JP6943872B2 - 多重全抗体及び抗体複合体化薬物定量化アッセイ - Google Patents
多重全抗体及び抗体複合体化薬物定量化アッセイ Download PDFInfo
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Description
37CFR§1.53(b)で出願されたこの正規の出願は、2016年3月25日に出願された米国仮出願第62/313,608号の35USC§119(e)の利益を主張し、これは、参照により全体が組み込まれる。
(項目1)
抗体−薬物複合体の抗体複合体化薬物濃度及び全抗体濃度の両方を定量化する方法であって、
(a)抗体−薬物複合体(ADC)を、前記抗体を還元する組成物と接触させて、変性抗体を形成することと、
(b)前記変性抗体を消化して、単一の分析試料中で、消化された抗体−薬物複合体ペプチド混合物を形成することと、
(c)前記消化された抗体−薬物複合体ペプチド混合物をLC−MS/MSにより分析して、前記単一の分析試料中で、少なくとも1つの抗体署名ペプチド及び薬物部分を検出することと、を含む、前記方法。
(項目2)
前記ADCが、前記接触させるステップの前に、緩衝液、全血、血清、血漿、脳脊髄液、唾液、尿、リンパ液、胆汁、糞便、汗、硝子体、涙、及び組織から選択されるマトリックス中で懸濁される、項目1に記載の方法。
(項目3)
前記ADCが、前記消化するステップの前に、サイズ排除クロマトグラフィー、透析、選択的沈降、分画遠心分離、ろ過、ゲル電気泳動、液体クロマトグラフィー、逆相クロマトグラフィー、免疫沈降、プロテインA及びプロテインG、NHS及びストレプトアビジン鉄もしくはリン、または固定化抗体もしくはレクチンを含むスピントラップカラム、常磁性ビーズ、免疫除去、分画、固相抽出法、リンペプチド富化、ポリアクリルアミドゲル電気泳動、ならびに脱塩処理から選択される技法により富化される、項目1に記載の方法。
(項目4)
前記ADCが、親和性捕捉培地に結合される、項目1に記載の方法。
(項目5)
前記親和性捕捉培地が、ビーズまたは樹脂により支持されたプロテインA/G、標的抗原−常磁性ビーズ捕捉培地、抗イディオタイプ抗体、抗Hu抗体、及び抗薬物抗体のうちの少なくとも1つである、項目4に記載の方法。
(項目6)
前記親和性捕捉培地に結合されたADCを洗浄して、前記ADCと接触している非抗体タンパク質を減少させることをさらに含む、項目4に記載の方法。
(項目7)
前記親和性捕捉培地に結合された前記ADCを脱リン酸することをさらに含む、項目4に記載の方法。
(項目8)
前記ADCが前記親和性捕捉培地に結合されている間に、前記変性抗体を消化して、消化された抗体−薬物複合体ペプチド混合物を形成する前記ステップが起こる、項目4に記載の方法。
(項目9)
前記ADCを酵素消化する前記ステップの前に、前記ADCを前記親和性捕捉培地から溶出することをさらに含む、項目4に記載の方法。
(項目10)
前記抗体を還元する前記組成物が、ジチオールトレイトール(DTT)、2−メルカプトエタノール、及びトリス(2−カルボキシエチル)ホスフィン(TCEP)から選択される少なくとも1つの還元剤を含む、項目1に記載の方法。
(項目11)
前記抗体を還元する前記組成物が、ホルムアミド、ジメチルホルムアミド、アセトニトリル、SDS、尿素、酸分解性界面活性剤、デシルフラニルスルホン酸塩、及びグアニジンHClから選択される少なくとも1つの変性剤をさらに含む、項目10に記載の方法。
(項目12)
前記抗体を還元する前記組成物が、メタノール、エタノール、HCl、重炭酸アンモニウム、トリス緩衝液、HEPES、酢酸アンモニウム、及びアセトニトリルから選択される少なくとも1つの化学物質を含む、項目1に記載の方法。
(項目13)
前記変性抗体を消化する前記ステップが、鉱酸、トリフルオロ酢酸、ギ酸の存在下の酸性加水分解、臭化シアンによるタンパク質分解、及び250℃を上回る熱誘導性タンパク質分解のうちの少なくとも1つを含む、項目1に記載の方法。
(項目14)
前記変性抗体を消化する前記ステップが、前記変性抗体をタンパク質分解酵素と接触させることを含む、項目1に記載の方法。
(項目15)
前記タンパク質分解酵素が、トリプシン、キモトリプシン、パパイン、ペプシン、LysN、LysC、AspN、GluC、ArgC、及びPNGaseFのうちの少なくとも1つである、項目14に記載の方法。
(項目16)
前記変性抗体を消化する前記ステップが、前記薬物を前記変性抗体から分離することを含む、項目1に記載の方法。
(項目17)
前記変性抗体を消化する前記ステップが、前記変性抗体を、前記薬物を前記変性抗体から切断する化学物質と接触させることをさらに含む、項目1に記載の方法。
(項目18)
前記消化された抗体−薬物複合体ペプチド混合物を分析する前記ステップの前に、前記消化された抗体−薬物複合体ペプチド混合物を前記親和性捕捉培地から溶出することをさらに含む、項目4に記載の方法。
(項目19)
前記消化された抗体−薬物複合体ペプチド混合物をLC−MS/MSにより分析することが、前記消化された抗体−薬物複合体のペプチド断片を検出することを含む、項目1に記載の方法。
(項目20)
前記ペプチド断片が、前記ADCの可変領域の少なくとも1つの部分を含む、項目19に記載の方法。
(項目21)
前記ペプチド断片が、前記ADCの少なくとも1つの相補性決定領域(CDR)を含む、項目19に記載の方法。
(項目22)
前記ペプチド断片が、前記ADCの非可変領域の少なくとも1つの部分を含む、項目19に記載の方法。
(項目23)
前記薬物が、前記消化された抗体−薬物複合体ペプチド混合物中で、ペプチド−リンカー−薬物複合物として検出される、項目19に記載の方法。
(項目24)
前記抗体−薬物複合体の前記全抗体濃度が、前記消化された抗体−薬物複合体ペプチド混合物の前記分析から算出される、項目19に記載の方法。
(項目25)
前記ADCの抗体複合体化薬物濃度が、前記消化された抗体−薬物複合体ペプチド混合物の前記分析から算出される、項目19に記載の方法。
(項目26)
前記ADCの平均薬物対抗体比(DAR)が、前記消化された抗体−薬物複合体ペプチド混合物の前記分析から算出される、項目19に記載の方法。
(項目27)
前記薬物部分が、マイタンシノイド、ドラスタチン、オーリスタチン、カリケアマイシン、ピロロベンゾジアゼピン(PBD)、PNU−159682、アントラサイクリン、デュオカルマイシン、ビンカアルカロイド、タキサン、トリコテセン、CC1065、デュオカルマイシン、カンプトテシン、エリナフィド、抗生物質、ならびにそれらの立体異性体、イソスター(isosteres)、代謝体、類似体、または誘導体から選択される、項目1に記載の方法。
(項目28)
前記ADCの前記抗体部分が、抗体断片である、項目1に記載の方法。
(項目29)
前記ADCの前記抗体部分が、抗体変異形であり、前記抗体の1つ以上の残基がシステイン残基で置換される、項目1に記載の方法。
(項目30)
前記ADCの前記抗体部分が、ヒトまたはヒト化抗体である、項目1に記載の方法。
(項目31)
前記ADCが、1つ以上の特定の場所で操作システインを有するTDCである、項目1に記載の方法。
(項目32)
前記ADCの前記抗体部分が、下記(1)〜(53):
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)MUC16(0772P、CA125)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi2b(NAPI−3B、NPTIIb、SLC34A2、溶質輸送体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)、及び短い細胞質ドメイン、(セマフォリン)5B)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺の6回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌種由来の成長因子)、
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタイン・バーウイルス受容体)またはHs 73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)Brevican、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3)、
(27)CD22(B細胞受容体CD22−Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ)、
(29)CXCR5(バーキットリンパ腫受容体1)、
(30)HLA−DOB(MHCクラスII分子のベータサブユニット(Ia抗原))、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb−2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)FcRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(38)TMEFF1(EGF様ドメイン及び2つのフォリスタチン様ドメインを有する膜貫通タンパク質1、トモレグリン−1)、
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、
(40)Ly6E(リンパ球抗原6複合物、遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、
(41)TMEM46(shisa相同体2(Xenopus laevis)、SHISA2)、
(42)Ly6G6D(リンパ球抗原6複合物、遺伝子座G6D、Ly6−D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(retがん原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、
(45)LY6K(リンパ球抗原6複合物、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL−1から選択される1つ以上の腫瘍関連抗原または細胞表面受容体に結合する抗体である、項目1に記載の方法。
(項目33)
生体試料中に存在する抗体−薬物複合体の抗体複合体化薬物濃度及び全抗体濃度の両方を定量化する方法であって、
(a)動物からの血液、血清、血漿、組織、または細胞から選択される生体試料を抗体−薬物複合体(ADC)と接触させることと、
(b)前記ADCを含む前記生体試料を親和性捕捉培地と接触させて、ADC−親和性捕捉培地複合物を形成することと、
(c)前記ADC−親和性捕捉培地複合物を洗浄して、前記ADCと接触している非抗体タンパク質を減少させることと、
(d)前記ADC−親和性捕捉培地複合物を、前記抗体を還元する組成物と接触させて、変性抗体を形成することと、
(e)前記変性抗体を酵素消化して、単一の分析試料中で、消化されたADCペプチド混合物を形成することと、
(f)前記消化されたADCペプチド混合物をLC−MS/MSにより分析して、前記単一の分析試料中で、少なくとも1つの抗体署名ペプチド及び薬物部分を検出することと、
(g)前記少なくとも1つの抗体署名ペプチド及び薬物部分の前記LC−MS/MS分析検出から、前記ADCの全抗体濃度、前記ADCの抗体複合体化薬物濃度、及び前記ADCの平均薬物対抗体比(DAR)から選択される前記ADCの少なくとも1つの特徴付けを決定する。
(項目34)
前記消化されたADCペプチド混合物をLC−MS/MSにより分析する前記ステップの前に、ペプチド断片を前記親和性捕捉培地から溶出することをさらに含む、項目32に記載の方法。
(項目35)
前記ADC複合物を、前記抗体を還元する組成物と接触させる前記ステップの前に、前記ADCを前記親和性捕捉培地から溶出することをさらに含む、項目32に記載の方法。
本発明の概要は、本開示の全体及び全範囲を表すことを意図せず、かつそのように解釈されるべきではない。さらに、ここで本明細書における「本開示」またはそれらの態様に対してなされる参照が、本開示のある特定の実施形態を意味すると理解されたく、必ずしも全ての実施形態を特定の記述に限定すると解釈されるべきではない。本開示は、本発明の概要、ならびに添付図面及び実施形態の説明において様々なレベルで詳細に記載され、本発明の概要における要素、成分などの包含または非包含のいずれかにより、本開示の範囲に関して限定されないことが意図される。本開示の追加の態様は、実施形態の説明により、特に図面とともに用いられるとき、より容易に明らかになるであろう。
本開示は、単一の試料調製物からの全抗体及び抗体複合体化薬物量を堅牢測定し、それにより、薬物対抗体比(DAR)の算出、ならびに著しい時間及び資源の節約を提供する、抗体薬物複合体(ADC)の抗体及び薬物成分を検出及び定量化するための単一の測定方法に対して記載される。
「生体試料」という用語は、動物に由来するか、または動物から分離された任意の成分であり、血液、血漿、血清、細胞、尿、脳脊髄液(CSF)、乳、気管支洗浄液、骨髄、羊水、唾液、胆汁、硝子体、涙、または組織が含まれる。
ある特定の実施形態において、本明細書に提供される抗体のアミノ酸配列変異形が企図される。例えば、抗体の結合親和性及び/または他の生物学的特性を改善することが望ましい場合がある。抗体のアミノ酸配列変異形は、抗体をコードするヌクレオチド配列中に適切な修飾を導入することによるか、またはペプチド合成により調製され得る。かかる修飾には、例えば、抗体のアミノ酸配列内における、残基からの欠失、及び/またはそこへの挿入、及び/またはその置換が含まれる。最終構築物に到達するために欠失、挿入、及び置換の任意の組み合わせを行うことができるが、但し、その最終構築物が所望の特徴、例えば、抗原結合を保有することを条件とする。
ある特定の実施形態において、1つ以上のアミノ酸置換を有する抗体変異形が提供される。置換型突然変異誘発の目的とする部位は、HVR及びFRを含む。保存的置換が、「保存的置換」という見出しで表1に示される。より実質的な変化が、「例示の置換」という見出しで表1に提供され、アミノ酸側鎖クラスを参照して以下にさらに記載される。アミノ酸置換が目的とする抗体中に導入され得、所望の活性、例えば、抗原結合の保持/改善、免疫原性の減少、またはADCCもしくはCDCの改善に関して産生物がスクリーニングされ得る。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile
(2)中性親水性:Cys、Ser、Thr、Asn、Gln
(3)酸性:Asp、Glu
(4)塩基性:His、Lys、Arg
(5)鎖配向に影響を及ぼす残基:Gly、Pro
(6)芳香族:Tip、Tyr、Phe
ある特定の実施形態において、本明細書に提供される抗体は、抗体がグリコシル化される程度を増加または減少させるように改変される。抗体へのグリコシル化部位の付加または欠失は、1つ以上のグリコシル化部位が作り出されるか、または除去されるようにアミノ酸配列を改変させることにより好都合に達成され得る。
ある特定の実施形態において、1つ以上のアミノ酸修飾が、本明細書に提供される抗体のFc領域に導入され、それによりFc領域変異形が生成され得る。Fc領域変異形は、1つ以上のアミノ酸位置にアミノ酸修飾(例えば、置換)を含むヒトFc領域配列(例えば、ヒトIgG1、IgG2、IgG3、またはIgG4 Fc領域)を含み得る。
抗体の1つ以上の残基がシステイン残基(複数可)で置換されている、システイン操作抗体、(例えば、「THIOMAB(商標)」)を作り出すことが望ましい。置換された残基は、抗体の到達可能な部位で起こり得る。それらの残基をシステインで置換することにより、反応性チオール基が抗体の到達可能な部位に位置付けられ、それを使用して、抗体を他の部分、例えば、薬物部分またはリンカー−薬物部分に複合体化して、免疫複合体とも称される抗体−薬物複合体(ADC)を作り出すことができる。かかるTHIOMABの例には、システイン操作抗体が含まれ、以下の残基のうちのいずれか1つ以上がシステインで置換され得る:軽鎖のV205(Kabat番号付け)、重鎖のA118(EU番号付け)、ならびに重鎖Fc領域の5400(EU番号付け)、ならびに軽鎖のS121及びK149。システイン操作抗体を作製する例示的な方法には、例えば、米国特許第7,521,541号に記載されている方法が含まれるが、これに限定されず、参照によりその全体が本明細書に組み込まれる。
(1)BMPR1B(骨形成タンパク質受容体−IB型、Genbank受託番号NM_001203)ten Dijke,P.,et al Science 264(5155):101−104(1994)、Oncogene 14(11):1377−1382(1997))、WO2004063362(請求項2)、WO2003042661(請求項12)、US2003134790−A1(ページ38〜39)、WO2002102235(請求項13、ページ296)、WO2003055443(ページ91〜92)、WO200299122(実施例2、ページ528〜530)、WO2003029421(請求項6)、WO2003024392(請求項2、図112)、WO200298358(請求項1、ページ183)、WO200254940(ページ100〜101)、WO200259377(ページ349〜350)、WO200230268(請求項27、ページ376)、WO200148204(実施例、図4)
NP_001194骨形成タンパク質受容体、IB型/pid=NP_001194.1−
相互参照:MIM:603248、NP_001194.1、AY065994
Biochem.Biophys.Res.Commun.255(2),283−288(1999)、Nature 395(6699):288−291(1998)、Gaugitsch,H.W.,et al(1992)J.Biol.Chem.267(16):11267−11273)、WO2004048938(実施例2)、WO2004032842(実施例IV)、WO2003042661(請求項12)、WO2003016475(請求項1)、WO200278524(実施例2)、WO200299074(請求項19、ページ127〜129)、WO200286443(請求項27、ページ222、393)、WO2003003906(請求項10、ページ293)、WO200264798(請求項33、ページ93〜95)、WO200014228(請求項5、ページ133〜136)、US2003224454(図3)、WO2003025138(請求項12、ページ150)、NP_003477溶質輸送体ファミリー7(カチオン性アミノ酸輸送体、y+システム)、メンバー5/pid=NP_003477.3−Homo sapiens、相互参照:MIM:600182、NP_003477.3、NM_015923、NM_003486_1
相互参照:MIM:604217、NP_006415.1、NM_006424_1
Nagase T.,et al(2000)DNA Res.7(2):143〜150)、WO2004000997(請求項1)、WO2003003984(請求項1)、WO200206339(請求項1、ページ50)、WO200188133(請求項1、ページ41〜43、48〜58)、WO2003054152(請求項20)、WO2003101400(請求項11)、受託番号:Q9P283、EMBL、AB040878、BAA95969.1.Genew、HGNC:10737。
WO2003104275(請求項1)、WO2004046342(実施例2)、WO2003042661(請求項12)、WO2003083074(請求項14、ページ61)、WO2003018621(請求項1)、WO2003024392(請求項2、図93)、WO200166689(実施例6)、相互参照:LocusID:54894、NP_060233.2、NM_017763_1
Lab.Invest.82(11):1573−1582(2002))、WO2003087306、US2003064397(請求項1、図1)、WO200272596(請求項13、ページ54〜55)、WO200172962(請求項1、図4B)、WO2003104270(請求項11)、WO2003104270(請求項16)、US2004005598(請求項22)、WO2003042661(請求項12)、US2003060612(請求項12、図10)、WO200226822(請求項23、図2)、WO200216429(請求項12、図10)、相互参照:GI:22655488、AAN04080.1、AF455138_1
相互参照:MIM:606936、NP_060106.2、NM_017636_1
相互参照:MIM:187395、NP_003203.1、NM_003212_1
受託番号:P04626、EMBL、M11767、AAA35808.1.EMBL、M11761、AAA35808.1。
受託番号:P40199、Q14920、EMBL、M29541、AAA59915.1.EMBL、M18728。
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Reiter R.E.,et al Proc.Natl.Acad.Sci.U.S.A.95,1735−1740,1998、Gu Z.,et al Oncogene 19,1288−1296,2000、Biochem.Biophys.Res.Commun.(2000)275(3):783−788、WO2004022709、EP1394274(実施例11)、US2004018553(請求項17)、WO2003008537(請求項1)、WO200281646(請求項1、ページ164)、WO2003003906(請求項10、ページ288)、WO200140309(実施例1、図17)、US2001055751(実施例1、図1b)、WO200032752(請求項18、図1)、WO9851805(請求項17、ページ97)、WO9851824(請求項10、ページ94)、WO9840403(請求項2、図1B)、受託番号:O43653、EMBL、AF043498、AAC39607.1。
本明細書に提供される抗体は、当該技術分野で既知であり、かつ容易に入手可能な追加の非タンパク質性部分を含有するようにさらに修飾され得る。抗体の誘導体化に好適な部分には、水溶性ポリマーが含まれるが、これに限定されない。水溶性ポリマーの非限定的な例には、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/無水マレイン酸コポリマー、ポリアミノ酸(ホモポリマーまたはランダムコポリマーのいずれか)、及びデキストランまたはポリ(n−ビニルピロリドン)ポリエチレングリコール、プロプロピレングリコールホモポリマー、ポリプロピレンオキシド/エチレンオキシドコポリマー、ポリオキシエチル化ポリオール(例えば、グリセロール)、ポリビニルアルコール、ならびにこれらの混合物が含まれるが、これらに限定されない。ポリエチレングリコールプロピオンアルデヒドは、水中でのその安定性のため、製造時に有利であり得る。ポリマーは、任意の分子量のものであり得、分岐状または非分岐状であり得る。抗体に結合したポリマーの数は異なり得、1つより多くのポリマーが結合している場合、それらは同じ分子または異なる分子であり得る。一般に、誘導体化に使用されるポリマーの数及び/または種類は、改善される抗体の特定の特性または機能、抗体誘導体が定義された条件下である療法に使用されるかなどを含むが、これらに限定されない考慮すべき事項に基づいて決定され得る。
単一の試料アッセイにおける抗体及び薬物部分の同時定量化の方法
本開示の多重アッセイを試験及び検証するために、市販供給されているカニクイザル血漿を使用して、ADC(米国特許公開第7,521,541号に記載されているように調製されたシステイン操作抗体である、ピロロベンゾジアゼピン二量体に結合するジスフルフィド(disfulfide))を強化して、標準較正試料を提供する。事前にADCが投与されたカニクイザルから得られた凍結血漿試料も試験のために使用した。プロテインA磁性ビーズ(Pure Proteome)を、0.1体積%のTween20、5.0体積%のトリズマ塩酸塩(1M)、3.0体積%の塩化ナトリウム(5M)、0.2体積%のEDTA(0.5M)、0.1重量%のウシ血清アルブミン、及び91.7体積%の水を含有する緩衝液中で洗浄し、3回洗浄した。次いで、プロテインAビーズを上の洗浄緩衝液を用いてインキュベーションし、血漿試料を常に振りながら、室温で2時間解凍した。
1)75μlの変性溶液(0.05重量%のRapiGest(商標)SF界面活性剤(Waters Corporation,Milford,MA)、37.5体積%の重炭酸アンモニウム(50mM)、及び10体積%のアセトニトリル)、
2)10μlの還元溶液(200mMのトリス(2−カルボキシエチル)ホスフィン(TCEP))、及び
3)25μlの安定標識化内部標準。
実施例1に記載されているように、ADCを含有する凍結血漿試料を解凍し、LC−MS/MSにより分析した。実施例1に記載されているように、軽度な界面活性剤変性剤(RapiGest(商標)SF界面活性剤)を使用して、可溶化し、タンパク質の折り畳みを解き、それにより、タンパク質構造を開いてタンパク質分解部位を露出させた。LC−MS/MS分析のための試料の調製の消化ステージにおいて、プロセスした試料の半分は、クエンチされた酵素消化を有しなかったが一方で、プロセスした試料のもう半分は、酸の添加(実施例1に記載されているようなHClの添加)によりクエンチされた酵素消化を有した。使用した界面活性剤は、酸性条件で加水分解を経て、不活性及び非妨害性副産物を形成する酸不安定性界面活性剤であり、これは、後のMS分析でペプチドのイオン化を抑制しない。軽度な界面活性剤変性剤は、プロテアーゼ活性に対して破壊的ではなく、それにより、試料プロセンシングの消化ステップで必要とされる量の酵素(複数可)を還元する。
還元及び消化した試料中の薬物の安定性を評定するために、実施例1に記載されているように、LC−MS/MS分析のために試料を調製し、(HClを含有する酸性溶液中、または重炭酸アンモニウムを含有する塩基性溶液中のいずれかの)メタノールの添加により保存した。試料をすぐに分析するか、または保全し、12時間、24時間、もしくは72時間後に分析した。図4Aは、調製及び酸性溶液中のメタノールの添加後の、分析された薬物のピーク領域のプロットを示す。同様に、図4Bは、調製及び塩基性溶液中のメタノールの添加後の、分析された薬物のピーク領域のプロットを示す。これらのデータは、放出薬物が塩基性溶液または酸性溶液中のメタノールを含有する溶液中に残っていることを示す。酵素消化の酸クエンチを含む試料調製技法の使用に関して、図4Aは、放出薬物が、酸及び有機タンパク質沈降の存在下で試料調製後、最大72時間、安定したままであり、可溶性を保ったままであったことを示す。
還元及び消化した試料中の全抗体の定量化における酸クエンチ及びメタノール沈降の効果を評定するために、実施例1に記載されているように、LC−MS/MS分析のために試料を調製し、(HClを含有する酸性溶液中、または重炭酸アンモニウムを含有する塩基性溶液中のいずれかの)メタノールの添加により保存した。試料をすぐに分析するか、または保全し、12時間、24時間、もしくは72時間後に分析した。図5Aは、調製及び酸性溶液中のメタノールの添加後の、全抗体を定量化するために使用される、抗体消化によるペプチドのピーク領域のプロットを示す。同様に、図5Bは、調製及び塩基性溶液中のメタノールの添加後のペプチドのピーク領域のプロットを示す。これらのデータは、全抗体の定量化も、酸クエンチ及び有機タンパク質沈降からなる試料調製後、最大72時間、安定していたことを示す。
Claims (16)
- 抗体−薬物複合体(ADC)の抗体複合体化薬物濃度及び全抗体濃度の両方を定量化する方法であって、
(a)親和性捕捉培地に結合された前記ADCを、(i)前記ADCの抗体部分を還元して、前記ADCの変性抗体部分を形成する還元剤であって、ジチオールトレイトール(DTT)、2−メルカプトエタノール、及びトリス(2−カルボキシエチル)ホスフィン(TCEP)から選択される還元剤;(ii)ホルムアミド、ジメチルホルムアミド、アセトニトリル、SDS、尿素、酸分解性界面活性剤、デシルフラニルスルホン酸塩、及びグアニジンHClから選択される少なくとも1つの変性剤;及び(iii)メタノール、エタノール、HCl、重炭酸アンモニウム、トリス緩衝液、HEPES、酢酸アンモニウム、及びアセトニトリルから選択される少なくとも1つの化学物質と接触させることであって、前記親和性捕捉培地が、ビーズまたは樹脂により支持されたプロテインA/G、標的抗原−常磁性ビーズ捕捉培地、抗イディオタイプ抗体、抗Hu抗体、及び抗薬物抗体のうち少なくとも1つを含み、前記ADCの前記抗体部分が変性される、ことと、
(b)前記ADCの前記変性抗体部分を、トリプシン、キモトリプシン、パパイン、ペプシン、LysN、LysC、AspN、GluC、ArgC及びPNGaseFからなる群より選択されるタンパク質分解酵素により消化して、単一の分析試料中で、消化されたADCペプチド混合物を形成することであって、前記変性抗体から薬物部分が分離されて、消化されたADCペプチド混合物が形成されることと、
(c)前記消化されたADCペプチド混合物をLC−MS/MSにより分析して、少なくとも1つの抗体署名ペプチド及び前記薬物部分を含むペプチド−リンカー−薬物複合物を検出し、少なくとも1つの抗体署名ペプチドを含むペプチドを検出することと、を含む、前記方法。 - 前記ADCが、前記接触させるステップの前に、緩衝液、全血、血清、血漿、脳脊髄液、唾液、尿、リンパ液、胆汁、糞便、汗、硝子体、涙、及び組織から選択されるマトリックス中で懸濁される、請求項1に記載の方法。
- 前記ADCが、前記接触させるステップの前に、サイズ排除クロマトグラフィー、透析、選択的沈降、分画遠心分離、ろ過、ゲル電気泳動、液体クロマトグラフィー、逆相クロマトグラフィー、免疫沈降、プロテインA及びプロテインGを含むスピンカラム、ならびに脱塩処理から選択される技法により富化される、請求項1に記載の方法。
- 前記親和性捕捉培地に結合されたADCを洗浄して、前記ADCと接触している非抗体タンパク質を減少させることをさらに含む、請求項1に記載の方法。
- 前記親和性捕捉培地に結合された前記ADCを脱リン酸することをさらに含む、請求項1に記載の方法。
- 前記ADCが前記親和性捕捉培地に結合されている間に、前記変性抗体を消化して、消化された抗体−薬物複合体ペプチド混合物を形成することが起こる、請求項1に記載の方法。
- 前記変性ADCを消化する前に、前記変性ADCを前記親和性捕捉培地から溶出することをさらに含む、請求項1に記載の方法。
- 前記消化されたADCペプチド混合物を分析する前に、前記消化されたADCペプチド混合物を前記親和性捕捉培地から溶出することをさらに含む、請求項1に記載の方法。
- 前記ADCの前記全抗体濃度が、前記消化されたADCペプチド混合物の前記分析から算出される、請求項1に記載の方法。
- 前記ADCの前記抗体複合体化薬物濃度が、前記消化されたADCペプチド混合物の前記分析から算出される、請求項1に記載の方法。
- 前記ADCの平均薬物対抗体比(DAR)が、前記消化されたADCペプチド混合物の前記分析から算出される、請求項1に記載の方法。
- 前記薬物部分が、マイタンシノイド、ドラスタチン、オーリスタチン、カリケアマイシン、ピロロベンゾジアゼピン(PBD)、PNU−159682、アントラサイクリン、デュオカルマイシン、ビンカアルカロイド、タキサン、トリコテセン、CC1065、デュオカルマイシン、カンプトテシン、及びエリナフィドからなる群から選択される、請求項1に記載の方法。
- 前記ADCの前記抗体部分が、抗体断片である、請求項1に記載の方法。
- 前記ADCの前記抗体部分が、抗体変異形であり、前記抗体の1つ以上の残基がシステイン残基で置換される、請求項1に記載の方法。
- 前記ADCの前記抗体部分が、ヒトまたはヒト化抗体である、請求項1に記載の方法。
- 前記ADCの前記抗体部分が、下記(1)〜(53):
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)MUC16(0772P、CA125)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi2b(NAPI−3B、NPTIIb、SLC34A2、溶質輸送体ファミリー34(リン酸ナトリウム),メンバー2、II型ナトリウム依存性リン酸輸送体3b)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)、及び短い細胞質ドメイン、(セマフォリン)5B)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺の6回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル,サブファミリーM,メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌種由来の成長因子)、
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタイン・バーウイルス受容体)またはHs 73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)Brevican、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3)、
(27)CD22(B細胞受容体CD22−Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ)、
(29)CXCR5(バーキットリンパ腫受容体1)、
(30)HLA−DOB(MHCクラスII分子のベータサブユニット(Ia抗原))、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb−2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)FcRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(38)TMEFF1(EGF様ドメイン及び2つのフォリスタチン様ドメインを有する膜貫通タンパク質1、トモレグリン−1)、
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、
(40)Ly6E(リンパ球抗原6複合物,遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、
(41)TMEM46(shisa相同体2(Xenopus laevis)、SHISA2)、
(42)Ly6G6D(リンパ球抗原6複合物,遺伝子座G6D、Ly6−D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(retがん原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、
(45)LY6K(リンパ球抗原6複合物,遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質,膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL−1
から選択される1つ以上の腫瘍関連抗原または細胞表面受容体に結合する抗体である、請求項1に記載の方法。
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KR102158048B1 (ko) | 2018-08-23 | 2020-09-22 | 한국전자기술연구원 | 유연패치를 포함하는 탈부착 가능 웨어러블 장치 |
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2017
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US20210123928A1 (en) | 2021-04-29 |
EP3433621A1 (en) | 2019-01-30 |
EP4273551A2 (en) | 2023-11-08 |
JP2019518195A (ja) | 2019-06-27 |
EP4273551A3 (en) | 2024-01-17 |
CN108700598A (zh) | 2018-10-23 |
US20240012003A1 (en) | 2024-01-11 |
US20170315132A1 (en) | 2017-11-02 |
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