JP2021521273A - Lgals3bp抗体−薬剤結合体及びがん治療のためのその使用 - Google Patents
Lgals3bp抗体−薬剤結合体及びがん治療のためのその使用 Download PDFInfo
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Abstract
Description
QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYYWTWIRQPPGKGLEWIGYITYDGKNNYSPSLKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSSVITTGFTFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSSDKTHTSPPSPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
本組成物および方法に従って使用するために適した抗LGALS3BP抗体は、典型的にはモノクローナルであり、例えば、キメラ(例えば、ヒト定常領域およびマウス可変領域を有する)、ヒト化、又はヒト抗体;一本鎖抗体;などを含むことができる。免疫グロブリン分子は、免疫グロブリン分子のいかなる型(例えば、IgG、IgE、IgM、IgD、IgA及びIgY)、クラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1及びIgA2)、又はサブクラスであってもよい。
また、抗原結合フラグメントは、可変領域と、ヒンジ領域、CH1、CH2、CH3、及びCLドメインの任意の組み合わせを含むことができる。典型的には、抗体は、ヒト、げっ歯類(例えば、マウスとラット)、ロバ、ヒツジ、ウサギ、ヤギ、モルモット、ラクダ類、ウマ、又はニワトリである。本明細書中で使用される「ヒト」抗体は、下記と例えば米国特許番号5,939,598と6,111,166において記載される、ヒト免疫グロブリンのアミノ酸配列を有する抗体を含み、及び、ヒト免疫グロブリンライブラリーから、ヒトB細胞から、又は1つ以上のヒト免疫グロブリンについて形質転換された動物から単離された抗体を含む。
(ii)多量体化(例えば、二量体化)ポリペプチド領域を含んでもよく、その結果、抗体誘導体は、LGALS3BPに特異的に結合する多量体(例えば、ホモ二量体)を形成することができる。典型的な実施形態において、抗LGALS3BP抗体の抗原結合領域、又はそれに由来するポリペプチド領域は、組換えにより又は化学的に異種タンパク質と融合し、本異種タンパク質は二量体化または多量体化ドメインを含む。本抗体誘導体をホモ二量体またはヘテロ二量体の形成を可能にする状態に供した後、LGALS3BPを発現するがんを治療または予防する目的で、本抗体誘導体を被験体に投与する。本明細書で使用されるヘテロダイマーは、異なるLGALS3BP抗原結合領域を有する同一の二量体化ドメイン、同一のLGALS3BP抗原結合領域を有する異なる二量体化ドメイン、又は異なるLGALS3BP抗原結合領域及と二量体化ドメインを含んでもよい。
LGALS3BPを発現するがんの治療に有用な組成物は、抗LGALS3BP抗体-薬剤結合体(ADC)又は抗LGALS3BP ADC誘導体を含む。本明細書で使用される「抗LGALS3BP ADC」とは、治療剤に結合した抗LGALS3BP抗体を言う。本明細書で使用される「抗LGALS3BP誘導体ADC」とは、治療剤に結合した抗LGALS3BP抗体の誘導体を言う。ある実施形態において、ADCは、抗LGALS3BP抗体(例えば、1959抗体若しくはそのフラグメント、又はその誘導体)を含む。本明細書に記載されるADC又はADC誘導体は、LGALS3BPを発現するがんの患者に、典型的には単独で、また他の治療剤と組み合わせて投与された場合、LGALS3BPを発現する細胞に臨床的に有益な効果をもたらす。
適切な細胞毒性剤は、例えば、オーリスタチン、DNA副溝結合剤、DNA副溝アルキル化剤、エンジイン、レキシトロプシン、デュオカルマイシン、タキサン、ピューロマイシン、ドラスタチン、メイタンシノイド、及びビンカアルカロイドであってもよい。特定の実施形態において、薬剤は細胞毒性剤であり、DM1、DM3、DM4、AFP、MMAF、MMAE、AEB、AEVB、オーリスタチンE、パクリタキセル、ドセタキセル、CC-1065、SN-38、トポテカン、モルホリノ-ドキソルビシン、リゾキシン、シアノモルホリノドキソルビシン、ドラスタチン-10、エキノマイシン、コンブレタスタチン、カリキアマイシン、メイタンシン、DM-1、又はネトロプシンである。他の適した細胞毒性剤には、オーリスタチン、ビンカアルカロイド、ポドフィロトキシン、タキサン、バッカチン誘導体、クリプトフィジン、メイタンシノイド、コンブレタスタチン、またはドラスタチンなどの抗チューブリン剤が含まれる。特定の実施形態において、抗チューブリン剤は、メイタンシノイドDM1、DM3、及びDM4である。
上記の通り、他の実施形態において、LGALS3BP−標的化部分は、本明細書に記載の方法に従って使用できる抗体である必要はない。従って、LGALS3BP-標的化部分は、LGALS3BPに結合する抗体に由来する1以上のCDRを含み、細胞毒性剤に結合した場合には腫瘍細胞を死滅させることができる。典型的にはタンパク質は多量体であり、最も典型的には二量体である。
本発明の方法に従って、本明細書に記載の抗LGALS3BP ADC又はADC誘導体を含む組成物は、LGALS3BP発現がんを有する被験体に投与される。本明細書で使用される用語「被験体」は、ヒト及び非ヒト哺乳動物、例えば霊長類、げっ歯類、及びイヌなどを含む、LGALS3BP−結合タンパク質−薬剤結合体が投与され得る任意の哺乳動物患者を意味する。本明細書に記載の方法を用いて治療を特に意図する被験体には、ヒトが含まれる。ADC又はADC誘導体は、LGALS3BPを発現するがんの予防または治療において、単独で又は他の組成物と組み合わせて投与することができる。
1.抗体1959-sss(C220S-C226S-C229S)、PBS、pH7.4中11mg/ml
抗体1959-sssは、PBS pH7.4中、11mg/mlの濃度で使用した。
2.SH誘導体としてのメイタンシノイドDM1、DM3、及びDM4は、XDCEXPLORER CO., LTD(Shanghai, China)から購入した。
(材料及び方法)
抗体1959-sssは、60モル過剰のTCEP(トリス(2-カルボキシエチル)ホスフィン(Sigma-Aldrich)、リン酸緩衝生理食塩水に溶解したストック、pH = 7.4(PBS)を使用して還元した。反応は室温(約25℃)で一晩行った。
1959-sssを100モル過剰のDTNBと反応させ、G25カラムを通して反応を停止した。スペクトルはG25カラム後のタンパク質を表し、誘導体化反応がタンパク質を不安定化することはないことを示す。
(材料及び方法)
DM3結合体。1959-sss DTNB誘導体化抗体を、PBS/5%スクロース/10%DMA中、10モル過剰のDM3(DMA中1mg/mlストック、Sigma-aldrich)と室温で一晩反応した。混合物に500モル過剰のヨードアセトアミド(Sigma-aldrich)を加えて反応を停止した。
1959-sss-DM3複合体は、ゲルろ過によって未反応の遊離DM3から分離された。クロマトグラムの最初のピーク(15〜20分)は1959-sss-DM3を含み、2番目のピーク(30〜40分)は未反応の遊離DM3を含んでいた。
(材料及び方法)
1959-sssを10モル過剰のDM3と反応し、G25カラムに通過して反応を停止した。
スペクトルはG25カラム後のタンパク質を表し、この2回目の誘導体化反応でもタンパク質は不安定化しないことを示す(図3)。
(材料及び方法)
60モル過剰のTCEPで還元した後のDM3放出について254nmでのHPLC-C18(Vertex plusカラム、Knauer)分析の結果、抗体分子あたり2つのDM3分子のDARが推定された。使用したプロトコルは次の通りである:
TFA 0.1%(Sigma-Aldrich)
TFA 0.1%+アセトニトリル80%(Sigma-Aldrich)
以下のグラジエントを用いて、254(0.80ml/min)で検出した(表1)。
種々の量の遊離DM3を含む500ml溶液を、C18カラムのHPLCクロマトグラフィーで分析した。33分におけるピーク面積を使用して検量線を決定し、1959-sss-DM3結合体から放出されるDM3を推定した(図4)。
(材料及び方法)
還元及び非還元の1959-sss-DM3 500 ml(0.4 mg/ml)を、C18 HPLCカラムで分析し、還元1959-sss-DM3から放出されたDM3に対応するピーク(33分)(図5)を検量線で内挿した。
Ab1959-SSS -DM3のDARは2と計算された。
(材料及び方法)
ネイキッド1959-sss抗体及び結合型1959-sss-DM3を、以下の条件でHICクロマトグラフィーによって分析した:
A:1.5 M硫酸アンモニウム、50mMリン酸ナトリウムpH7.0、5%イソプロパノール
B:50 mMリン酸ナトリウムpH7、20%イソプロパノール。グラジエントは表2に示す。
両方のサンプルに単一種が存在することをクロマトグラムは示し(図6)、遊離した(非結合の)1959-sss抗体を完全に回避する均一な生成物(緑色のピーク)が、結合反応によって生じることを示す。
(材料及び方法)
抗体1959-sss及びADC1959-sss-DM3をPD Spin TrapG25によって脱塩し、数マイクロリットルをMALDIマス分析に使用した。簡単に説明すると、蒸留水/アセトニトリル(50:50)の0.1%TFA中、s-DHB飽和溶液2マイクロリットルと2マイクロリットルの各サンプルを混合した。混合物をステンレススチールターゲットに置き、乾燥させた。Ultraflex MALDI TOF/TOF(Bruker、GmBH)を線形ポジティブモードで使用して、質量スペクトルを取得した。
ネイキッド1959-sss抗体及び結合型1959-sss抗体で、MALDIマススペクトロメトリーを実施した。予想通り(図7)、重鎖と軽鎖は還元しなくても容易に分離し、設計された抗体には鎖間ジスルフィドが存在しなかった。重鎖は、両方のサンプルにおいて51200 Daの質量ピークとして現れた。一方、軽鎖はネイキッド1959-sss抗体において不均一であったが(図8も参照)、結合型1959-sss-DM3抗体では単一のピークを示した。
(材料及び方法)
実施例7を参照。
図8に示すように、ネイキッド1959-sss由来の軽鎖は、質量23276と23582の2つのピークで表され、1959-sss-DM3由来の軽鎖は、質量24053 Daの単一のピークで表される。
(材料及び方法)
実施例7を参照。
このプロファイルは、TCEPで還元すると、1959-sssネイキッド抗体で観察された2つのピークが、質量23261 Daの単一のピークに均一にシフトすることを示す(図9)。軽鎖間の約320 Daの違いは、グルタチオンの放出が原因である可能性があり、おそらくCHO細胞での組換え1959-sssの発現から残っているのであろう。
(材料及び方法)
実施例6を参照。
図10は、ネイキッド1959-sss(下のパネル)と比較して、還元前(上のパネル)と還元後(中央のパネル)の抗体1959-sss-DM3を示す。1959-sss-DM3のTCEP還元により、ピークの位置がネイキッド抗体に対応する位置にシフトダウンする。
(材料及び方法)
ヒト組換えLGALS3BP(2 μg/ml)を、96ウェルプレートNUNC Maxisorp モジュールに4℃で一晩プレコートした。0.1%Tween-20を含むPBS中、1%BSAで、室温で1時間ブロッキングした後、非結合1959-sss抗体又は1959-sss-DM3を添加し、所定の濃度で室温で2時間インキュベートした。PBS-0.1%Tween-20で数回洗浄した後、抗ヒトIgG-HRPを添加し、室温で1時間インキュベートした。洗浄後、安定化色素原を暗所で少なくとも10分間添加した後、1NのH2SO4を添加して反応を停止した。得られた492nmの色を、Elisaリーダーで読み取った。
非結合の1959-sssと1959-sss DM3は、LGALS3BPに対して同じ結合作用を示す(図11)。
(材料及び方法)
ヒト腫瘍細胞をガラスのカバーガラス上で24時間増殖させた。カバーガラスを1959-sss又は1959-sss-DM3と室温で2時間インキュベートした。インキュベーションの終わりに、4%パラホルムアルデヒドで15分間室温で細胞を固定し、0.25%Triton X-100で5分間透過処理した後、室温で1時間、0.1%BSAでブロッキングした。続いて、カバーガラスを、結合抗ヒトIgG-Alexa Fluor488とインキュベートした。核を視覚化するためにDRAQ5を使用した。488nmと633nmのレーザーを使用したZeiss LSM 510メタ共焦点顕微鏡を用いて画像を取得した。
A、C、E、G、非結合1959-sss; B、D、F、H、1959-sss-DM3
A-B; MDA-MB-231 乳がん; C-D、A375 黒色腫; E-F、FADU、H&Nがん;
G-H、HBF、正常な気管支線維芽細胞
図12は、正常細胞ではないヒト腫瘍細胞の細胞膜における、1959-sss-ADC又は非結合抗体と、それに続く抗ヒト蛍光標識IgGとのインキュベーションによる染色の結果を示す。染色は粒状であり、おそらく分泌時にLGALS3BPによって引き起こされる凝集を示している。
(材料及び方法)
A375ヒト腫瘍細胞をガラスカバーガラス上で24時間増殖させた。カバーガラスをPBSで洗浄し、4%パラホルムアルデヒドで室温15分間、細胞を固定した。PBSで2回洗浄した後、細胞を3%ウシ血清アルブミンを含むPBS中、室温で20分間インキュベートした。次に、細胞を以下の抗体とともに4℃で一晩インキュベートした:(A)、抗CD63(マウス由来、Thermo Fisher、1:50希釈)、(B)、抗ヒトCD81(マウス由来、Thermo Fisher、1:20希釈)、抗ヒトGal-3BP(1959-sss、2−g/mlに希釈)。PBSで洗浄した後、カバーガラスをAlexa Fluor 633抗ヒトIgG(Invitrogen)又はAlexa Fluor 488抗マウスIgG(Invitrogen)のいずれかと、室温で30分間インキュベートした。核を視覚化するためにDAPIを使用した。TCS SP5 Leica-共焦点顕微鏡を用いて画像を取得した。
図13は、1959-sssを単独で、又はCD 63とCD81と組み合わせて、抗ヒト蛍光標識IgG又は抗マウス蛍光標識IgGのいずれかと組み合わせてインキュベートした場合の、ヒト黒色腫細胞の細胞膜における染色を示す。LGALS3BPは、細胞膜でエクソソームマーカータンパク質と共局在する。染色は粒状であり、おそらく分泌時にLGALS3BPによって引き起こされる凝集を示している。
(材料及び方法)
5〜6週齢のCD-1 nu/nuヌードマウスに5x106 のA375細胞を皮下注射することによってヒト黒色腫異種移植を行った。グループ内の平均腫瘍サイズが約100mm3の場合、各グループにおける腫瘍サイズの範囲が同様となるように、マウスを4つのグループに分けた。各グループは、PBS(コントロール)、非結合1959-sss抗体(10 mg/kg)、1959-sss-DM1(10 mg/kg)、又は1959-sss-DM3(10 mg/kg)で実施した。5日間毎日の静脈内注射の治療を行った(矢印)。腫瘍体積は、次の式に従って計算した。:腫瘍体積=(長さ×幅2)/2。腫瘍体積は毎週モニターした。A、腫瘍増殖曲線。データは平均腫瘍体積(±SEM)、n=5又は6マウス/グループを表す。B、パネルAに示されるマウスグループの体重。
図14は、非結合1959-sss抗体で処理をしたマウスでは治療活性がないことを示す。1959-sss-DM1グループの腫瘍増殖率は、対照グループ又は非結合1959-sss抗体グループのいずれとも有意差がなく、1959-sss-DM1の治療活性はほとんど検出されなかった。1959-sss-DM3の治療は、マウスの腫瘍の成長を有意に抑制した。1959-sss DM3とコントロールの差、P <0.00001。
(材料及び方法)
A、PBS(対照)、1959-sss-DM3(10 mg/kg)を毎日若しくは週に2回(t/w)、合計5回の注射、又は1959-sss-DM4(10 mg/Kg)t/w、合計5回の注射で処理したヌードマウスにおける、皮下移植ヒトA375黒色腫異種移植片の増殖。データは平均腫瘍体積(±SEM)、n=5又は6マウス/グループを表す。B、パネルAに示す治療群の生存を示すカプランマイヤープロット。
図15は、1959-sss-DM3又は1959-sss-DM4によってマウスを治療した結果、腫瘍増殖の有意な阻害が引き起こされたことを示す。1959-sssDM3と1959-sss-DM4の差。
(材料及び方法)
PBS(コントロール)又は1959-sss-DM3を10、3、若しくは1 mg/Kg、t/w、合計5回注射して処理したヌードマウスにおける、皮下移植ヒトA375黒色腫異種移植片の増殖。
3 mg/Kg又は10 mg/Kgの1959-sssDM3でマウスを治療した場合に、対照と比較して同様の腫瘍増殖阻害を引き起こした(P <0.0001)(図16)。
(材料及び方法)
神経芽細胞腫細胞株を完全培地で培養した。48時間後、細胞ペレットと上清を回収した。リアルタイムPCR(A)の場合、RNeasy Mini Kitを用いて細胞からトータルRNAを抽出し、製造元の指示に従い、1μgのRNAをHyperScript(商標)逆転写酵素で逆転写した。RNAの量と質をNanoDrop分光計によって評価した。SsoAdvanced Universal SYBR(登録商標) Green Supermixにより、以下のプライマーを使用してリアルタイムPCRを行った:LGALS3BP Fw 5'-gaacccaaggcgtgaacgat-3 '(配列番号12)、Rw 5'-gtcccacaggttgtcacaca-3'(配列番号13)。LGALS3BP mRNAの発現は、ハウスキーピング遺伝子のヒトβ-アクチンと比較して計算した;使用したプライマーは、Act Fw 5'-cagctcaccatggatgatgatatc-3 '(配列番号14)及びRw 5'-aagccggccttgcacat -3'(配列番号15)であり、以下の増幅プロトコルを用いた:リアルタイム検出システムCFX96により、95℃で30秒間の1サイクル、及び95℃で15秒間と60℃で30秒間の40サイクル。内在性コントロールのβ-アクチンによって標準化した相対的なmRNAの発現量は、-Δct法にて決定した。
Chaiwatanasikul et al(Cell Death Dis. 2011 Oct20; 2:e219. doi:10.1038/cddis.2011.99)に記載の初代HB細胞株を除いて、すべての細胞株はAmerican Type Culture Collection(ATCC)から入手した。
調べた7つの神経芽細胞腫細胞株のうち6細胞株は、(A)RNA及び(B)WBによって、又はELISA(C)によって、培地中の分泌タンパク質として検出されたことより、LGALS3BPを発現して分泌する。Gal-3BPが陰性となった初代ヒトNB細胞株を除いて、発現と分泌は神経芽細胞腫細胞株間で異なる。
(材料及び方法)
神経芽細胞腫細胞株(ケリー、SKNAS及びhNB)をカバーガラスに置き、完全培地で24時間増殖させた。その後、細胞を10μg/mlの1959-sss抗体とともに37℃で90分間インキュベートした。インキュベーションの最後に、細胞を4%パラホルムアルデヒドで固定し、抗ヒトAlexaFluor488標識二次抗体で染色した。核を視覚化するためにDraq5を使用した。
1959抗体は、LGALS3BPに陽性であるが陰性ではない細胞の膜でLGALS3BPを染色する。
(材料及び方法)
神経芽細胞腫細胞株(SHSY5Y、ケリー及びhNB)並びにA375m黒色腫細胞株をプレーティングし、SH-DM3の濃度を増加させて72時間処理した。薬剤の細胞殺傷活性は、MTTアッセイによって評価した。
SH DM3は、陽性コントロールとして使用した、A375m黒色腫細胞に関する神経芽細胞腫細胞株に対してin vitroで強力な細胞殺傷活性を示す。
(材料及び方法)
A)SKNAS細胞(LGALS3BP陽性)およびhNB細胞(LGALS3BP陰性)由来の異種移植モデルを、200μlPBS中の3×106個の細胞をマウスの右脇腹へ皮下注射して作製した。異種移植片が触知可能になったとき、各グループにおいて同じ大きさの腫瘍サイズとなるように、動物を2つのグループに分けた。治療群は、1959-sss/DM3(10 mg/kg)を週2回、4回静脈内注射し、コンロトール群はPBSのみを投与した。腫瘍体積をカリパスによって毎週監視し、次の式で計算した:腫瘍体積(mm3)=(長さ×幅2)/2。2cm3の腫瘍体積に達した点で、マウスを屠殺した。生存曲線は、カプランマイヤー推定から導き出され、ログランク検定(GraphPad Prism 5)によって比較した。B)腫瘍組織における1959-sss/DM3の蓄積を、SKNAS及びhNB腫瘍異種移植片の免疫蛍光分析によって評価した。腫瘍を有する動物に1959-sss/DM3を10 mg/kgの用量で単回注射し、その後、72時間後に屠殺した。新鮮な腫瘍組織を凍結包埋培地で凍結し、クリオスタット切片を抗CD31/CD105抗体(赤)で染色して血管を可視化した;細胞核はDRAQ5(青)で染色した。スケールバー:50μm。
10 mg/kgの用量で1959sss/DM3を投与すると、LGALS3BP陽性であるが陰性ではない神経芽細胞腫細胞由来の腫瘍異種移植片が減少する。これと一致して、1959sss/DM3の静脈内注射から72時間後、LGALS3BP陰性ではなく、LGALS3BP陽性の腫瘍組織の免疫蛍光は、抗体薬剤結合体の蓄積を示す。これらのデータは、1959-sss/DM3のin vivo治療に応答する腫瘍縮小の主要な決定因子がLGALS3BPの発現である可能性を示唆する。
(材料及び方法)
SKNAS(B)及びケリー(C)神経芽細胞腫細胞モデルで実施した試験的転移アッセイ(A)の概略図。神経芽細胞腫細胞を生後8週のNSGマウスの尾静脈に注射し、注射から14日後に静脈内治療(1959-sss/DM3又は所定の用量の遊離DM3、対照としてPBS)を開始し、週2回、4回注射した。28日後、マウスを屠殺し、臓器(肝臓、腎臓、肺、骨髄)の転移分析を行った。肝臓、腎臓、肺を採取して、10%中性緩衝ホルマリンで固定した後パラフィン包埋して切片化し、ヘマトキシリンとエオシンで染色した。すべての神経芽細胞腫の転移性病変を分析し、グラフにプロットした(上図)。代表的な画像を示す(下図)。骨髄分析については、屠殺後、大腿骨と脛骨をマウスから切り出し、軟組織を確実に除去し、針付き1mlシリンジを使用して、1mlの冷PBSでシャフトを洗い流すことにより骨髄細胞懸濁液をチューブに収集した。骨髄細胞を再懸濁し、数回洗浄した後、細胞を抗ヒトGD2で染色し、続いてフローサイトメトリー分析のために蛍光二次抗体で染色した。GD2陽性細胞率をドットプロットで示す。
10 mg/kgの用量の1959-sss/DM3で治療すると、神経芽細胞腫の転移性病変の形成は強力に阻害されるが、10 mg/kgでADCの遊離薬剤量と同等の用量で治療しても、転移性病変の減少に有意な影響はなく、これは、1959-sss/DM3を使用すると治療上の利点があることを裏付ける。
(材料及び方法)
腫瘍のない無胸腺CD-1 nu/nuマウスに、1959-sss/DM3(10 mg/kg)を1回静脈内注射し、その後さまざまな時点で血液サンプルを採取した。全抗体の血清濃度は、検出用の捕捉抗原組換えLGALS3BPとヤギ抗ヒトIgG-HRPを使用して、サンドイッチELISAにより測定した。半減期(t 1/2)とAUC値をKinetica 5.0 ソフトウェアにより取得した。
マウス血清の薬物動態研究により、1959 sss/DM3 ADCの半減期が約97.9時間であることが明らかとなった。
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Claims (16)
- 式:B-D
の標的治療剤、又はその薬学的に許容される塩であって、ここで、
Bはがん関連タンパク質に対して特異的な非内在化結合部分であり;及び
Dは細胞毒性剤部分である、
標的治療剤。 - 前記結合部分Bが抗体又は抗体断片ではない、請求項1に記載の標的治療剤。
- 前記がん関連タンパク質が分泌されたLGALS3BPである、請求項1又は2に記載の標的治療剤。
- 前記結合部分Bが、標的エンティティに結合するための2つ以上のリガンドを有する多価結合部分である、先行する請求項の何れか1項に記載の標的治療剤。
- 前記結合部分Bが、非内在化IgG又はscFv又はFab又はSIP又はダイアボディー等の非内在化抗体を含む、請求項1に記載の標的治療剤。
- 非内在化抗体がLGALS3BPに対して特異的である、請求項5に記載の標的治療剤。
- 前記細胞毒性剤部分Dが、チューブリン攪乱剤、例えばメイタンシノイド、特にDM1、DM3、及びDM4から選択される、先行する請求項の何れか1項に記載の標的治療剤。
- 非内在化結合部分Bが、リンカーを介して細胞毒性剤部分Dと結合する、先行する請求項の何れか1項に記載の治療剤。
- 前記リンカーがジスルフィド結合を介して前記剤部分と連結するためのシステイン基を含む、請求項8に記載の標的治療剤。
- 活性型の前記細胞毒性剤部分Dが、前記化合物中のリンカー又は前記結合部分B(抗体若しくは他のもの)とのジスルフィド結合を形成するためのチオール基を含む、先行する請求項の何れか1項に記載の標的治療剤。
- 皮下A375腫瘍を有するbalb/c nu/nuマウスに前記剤を投与したときに、連続5日間に毎日又は週に2回、合計5回注射した後に、少なくとも50日間続く有意な腫瘍の減少を引き起こす、先行する請求項の何れか1項に記載の標的治療剤。
- 皮下SKNAS腫瘍を有するbalb/c nu/nuマウスに前記剤を投与したときに、週に2回、合計4回注射した後に、有意な腫瘍の減少を引き起こす、先行する請求項の何れか1項に記載の標的治療剤。
- SKNAS細胞又はKelly細胞の静脈内注射に由来する転移を有するNSG免疫不全マウスに前記剤を投与したときに、週に2回、合計3回注射した後に、転移性沈着物の数と大きさの有意な縮小を引き起こす、先行する請求項の何れか1項に記載の標的治療剤。
- 腫瘍性疾患の治療における使用のための、好ましくは腫瘍の治療における使用のための、より好ましくは黒色腫又は神経芽細胞腫の治療における使用のための、先行する請求項の何れか1項に記載の標的治療剤。
- 腫瘍性疾患がLGALS3BPを発現する腫瘍である、請求項14に記載の使用のための標的治療剤。
- 先行する請求項の何れか1項に記載の標的治療剤を含む、医薬組成物。
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