudina 18.2 e conjugado anticorpo-fármaco do mesmo |
CN117412991A (zh) * | 2021-06-18 | 2024-01-16 | 南京再明医药有限公司 | 抗人msln人源化抗体及其应用 |
CN116410332A (zh) * | 2021-12-29 | 2023-07-11 | 上海细胞治疗集团有限公司 | 抗间皮素纳米抗体嵌合抗原受体及其应用 |
WO2023157989A1 (ko) * | 2022-02-17 | 2023-08-24 | 주식회사 노벨티노빌리티 | 항체-약물 접합체 |
CN117843793A (zh) * | 2024-03-07 | 2024-04-09 | 深圳真实生物医药科技有限公司 | 抗间皮素抗体、抗原结合片段及其用途 |
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