JP6472746B2 - 抗gcc抗体分子、およびgcc標的化療法への感受性を試験するためのその使用 - Google Patents
抗gcc抗体分子、およびgcc標的化療法への感受性を試験するためのその使用 Download PDFInfo
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Description
本出願は、2012年4月27日に出願された米国仮特許出願第61/639,376号の利益および優先権を主張する。米国仮特許出願第61/639,376号の全体の内容は、本明細書中にこの参照により援用される。
本発明は、例えば、以下を提供する。
(項目1)
それぞれ配列番号21、22、および23、またはそれぞれ配列番号33、34、および35のアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29のアミノ酸配列、またはそれぞれ配列番号39、40、および41のアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、抗GCC抗体分子。
(項目2)
それぞれ配列番号21、22、および23のアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29のアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、抗GCC抗体と同じエピトープへの結合について競合する、またはそれに結合する、抗GCC抗体分子。
(項目3)
それぞれ配列番号33、34、および35のアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号39、40、および41のアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、抗GCC抗体と同じエピトープへの結合について競合する、またはそれに結合する、抗GCC抗体分子。
(項目4)
前記抗GCC抗体分子は、モノクローナル抗体である、項目1〜3のいずれかに記載の抗GCC抗体分子。
(項目5)
前記抗GCC抗体分子は、ウサギまたはウサギ由来抗体である、項目1〜4のいずれかに記載の抗GCC抗体分子。
(項目6)
前記抗体は、ウサギモノクローナル抗体である、項目5に記載の抗GCC抗体分子。
(項目7)
配列番号11または配列番号15によるアミノ酸配列を含む重鎖可変領域と、配列番号13または配列番号17によるアミノ酸配列を含む軽鎖可変領域とをさらに含む、項目1に記載の抗GCC抗体分子。
(項目8)
前記重鎖CDR1、CDR2、およびCDR3は、それぞれ配列番号21、22、および23による前記アミノ酸配列を含み、前記軽鎖CDRは、それぞれ配列番号27、28、および29による前記アミノ酸配列を含む、項目1に記載の抗GCC抗体分子。
(項目9)
前記重鎖可変領域は、配列番号11によるアミノ酸配列を含み、前記軽鎖可変領域は、配列番号13によるアミノ酸配列を含む、項目7に記載の抗GCC抗体分子。
(項目10)
前記抗GCC抗体分子は、検出可能な標識と結合体化されている、項目1〜9のいずれかに記載の抗GCC抗体。
(項目11)
前記検出可能な標識は、西洋ワサビペルオキシダーゼ(HRP)、アルカリホスファターゼ、ガラクトシダーゼ、グルコアミラーゼ、リゾチーム、糖質酸化酵素、例えば、グルコース酸化酵素、ガラクトース酸化酵素、およびグルコース‐6‐リン酸脱水素酵素、過酸化水素を用いて、例えば、HRP、ラクトペルオシターゼ、またはミクロペルオキシダーゼ等の色素前駆体を酸化させる酵素と結合される、ウリカーゼならびにキサンチン酸化酵素等の複素環式酸化酵素、ビオチン/アビジン、スピン標識、バクテリオファージ標識、ならびに安定遊離ラジカルからなる群から選択される、項目10に記載の抗GCC抗体分子。
(項目12)
前記検出可能な標識は、フルオレセインまたはその誘導体、ローダミンまたはその誘導体、ダンシル、ウンベリフェロン、ルセリフェラーゼ、ルシフェリン、および2,3−ジヒドロフタラジンジオンから選択されるフルオロフォアである、項目10に記載の抗GCC抗体分子。
(項目13)
前記検出可能な標識は、 32 P、 3 H、 14 C、 188 Rh、 43 K、 52 Fe、 57 Co、 67 Cu、 67 Ga、 68 Ga、 77 Br、 81 Rb/ 81M Kr、 87M Sr、 99 Tc、 111 In、 113 M In、 123 I、 125 I、 127 Cs、 129 Cs、 131 I、 132 I、 197 Hg、 203 Pb、および 206 Bi、ならびに 213 Biからなる群から選択される放射性薬剤である、項目10に記載の抗GCC抗体分子。
(項目14)
項目1、7、8、および9のいずれかに記載の抗体分子をコードする、単離核酸配列。
(項目15)
項目14に記載の単離核酸配列を含む、細胞。
(項目16)
項目1、7、8、または9に記載の抗体分子を産生する方法であって、抗体分子の産生を可能にする条件下で項目15に記載の前記細胞を培養し、それによって項目1、7、8、または9に記載の前記抗体分子を産生することを含む、方法。
(項目17)
項目1、7、8、または9に記載の抗体分子の前記軽鎖および重鎖の一方または両方を含む、ベクター。
(項目18)
生体試料におけるGCC分子を検出する方法であって、前記生体試料を項目1〜13のいずれかに記載の抗体分子と接触させて、前記抗体分子が前記GCC分子に結合するかどうかを判定することを含む、方法。
(項目19)
前記方法検出方法が免疫組織化学アッセイを含む、項目18に記載の方法。
(項目20)
前記生体試料が、GCCを発現する癌を有する疑いのある患者に由来する腫瘍生検である、項目18または項目19に記載の方法。
(項目21)
前記生体試料におけるGCC発現を定量化するステップをさらに含む、項目18〜20のいずれかに記載の方法。
(項目22)
前記GCC発現の定量化が、前記生体試料における頂端のGCC発現、前記生体試料における細胞質GCC発現、または両方を含む、項目21に記載の方法。
(項目23)
前記定量化ステップが、Hスコア法を含む、項目21または22に記載の方法。
(項目24)
前記GCCを発現する癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍からなる群から選択される、項目20に記載の方法。
(項目25)
前記肺癌が、扁平上皮癌または腺癌である、項目24に記載の方法
(項目25)
前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫である、項目24に記載の方法。
(項目26)
前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、項目24に記載の方法。
(項目27)
項目1〜13に記載のいずれかの前記抗GCC抗体分子、および使用説明書を含むキット。
(項目28)
GCC標的化治療剤をさらに含む、項目27に記載のキット。
(項目29)
前記GCC標的化治療剤が、抗GCC抗体分子を含む、項目28に記載のキット。
(項目30)
前記治療用抗GCC抗体分子が、モノクローナル抗体である、項目29に記載のキット。
(項目31)
前記治療用抗GCC抗体分子が、ヒトIgG1抗体である、項目29または30に記載のキット。
(項目32)
項目29、30、または31に記載のキットであって、前記治療用抗GCC抗体分子は、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、キット。
(項目33)
前記治療用抗GCC抗体分子が、配列番号79のアミノ酸配列を含む重鎖可変領域と、配列番号80のアミノ酸配列を含む軽鎖可変領域とを含む、項目32に記載のキット。
(項目34)
前記治療用抗GCC抗体分子が、細胞傷害性薬剤と結合体化されている、項目29〜33に記載のキット。
(項目35)
前記細胞傷害性薬剤が、オーリスタチン分子である、項目34に記載のキット。
(項目36)
前記オーリスタチン分子が、モノメチルオーリスタチンE(MMAE)またはモノメチルオーリスタチンF(MMAF)である、項目35に記載のキット。
(項目37)
前記細胞傷害性薬剤が、マレイミド部分を含むリンカーを介して前記抗体と結合体化されている、項目34〜36に記載のキット。
(項目38)
前記マレイミドリンカーが、マレイミドカプロイル(mc)、マレイミドカプロイル−L−フェニルアラニン−L−リジン−p−アミノベンジルカルバメート、およびマレイミドカプロイル−L−バリン−L−シトルリン−p−アミノベンジルカルバメート(vc)からなる群から選択される、項目37に記載のキット。
(項目39)
前記GCC標的化治療剤が、式(I−4)、(I−5)、または(I−6)のうちのいずれか1つを特徴とする免疫結合体であり、
式中、Abは、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子であり、mは1〜8の整数である、項目28に記載のキット。
(項目40)
mが3〜5である、項目39に記載のキット。
(項目41)
mが約4である、項目39に記載のキット。
(項目42)
1つ以上のGCC発現細胞を特徴とする疾患を有する患者を治療する方法であって、
a.例えば項目18〜26のいずれかに記載の方法によって、前記患者から採取した生体試料におけるGCCタンパク質発現を検出することと、
b.生体試料がGCCを発現する場合、前記患者に、本明細書に記載のGCC標的化治療剤のようなGCC標的化治療剤を投与することと、
を含む、方法。
(項目43)
前記検出ステップが、
i)それぞれ配列番号21、22、および23、または配列番号33、34、および35によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29、または配列番号39、40、および41によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子のような、項目1〜13のいずれかに記載の抗GCC抗体分子のような、本明細書に記載の抗GCC抗体分子に前記生体試料を接触させるステップと、
ii)前記抗GCC抗体分子とGCCタンパク質との間の複合体の形成を検出するステップと、
を含む、項目42に記載の方法。
(項目44)
前記検出ステップが、免疫組織化学を用いて行われる、項目43に記載の方法。
(項目45)
前記GCC標的化治療剤が、抗GCC抗体分子を含む、項目43に記載の方法。
(項目46)
前記治療用抗GCC抗体分子が、モノクローナル抗体である、項目45に記載の方法。
(項目47)
前記治療用抗GCC抗体分子が、ヒトIgG1抗体である、項目45または46に記載の方法。
(項目48)
前記抗GCC抗体分子が、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、項目45に記載の方法。
(項目49)
前記抗GCC抗体分子が、配列番号79によるアミノ酸配列を含む重鎖可変領域と、配列番号80によるアミノ酸配列を含む軽鎖可変領域とをさらに含む、項目48に記載の方法。
(項目50)
前記抗GCC抗体分子が、細胞傷害性薬剤と結合体化されている、項目45に記載の方法。
(項目51)
前記細胞傷害性薬剤が、オーリスタチン分子である、項目50に記載の方法。
(項目52)
前記オーリスタチン分子が、モノメチルオーリスタチンE(MMAE)またはモノメチルオーリスタチンF(MMAF)である、項目51に記載の方法。
(項目53)
前記細胞傷害性薬剤が、マレイミド部分を含むリンカーを介して結合体化されている、項目50〜53に記載の方法。
(項目54)
前記マレイミドリンカーが、マレイミドカプロイル(mc)、マレイミドカプロイル−L−フェニルアラニン−L−リジン−p−アミノベンジルカルバメート、およびマレイミドカプロイル−L−バリン−L−シトルリン−p−アミノベンジルカルバメート(vc)からなる群から選択される、項目53に記載の方法。
(項目55)
項目42に記載の方法であって、前記GCC標的化療法が、式(I−4)、(I−5)、または(I−6)のうちのいずれか1つによって特徴付けられる免疫結合体:
(式中、Abは、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子であり、式中mは1〜8の整数である。)
(項目56)
mが約3〜約5である、項目55に記載の方法。
(項目57)
mが約4である、項目56に記載の方法。
(項目58)
1つ以上のGCC発現細胞によって特徴付けられる疾患が、癌、炎症性腸症候群、クローン病、またはパーキンソン病からなる群から選択される、項目42〜57のいずれかに記載の方法。
(項目59)
前記癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍からなる群から選択される、項目58に記載の方法。
(項目60)
前記肺癌が、扁平上皮癌または腺癌である、項目59に記載の方法
(項目61)
前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫である、項目59に記載の方法。
(項目62)
前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、項目59に記載の方法。
(項目63)
前記生体試料が細胞または組織生検である、項目42〜62に記載の方法。
(項目64)
前記細胞または組織生検が腫瘍生検である、項目63に記載の方法。
(項目65)
GCC標的化治療剤への癌細胞の感受性を判定する、および/または対象がGCC標的化療法に対して可能性のある候補であるかどうかを評価する方法であって、
i)癌を有する患者からの癌細胞からの試料を提供するステップと、
ii)それぞれ配列番号21、22、および23、または配列番号33、34、および35によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29、または配列番号39、40、および41によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子のような、項目1〜13のいずれかに記載の抗GCC抗体のような、本明細書に記載の抗GCC抗体分子に、前記試料を接触させるステップと、
iiii)前記抗GCC抗体分子とGCCタンパク質との間の複合体の形成を検出し、それによって、本明細書に記載のGC標的化治療剤のような前記GCC標的化治療剤に対する前記癌の前記感受性を判定する、および/または対象が本明細書に記載のGCC標的化療法のようなGCC標的化療法による治療に対する候補であるかどうかを判定するステップと、
を含む、方法。
(項目66)
前記検出ステップが、免疫組織化学を用いて行われる、項目65に記載の方法。
(項目67)
前記癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍からなる群から選択される、項目65または66に記載の方法。
(項目68)
前記肺癌が、扁平上皮癌または腺癌である、項目67に記載の方法
(項目69)
前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫である、項目67に記載の方法。
(項目70)
前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、項目67に記載の方法。
(項目71)
前記患者に、本明細書に記載のGCC標的化治療剤のような前記GCC標的化治療剤を投与するステップをさらに含む、項目65〜70のいずれかに記載の方法。
(項目72)
前記GCC標的化治療剤は、抗GCC抗体分子を含む、項目71に記載の方法。
(項目73)
前記治療用抗GCC抗体分子は、モノクローナル抗体である、項目72に記載の方法。
(項目74)
前記治療用抗GCC抗体分子は、ヒトIgG1抗体である、項目72または73に記載の方法。
(項目75)
前記治療用抗GCC抗体分子が、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む、項目72、73、または74のいずれかに記載の方法。
(項目76)
前記治療用抗GCC抗体分子が、配列番号79によるアミノ酸配列を含む重鎖可変領域と、配列番号80によるアミノ酸配列を含む軽鎖可変領域とをさらに含む、項目75に記載の方法。
(項目77)
前記抗GCC抗体分子が、細胞傷害性薬剤と結合体化されている、項目72〜76のいずれかに記載の方法。
(項目78)
前記細胞傷害性薬剤が、オーリスタチン分子である、項目77に記載の方法。
(項目79)
前記オーリスタチン分子が、モノメチルオーリスタチンE(MMAE)またはモノメチルオーリスタチンF(MMAF)である、項目78に記載の方法。
(項目80)
前記細胞傷害性薬剤が、マレイミド部分を含むリンカーを介して結合体化されている、項目77、78、または79のいずれかに記載の方法。
(項目81)
前記マレイミドリンカーが、マレイミドカプロイル(mc)、マレイミドカプロイル−L−フェニルアラニン−L−リジン−p−アミノベンジルカルバメート、およびマレイミドカプロイル−L−バリン−L−シトルリン−p−アミノベンジルカルバメート(vc)からなる群から選択される、項目80に記載の方法。
(項目82)
項目65〜71に記載の方法であって、前記GCC標的化治療剤が、式(I−4)、(I−5)、または(I−6)のうちのいずれか1つによって特徴付けられる免疫結合体:
(式中、Abは、それぞれ配列番号67、68、および69によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号70、71、および72によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子であり、式中mは1〜8の整数である。)
(項目83)
mが約3〜約5である、項目82に記載の方法。
(項目84)
mが約4である、項目83に記載の方法。
(項目85)
それぞれ配列番号21、22、および23、または配列番号33、34、および35によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29、または配列番号39、40、および41によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子のような、項目1〜13のいずれかに記載の抗GCC抗体のような、本明細書に記載の生体試料および抗GCC抗体分子を含む反応混合物。
(項目86)
前記生体試料が、1つ以上の細胞を含む、項目85に記載の反応混合物。
(項目87)
前記生体試料が、組織試料を含む、項目85に記載の反応混合物。
(項目88)
前記組織試料が、パラフィン包埋組織試料である、項目87に記載の反応混合物。
(項目89)
前記生体試料が、原発性または転移性腫瘍生検試料である、項目85に記載の反応混合物。
(項目90)
前記生体試料が、スライド上に載置される、項目85に記載の反応混合物。
(項目91)
前記腫瘍が、大腸腫瘍、胃腫瘍、小腸腫瘍、食道腫瘍、膵臓腫瘍、肺腫瘍、柔部組織肉腫、神経外胚様性腫瘍、または神経内分泌腫瘍である、項目89に記載の反応混合物。
(項目92)
前記肺腫瘍が、扁平上皮癌または腺癌である、項目91に記載の反応混合物。
(項目93)
前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫である、項目91に記載の反応混合物。
(項目94)
前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、項目91に記載の反応混合物。
(項目95)
前記生体試料が、GCCタンパク質を含む疑いがある、項目85に記載の反応混合物。
(項目96)
前記抗GCC抗体とGCCタンパク質との間の複合体の形成を検出するために好適な試薬をさらに含む、項目85〜95のいずれかに記載の反応混合物。
(項目97)
個別の癌治療レポートを作成するための方法であって、前記方法が、
GCC発現癌を有する疑いのある癌患者から採取された1つ以上の癌細胞を含む生体試料を、それぞれ配列番号21、22、および23、または配列番号33、34、および35によるアミノ酸配列を含む3つの重鎖相補性決定領域(CDR1、CDR2、およびCDR3)と、それぞれ配列番号27、28、および29、または配列番号39、40、および41によるアミノ酸配列を含む3つの軽鎖相補性決定領域(CDR1、CDR2、およびCDR3)とを含む抗GCC抗体分子のような、項目1〜13のいずれかに記載の抗GCC抗体分子のような、本明細書に記載の抗GCC抗体分子に接触させるステップと、
項目18〜26のいずれかに記載のような方法によって、前記生体試料における前記抗GCC抗体分子とGCCタンパク質との間の複合体の形成を検出するステップと、
前記生物試料におけるGCC発現を定量化するステップと、
前記GCC発現レベルを、本明細書に記載のGCC標的化療法のようなGCC標的化療法を含むデータベースと比較するステップと、
前記GCC発現レベルに基づいて、GCC標的化療法、および必要に応じて投与計画を選択するステップと、
を含む、方法。
(項目98)
前記GCC発現癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、または神経内分泌腫瘍である、項目97に記載の方法。
(項目99)
前記肺腫瘍が、扁平上皮癌または腺癌である、項目98に記載の方法。
(項目100)
前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫である、項目98に記載の方法。
(項目101)
前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、項目98に記載の反応混合物。
(項目102)
前記検出ステップが、免疫組織化学を用いて行われる、項目97〜101のいずれかに記載の方法。
(項目103)
前記GCC発現の定量化が、前記生体試料における頂端のGCC発現、前記生体試料における細胞質GCC発現、または両方を含む、項目97〜102のいずれかに記載の方法。
(項目104)
前記定量化ステップが、Hスコア法を含む、項目97〜103に記載の方法。
1 gaccagagag aagcgtgggg aagagtgggc tgagggactc cactagaggc tgtccatctg
61 gattccctgc ctccctagga gcccaacaga gcaaagcaag tgggcacaag gagtatggtt
121 ctaacgtgat tggggtcatg aagacgttgc tgttggactt ggctttgtgg tcactgctct
181 tccagcccgg gtggctgtcc tttagttccc aggtgagtca gaactgccac aatggcagct
241 atgaaatcag cgtcctgatg atgggcaact cagcctttgc agagcccctg aaaaacttgg
301 aagatgcggt gaatgagggg ctggaaatag tgagaggacg tctgcaaaat gctggcctaa
361 atgtgactgt gaacgctact ttcatgtatt cggatggtct gattcataac tcaggcgact
421 gccggagtag cacctgtgaa ggcctcgacc tactcaggaa aatttcaaat gcacaacgga
481 tgggctgtgt cctcataggg ccctcatgta catactccac cttccagatg taccttgaca
541 cagaattgag ctaccccatg atctcagctg gaagttttgg attgtcatgt gactataaag
601 aaaccttaac caggctgatg tctccagcta gaaagttgat gtacttcttg gttaactttt
661 ggaaaaccaa cgatctgccc ttcaaaactt attcctggag cacttcgtat gtttacaaga
721 atggtacaga aactgaggac tgtttctggt accttaatgc tctggaggct agcgtttcct
781 atttctccca cgaactcggc tttaaggtgg tgttaagaca agataaggag tttcaggata
841 tcttaatgga ccacaacagg aaaagcaatg tgattattat gtgtggtggt ccagagttcc
901 tctacaagct gaagggtgac cgagcagtgg ctgaagacat tgtcattatt ctagtggatc
961 ttttcaatga ccagtacttt gaggacaatg tcacagcccc tgactatatg aaaaatgtcc
1021 ttgttctgac gctgtctcct gggaattccc ttctaaatag ctctttctcc aggaatctat
1081 caccaacaaa acgagacttt gctcttgcct atttgaatgg aatcctgctc tttggacata
1141 tgctgaagat atttcttgaa aatggagaaa atattaccac ccccaaattt gctcatgctt
1201 tcaggaatct cacttttgaa gggtatgacg gtccagtgac cttggatgac tggggggatg
1261 ttgacagtac catggtgctt ctgtatacct ctgtggacac caagaaatac aaggttcttt
1321 tgacctatga tacccacgta aataagacct atcctgtgga tatgagcccc acattcactt
1381 ggaagaactc taaacttcct aatgatatta caggccgggg ccctcagatc ctgatgattg
1441 cagtcttcac cctcactgga gctgtggtgc tgctcctgct cgtcgctctc ctgatgctca
1501 gaaaatatag aaaagattat gaacttcgtc agaaaaaatg gtcccacatt cctcctgaaa
1561 atatctttcc tctggagacc aatgagacca atcatgttag cctcaagatc gatgatgaca
1621 aaagacgaga tacaatccag agactacgac agtgcaaata cgacaaaaag cgagtgattc
1681 tcaaagatct caagcacaat gatggtaatt tcactgaaaa acagaagata gaattgaaca
1741 agttgcttca gattgactat tacaacctga ccaagttcta cggcacagtg aaacttgata
1801 ccatgatctt cggggtgata gaatactgtg agagaggatc cctccgggaa gttttaaatg
1861 acacaatttc ctaccctgat ggcacattca tggattggga gtttaagatc tctgtcttgt
1921 atgacattgc taagggaatg tcatatctgc actccagtaa gacagaagtc catggtcgtc
1981 tgaaatctac caactgcgta gtggacagta gaatggtggt gaagatcact gattttggct
2041 gcaattccat tttacctcca aaaaaggacc tgtggacagc tccagagcac ctccgccaag
2101 ccaacatctc tcagaaagga gatgtgtaca gctatgggat catcgcacag gagatcatcc
2161 tgcggaaaga aaccttctac actttgagct gtcgggaccg gaatgagaag attttcagag
2221 tggaaaattc caatggaatg aaacccttcc gcccagattt attcttggaa acagcagagg
2281 aaaaagagct agaagtgtac ctacttgtaa aaaactgttg ggaggaagat ccagaaaaga
2341 gaccagattt caaaaaaatt gagactacac ttgccaagat atttggactt tttcatgacc
2401 aaaaaaatga aagctatatg gataccttga tccgacgtct acagctatat tctcgaaacc
2461 tggaacatct ggtagaggaa aggacacagc tgtacaaggc agagagggac agggctgaca
2521 gacttaactt tatgttgctt ccaaggctag tggtaaagtc tctgaaggag aaaggctttg
2581 tggagccgga actatatgag gaagttacaa tctacttcag tgacattgta ggtttcacta
2641 ctatctgcaa atacagcacc cccatggaag tggtggacat gcttaatgac atctataaga
2701 gttttgacca cattgttgat catcatgatg tctacaaggt ggaaaccatc ggtgatgcgt
2761 acatggtggc tagtggtttg cctaagagaa atggcaatcg gcatgcaata gacattgcca
2821 agatggcctt ggaaatcctc agcttcatgg ggacctttga gctggagcat cttcctggcc
2881 tcccaatatg gattcgcatt ggagttcact ctggtccctg tgctgctgga gttgtgggaa
2941 tcaagatgcc tcgttattgt ctatttggag atacggtcaa cacagcctct aggatggaat
3001 ccactggcct ccctttgaga attcacgtga gtggctccac catagccatc ctgaagagaa
3061 ctgagtgcca gttcctttat gaagtgagag gagaaacata cttaaaggga agaggaaatg
3121 agactaccta ctggctgact gggatgaagg accagaaatt caacctgcca acccctccta
3181 ctgtggagaa tcaacagcgt ttgcaagcag aattttcaga catgattgcc aactctttac
3241 agaaaagaca ggcagcaggg ataagaagcc aaaaacccag acgggtagcc agctataaaa
3301 aaggcactct ggaatacttg cagctgaata ccacagacaa ggagagcacc tatttttaaa
1 mktllldlal wsllfqpgwl sfssqvsqnc hngsyeisvl mmgnsafaep lknledavne
61 gleivrgrlq naglnvtvna tfmysdglih nsgdcrsstc egldllrkis naqrmgcvli
121 gpsctystfq myldtelsyp misagsfgls cdyketltrl msparklmyf lvnfwktndl
181 pfktyswsts yvykngtete dcfwylnale asvsyfshel gfkvvlrqdk efqdilmdhn
241 rksnviimcg gpeflyklkg dravaedivi ilvdlfndqy fednvtapdy mknvlvltls
301 pgnsllnssf srnlsptkrd falaylngil lfghmlkifl engenittpk fahafrnltf
361 egydgpvtld dwgdvdstmv llytsvdtkk ykvlltydth vnktypvdms ptftwknskl
421 pnditgrgpq ilmiavftlt gavvllllva llmlrkyrkd yelrqkkwsh ippenifple
481 tnetnhvslk idddkrrdti qrlrqckydk krvilkdlkh ndgnftekqk ielnkllqid
541 yynltkfygt vkldtmifgv ieycergslr evlndtisyp dgtfmdwefk isvlydiakg
601 msylhsskte vhgrlkstnc vvdsrmvvki tdfgcnsilp pkkdlwtape hlrqanisqk
661 gdvysygiia qeiilrketf ytlscrdrne kifrvensng mkpfrpdlfl etaeekelev
721 yllvkncwee dpekrpdfkk iettlakifg lfhdqknesy mdtlirrlql ysrnlehlve
781 ertqlykaer dradrlnfml lprlvvkslk ekgfvepely eevtiyfsdi vgfttickys
841 tpmevvdmln diyksfdhiv dhhdvykvet igdaymvasg lpkrngnrha idiakmalei
901 lsfmgtfele hlpglpiwir igvhsgpcaa gvvgikmpry clfgdtvnta srmestglpl
961 rihvsgstia ilkrtecqfl yevrgetylk grgnettywl tgmkdqkfnl ptpptvenqq
1021 rlqaefsdmi anslqkrqaa girsqkprrv asykkgtley lqlnttdkes tyf
定義
[結合]=N・[遊離]/((1/KA)+[遊離])。
抗GCC抗体
(a)上で参照されるウサギハイブリドーマ抗体のうちの1つの、1個、2個、3個、または抗原結合数の軽鎖CDR(LCDR1、LCDR2、および/またはLCDR3)。実施形態では、このCDR(複数可)は、以下のとおり、LCDR1〜3のうちの1個以上またはすべてのアミノ酸配列を含んでいてもよい:LCDR1または1〜7個のアミノ酸が保存的に置換された改変LCDR1)、LCDR2または1もしくは2個のアミノ酸が保存的に置換された改変LCDR2)、またはLCDR3または1もしくは2個のアミノ酸が保存的に置換された改変LCDR3、ならびに
(b)上で参照されるウサギハイブリドーマ抗体のうちの1つの、1個、2個、3個、または抗原結合数の重鎖CDR(HCDR1、HCDR2、および/またはHCDR3)。実施形態では、このCDR(複数可)は、以下のとおり、HCDR1〜3のうちの1個以上またはすべてのアミノ酸配列を含んでいてもよい:HCDR1または1もしくは2個のアミノ酸が保存的に置換された改変HCDR1、HCDR2または1〜4個のアミノ酸が保存的に置換された改変HCDR2、またはHCDR3または1もしくは2個のアミノ酸が保存的に置換された改変HCDR3、のうちの一方または両方を含む。
a)結合について、例えば、細胞表面GCCまたは精製GCCへの結合について、表1および表2に要約される、上で参照される抗GCC抗体分子のうちの1つ、例えばウサギハイブリドーマ抗体(例えばMIL−44−148−2)と競合する;
b)表1および表2に要約される、上で参照される抗GCC抗体分子のうちの1つとして、例えば、例えば、ウサギハイブリドーマ抗体(例えばMIL−44−148−2)として、同じまたは実質的に同じ、GCCのエピトープに結合する。一実施形態では、抗体は同じエピトープに結合するが、それは1つ以上のペプチドアレイアッセイによって判定されるとおりであるかまたは例えば、細胞表面上に発現される切断変異体、キメラ、もしくは点変異体または膜調製物への結合によって判定されるとおりであり、それらのアッセイは本明細書に記載のとおりである;
c)表1および表2に要約される、上で参照される抗GCC抗体分子のうちの1つ、例えばウサギハイブリドーマ抗体(例えばMIL−44−148−2)のエピトープと共通の、少なくとも1、2、3、4、5、8、10、15、または20の隣接アミノ酸残基を有するエピトープに結合する;
d)本発明の抗GCC抗体が結合するヒトGCCの領域に結合し、その領域、例えば細胞外領域または細胞質領域は、長さが10〜15、10〜20、20〜30、または20〜40の残基であり、その結合は、例えば、切断変異体への結合によって判定される。一実施形態では、抗GCC抗体分子は、ヒトGCCの細胞外領域に結合する。一実施形態では、抗GCC抗体分子は、配列番号3のアミノ酸残基24〜420によって定められる細胞外ドメインのヒトGCCの部分に結合することができる。一実施形態では、抗GCC抗体分子は、配列番号3のアミノ酸残基931〜954のグアニル酸シクラーゼ識別特性部位(signature site)に結合することができる;または
e)本明細書に記載の参照エピトープに結合する。
VTLDDWGDV(配列番号9)に結合する。
体分子は、線状エピトープに結合する。
ヒト化およびディスプレイ技術および抗体に対する改変
(a)(i)表3由来の軽鎖可変領域アミノ酸配列、例えば配列番号13もしくは(ii)表4由来のヌクレオチド配列によってコードされる軽鎖可変領域アミノ酸、例えば配列番号12のいずれかの、すべての軽鎖アミノ酸配列または上記いずれかの抗原結合断片;および
(b)(i)表3由来の重鎖可変領域アミノ酸配列、例えば配列番号11もしくは(ii)表4由来のヌクレオチド配列によってコードされる重鎖アミノ酸配列、例えば配列番号10のいずれかの、すべての重鎖アミノ酸配列または上記いずれかの抗原結合断片、の一方または両方を含む。
a)本発明の抗GCC抗体分子の軽鎖可変領域と少なくとも85、90、95、97、または99%の相同性を有する軽鎖可変領域またはその抗原結合断片、および
b)本発明の抗GCC抗体分子の重鎖可変領域と少なくとも85、90、95、97、または99%の相同性を有する重鎖可変領域またはその抗原結合断片、の一方または両方を含む。
他の治療剤の設計および生成
核酸およびポリペプチド
軽鎖可変領域をコードする配列、例えば表3に記載の軽鎖可変領域、例えば表4に列挙される配列、その抗原結合断片、または本明細書に記載の、軽鎖由来の1、2、もしくは3個のCDR(および必要に応じてフレームワーク領域)、例えば表5に記載のCDR、例えば表6に記載のCDRをコードする配列;ならびに
重鎖可変領域をコードする配列、例えば表3に記載の重鎖可変領域、例えば表4に列挙される配列、その抗原結合断片、または本明細書に記載の、重鎖由来の1、2、もしくは3個のCDR(および必要に応じてフレームワーク領域)、例えば表5に記載のCDR、例えば表6に記載のCDRをコードする配列、
の一方または両方を含む、ベクター、例えば発現ベクターが提供される。
(a)(i)本明細書に記載の、例えば表4に記載の抗GCC抗体分子コード核酸配列の相補体または(ii)本発明の抗GCC抗体分子、例えば、表1および表2に要約される上で参照されるウサギ抗体のうちの1つの軽鎖をコードする任意の核酸配列と、選択されるストリンジェンシー条件下でハイブリダイズする核酸によってコードされる軽鎖可変領域またはその抗原結合断片、ならびに
(b)(i)本明細書に記載の、例えば表4に記載の抗GCC抗体分子コード核酸配列の相補体または(ii)本発明の抗GCC抗体分子、例えば、表1および表2に要約される上で参照されるウサギ抗体のうちの1つの重鎖をコードする任意の核酸配列と、選択されるストリンジェンシー条件下でハイブリダイズする核酸によってコードされる重鎖可変領域またはその抗原結合断片の、一方または両方を含む。
融合タンパク質および免疫結合体
Abは、本明細書に記載の抗GCC抗体分子であり、
Xは、AbとZとを接続する部分、例えば、AbおよびZの一方または両方への共有結合の後の、本明細書に記載のリンカーの残基であり、
Zは、治療剤または標識であり、ならびに
mは、約1〜約15の範囲である。
抗GCC抗体配列
ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCAGTGAAGGAGTCCGGGGGAGGCCTCTTCAAGCCAACGGATACCCTGACACTCACCTGCACCGTCTCTGGATTCTCCCTCAGTAGTCATAGAATGAACTGGGTCCGCCAGACTCCAGGGAAGGGGCTGGAATGGATCGCAATCATTACTCATAATAGTATCACATACTACGCGAGCTGGGCGAAAAGCCGATCCACCATCACCAGAAACACCAGCGAGAACACGGTGACTCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACTTATTTCTGTGCCAGAGAGGATAGTATGGGGTATTATTTTGACTTGTGGGGCCCAGGCACCCTGGTCACCATCTCCTCA
GGGCAACCTAAGGCTCCATCAGTCTTCCCACTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGGTGACCCTGGGCTGCCTGGTCAAAGGGTACCTCCCGGAGCCAGTGACCGTGACCTGGAACTCGGGCACCCTCACCAATGGGGTACGCACCTTCCCGTCCGTCCGGCAGTCCTCAGGCCTCTACTCGCTGAGCAGCGTGGTGAGCGTGACCTCAAGCAGCCAGCCCGTCACCTGCAACGTGGCCCACCCAGCCACCAACACCAAAGTGGACAAGACCGTTGCGCCCTCGACATGCAGCAAGCCCACGTGCCCACCCCCTGAACTCCTGGGGGGACCGTCTGTCTTCATCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCACGCACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCAGGATGACCCCGAGGTGCAGTTCACATGGTACATAAACAACGAGCAGGTGCGCACCGCCCGGCCGCCGCTACGGGAGCAGCAGTTCAACAGCACGATCCGCGTGGTCAGCACCCTCCCCATCGCGCACCAGGACTGGCTGAGGGGCAAGGAGTTCAAGTGCAAAGTCCACAACAAGGCACTCCCGGCCCCCATCGAGAAAACCATCTCCAAAGCCAGAGGGCAGCCCCTGGAGCCGAAGGTCTACACCATGGGCCCTCCCCGGGAGGAGCTGAGCAGCAGGTCGGTCAGCCTGACCTGCATGATCAACGGCTTCTACCCTTCCGACATCTCGGTGGAGTGGGAGAAGAACGGGAAGGCAGAGGACAACTACAAGACCACGCCGGCCGTGCTGGACAGCGACGGCTCCTACTTCCTCTACAGCAAGCTCTCAGTGCCCACGAGTGAGTGGCAGCGGGGCGACGTCTTCACCTGCTCCGTGATGCACGAGGCCTTGCACAACCACTACACGCAGAAGTCCATCTCCCGCTCTCCGGGTAAATGA
METGLRWLLLVAVLKGVQCQSVKESGGGLFKPTDTLTLTCTVSGFSLSSHRMNWVRQTPGKGLEWIAIITHNSITYYASWAKSRSTITRNTSENTVTLKMTSLTAADTATYFCAREDSMGYYFDLWGPGTLVTISSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK
ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAACTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGTCTCCCAAGCCCCTGATCTACAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAGAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGTGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAGCAGACTTATACTAATAATCATCTTGATAATGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA
GGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAGGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG
MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASQSISNWLAWYQQKPGQSPKPLIYRASTLASGVSSRFRGSGSGTQFTLTISGVECADAATYYCQQTYTNNHLDNGFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCRVTQGTTSVVQSFNRGDC
ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATCCGACATCAGTAACTATGCAATATCCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATTCATCGGATATATTAGTTATGGTAAAAGTATATACTACGCGAGCTGGGCGAAAGGCCGGTTCGCCATCTCCAAAACCTCGTCGACCACGGTGGATCTGGAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTTTGTGCCAGAGAGGATAGTGCTACTTATAGTCCTAACTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCA
GGGCAACCTAAGGCTCCATCAGTCTTCCCACTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGGTGACCCTGGGCTGCCTGGTCAAAGGGTACCTCCCGGAGCCAGTGACCGTGACCTGGAACTCGGGCACCCTCACCAATGGGGTACGCACCTTCCCGTCCGTCCGGCAGTCCTCAGGCCTCTACTCGCTGAGCAGCGTGGTGAGCGTGACCTCAAGCAGCCAGCCCGTCACCTGCAACGTGGCCCACCCAGCCACCAACACCAAAGTGGACAAGACCGTTGCGCCCTCGACATGCAGCAAGCCCACGTGCCCACCCCCTGAACTCCTGGGGGGACCGTCTGTCTTCATCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCACGCACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCAGGATGACCCCGAGGTGCAGTTCACATGGTACATAAACAACGAGCAGGTGCGCACCGCCCGGCCGCCGCTACGGGAGCAGCAGTTCAACAGCACGATCCGCGTGGTCAGCACCCTCCCCATCGCGCACCAGGACTGGCTGAGGGGCAAGGAGTTCAAGTGCAAAGTCCACAACAAGGCACTCCCGGCCCCCATCGAGAAAACCATCTCCAAAGCCAGAGGGCAGCCCCTGGAGCCGAAGGTCTACACCATGGGCCCTCCCCGGGAGGAGCTGAGCAGCAGGTCGGTCAGCCTGACCTGCATGATCAACGGCTTCTACCCTTCCGACATCTCGGTGGAGTGGGAGAAGAACGGGAAGGCAGAGGACAACTACAAGACCACGCCGGCCGTGCTGGACAGCGACGGCTCCTACTTCCTCTACAGCAAGCTCTCAGTGCCCACGAGTGAGTGGCAGCGGGGCGACGTCTTCACCTGCTCCGTGATGCACGAGGCCTTGCACAACCACTACACGCAGAAGTCCATCTCCCGCTCTCCGGGTAAATGA
METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGSDISNYAISWVRQAPGKGLEFIGYISYGKSIYYASWAKGRFAISKTSSTTVDLEITSPTTEDTATYFCAREDSATYSPNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK
ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGTATTAACACCTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTTATAATAATCTTGATCGTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCACA
GGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAACAACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGACCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTCAATAGGGGTGACTGTTAG
MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASQSINTYLAWYQQKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISGVECADAATYYCQQGYSYNNLDRAFGGGTEVVVTGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC
抗体の標識化および検出
インビトロ診断
インビボ診断
GCC標的化療法のためのコンパニオン診断
GAATTCCTCACCATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGTGTCCACTCCCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTTTGGTGGGTCTTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATCGTGGAAACACCAACGACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCGCCCTGAAGCTGAGTTCTGTGACCGCCGCGGACACGGCTGTTTATTACTGTGCGAGAGAACGTGGATACACCTATGGTAACTTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCAGCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAATAGGGATAACAGGGTAATACTAGAG(配列番号83)
MGWSCIILFLVATATGVHSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTNDNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
(配列番号84)
GCGGCCGCCTCACCATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGTGTCCACTCCGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGAAACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGAATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCGGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAAAACCTGGCCTCGGACGTTCGGCCAAGGGACCAACGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACCCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAGTCTAGA(配列番号85)
MGWSCIILFLVATATGVHSEIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号86)
キット
cgcggatccctcaccATGAAGACGTTGCTGTTGGACTTGGCTTTGTGGTCACTGCTCTTCCAGCCCGGGTGGCTGTCCTTTAGTTCCCAGGTGAGTCAGAACTGCCACAATGGCAGCTATGAAATCAGCGTCCTGATGATGGGCAACTCAGCCTTTGCAGAGCCCCTGAAAAACTTGGAAGATGCGGTGAATGAGGGGCTGGAAATAGTGAGAGGACGTCTGCAAAATGCTGGCCTAAATGTGACTGTGAACGCTACTTTCATGTATTCGGATGGTCTGATTCATAACTCAGGCGACTGCCGGAGTAGCACCTGTGAAGGCCTCGACCTACTCAGGAAAATTTCAAATGCACAACGGATGGGCTGTGTCCTCATAGGGCCCTCATGTACATACTCCACCTTCCAGATGTACCTTGACACAGAATTGAGCTACCCCATGATCTCAGCTGGAAGTTTTGGATTGTCATGTGACTATAAAGAAACCTTAACCAGGCTGATGTCTCCAGCTAGAAAGTTGATGTACTTCTTGGTTAACTTTTGGAAAACCAACGATCTGCCCTTCAAAACTTATTCCTGGAGCACTTCGTATGTTTACAAGAATGGTACAGAAACTGAGGACTGTTTCTGGTACCTTAATGCTCTGGAGGCTAGCGTTTCCTATTTCTCCCACGAACTCGGCTTTAAGGTGGTGTTAAGACAAGATAAGGAGTTTCAGGATATCTTAATGGACCACAACAGGAAAAGCAATGTGATTATTATGTGTGGTGGTCCAGAGTTCCTCTACAAGCTGAAGGGTGACCGAGCAGTGGCTGAAGACATTGTCATTATTCTAGTGGATCTTTTCAATGACCAGTACTTGGAGGACAATGTCACAGCCCCTGACTATATGAAAAATGTCCTTGTTCTGACGCTGTCTCCTGGGAATTCCCTTCTAAATAGCTCTTTCTCCAGGAATCTATCACCAACAAAACGAGACTTTGCTCTTGCCTATTTGAATGGAATCCTGCTCTTTGGACATATGCTGAAGATATTTCTTGAAAATGGAGAAAATATTACCACCCCCAAATTTGCTCATGCTTTCAGGAATCTCACTTTTGAAGGGTATGACGGTCCAGTGACCTTGGATGACTGGGGGGATGTTGACAGTACCATGGTGCTTCTGTATACCTCTGTGGACACCAAGAAATACAAGGTTCTTTTGACCTATGATACCCACGTAAATAAGACCTATCCTGTGGATATGAGCCCCACATTCACTTGGAAGAACTCTAAACTTCCTAATGATATTACAGGCCGGGGCCCTCAGCCCAGAGTGCCCATAACACAGAACCCCTGTCCTCCACTCAAAGAGTGTCCCCCATGCGCAGCTCCAGACCTCGCAGGTGCACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATGGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGACGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGCATTCAAATGCAAGGTCAACAACAGAGCCCTCCCATCCCCCATCGAGAAAACCATCTCAAAACCCAGAGGGCCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGCAGAAGAGATGACTAAGAAAGAGTTCAGTCTGACCTGCATGATCACAGGCTTCTTACCTGCCGAAATTGCTGTGGACTGGACCAGCAATGGGCGTACAGAGCAAAACTACAAGAACACCGCAACAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTCAGAGTACAAAAGAGCACTTGGGAAAGAGGAAGTCTTTTCGCCTGCTCAGTGGTCCACGAGGGTCTGCACAATCACCTTACGACTAAGACCATCTCCCGGTCTCTGGGTAAATAAtctagagca
実施例2:タンパク質免疫によるウサギmAbsの生成
mCRCのヒト腫瘍異種移植片モデルにおけるGCC発現の検出
ヒト結腸試料および腫瘍マイクロアレイにおけるGCC発現の検出
実施例4:非結腸直腸PHTXモデルおよび腫瘍マイクロアレイ、ならびに結腸直腸および非結腸直腸ヒト臨床試料における追加的な免疫組織化学
Claims (34)
- 抗GCC抗体分子またはその抗原結合断片であって、それぞれ配列番号21、22、および23のアミノ酸配列を含む3つの重鎖相補性決定領域(HCDR1、HCDR2、およびHCDR3)、およびそれぞれ配列番号27、28、および29のアミノ酸配列を含む3つの軽鎖相補性決定領域(LCDR1、LCDR2、およびLCDR3)を含む、抗GCC抗体分子またはその抗原結合断片。
- 配列番号11のアミノ酸配列を含む重鎖可変領域、および配列番号13のアミノ酸配列を含む軽鎖可変領域を含む、請求項1に記載の抗GCC抗体分子またはその抗原結合断片。
- モノクローナル抗体である、請求項1または2に記載の抗GCC抗体分子またはその抗原結合断片。
- 前記抗GCC抗体分子の抗原結合断片である、請求項1〜3のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片。
- 検出可能な標識と結合体化されている、請求項1〜4のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片。
- 前記検出可能な標識は、西洋ワサビペルオキシダーゼ(HRP);アルカリホスファターゼ;ガラクトシダーゼ;グルコアミラーゼ;リゾチーム;糖質酸化酵素;複素環式酸化酵素;ラクトペルオキシダーゼ;ミクロペルオキシダーゼ;ビオチン;アビジン;スピン標識;バクテリオファージ標識;安定な遊離ラジカル;フルオレセインまたはその誘導体、ローダミンまたはその誘導体、ダンシル、ウンベリフェロン、ルシフェラーゼ、ルシフェリン、および2,3−ジヒドロフタラジンジオンから必要に応じて選択されるフルオロフォア;ならびに32P、3H、14C、188Rh、43K、52Fe、57Co、67Cu、67Ga、68Ga、77Br、81Rb、81MKr、87MSr、99Tc、111In、113MIn、123I、125I、127Cs、129Cs、131I、132I、197Hg、203Pb、206Bi、および213Biから必要に応じて選択される放射性薬剤、から選択される、請求項5に記載の抗GCC抗体分子またはその抗原結合断片。
- 請求項1〜4のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片、または請求項1〜4のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片の可変領域をコードする、単離核酸配列。
- 請求項7に記載の単離核酸配列を含む、発現ベクター。
- 請求項7に記載の単離核酸配列または請求項8に記載の発現ベクターを含む、単離細胞。
- 請求項1〜4のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片を産生する方法であって、抗体分子またはその抗原結合断片の発現を可能にする条件下で請求項9に記載の細胞を培養し、それによって前記抗GCC抗体分子またはその抗原結合断片を産生することを含む、方法。
- 生体試料におけるGCC分子を検出する方法であって、該生体試料を請求項1〜6のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片と接触させること、および該抗GCC抗体分子またはその抗原結合断片が該GCC分子に結合するかどうかを判定することを含む、方法。
- 前記GCC分子の検出が免疫組織化学アッセイを含む、請求項11に記載の方法。
- 前記生体試料が、GCC発現癌を有する疑いのある患者に由来する腫瘍生検試料であり、該癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍から必要に応じて選択される、請求項11または12に記載の方法。
- (a)前記肺癌が、扁平上皮癌または腺癌であり;
(b)前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫であり;そして/あるいは
(c)前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、
請求項13に記載の方法。 - 前記生体試料におけるGCC発現を定量化することをさらに含む、請求項11〜14のいずれか1項に記載の方法。
- 前記生体試料における前記GCC発現を定量化することが、頂端のGCC発現、細胞質GCC発現、または両方を定量化すること含む、請求項15に記載の方法。
- 前記生体試料におけるGCC発現を定量化することが、Hスコア法を含む、請求項15または16に記載の方法。
- 請求項1〜6のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片、および生体試料においてGCC分子を検出することにおける使用説明書を含むキット。
- GCC標的化治療剤への癌細胞の感受性を判定するため、および/または対象がGCC標的化療法に対して可能性のある候補であるかどうかを評価するための、請求項1〜6のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片を含む組成物であって、
該対象から採取された1つ以上の癌細胞を含む生体試料が、前記抗GCC抗体分子またはその抗原結合断片と接触させられること、および該抗GCC抗体分子またはその抗原結合断片と該生体試料中のGCCタンパク質との間の複合体の形成が検出されることを特徴とし、該複合体の形成は、癌細胞がGCC標的化治療剤に対して感受性であること、および/または該対象がGCC標的化療法に対する候補であることを示す、組成物。 - 前記複合体の形成が、免疫組織化学アッセイを用いて検出される、請求項19に記載の組成物。
- 前記癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍から選択される、請求項19または20に記載の組成物。
- (a)前記肺癌が、扁平上皮癌または腺癌であり;
(b)前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫であり;そして/あるいは
(c)前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、
請求項21に記載の組成物。 - 生体試料および請求項1〜6のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片を含む、反応混合物であって、該生体試料が、1つ以上の細胞を含み、および/または該生体試料が組織試料を含む、反応混合物。
- 前記生体試料が、原発性または転移性腫瘍生検試料である、請求項23に記載の反応混合物。
- 前記腫瘍生検試料が、結腸直腸腫瘍、胃腫瘍、小腸腫瘍、食道腫瘍、膵臓腫瘍、肺腫瘍、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍試料から選択される、請求項24に記載の反応混合物。
- (a)前記肺腫瘍が、扁平上皮癌または腺癌であり;
(b)前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫であり;そして/あるいは
(c)前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、
請求項25に記載の反応混合物。 - 前記生体試料における前記抗GCC抗体分子またはその抗原結合断片とGCCタンパク質との間の複合体の形成を検出するために好適な試薬をさらに含む、請求項23〜26のいずれか1項に記載の反応混合物。
- 個別の癌治療レポートを作成するための、請求項1〜6のいずれか1項に記載の抗GCC抗体分子またはその抗原結合断片を含む組成物であって、
GCC発現癌を有する疑いのある患者から採取された1つ以上の癌細胞を含む生体試料が、該抗GCC抗体分子またはその抗原結合断片と接触させられること;
該生体試料における該抗GCC抗体分子またはその抗原結合断片とGCCタンパク質との間の複合体の形成が検出されること;
該検出された複合体から該生体試料におけるGCC発現が定量化されること;
該GCC発現レベルが、正常GCC発現レベルのデータベースに対して比較されること;および
該生体試料において決定された該GCC発現レベルに基づいて、GCC標的化療法、および必要に応じて投与計画が選択されること
を特徴とする、組成物。 - 前記GCC発現癌が、結腸直腸癌、胃癌、小腸癌、食道癌、膵臓癌、肺癌、軟部組織肉腫、神経外胚様性腫瘍、および神経内分泌腫瘍から選択される、請求項28に記載の組成物。
- (a)前記肺癌が、扁平上皮癌または腺癌であり;
(b)前記軟部組織肉腫が、平滑筋肉腫または横紋筋肉腫であり;そして/あるいは
(c)前記神経内分泌腫瘍が、消化管または気管支肺神経内分泌腫瘍である、
請求項29に記載の組成物。 - 複合体の前記形成が、免疫組織化学アッセイを用いて検出される、請求項28〜30のいずれか1項に記載の組成物。
- 前記生体試料におけるGCC発現を定量化することが、頂端のGCC発現、細胞質GCC発現、または両方を定量化することを含む、請求項28〜31のいずれか1項に記載の組成物。
- 前記生体試料におけるGCC発現を定量化することが、Hスコア法を含む、請求項28〜32のいずれか1項に記載の組成物。
- 前記生体試料におけるGCC発現レベルが、前記患者がGCC標的化療法に対する候補であることを示す、請求項28〜33のいずれか1項に記載の組成物。
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