JP2022062018A - ポドカリキシン及びtra関連抗体、調製方法、並びに抗癌治療剤としての使用 - Google Patents
ポドカリキシン及びtra関連抗体、調製方法、並びに抗癌治療剤としての使用 Download PDFInfo
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- JP2022062018A JP2022062018A JP2022001576A JP2022001576A JP2022062018A JP 2022062018 A JP2022062018 A JP 2022062018A JP 2022001576 A JP2022001576 A JP 2022001576A JP 2022001576 A JP2022001576 A JP 2022001576A JP 2022062018 A JP2022062018 A JP 2022062018A
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Classifications
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
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Abstract
Description
本願は、米国特許法第119条(e)に基づいて、2016年3月14日出願の米国仮特許出願第62/307,690号(表題「PODOCALYXIN AND TRA-RELATED ANTIBODY,METHODS FOR PREPARATION AND USES FOR TREATMENT OF AGGRESSIVE AND/OR METASTATIC CANCER」)の優先権を主張する。この出願の内容は、その全体として参照によって本明細書に組み込まれる。
添付の配列表で一覧にされるアミノ酸配列は、標準的な文字略語を用いて示されており、配列表は、参照によって本明細書に組み込まれる。
- hcCDR #1 GFTFSDFY(配列番号1)
- hcCDR #2 SRNKANDYTT(配列番号2)
- hcCDR #3 ARDGWVEAMDY(配列番号3)
- lcCDR #1 QSLVHSNGNTY(配列番号4)
- lcCDR #2 KVS(配列番号5)
- lcCDR #3 SQSTHVPWT(配列番号6)
本発明のモノクローナル抗体(本明細書では、Bstrongomab又はCM-918と称する)を、標準的なマウスハイブリドーマ技術を用いて作製した。採取したてのNCCIT細胞を滅菌PBS中に懸濁させて、マウスに腹膜内注射した。各マウスは、1注射あたり10e6個の細胞を受け入れた。2週間の間隔を空けた4回の注射の後、免疫化されたマウスの血清を、ELISA及びウェスタンブロットアッセイで試験して、タイターが陽性のマウスを同定した。次に、タイターが最も高いマウスに、プレフュージョンブースト免疫化(prefusion boost immunization)を受けさせてから2~7日後に、脾臓からB細胞を採取して、NS0又はP3X63Ag8.653マウス骨髄腫細胞に融合させた。
CM-918抗体を用いた多能性胚性癌細胞NCCIT(ATCC # CRL2073)及びヒト胚性幹細胞(ESI-017)由来の膜タンパク質サンプルのウェスタンブロットは、双方のタンパク質膜画分において、200~240kDaの分子量にて単一のぼやけたバンドを示したが、TRA-ポドカリキシンを発現しない非多能性細胞系PC3(ATCC # CRL1435)又はA172(ATCC # CRL1620)において、反応性は、検出されなかった。全く同じブロット結果が、市販のIgM抗体、抗TRA-1-60(abcam 16288)を用いて、全く同じウェスタンブロットで得られた。これらの結果は、CM-918抗体及び抗TRA-1-60抗体が、同種のエピトープに結合することを裏付ける。SDS-PAGE及びウェスタンブロッティングを、標準的な手順で実行した。リン酸バッファ中1%CHAPS洗浄剤(Sigma)中の細胞膜画分を、8%ゲル上で流して、ニトロセルロースに移した。ブロットを、1:1000のCM-918又は抗TRA-1-60抗体(1μg/mlの濃度)とインキュベートしてから、1~5000(.2ug/ml)の二次抗IGG-HRP抗体又は抗IGM-HRP抗体(Millipore)とインキュベートし、バンドを、ECL検出(Amersham Biosciences)によって視覚化した。
胚性幹細胞(ESL017)及び多能性NCCIT胚性癌細胞を、Alexa 647(Sigma)と結合させたCM-918抗体(0.5μg/ml)で、そして抗TRA-1-60抗体(0.5μg/ml)及び抗IgM-Alexa F488抗体(Millipore)(0.5μg/ml)で染色した。Redチャンネルによる蛍光顕微鏡観察画像は、CM-918抗体が、胚性幹細胞及び多能性胚性癌細胞の原形質膜に強く結合するが、TRA-ポドカリキシンを発現しないコントロール細胞系PC3(ATCC # CRL1435)又はA172(ATCC # CRL1620)にはそうならないことを示した。Redチャンネル及びGreenチャンネル由来の重ね合わせた蛍光画像は、CM-918抗体及び抗TRA-1-60抗体の全く同じ染色オーバーラップを示し、双方の抗体が幹細胞の表面上の同じエピトープに結合することが示された。
CM-918による正常組織及び癌の免疫組織化学染色を、以下に記載するように実行した。0~3のグレーディングシステムを用いた:0は観察される染色なし;1は限局的な染色(<5%);2は中程度の染色(<50%);そして3は強い染色(>50%)。染色した組織スライドを、病理医がスコア化した。2又は3の染色スコアを、以下の癌組織で観察した:膵癌の38サンプルのうち22;前立腺癌の41サンプルのうち19;乳癌の145サンプルのうち45;卵巣癌の30サンプルのうち18;胃癌の8サンプルのうち8;結腸癌の30サンプルのうち15;肺癌の66サンプルのうち32。正常なヒト組織での発現は、骨髄を含む殆ど全ての正常な組織でのゼロ発現から、膵臓、食道、及び結腸の一部の場合における微量の限局的発現に非常に限定された。腎臓は、全サンプルでスコア化が陽性であり、CM-918染色が細管において約1%であった。スコア化が2であった唯一の正常組織は、副甲状腺であり、9サンプルのうち2つが染色スコア2であった。結果から、CM-918が多くの異なる癌で膜染色を示し、正常な組織では染色が非常に限られていることが示される。
CM-919-vc-MMAE抗体薬物複合体を製造した。CM-918のPBS溶液を、TCEPで37℃にて処理して、鎖間ジスルフィド結合を還元した。MC-vc-PAB-MMAE(マレイミドカプロイル-バリン-シトルリン-p-アミノベンジルオキシカルボニル-モノメチルオーリスタチンE)の溶液を反応混合物に加えて、MC-vc-PAB-MMAEのマレイミド部分をCM-918に連結させた。結果として生じた抗体薬物複合体(ADC)を、Sephadex G50カラム上で脱塩して、残留する未反応の毒物を除去し、且つPBSにバッファ交換した(pH7.2)。薬物抗体比(DAR)を、248nmと280nmでのUV吸光度の比率から判定した。HIC(疎水性相互作用クロマトグラフィ)及びSEC(サイズ排除クロマトグラフィ)分析を実行して、DAR種分布を判定した。
15頭のヌードマウスに、2×106個のNCCIT多能性癌幹細胞を皮下注射して、腫瘍を200mm3のサイズに発達させて、この時にマウスを以下の5頭の3群に分けた;5頭のマウスは、生理食塩水の注射で4回処理した;5頭のマウスは、3mg/kgのCM-vc-MMAEでQ4D×4回処理した;最後の5頭は、3mg/kgのアイソタイプ抗体コントロール-vc-MMAEでQ4D×4回処理した。これらの結果は、35日目の終了時に、生理食塩水を注射したマウス及びアイソタイプコントロールを注射したマウスの双方が、1000mm3の平均サイズの腫瘍を有したことを示す。結合CM-918抗体薬物処理マウスにおいて、5頭のマウスのうち4頭が、検出可能な腫瘍を有しておらず、1頭のマウスがおよそ25mm3の腫瘍を有した。CM-918と同様にMMAEが結合したアイソタイプコントロール抗体では、平均腫瘍サイズが1000mm3の生理食塩水処理マウスと同程度の結果が示された。これらの結果は、CM-919-vc-MMAE抗体薬物複合体が、マウスにおいて、多能性癌幹細胞腫瘍を処置するのに有効且つ有力であることを示している。
CM-918抗体を用いたADCCアッセイは、多能性癌NCCIT細胞で12~15%の細胞毒性を示し、CM-918 ADCC活性は、TRA-ポドカリキシンを発現しないコントロール細胞で2%の細胞毒性を有した。コントロールIgG抗体は、NCCIT細胞で、細胞毒性が2%であった。これらの結果は、CM-918抗体が、TRA-ポドカリキシンを発現する多能性癌細胞でADCC活性を有することを示している。
CDCアッセイを実行して、NCCIT多能性癌幹細胞について、100nM CM-918抗体による細胞毒性が18%であり、10nM CM-918抗体による細胞毒性が10%であることが示された。100nMコントロール抗体を用いたCDCアッセイのNCCIT細胞毒性の結果は、細胞毒性が<1%であった。これらの結果は、CM-918抗体が、TRA-ポドカリキシンを原形質膜細胞表面上で発現する多能性癌幹細胞に対して、CDC活性を誘発できることを示している。
Claims (14)
- 重鎖及び軽鎖を含むモノクローナル抗体又はその抗原結合フラグメントであって、重鎖相補性決定領域1乃至3が夫々、配列番号1乃至3のアミノ酸配列を有し、軽鎖相補性決定領域1乃至3が夫々、配列番号4乃至6のアミノ酸配列を有する、モノクローナル抗体又はその抗原結合フラグメント。
- 前記抗体又はそのフラグメントは、組換え抗体である、請求項1に記載のモノクローナル抗体又はその抗原結合フラグメント。
- 前記組換え抗体は、ヒトキメラ抗体、ヒト化抗体、及びヒト抗体からなる群から選択される、請求項2に記載のモノクローナル抗体又はその抗原結合フラグメント。
- フラグメントが、Fab、Fab’、F(ab’)2、scFv、ダイアボディ、dsFv、及びCDRを含むペプチドからなる群から選択される、請求項1に記載のモノクローナル抗体又はその抗原結合フラグメント。
- 重鎖及び軽鎖を含むモノクローナル抗体又はその抗原結合フラグメントであって、重鎖相補性決定領域1乃至3が夫々、配列番号1乃至3のアミノ酸配列に対して少なくとも80%のアミノ酸配列類似性を有し、軽鎖相補性決定領域1乃至3が夫々、配列番号4乃至6のアミノ酸配列を有する、モノクローナル抗体又はその抗原結合性フラグメント。
- 前記軽鎖相補性決定領域1乃至3は夫々、配列番号4乃至6のアミノ酸配列に対して少なくとも80%のアミノ酸配列類似性を有する、請求項5に記載のモノクローナル抗体又はその抗原結合フラグメント。
- 前記抗体又はそのフラグメントは、組換え抗体である、請求項5に記載のモノクローナル抗体又はその抗原結合フラグメント。
- 前記組換え抗体は、ヒトキメラ抗体、ヒト化抗体、及びヒト抗体からなる群から選択される、請求項7に記載のモノクローナル抗体又はその抗原結合フラグメント。
- フラグメントが、Fab、Fab’、F(ab’)2、scFv、ダイアボディ、dsFv、及びCDRを含むペプチドからなる群から選択される、請求項5に記載のモノクローナル抗体又はその抗原結合フラグメント。
- 請求項1に記載のモノクローナル抗体又は抗原結合フラグメントを含む抗癌治療剤。
- 薬学的に許容可能なリンカー、ペイロード、及びそれらの組合せからなる群から選択される構成要素を更に含む組成物形態である、請求項10に記載の抗癌治療剤。
- 薬物を更に含んで抗体-薬物結合体を形成する組成物形態である、請求項10に記載の抗癌治療剤。
- 胚性幹細胞に由来する分化細胞から胚性幹細胞を標的化し、選択し、且つ消失させる、請求項10に記載の抗癌治療剤。
- 胃癌細胞、膵癌細胞、食道癌細胞、結腸癌細胞、乳癌細胞、及び前立腺癌細胞からなる群から選択される癌細胞を標的化する、請求項10に記載の抗癌治療剤。
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US20140273016A1 (en) * | 2013-03-14 | 2014-09-18 | William Michael Schopperle | Device and method for the detection and diagnosis of aggressive and metastatic cancer and cancer stem cells employing podocalyxin and tra biomarkers |
US20140275292A1 (en) * | 2013-03-14 | 2014-09-18 | William Michael Schopperle | Systems and methods employing human stem cell markers for detection, diagnosis and treatment of circulating tumor cells |
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US20140274773A1 (en) * | 2013-03-14 | 2014-09-18 | William Michael Schopperle | Systems and methods for employing podocalyxin and tra human stem cell markers as prognostic markers for aggressive and metastatic cancer |
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US20160264663A1 (en) * | 2013-10-21 | 2016-09-15 | The Centre For Drug Research And Development | Anti-podocalyxin antibodies and methods of using the same |
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US20140273016A1 (en) * | 2013-03-14 | 2014-09-18 | William Michael Schopperle | Device and method for the detection and diagnosis of aggressive and metastatic cancer and cancer stem cells employing podocalyxin and tra biomarkers |
US20140275292A1 (en) * | 2013-03-14 | 2014-09-18 | William Michael Schopperle | Systems and methods employing human stem cell markers for detection, diagnosis and treatment of circulating tumor cells |
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ANTICANCER RESEARCH, vol. 26, JPN6012050815, 2006, pages 1057 - 1064, ISSN: 0004978444 * |
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KR20180119676A (ko) | 2018-11-02 |
EP3430166A4 (en) | 2019-11-13 |
EP3430166A2 (en) | 2019-01-23 |
AU2017234134A1 (en) | 2018-09-20 |
RU2018136094A (ru) | 2020-04-15 |
CN108779497B (zh) | 2022-08-02 |
MX2018011039A (es) | 2019-02-28 |
US10509038B2 (en) | 2019-12-17 |
KR102564754B1 (ko) | 2023-08-08 |
AU2017234134B2 (en) | 2023-08-17 |
JP2019512548A (ja) | 2019-05-16 |
WO2017160725A2 (en) | 2017-09-21 |
RU2018136094A3 (ja) | 2020-07-31 |
US20170328907A1 (en) | 2017-11-16 |
CN108779497A (zh) | 2018-11-09 |
BR112018068637A2 (pt) | 2019-07-30 |
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