JP6599859B2 - ヒト化抗カリクレイン−2抗体 - Google Patents
ヒト化抗カリクレイン−2抗体 Download PDFInfo
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- JP6599859B2 JP6599859B2 JP2016532031A JP2016532031A JP6599859B2 JP 6599859 B2 JP6599859 B2 JP 6599859B2 JP 2016532031 A JP2016532031 A JP 2016532031A JP 2016532031 A JP2016532031 A JP 2016532031A JP 6599859 B2 JP6599859 B2 JP 6599859B2
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- Peptides Or Proteins (AREA)
Description
(a)配列番号1および配列番号2および配列番号3のアミノ酸配列を含む重鎖可変領域CDRH1: SDYAWN 配列番号1
CDRH2: YISYSGSTTYNPSLKS 配列番号2
CDRH3: GYYYGSGF 配列番号3
ならびに/または
(b)配列番号4および配列番号5および配列番号6のアミノ酸配列を含む軽鎖可変領域CDRL1: KASESVEYFGTSLMH 配列番号4
CDRL2: AASNRES 配列番号5
CDRL3: QQTRKVPYT 配列番号6
を含み、重鎖可変領域および軽鎖可変領域は、1つまたはそれ以上のヒト抗体に由来するフレームワークアミノ酸配列を含む、抗体ポリペプチドを提供する。
ensembl.org/Homo_sapiens/Transcript/Sequence_Protein?g=ENSG00000167751;r=19:51376689−51383822;t=ENST00000325321
で見ることができるアンサンブルデータベースにあるように、転写産物:KLK2−201(ENST00000325321)、遺伝子産物ENSG00000167751と記述され、以下の配列:
MWDLVLSIAL SVGCTGAVPL IQSRIVGGWE CEKHSQPWQV AVYSHGWAHC GGVLVHPQWV LTAAHCLKKN SQVWLGRHNL FEPEDTGQRV PVSHSFPHPL YNMSLLKHQS LRPDEDSSHD LMLLRLSEPA KITDVVKVLG LPTQEPALGT TCYASGWGSI EPEEFLRPRS LQCVSLHLLS NDMCARAYSE KVTEFMLCAG LWTGGKDTCG GDSGGPLVCN GVLQGITSWG PEPCALPEKP AVYTKVVHYR KWIKDTIAANP
[配列番号7]
を有する(成熟した、活性なhK2タンパク質の配列に下線を施し、その配列は、N末端においてシグナルペプチドおよびプロペプチド配列が前にある)。
(a)GenBank:AAF08277.1;
(b)GenBank:AAF08275.1;および
(c)UniProtKB/Swiss−Prot:P20151.1
一般に、各可変ドメインは、4つのフレームワーク領域を含むことになり、FR1〜FR4と称され、その中にCDR配列が位置する:
FR1−CDR1−FR2−CDR2−FR3−CDR3−FR4
・高速ペアワイズ整列化パラメータ:K組(ワード)サイズ;1、ウィンドウサイズ;5、ギャップペナルティ;3、トップダイアゴナル数;5。スコア法:xパーセント。
・多重整列化パラメータ:ギャップ開始ペナルティ;10、ギャップ伸長ペナルティ;0.05。
・スコア行列:BLOSUM。
[配列番号8]
[配列番号9]
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[配列番号10]
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[配列番号11]
・細胞増殖抑止剤、特に、用量規制副作用があるシクロホスファミド、クロラムブシル、イホスファミド、ブスルファン、ロムスチン、タキサン、エストラムスチンリン酸および他のナイトロジェンマスタード、抗生物質(ドキソルビシン、カリケアマイシンおよびエスペラミシンを含む)、ビンカアルカロイド、アジリジン、白金含有化合物、エンドスタチン、アルキルスルホン酸塩、ニトロソ尿素、トリアゼン、葉酸類似体、ピリミジン類似体、プリン類似体、酵素、置換された尿素、メチルヒドラジン誘導体、ダウノルビシン、両親媒性アミンを含むがそれだけに限らない細胞増殖抑止剤
・フルタミドおよびビカルタミドならびにその代謝産物のような抗アンドロゲン;
・コルチゾンおよびその誘導体;
・ジホスホン酸塩およびビスホスホネートのようなホスホン酸塩;
・テストステロン−5−α−レダクターゼインヒビター;
・ホウ素付加物;
・サイトカイン;
・タプシガルジンおよびその代謝産物;
・前立腺癌の治療に使用される他の薬剤
を含むことができる。
(a)本発明の第3の態様は、本発明の第2の態様に記載の核酸分子を含むベクター(発現ベクターなど)を提供する;
(b)本発明の第4の態様は、本発明の第2の態様に記載の核酸分子を含む宿主細胞(哺乳動物細胞、例えばヒト細胞など)または本発明の第3の態様に記載のベクターを提供する;および
(c)本発明の第5の態様は、前記ポリペプチドが発現される条件下で本発明の第4の態様に記載の宿主細胞の集団を培養する工程と、そこからポリペプチドを単離する工程とを含む、本発明の第1の態様に記載の抗体ポリペプチドを製作する方法を提供する。
(a)試験する対象から血液のサンプルを得る工程と;
(b)場合により、血液サンプル中に存在する細胞を抽出および/または精製する工程と;
(c)本発明の第1の態様に記載の抗体ポリペプチドを、血液サンプル中に存在する細胞と接触させる工程と;
(d)抗体ポリペプチドが遊離(すなわち複合体形成していない)hK2に結合するかどうか(直接または間接的に)決定する工程と
を含み、遊離hK2に対する抗体ポリペプチドの結合が、対象の血液における前立腺腫瘍細胞の存在を示す、方法を提供する。
(a)試験する対象から血液のサンプルを得る工程と;
(b)場合により、血液サンプル中に存在する細胞を抽出および/または精製する工程と;
(c)本発明の第1の態様に記載の固相固定化抗体ポリペプチドを、血液サンプル中に存在する細胞と接触させる工程と;
(d)洗浄して可溶性成分(固体表面に結合していない)を除去する工程と;
(e)トレーサ、すなわち、レポータ分子/粒子で標識した別の抗hK2特異的抗体を添加する工程と;
(f)洗浄して結合していないトレーサ抗体を除去する工程と;
(g)トレーサ抗体からのシグナルを検出する工程と
であってもよい。
(a)試験する対象から組織のサンプル(組織学的なサンプルのような)を得る工程と;
(b)場合により、組織サンプル中に存在する細胞を抽出および/または精製する工程と;
(c)本発明の第1の態様に記載の抗体ポリペプチドを、組織サンプル中に存在する細胞と接触させる工程と;
(d)抗体ポリペプチドが遊離(すなわち複合体形成していない)hK2に結合するかどうか(直接または間接的に)決定する工程と
を含み、遊離hK2に対する抗体ポリペプチドの結合が、対象の組織における前立腺腫瘍細胞の存在を示す、方法を提供する。
試薬
モノクローナル抗体11B6産生ハイブリドーマ細胞系を使用して、mRNA抽出および抗体産生行い、タンパク質配列決定のためにさらに親和性精製した(Vaisanenら、2004年)。
mRNAを、QuickPrep Micro mRNA精製キット(Amersham Biosciences)で11B6 MAb産生ハイブリドーマ細胞(5E6細胞)から抽出し、mRNAからのcDNA合成を、説明書にしたがってApplied BiosystemsのHigh−capacity cDNA archiveキットで行った。
精製した11B6 MAbの重鎖(H)および軽鎖(L)のN末端配列を、ヘルシンキ大学のタンパク質配列決定サービスでエドマン分解によって決定した。軽鎖配列は、DIVLTQSPAS[配列番号16]、重鎖配列は、DVQLQESGPG[配列番号17]であった。アミノ酸のIMGTデータベース比較により、遺伝子:IGKV3およびIGHV3をそれぞれ同定した。フォワードPCRプライマー(縮重)の相補領域を、N末端アミノ酸をコードしているDNA配列(NCBI BLASTによって見出した)に基づいて設計した。重鎖をクローニングするために使用したリバースプライマーは、CH1に結合するように設計した。軽鎖の場合、2つのリバースプライマーを使用し;第1のPCRに使用した方は、CLに結合し、第2のPCRに使用したもう一方は、VLとCLの境界に結合する。すべてのプライマーは、クローニングに必要な制限酵素認識部位も含有していた(後に下線を施した)。
(5’−TTACTCGCGGCCCAGCCGGCCATGGCGGAYATHGTRYTVACNCARTCTCC−3’;[配列番号18])
であり、リバースプライマーは、WO252
(5’−GCGCCGTCTAGAATTAACACTCATTCCTGTTGAA−3’、XbaI;[配列番号19])
およびCpoI_JK2
(5’−GATACAGTTGGTGCAGCATCGGTCCGTTTTATTTCCAGCTTGGTCCCCCCT−3’;[配列番号20])
であった。
(5’−TGCTGCTGGCGGCCGCTCCAGCCATGGCTGAYGTVCARCTKCAGGAGTCDGG−3’;[配列番号21])
であり、リバースプライマーはasCH1_SacI
(5’−CGCCACCAGAGCTCTCACAATCCCTGGGCACAATTTTC−3’;[配列番号22])。
であった。
正しいサイズの産物を、分取アガロースゲルから精製した。VLを、SfiIおよびCpoIで、VH+CH1をSacIおよびNotIで消化した。レシピエントベクターpAK400 5404FAb lch(pAK400から修飾した、Krebberら、1997年)を、両方の酵素の組合せで別々に消化し、フラグメントをFastAPで脱リン酸化し、分取ゲルから精製した。
Barbas CF 3rd, Kang AS, Lerner RA, Benkovic SJ. (1991) Assembly of combinatorial
antibody libraries on phage surfaces: The gene III site. Proc. Nat. Acad. Sci.,
Vol. 88, pp. 7978-7982
Biomagnetic Techniques in Molecular Biology: Technical handbook. Dynal A.S, 2ndedition, 1995
Krebber A, Bornhauser S, Burmester J, Honegger A, Willuda J, Bosshard HR, Pluckthun A. (1997) Reliable cloning of functional antibody variable domains from hybridomas and spleen cell repertoires employing a reengineered phage display system. J Immunol Methods. 201(1):35-55
Lilja H, Christensson A, Dahlen U, Matikainen MT, Nilsson O, Pettersson K, Lovgr
en T. (1991) Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem. 37(9):1618-25
Pajunen M, Saviranta P, Jauria P, Karp M, Pettersson K, Mantsala P, Lovgren T. (1997) Cloning, sequencing, expression and characterization of three anti-estradiol-17beta Fab fragments. Biochim Biophys Acta. 1351(1-2):192-202
Vaisanen V, Eriksson S, Ivaska KK, Lilja H, Nurmi M, Pettersson K. (2004) Development of sensitive immunoassays for free and total human glandular kallikrein 2.
Clin Chem. 50(9):1607-17
マウス抗hK2抗体11B6の可変ドメインを、CDR移植法を使用してヒト化した。この手法において、マウス抗体の相補性決定領域(CDR)を、可変重鎖および軽鎖ドメインフレームワークに移植した。CDR領域の残基に加えて、フレームワーク領域の特定の重要な位置にある残基を、ヒト様に変えるのではなくマウス様として保持して、移植したCDRループのコンフォメーションがマウス親抗体におけるそのコンフォメーションと可能な限り類似するように維持した。
マウス11B6抗体の相同性モデルを、自動Web抗体モデリングサーバ(VAM;http://antibody.bath.ac.uk/index.html)を使用して生成した。モデルを使用して、マウス親抗体と、可変ドメインのヒト化のフレームワークとして使用したヒト免疫グロブリン配列との間で異なる残基の重要性を目で見て検討することによりそれぞれ評価した。
VLドメイン設計
マウス11B6軽鎖可変ドメインのアミノ酸配列を、NCBIのClustalW配列整列化プログラムを使用して、ヒト免疫グロブリン生殖細胞系配列のデータベースと比較した。11B6 VLは、ヒトVκ4ファミリーの唯一のメンバーであるヒト生殖細胞遺伝子B3(IGKV4−1*01)と最も高い類似性を共有することが判明した。可変ドメイン配列のC末端部をコードしているJ−区分に関しては、ヒトJκ2が、マウス11B6の対応する領域と最も類似していることが判明した。
マウス11B6重鎖可変ドメインのアミノ酸配列を、NCBIのClustalW配列整列化プログラムを使用して、ヒト免疫グロブリン生殖細胞系配列のデータベースと比較した。11B6 VHは、ヒトVH4ファミリーメンバーVH4−28と最も高い類似性を有することが判明した。可変ドメイン配列のC末端部をコードしているJ−区分に関しては、ヒトJH1が、マウス11B6の対応する領域と最も類似していることが判明した。
Chothia, C., Lesk, A. M., Tramontano, A., Levitt, M., Smith-Gill, S.J., Air, G.,
Sheriff, S., Padlan, E.A., Davies, D., Tulip, W.R., Colman, P.M., Spinelli, S., Alzari, P.M., and Poljak, R. J. (1989) Conformations of immunoglobulin hypervariable regions Nature, 342, 877-883
Kabat, E.A., Wu, T.T., Perry, H.M., Gottesman, K. S and Foeller, C . (1991) Sequences of Immunoglogical Interest, 5th edit., NIH, Bethesda, MD
Krebber A, Bornhauser S, Burmester J, Honegger A, Willuda J, Bosshard HR, Pluckthun A. (1997) Reliable cloning of functional antibody variable domains from hybridomas and spleen cell repertoires employing a reengineered phage display system. J Immunol Methods. 201(1):35-55
Tramontano, A., Chothia, C. and Lesk, A. M. (1990) Framework Residue 71 is a Major Determinant of the Position and Conformation of the Second Hypervariable Region in the VHDomains of Immunoglobulins. J. Mol. Biol. 215, 175-182
HEK293細胞を、FreeStyle 293発現培地(Life Technologies)中に2Lの懸濁培養に展開した。細胞密度は、トランスフェクションの日に1×106個細胞/mLであった。
DNA:軽鎖:p11B6VLhV1hk(4300bp)量:0.35mg
重鎖:p11B6VHhV1hIgG1(4900bp)量:0.6mg
研究の目的
本研究の目的は、Biacore器械で表面プラスモン共鳴(SPR)技術を使用することにより、抗体11B6の4つのバリアントと抗原hK2との結合速度論を精査することであった。
以下の4つの抗体および1つの抗原の溶液を、Diaprost ABから得た:
・m11B6ストック:a−ehk211B6 14.12013 PP、3.41mg/mL:0.9% NaCl、100μL
・h11B6ストック:Innovagenロット90476.30 2013−04−12、1mg/mL:PBS pH7.4、320μL
・h11B6−DTPAストック:0.2M酢酸ナトリウムpH5.5、0.9mg/mL、340μL
・h11B6−DFOストック:0.2M酢酸アンモニウムpH 5.5、1.6mg/mL中に5mg/mLゲンチシン酸、400μL
・hK2ストック:26.6μg/mL frakt 2 fr 7 SL+タンパク質inh 5/2−02 1% BSA
(a)実験の説明
Diaprost ABによって提供される試薬を、製造者のガイドラインにしたがってNovex製TRIS−Tricine 10〜20%アクリルアミドゲルに流した。
結果を、図2に示す。
(a)CM4チップへの抗原の固定化
CM4−2チップの活性化を、EDCおよびNHS混合物を使用するアミンカップリングの製造者のガイドラインにしたがって実行した。
標的Ru≦MW/10 MW(hk2)=25900Da 標的Ru(hk2)≦2590
fc2=1104RU fc3=731RU fc4=688RU
異なる5つの濃度の各抗体溶液(HSP−緩衝液に希釈したストック溶液)を、30μL/分の速度でCM4−2チップのチャネルfc2〜4上に流した場合、CM4−2チップに対する4つの抗体の結合段階を4〜5分間追跡した。
CM4−2チップのチャネルfc2〜4上に50nM抗体溶液を30μL/分の速度で5分間流した後に、解離段階を抗体のそれぞれについて480分間追跡した(図4)。
解離段階データをフィッティングし、解離速度定数(koff)を推定した(表2を参照のこと)。
結合速度定数を推定するために、解離速度定数(表2)を、フィッティングした方程式に使用した。
試験した抗体のそれぞれの解離定数(KD)を、表4に示した。
・結合過程は、4つすべての抗体について非常に速く、各抗体に対する15〜18回の実験に基づくと結合速度定数(kon)は、すべて105M−1s−1の範囲にあった。
・解離過程は、非常に遅く、ほとんど、Biacoreの技術的制限の範囲であった。解離速度定数(koff)はすべて、各抗体についての2つの実験に基づいて10−5s−1の範囲であった。
・解離定数(KD)は、4つすべての抗体について10−12Mの範囲であった。
概要
動的光散乱(DLS)研究を、IgGの4つのバリアントで実施して、凝集の傾向を研究した。DLSの結果は、すべての構築物が合理的なサイズ(球状タンパク質と仮定して200kDaまたはわずかに200kDaを超える)を有し、ほとんどまたは全く凝集しないことを示した。
動的光散乱を使用し、4つのIgG構築物をオリゴマー状態について特徴づけること。インスリンを対照として使用した。
動的光散乱
リン酸緩衝食塩水(PBS pH7.4)を、0.22ミクロンフィルターによって濾過した。得られたタンパク質を、PBS pH7.4中に0.1mg/mLへ希釈した。動的光散乱は、Malvern APS機器を使用して2連のサンプルで、20℃で測定した。各サンプルを3回測定した。希釈緩衝液を対照として使用して、緩衝液が塵および凝集体を合理的に含まないことを確認した(図1c)。すべてのサンプルを、数分布関数を使用して確実に測定できた。最も豊富な分子種の平均半径を、分子種の多分散とともに算出した。この分子種の平均質量分布も算出した、表5を参照のこと。
動的光散乱は、すべての構築物が合理的なサイズを有し、ほとんどまたはまったく凝集しないことを示した。4つすべての構築物のサイズ分布は、重複していた(データ不掲載)。
本研究は、177Luに標識した場合の、マウス11B6およびヒト11B6のin vivo体内分布を比較した。
材料
177Luを、Mallinkrodt Medical BV、Petten、Hollandから購入した。
DVQLQESGPGLVKPSQSLSLTCTVTGNSITSDYAWNWIRQFPGNRLEWMGYISYSGSTTYSPSLKSRFSITRDTSKNQFFLQLNSVTPEDTATYFCATGYYYGSGFWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLESDLYTLSSSVTVPSSPRPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
DIVLTQSPASLAVSLGQRATISCRASESVEYFGTSLMHWYRQKPGQPPKLLIYAASNVESGVPARFSGSGSGTDFSLNIQPVEEDDFSMYFCQQTRKVPYTFGGGTKLEIKRTDAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
CHX−A”−DTPAと11B6とのコンジュゲーション:Amicon Ultra−2遠心濾過(2mL、100K)で濃縮する前に、PBS中のマウスおよびヒト化11B6 mAbの溶液を、0.07Mホウ酸ナトリウム緩衝液を使用してpH9.2に調整した。次いで、得られたタンパク質溶液を、キレート化剤対抗体の3:1のモル比で、キレート化剤CHX−A”−DTPA(Macrocylics、USA)と40℃でコンジュゲートさせた。4時間後に反応を停止させ、CHX−A”−DTPA−11B6(DTPA−11B6)をNAP−5カラム(GE Healthcare)によるサイズ排除クロマトグラフィーで遊離キレートから分離し、0.2M酢酸アンモニウム緩衝液、pH5.5 20mLで平衡化した。コンジュゲートした11B6抗体を、酢酸アンモニウム緩衝液1mLで溶出した。
〜0.6MBqの最終活性を体内分布に使用し、または対象当たり18〜20MBqの最終活性をSPECT研究に使用した。室温で2時間のインキュベーション後に、標識を停止し、NAP−5カラムで精製し、PBSで平衡化した。
すべての動物実験は、実験動物保護に関する国の法令にしたがって実行した。
体内分布研究を、h11B6およびm11B6の両方で実行した。
%IA/g=(組織放射活性/注射した放射活性)/臓器重量x100
として算出し、ここで、iv注射の場合:
注射した放射活性=対照注射器における平均放射活性−使用した注射器における放射活性−尾部の放射活性
とした。
時間−%ID曲線は、直線、ID(t)=k*t+mとして最長48時間まで表した。第2および第3の時点(それぞれ48、72時間)のデータに基づいて、モノ指数曲線[ID(t)=ID(0)e−λt]を、時間間隔[48、∞]に適用した。しかしながら、ラムダが負の数になる、すなわちIDが48〜72時間の間で増加している場合、この時間間隔の時間ID曲線は、代わりに直線としてモデル化され、医薬品は、臓器内に72時間以降も保持されたと考えられた。時間活性曲線を得るために、物理的半減期を適用した。
ヒト化177Lu−11B6の体内分布
177Lu−h11B6の体内分布を、図5に示した。
ヒト化177Lu−11B6の体内分布データとマウス親抗体(177Lu−m11B6)のそれとの比較により、予想外の有利な差異がみられた。
吸収線量の算出により、マウス11B6親抗体の速度論と比較した本発明のヒト化抗体のそれにおける差異のより高度な尺度を得られた。
ヒト化およびマウス11B6抗体の血中レベルの分析を、図10に示した。
本研究の結果は、以下を実証した:
・ヒト化11B6抗体、177Lu−h11B6は、in vivoで前立腺腫瘍を効果的に標的する;
・ヒト化11B6抗体は、そのマウス親抗体より予想外に良好な治療可能比を呈する(腫瘍における取り込み、対、健康な骨における取り込みの比で決定した);および
・ヒト化11B6抗体は、マウス11B6抗体よりもわずかに速く血液から除去される。
本研究の目的は、非常に有毒な放射性核種を前立腺癌の成長の部位に特異的に送達するための媒体として、hK2の触媒溝内部のエピトープを特異的に標的するmAbである11B6の実用性を確認することであった。概念研究のこの証明において、γ放射も利用する低エネルギーβ粒子である177Luでマウス11B6親抗体を標識し、SPECT−画像診断を実行可能にした。
材料
177Luを、Mallinkrodt Medical BV、Petten、Hollandから購入した。Cyclone(商標) Storage PhosphorシステムならびにOptiQuant(商標)画像分析ソフトウェア(Perkin Elmer、Wellesley、MA、USA)を使用して、ITLC(即時薄層クロマトグラフィー)小片(Biodex、US)の放射活性を測定し、それにより標識速度論および放射化学純度を決定した。すべての化学物質はSigma Aldrichから入手し、緩衝液は、特に明記しない限り、分析品質水を使用して研究室内で調製した。mAb 11B6は、抗原に対して約1.2nMの親和性を持つヒトカリクレイン2に特異的な抗体である;図1参照のこと(University of Turku 、Finlandから入手した)。in vivo研究の場合、hK2(ATCC、Manassas、VA、USA)を発現している前立腺癌細胞系LNCaPを使用した。細胞を、10%ウシ胎仔血清およびPEST(ペニシリン100IU/mLおよび100μg/mLストレプトマイシン)で補充したRPMI1640培地中で培養した。細胞を、加湿したインキュベーター中で、5%CO2、37℃で維持し、トリプシン−EDTA溶液(緩衝液に0.25%トリプシン、0.02% EDTA、Thermo Scientific)ではがした。
CHX−A”−DTPAと11B6とのコンジュゲーション:PBS中のmAb 11B6溶液を、0.07Mホウ酸ナトリウム緩衝液を使用してpH9.2に調整した。サンプルを、Amicon Ultra−2遠心濾過(2mL、100K)で濃縮した。タンパク質溶液を、キレート化剤対抗体の3:1のモル比で、キレート化剤CHX−A”−DTPA(Macrocylics、USA)と40℃でコンジュゲートさせた。4時間後に反応を停止させ、CHX−A”−DTPA−11B6、以後DTPA−11B6と呼ぶ、をNAP−5カラム(GE Healthcare)によるサイズ排除クロマトグラフィーで遊離キレートから分離し、0.2M酢酸アンモニウム緩衝液、pH5.5 20mLで平衡化した。コンジュゲートした11B6および5A10を、酢酸アンモニウム緩衝液1mLで溶出した。
すべての動物実験は、実験動物保護に関する国の法令にしたがって実行した。動物研究は、地域の動物調査倫理委員会に承認された。Taconic Europe(Bomholt、Denmark)から購入した雄の免疫不全ヌードマウス、NMRI、(6〜8週齢)を、本研究に使用した。
90Yおよび177Luによる放射免疫療法を受けたラットの骨髄に対する吸収線量と生物学的効果の関係[Larssonら、2012年、Med.Phys.39(7):4434〜43頁を参照のこと]に基づいて、骨髄に対するLD50が、ほぼ12Gy程度になることが推定できた。文献において、ラットおよびマウスの急性照射に対するLD50は、約9Gyである[例えば、Radiobiology for the radiologist、HallおよびGiacca(編)、2006年、第6版を参照のこと]。
動物の腫瘍縮小
図11は、治療後の体積において、マウスのうち1匹の腫瘍(動物の腹部、皮下に見える)がどの程度減少したかを示す。
図12は、投与活性(a)D、(b)2xDおよび(c)対照群での研究群の結果を示す(D=26.7MBq)。
典型的な抗体177Lu−m11B6を用いる本研究は、前立腺癌腫瘍に対するhK2標的抗体のin vivo治療効果をはっきりと実証した。
材料および方法
抗体、コンジュゲーションおよび放射標識
抗体:配列番号12による重鎖および配列番号13による軽鎖を含む典型的なヒト化モノクローナル抗体11B6(IgG1/κ、HEK293細胞において一過性に発現させた)は、Innovagen AB、Lund(PBS pH7.4中に1mg/mL、ロット番号90476.30)から得た。非特異的IgG抗体を、アイソタイプ対照として利用した(マウス血清由来IgG抗体、SigmaI−8765)。
細胞系:LNCaP(hK2+)を、American Type Culture Collection(ATCC)から購入した。細胞を、10%ウシ胎仔血清(Thermo Scientific)、ペニシリン100IU/mLおよび100μg/mLストレプトマイシン(Thermo Scientific)で補充したRPMI1640培地(Thermo Scientific)中で培養した。細胞を、加湿したインキュベーター中で、5%CO2、37℃で維持し、トリプシン−EDTA溶液(Thermo Scientific)ではがした。
治療効果の判定
図14(a)に示すように、本発明の典型的なヒト化11B6抗体(177Lu−h11B6)の投与は、マウスにおいて腫瘍成長を予防した(試験した動物の1匹を除くすべてにおいて、腫瘍容積の顕著な減少をもたらした)。それに対し、IgG対照抗体(図14bを参照のこと)またはNaCl(図14cを参照のこと)で治療したマウスにおいて、腫瘍は急速に成長し続けた。
白血球数、赤血球数、血小板数、ヘモグロビン数および重量の判定は、177Lu−h11B6投与のいかなる毒性効果も表さなかった(データ不掲載)。
本研究の結果、前立腺癌異種移植片モデルにおいて177Lu−h11B6治療のかなりの治療効果が明らかになった。
Almqvist Y., et al. In vitro and in vivo characterization of 177Lu-huA33: a radio-immunoconjugate against colorectal cancer. Nucl Med Biol. 2006;33:991-998.
Pippin CG et al. Spectrophotometric method for the determination of a bifunctional DTPA ligand in DTPA-monoclonal antibody conjugates. Bioconjug Chem. 1992;3:342-5.
放射性核種療法(RNT)の場合、放射線源は全身に分布し、放射活性は放射性医薬品として全身的に通常投与される。放射活性分布は、異なる組織に経時的に蓄積する放射性医薬品の量で決まり、その量は患者間で異なる(1)。
1.111In標識h11B6(200〜300MBq)注射
2.採血−第1週に決定した血液および血漿中の活性濃度。
3.1週間にわたる(7回)画像診断(SPECT/二次元)
4.LundaDoseスキームに基づく臓器線量測定(3)
5.決定される療法活性は、骨髄(2〜3Gy)、腎臓(20〜30Gy)および肝臓(12〜36Gy)など放射線感受性臓器に対する特定の吸収線量によって制限された。
1.177Lu標識h11B6が投与される(前療法線量測定に基づく)
2.採血−血液および血漿中の活性濃度
3.1週間にわたる(6回)画像診断
4.臓器線量測定=>処方された療法吸収線量の確認。
累積の活性は、ある期間にわたって所与の領域において起こる崩壊の数である。単位は、Bq秒またはBq時間である。電離放射線が物質を通り抜けて移動する場合、それは、相互作用しエネルギーを蓄積させる。付与されたエネルギーは、所与の容積におけるすべての蓄積されたエネルギーの合計である。吸収線量は、平均付与エネルギーおよび容積の量の比である。吸収線量の単位は、グレイ(Gy)であり、1Gyは1J/kgと同じである。
1. Strand S-E, Zanzonico P, Johnson TK. Pharmacokinetic modeling. Med Phys 1993;20(2):515-27
2. ICRU report nr 67 - Dose Specifications in Nuclear Medicine. Adelstein SJ, DeLuca P, Feinendegen LE, Green L, Howell RW, Humm JL, Strand SE ICRU; 2002
3. The LundADose Method for Planar Image Activity Quantification and Absorbed-Dose Assessment in Radionuclide Therapy. Sjogreen,K., Ljungberg,M., Wingardh,K., Minarik,D., and Strand,S.E. (2005): Cancer Biother.Radiopharm., 20:92-97
4. Quantitative imaging for clinical dosimetry.
Bardies M, Flux G, Lassman M, Monsieurs N, Savolainen S, Strand S-E
Nucl Instr and Methods 2006:569:467-471.
5. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: Analysis of dosimetry with impact on future therapeutic strategy.
Garkavij Michael, Nickel Mattias, Sjogreen-Gleisner Katarina, Ljungberg Michael,
Ohlsson Tomas, Wingardh Karin, Strand Sven-Erik, Tennvall Jan.
Cancer 2010:116(4 Suppl):1084-92.
6. Dosimetry in patients with B-cell lymphoma treated with [(90)Y]ibritumomab tiuxetan or [(131)I]tositumomab Sjogreen-Gleisner K., Dewaraja YK., Chisea C., Tennvall J., Linden O., Strand SE, Ljungberg M.. Q J Nucl Med Mol Imaging, 2011 April;55(2):126-54.
Claims (24)
- ヒトカリクレイン−2(hK2)に対する結合特異性を持つ抗体ポリペプチドであって、前記抗体ポリペプチドは:
(a)配列番号8のアミノ酸配列を含むまたはそれからなる重鎖可変領域;および
(b)配列番号9のアミノ酸配列を含むまたはそれからなる軽鎖可変領域;
を含む、前記抗体ポリペプチド。 - 完全な抗体、またはFvフラグメント、Fab様フラグメント、およびドメイン抗体からなる群から選択される抗原結合フラグメント、を含むまたはそれからなる、請求項1に記載の抗体ポリペプチド。
- 重鎖定常領域をさらに含み、前記重鎖定常領域は、IgG1、IgG2、IgG3およびIgG4からなる群から選択される免疫グロブリンサブタイプのものである、請求項1または2に記載の抗体ポリペプチド。
- 軽鎖定常領域をさらに含み、前記軽鎖定常領域は、κまたはλ軽鎖のものである、請求項1〜3のいずれか1項に記載の抗体ポリペプチド。
- 配列番号10のアミノ酸配列を含むもしくはそれからなる重鎖定常領域、および/または、配列番号11のアミノ酸配列を含むもしくはそれからなる軽鎖定常領域を含む、請求項3または4に記載の抗体ポリペプチド。
- 配列番号12のアミノ酸配列を含むもしくはそれからなる重鎖、および/または、配列番号13のアミノ酸配列を含むもしくはそれからなる軽鎖を含む、請求項1〜5のいずれか1項に記載の抗体ポリペプチド。
- 抗体ポリペプチドが、直接または間接的に治療部分に連結されている、請求項1〜6のいずれか1項に記載の抗体ポリペプチド。
- 治療部分は、1つまたはそれ以上の放射性同位元素を含むまたはそれからなる細胞障害
性部分である、請求項7に記載の抗体ポリペプチド。 - 1つまたはそれ以上の放射性同位元素は、β放射体、オージェ−放射体、転換電子放射体、α放射体および低光子エネルギー放射体からなる群からそれぞれ独立に選択される、請求項8に記載の抗体ポリペプチド。
- 1つもしくはそれ以上の放射性同位元素は、90Y、32P、186Re/188Re、166Ho、76As/77As、153Smのような長距離β放射体;131I、177Lu、67Cu、161Tbのような中距離β放射体;45Caまたは35Sまたは14Cのような低エネルギーβ放射体;51Cr、67Ga、99Tcm、111In、123I、125I、201Tlのような転換もしくはオージェ放射体;ならびに212Bi、213Bi、225Acおよび221Atのようなα放射体からなる群からそれぞれ独立に選択される、請求項9に記載の抗体ポリペプチド。
- 抗体ポリペプチドが、検出可能な部分をさらに含む、請求項1〜10のいずれか1項に記載の抗体ポリペプチド。
- 検出可能な部分は、放射性同位元素を含むまたはそれからなる、請求項11に記載の抗体ポリペプチド。
- 放射性同位元素は、99mTc、111In、67Ga、68Ga、72As,89Zr、123Iおよび201Tlからなる群から選択される、請求項12に記載の抗体ポリペプチド。
- 治療部分および/または検出可能な部分は、連結部分を介して間接的に抗体ポリペプチドに繋がれている、請求項7〜13のいずれか1項に記載の抗体ポリペプチド。
- 連結部分は、1,4,7,10−テトラアザシクロドデカン−1,4,7,10四酢酸(DOTA)の誘導体、デフェロキサミン(DFO)、ジエチレントリアミン五酢酸(DTPA)の誘導体、S−2−(4−イソチオシアナトベンジル)−1,4,7−トリアザシクロノナン−1,4,7三酢酸(NOTA)の誘導体、および1,4,8,11−テトラアザシクロドデカン−1,4,8,11四酢酸(TETA)の誘導体からなる群から選択されるキレート化剤である、請求項14に記載の抗体ポリペプチド。
- 請求項1〜15のいずれか1項に記載の抗体ポリペプチド、またはそのポリペプチド鎖成分をコードする、単離された核酸分子。
- 配列番号14および/または配列番号15のヌクレオチド配列を含む、請求項16に記載の核酸分子。
- 請求項16または17に記載の核酸分子を含む、組換え宿主細胞。
- 請求項1〜15のいずれか1項に記載の抗体ポリペプチドおよび薬学的に許容できる賦形剤、希釈剤または担体を含む、医薬組成物。
- 医薬における使用のための、請求項1〜15のいずれか1項に記載の抗体ポリペプチド。
- 前立腺癌の治療および/またはin vivo診断における使用のための、請求項1〜15のいずれか1項に記載の抗体ポリペプチド。
- 治療しようとする前立腺癌は、転移性前立腺癌、場合により微小転移性前立腺癌である
、請求項21に記載の抗体ポリペプチド。 - 治療しようとする転移性前立腺癌は、リンパ系の転移;骨(脊椎、椎骨、骨盤、肋骨を含む)の転移;骨盤、直腸、膀胱、尿道内転移である、請求項22に記載の抗体ポリペプチド。
- 治療しようとする前立腺癌は、去勢抵抗性前立腺癌(CRPC)である、請求項21〜23のいずれか1項に記載の抗体ポリペプチド。
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JP2020022470A (ja) * | 2013-11-19 | 2020-02-13 | フレダックス・アクチエボラーグ | ヒト化抗カリクレイン−2抗体 |
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KR102351556B1 (ko) * | 2017-03-30 | 2022-01-14 | 프로가스트린 에 캔서스 에스.에이 알.엘. | 프로가스트린 결합 분자를 사용하는 전립선암의 검출 및 치료를 위한 조성물 및 방법 |
US10730944B2 (en) | 2017-07-24 | 2020-08-04 | Regeneron Pharmaceuticals, Inc. | Anti-CD8 antibodies and uses thereof |
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CN114174346A (zh) * | 2019-07-26 | 2022-03-11 | 詹森生物科技公司 | 抗hk2嵌合抗原受体(car) |
JP2022541332A (ja) * | 2019-07-26 | 2022-09-22 | ヤンセン バイオテツク,インコーポレーテツド | カリクレイン関連ペプチダーゼ2抗原結合ドメインを含むタンパク質及びその使用 |
MX2022014938A (es) | 2020-05-27 | 2023-03-06 | Janssen Biotech Inc | Proteínas que comprenden dominios de unión al antígeno de cd3 y usos de éstas. |
CA3189293A1 (en) * | 2020-07-17 | 2022-01-20 | Janssen Biotech, Inc. | Anti-idiotypic antibodies against anti-klk2 antibodies |
TW202233244A (zh) * | 2020-11-10 | 2022-09-01 | 美商健生生物科技公司 | 巨環化合物及其使用方法 |
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Cited By (2)
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JP2020022470A (ja) * | 2013-11-19 | 2020-02-13 | フレダックス・アクチエボラーグ | ヒト化抗カリクレイン−2抗体 |
JP7051777B2 (ja) | 2013-11-19 | 2022-04-11 | フレダックス・アクチエボラーグ | ヒト化抗カリクレイン-2抗体 |
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