JP6518199B2 - Micaおよびmicbタンパク質に対する抗体 - Google Patents
Micaおよびmicbタンパク質に対する抗体 Download PDFInfo
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- JP6518199B2 JP6518199B2 JP2015562400A JP2015562400A JP6518199B2 JP 6518199 B2 JP6518199 B2 JP 6518199B2 JP 2015562400 A JP2015562400 A JP 2015562400A JP 2015562400 A JP2015562400 A JP 2015562400A JP 6518199 B2 JP6518199 B2 JP 6518199B2
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
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Description
[0001]本出願は、2014年2月15日出願の米国仮出願第61/940,372号および2013年3月15日出願の米国仮出願第61/801,329号の恩典を請求する。各引用優先出願の内容は、その全体が本明細書に援用される。
配列表、表またはコンピュータプログラムに対する言及
[0002]配列表の公式コピーは、EFS−Webを通じ、ファイル名「NBI−001_ST25.txt」、生成日2014年3月15日、および94kbのサイズで、ASCIIフォーマットテキストファイルとして、明細書とともに提出される。EFS−Webを通じて提出された配列表は明細書の一部であり、そしてその全体が本明細書に援用される。
技術分野
[0003]本開示は、抗体、該抗体を生成するための免疫原、ならびに診断および治療のために該抗体を用いる方法に関する。
アミノ酸残基190〜229;
アミノ酸残基190〜238;
アミノ酸残基217〜238;
アミノ酸残基243〜256;
アミノ酸残基243〜274;または
アミノ酸残基243〜296/297
によって定義されるアルファ−3ドメイン内にあり、ここで、アミノ酸位は、それぞれ、MICA*001アレルのプロセシングされた成熟MICAタンパク質に、そしてMICB*001アレルのプロセシングされた成熟MICBタンパク質に関する。
190_RSEASEG_196(配列番号38);
217_RQDGV_221(配列番号39);
234_LPDGN_238(配列番号40);および
251_QGEEQR_256(配列番号41)
より選択されるアミノ酸配列内にあり、ここでアミノ酸位は、MICA*001アレルのプロセシングされた成熟MICAタンパク質に関して定義される。
190_CSEVSEG_196(配列番号43);
217_RQDGV_221(配列番号44);
234_LPDGN_238(配列番号45);および
250_RQGEEQR_256(配列番号46)
より選択されるアミノ酸配列内にあり、ここでアミノ酸位は、MICB*001アレルのプロセシングされた成熟MICBタンパク質に関して定義される。
(a)〜XA1−S−XA3−XA4−S−E−G〜(配列番号47)、
式中、XA1はRおよびCより選択され;XA3はEおよびKより選択され;そしてXA4はAおよびVより選択される;
(b)〜R−Q−D−G−XB5〜(配列番号48)、
式中、XB5はVおよびLより選択される;
(c)〜XD1−XD2−G−E−E−Q−XD7〜(配列番号49)、
式中、XD1はCまたはRより選択され;XD2はQ、RおよびEより選択され;そしてXD7はR、SおよびKより選択される;または
(d)〜L−P−D−G−N〜(配列番号50)
によって定義される配列内のエピトープに特異的に結合可能である。
アミノ酸残基190〜229;
アミノ酸残基190〜238;
アミノ酸残基217〜238;
アミノ酸残基243〜256;
アミノ酸残基243〜274;および
アミノ酸残基243〜296/297
より選択され、ここでアミノ酸番号付けは上記の通りである。
アミノ酸残基190〜196;
アミノ酸残基217〜221;
アミノ酸残基234〜238
アミノ酸残基250〜256;および
アミノ酸残基251〜256
より選択される配列領域を含み、ヒト集団に存在する任意のMICAアレル中の対応する領域、例えば本明細書に援用される、Robinsonら, 2003, “IMGT/HLA and IMGT/MHC: Sequence databases for the study of the major histocompatibility complex”, Nucleic Acids Res. 31:311−314およびAnthony Nolan Research Instituteワールドワイドウェブサイトwww.anthonynolan.org.uk/HIG/data.htmlにおいて入手可能な、同定されるMICAアレルが含まれる。したがって、本明細書に記載するMICA潜在性エピトープのあらゆる態様に関して、MICA*001、MICA*002:01、MICA*002:02、MICA*002:03、MICA*002:04、MICA*004、MICA*005、MICA*006、MICA*007:01、MICA*007:02、MICA*007:03、MICA*007:04、MICA*007:05、MICA*007:06、MICA*008:01:01、MICA*008:01:02、MICA*008:02、MICA*008:03、MICA*008:04、MICA*008:05、MICA*009:01、MICA*009:02、MICA*010:01、MICA*010:02、MICA*011、MICA*012:01、MICA*012:02、MICA*012:03、MICA*012:04、MICA*013、MICA*014、MICA*015、MICA*016、MICA*017、MICA*018:01、MICA*018:02、MICA*019、MICA*020、MICA*022、MICA*023、MICA*024、MICA*025、MICA*026、MICA*027、MICA*028、MICA*029、MICA*030、MICA*031、MICA*032、MICA*033、MICA*034、MICA*035、MICA*036、MICA*037、MICA*038、MICA*039、MICA*040、MICA*041、MICA*042、MICA*043、MICA*044、MICA*045、MICA*046、MICA*047、MICA*048、MICA*049、MICA*050、MICA*051、MICA*052、MICA*053、MICA*054、MICA*055、MICA*056、MICA*057、MICA*058、MICA*059、MICA*060、MICA*061、MICA*062、MICA*064N、MICA*065、MICA*066、MICA*067、MICA*068、MICA*069、MICA*070、MICA*072、MICA*073、MICA*074、MICA*075、MICA*076、およびMICA*077より選択されるヒトMICAアレル変異体を含む、MICAアレル変異体のあらゆる1つに関して、同等のエピトープもまた記載されることが理解されるものとする。
アミノ酸残基190〜196;
アミノ酸残基217〜221;
アミノ酸残基234〜238;および
アミノ酸残基250〜256
より選択される配列領域を含み、ヒト集団に存在する任意のMICBアレル中の領域、例えば本明細書に援用される、Robinsonら, 2003, “IMGT/HLA and IMGT/MHC: Sequence databases for the study of the major histocompatibility complex”, Nucleic Acids Res. 31:311−314およびAnthony Nolan Research Instituteワールドワイドウェブサイトwww.anthonynolan.org.uk/HIG/data.htmlにおいて入手可能な、同定されるMICBアレルが含まれる。したがって、本明細書に記載するMICB潜在性エピトープのあらゆる態様に関して、MICB*001、MICB*002:01:01、MICB*002:01:02、MICB*003、MICB*004:01:01、MICB*004:01:02、MICB*005:01、MICB*005:02:01、MICB*005:02:02、MICB*005:02:03、MICB*005:02:04、MICB*005:03、MICB*005:04、MICB*005:05、MICB*005:06、MICB*005:07、MICB*005:08、MICB*006、MICB*007、MICB*008、MICB*009N、MICB*010、MICB*011、MICB*012、MICB*013、MICB*014、MICB*015、MICB*016、MICB*018、MICB*019、MICB*020、MICB*021N、MICB *022; MICB*023、MICB*024、MICB*025、MICB*026、MICB*027、MICB*028、およびMICB*029より選択されるヒトMICBアレル変異体を含む、MICBアレル変異体のあらゆる1つに関して、同等のエピトープもまた記載されることが理解されるものとする。
190_RSEASEG_196、アルファ−3ドメインの最下部に位置する(配列番号38);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号39);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号40);
251_QGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号41);または
251_RGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号42)
によって定義されるエピトープに特異的に結合し、ここでアミノ酸位は、MICA*001アレルのプロセシングされた成熟MICAタンパク質に関して定義される。
251_RGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号42)
によって定義されるエピトープに特異的に結合し、ここで、アミノ酸残基番号付けは、MICA*001アレルのプロセシングされた成熟MICAタンパク質に関する。このエピトープは、限定されるわけではないが、MICAアレル*005; *008:01:01; *008:01:02; *008:02; *008:03; *008:04; *008:05; *010:01; *010:02; *013; *016; *019; *022; *027; *033; *035; *037; *039; *042; *048; *053; *054; *056; *058; *062; *065; *069; *070; *073および*076に見られる(例えば、Robinsonら、上記;およびAnthony Nolan Research Instituteウェブサイト、www.anthonynolan.org.uk/HIG/data.htmlを参照されたい)。
190_CSEVSEG_196、アルファ−3ドメインの最下部に位置する(配列番号43);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号44);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号45);または
250_RQGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号46)
によって定義されるMICBのエピトープに特異的に結合し、ここでアミノ酸位は、MICB*001アレルのプロセシングされたMICBタンパク質に関して定義される。
(a)〜XA1−S−XA3−XA4−S−E−G〜(配列番号47)、
式中、XA1はRおよびCより選択され;XA3はEおよびKより選択され;そしてXA4はAおよびVより選択される;
(b)〜R−Q−D−G−XB5〜(配列番号48)、
式中、XB5はVおよびLより選択される;
(c)〜XD1−XD2−G−E−E−Q−XD7〜(配列番号49)、
式中、XD1はCまたはRより選択され;XD2はQ、R、およびEより選択され;そしてXD7はR、S、およびKより選択される;または
(d)〜L−P−D−G−N〜(配列番号50)
によって定義されるアミノ酸配列内にある。
(a)〜XA1−S−XA3−XA4−S−E−G〜(配列番号47)、
式中、XA1はRおよびCより選択され;XA3はEおよびKより選択され;そしてXA4はAおよびVより選択される
内のエピトープに特異的に結合する。
(b)〜R−Q−D−G−XB5〜(配列番号48)、
式中、XB5はVおよびLより選択される
内のエピトープに特異的に結合する。
(c)〜XD1−XD2−G−E−E−Q−XD7〜(配列番号49)、
式中、XD1はCまたはRより選択され;XD2はQ、R、およびEより選択され;そしてXD7はR、S、およびKより選択される
内のエピトープに特異的に結合する。
(d)〜L−P−D−G−N〜(配列番号50)
内のエピトープに特異的に結合する。
アミノ酸残基190〜229;
アミノ酸残基190〜238;
アミノ酸残基217〜238;
アミノ酸残基243〜256;
アミノ酸残基243〜274;または
アミノ酸残基243〜296/297
より選択され、ここで、アミノ酸位は、それぞれ、MICA*001アレルのMICAタンパク質およびMICB*001アレルのMICBタンパク質に関して定義される。
アミノ酸残基190〜196;
アミノ酸残基217〜221;
アミノ酸残基234〜238
アミノ酸残基250〜256;および
アミノ酸残基251〜256
より選択される配列を含むアルファ−3ドメイン内のペプチドを含み、ヒト集団に存在する任意のMICAアレル中の対応する領域、例えば本明細書に援用される、Robinsonら, 2003, “IMGT/HLA and IMGT/MHC: Sequence databases for the study of the major histocompatibility complex”, Nucleic Acids Res. 31:311−314およびAnthony Nolan Research Instituteワールドワイドウェブサイトwww.anthonynolan.org.uk/HIG/data.htmlにおいて入手可能な、同定されるMICAアレルが含まれる。
アミノ酸残基190〜196;
アミノ酸残基217〜221;
アミノ酸残基234〜238;および
アミノ酸残基250〜256
より選択される配列を含むアルファ−3ドメイン内のペプチドを含み、ヒト集団に存在する任意のMICBアレル中の領域、例えば本明細書に援用される、Robinsonら, 2003, “IMGT/HLA and IMGT/MHC: Sequence databases for the study of the major histocompatibility complex”, Nucleic Acids Res. 31:311−314およびAnthony Nolan Research Instituteワールドワイドウェブサイトwww.anthonynolan.org.uk/HIG/data.htmlにおいて入手可能な、同定されるMICAアレルが含まれる。
190_RSEASEG_196、アルファ−3ドメインの最下部に位置する(配列番号38);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号39);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号40);または
251_QGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号41)
を含み、ここで、アミノ酸位は、MICA*001アレルのMICAタンパク質に関して定義される。
251_RGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号42)
を含み、ここで、アミノ酸残基番号付けは、MICA*001アレルのMICAタンパク質に関するものである。上述のように、このエピトープは、限定されるわけではないが、MICAアレル*005; *008:01:01; *008:01:02; *008:02; *008:03; *008:04; *008:05; *010:01; *010:02; *013; *016; *019; *022; *027; *033; *035; *037; *039; *042; *048; *053; *054; *056; *058; *062; *069; *070; *073および*076に見られる。
190_CSEVSEG_196、アルファ−3ドメインの最下部に位置する(配列番号43);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号44);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号45);または
250_RQGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号46)
を含み、ここで、アミノ酸位は、MICB*001アレルのMICBタンパク質に関して定義される。
(a)〜XA1−S−XA3−XA4−S−E−G〜(配列番号47)、
式中、XA1はRおよびCより選択され;XA3はEおよびKより選択され;そしてXA4はAおよびVより選択される;
(b)〜R−Q−D−G−XB5〜(配列番号48)、
式中、XB5はVおよびLより選択される;
(c)〜XD1−XD2−G−E−E−Q−XD7〜(配列番号49)、
式中、XD1はCまたはRより選択され;XD2はQ、RおよびEより選択され;そしてXD7はR、SおよびKより選択される;または
(d)〜L−P−D−G−N〜(配列番号50)
を含む。
(a)抗体がsMICAまたはsMICBと相互作用するために適した条件下で、sMICAまたはsMICBと候補抗体を接触させ:
(b)アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBと抗体を接触させ;そして
(c)抗体がsMICAまたはsMICBに特異的に結合するが、アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBに特異的に結合しないかどうかを決定する
工程を含むことも可能である。
(a)アルファ−3ドメイン上の潜在性エピトープが抗体と相互作用することが可能な条件下で、MICAまたはMICBのアルファ−3ドメインを含むポリペプチドと候補抗体を接触させ:
(b)アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBと候補抗体を接触させ;そして
(c)抗体がMICAまたはMICBのアルファ−3ドメインに特異的に結合するが、アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBに特異的に結合しないかどうかを決定する
工程を含むことも可能である。
(a)潜在性エピトープが抗体と相互作用することが可能な条件下で、MICAのアルファ−3ドメイン上の潜在性エピトープと候補抗体を接触させ:
(b)アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBと候補抗体を接触させ;そして
(c)抗体がMICAの潜在性エピトープに特異的に結合するが、アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBに特異的に結合しないかどうかを決定する
工程を含むことも可能である。
(a)潜在性エピトープが抗体と相互作用することが可能な条件下で、MICBのアルファ−3ドメイン上の潜在性エピトープと候補抗体を接触させ:
(b)アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBと候補抗体を接触させ;そして
(c)抗体がMICBの潜在性エピトープに特異的に結合するが、アルファ−3ドメインおよび膜貫通ドメインを含むMICAまたはMICBポリペプチド、あるいは膜結合型MICAまたはMICBに特異的に結合しないかどうかを決定する
工程を含むことも可能である。
アミノ酸残基190〜229;
アミノ酸残基190〜238;
アミノ酸残基217〜238;
アミノ酸残基243〜256;
アミノ酸残基243〜274;または
アミノ酸残基243〜296/297
によって示される配列を含むことも可能であり、ここで、アミノ酸位は、それぞれ、MICA*001アレルのMICAタンパク質またはMICB*001アレルのMICBタンパク質に関して定義される。
190_RSEASEG_196、アルファ−3ドメインの最下部に位置する(配列番号38);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号39);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号40);
251_QGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号41);または
251_RGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号42)
を含んでもよく、ここで、アミノ酸位は、MICA*001アレルのMICAタンパク質に関して定義される。
190_CSEVSEG_196、アルファ−3ドメインの最下部に位置する(配列番号43);
217_RQDGV_221、アルファ−3ドメインの下部に位置する(配列番号44);
234_LPDGN_238、アルファ−3ドメインの最上部近傍に位置する(配列番号45);または
250_RQGEEQR_256、アルファ−3ドメインの最下部に位置する(配列番号46)
を含んでもよく、ここで、アミノ酸位は、MICB*001アレルのMICBタンパク質に関して定義される。
(a)〜XA1−S−XA3−XA4−S−E−G〜(配列番号47)、
式中、XA1はRおよびCより選択され;XA3はEおよびKより選択され;そしてXA4はAおよびVより選択される;
(b)〜R−Q−D−G−XB5〜(配列番号48)、
式中、XB5はVおよびLより選択される;
(c)〜XD1−XD2−G−E−E−Q−XD7〜(配列番号49)、
式中、XD1はCまたはRより選択され;XD2はQ、RおよびEより選択され;そしてXD7はR、SおよびKより選択される;または
(d)〜L−P−D−G−N〜(配列番号50)
を含んでもよい。
(a)生物学的試料を、sMICAに特異的に結合する本開示の任意の抗体と接触させ;そして
(b)抗体の特異的結合を決定するかまたは測定して、試料におけるsMICAのレベルを決定する
工程を含むことも可能である。
(a)生物学的試料を、sMICBに特異的に結合する本開示の任意の抗体と接触させ;そして
(b)抗体の特異的結合を決定するかまたは測定して、試料におけるsMICBのレベルを決定する
工程を含むことも可能である。
本明細書記載の抗sMICAおよび/または抗sMICB抗体の療法的有効量を、必要な被験体に投与する
工程を含む。
本明細書記載の抗体の療法的有効量を、MIC+腫瘍または癌に罹患した被験体に投与する
工程を含む。
本明細書記載の抗体の療法的有効量を、MIC+血液学的悪性腫瘍に罹患した被験体に投与する
工程を含む。
本開示の抗体の療法的有効量を、sMIC+タンパク質の上昇したレベルによって特徴付けられるウイルス疾患に罹患した被験体に投与する
工程を含むことも可能である。
本開示の抗体の療法的有効量を、HBV、RSV、HCMV、HCVまたはHIV−1に感染した被験体に投与する
工程を含むことも可能である。
[0310]バキュロウイルス発現による、細胞外アルファ−3ドメインMICA免疫原の産生。抗体産生のための免疫原として、MICAの細胞外アルファ−3ドメインを調製するため、バキュロウイルスタンパク質発現系を用いて、発現されたMICA上に適切なタンパク質グリコシル化を生成した。プロセシングされたMICAタンパク質(例えば図4−1)のアミノ酸残基182〜274である、MICAのアルファ−3ドメインの残基205〜297(図1C:配列番号3)をコードするGenBank MICA配列NP_000238.1(図1)に対応する組換えアルファ−3ドメインMICA cDNA(アレル001)を、バキュロウイルストランスファーベクター内にさらにサブクローニングするための慣用的な制限酵素部位と一緒に合成的に生成し、そして次いで、適切なDNAクローニングベクター内に連結した。バキュロウイルストランスファーベクターは、精製のため、6つのC末端ヒスチジン残基タグを含有した。精製タグおよび切断部位を持つ例示的なMICAペプチド免疫原もまた、以下から選択可能であり、ここでMICA配列を下線で示す:
[0321]結合アフィニティの分析。Pall ForteBio Octet RED96装置(Pall ForteBio、米国カリフォルニア州)を用いて、Bio−Layerインターフェロメトリー(BLI)によって、抗原および抗体の間の生体分子相互作用を直接測定した。試験MICAモノクローナル抗体1F5および8C7、ならびに、先にELISAによって決定されるように、そのうちの1つがアルファ−3 MICAサブドメイン抗原(陽性対照)に結合可能であり、そしてそのうちの一方が結合不能である(陰性対照、他のMICAドメインに結合する)2つの対照抗体に関して、リアルタイム動力学的分析を行った。Octet RED96装置は、Bio−Layerインターフェロメトリーの原理の元に作動し、これは、分子相互作用および複合体形成を測定する標識不含技術である。技術の重要な構成要素は、光学バイオセンサーであり、そのチップを試験ウェルの液体に浸し、そして次いで、これを用いて、光波間の干渉パターンをアッセイする。ここで、リガンド(モノクローナル抗体)は、先に結合した抗マウスIgGによる捕捉を通じてバイオセンサー表面に局在し、一方、分析物生体分子(抗原)は、溶液中に維持される。リガンドおよび分析物間の結合反応を測定し、そしてリアルタイムで報告した。会合および解離動力学の両方を監視し、そしてKD値を計算した。このモデルは、リガンド対分析物の1:1相互作用を仮定した。
本発明は、非限定的に以下の態様を含む。
[態様1]
(a)MICAの細胞外ドメインに特異的に結合するが、全長MICAまたはMICAの膜結合型の細胞外ドメインに特異的に結合しない;または
(b)MICBの細胞外ドメインに特異的に結合するが、全長MICBまたはMICBの膜結合型の細胞外ドメインに特異的に結合しない
単離抗体。
[態様2]
アルファ−3ドメインを含むMICAの可溶性細胞外ドメイン(sMICA)に特異的に結合し、そして全長MICAまたはMICAの膜結合型の細胞外ドメインに特異的に結合しない、態様1の単離抗体。
[態様3]
アルファ−3ドメインを含むMICBの可溶性細胞外ドメイン(sMICB)に特異的に結合し、そして全長MICBまたはMICBの膜結合型の細胞外ドメインに特異的に結合しない、態様1の単離抗体。
[態様4]
被験体に投与した際、わずかな自己免疫疾患誘導活性を有する、態様2または3の単離抗体。
[態様5]
sMICAおよび/またはsMICBの受容体NKG2Dへの結合に対するわずかなアンタゴニスト活性を有する、態様2または3の単離抗体。
[態様6]
MICAのアルファ−3ドメイン上の潜在性(cryptic)エピトープに特異的に結合する、態様1〜5のいずれか一項の単離抗体。
[態様7]
MICAのアルファ−3ドメインがMICA * 001アレルのプロセシングされないMICAタンパク質のアミノ酸残基205〜297由来のアミノ酸配列を含む、態様6の単離抗体。
[態様8]
MICBのアルファ−3ドメイン上の潜在性エピトープに特異的に結合する、態様1〜5のいずれか一項の単離抗体。
[態様9]
MICBのアルファ−3ドメインがMICB * 001アレルのプロセシングされないMICBタンパク質のアミノ酸残基205〜297由来のアミノ酸配列を含む、態様8の単離抗体。
[態様10]
潜在性エピトープが、MICAのアミノ酸残基190〜256内にある、態様7の単離抗体。
[態様11]
MICAの潜在性エピトープが:
(a)アミノ酸残基190〜196;
(b)アミノ酸残基217〜221;
(c)アミノ酸残基250〜256;
(d)アミノ酸残基251〜256;または
(e)アミノ酸残基234〜238
内の配列を含む、態様10の単離抗体。
[態様12]
配列:
190_RSEASEG_196(配列番号38);
217_RQDGV_221(配列番号39);
234_LPDGN_238(配列番号40)
251_QGEEQR_256(配列番号41);または
251_RGEEQR_256(配列番号42)
内のエピトープに特異的に結合する、態様11の単離抗体。
[態様13]
潜在性エピトープが、MICBのアミノ酸残基190〜256内のアミノ酸配列を含む、態様9の単離抗体。
[態様14]
MICBの潜在性エピトープが:
(a)アミノ酸190〜196;
(b)アミノ酸217〜221;
(c)アミノ酸250〜256;または
(d)アミノ酸234〜238
内の配列を含む、態様13の単離抗体。
[態様15]
配列:
190_CSEVSEG_196(配列番号43);
217_RQDGV_221(配列番号44);
234_LPDGN_238(配列番号45);または
250_RQGEEQR_256(配列番号46)
内のエピトープに特異的に結合する、態様14の単離抗体。
[態様16]
配列:
(a)〜X A1 −S−X A3 −X A4 −S−E−G〜(配列番号47)、
式中、X A1 はRおよびCより選択され;X A3 はEおよびKより選択され;そしてX A4 はAおよびVより選択される;
(b)〜R−Q−D−G−X B5 〜(配列番号48)、
式中、X B5 はVおよびLより選択される;
(c)〜X D1 −X D2 −G−E−E−Q−X D7 〜(配列番号49)、
式中、X D1 はCまたはRより選択され;X D2 はQ、RおよびEより選択され;そしてX D7 はR、SおよびKより選択される;
(d)〜L−P−D−G−N〜(配列番号50)
内のエピトープに特異的に結合する、態様11または14の単離抗体。
[態様17]
ポリクローナル抗体を含む、態様1〜16のいずれか一項の単離抗体。
[態様18]
配列番号23の軽鎖可変領域アミノ酸配列中のCDR、および配列番号27の重鎖可変領域アミノ酸配列中のCDRを含む、態様1の単離抗体。
[態様19]
アミノ酸配列RASKSVSTSGYSYMH(配列番号83)を含むCDR L1;アミノ酸配列RASNLES(配列番号84)を含むCDR L2;アミノ酸配列QHSRELPLT(配列番号85)を含むCDR L3;アミノ酸配列DYSVH(配列番号89)、GYTFTDY(配列番号95)、またはGYTFTDYSVH(配列番号99)を含むCDR H1;アミノ酸配列WINTETGEPTYADDFKG(配列番号90)、NTETG(配列番号96)、またはWINTETGEP(配列番号100)を含むCDR H2;およびアミノ酸配列AGGNAFAY(配列番号91)を含むCDR H3を含む、態様18の単離抗体。
[態様20]
配列番号23のアミノ酸配列を含む軽鎖可変領域VL、および配列番号27のアミノ酸配列を含む重鎖可変領域VHを含む、態様1の単離抗体。
[態様21]
配列番号31の軽鎖可変領域アミノ酸配列中のCDR、および配列番号35の重鎖可変領域アミノ酸配列中のCDRを含む、態様1の単離抗体。
[態様22]
アミノ酸配列RSSKSLLQSNGNTFLY(配列番号86)を含むCDR L1;アミノ酸配列RMSNLAS(配列番号87)を含むCDR L2;アミノ酸配列MQHLEYPFT(配列番号88)を含むCDR L3;アミノ酸配列NYGMN(配列番号92)、GYTFTNY(配列番号97)、またはGYTFTNYGMN(配列番号101)を含むCDR H1;アミノ酸配列WINTNTGEPTYAEEFKG(配列番号93)、NTNTG(配列番号98)、またはWINTNTGEP(配列番号102)を含むCDR H2;およびアミノ酸配列SGGSSPFAY(配列番号94)を含むCDR H3を含む、態様21の単離抗体。
[態様23]
配列番号31のアミノ酸配列を含む軽鎖可変領域VL、および配列番号35のアミノ酸配列を含む重鎖可変領域VHを含む、態様1の単離抗体。
[態様24]
モノクローナル抗体を含む、態様1〜16および18〜23のいずれか一項の単離抗体。
[態様25]
キメラ抗体を含む、態様1〜24のいずれか一項の単離抗体。
[態様26]
ヒト化抗体を含む、態様1〜25のいずれか一項の単離抗体。
[態様27]
全長ヒト抗体を含む、態様1〜24のいずれか一項の単離抗体。
[態様28]
抗体断片を含む、態様1〜25のいずれか一項の単離抗体。
[態様29]
精製抗体を含む、態様1〜28のいずれか一項の単離抗体。
[態様30]
検出可能標識で標識されている、態様1〜29のいずれか一項の抗体。
[態様31]
態様1〜29のいずれか一項の単離抗体、および薬学的に許容されうるキャリアーを含む、薬学的組成物。
[態様32]
sMICAおよび/またはsMICBのレベルを減少させる方法であって、必要とする被験体に、態様1〜29のいずれか一項の抗体の有効量を投与することによる、前記方法。
[態様33]
上昇したレベルのsMICAおよび/またはsMICBによって特徴付けられる疾患または障害を有する被験体を治療する方法であって、態様1〜29のいずれか一項の抗体の療法的有効量を投与する工程を含む、前記方法。
[態様34]
疾患または障害が、MIC + 上皮細胞腫瘍、あるいはsMICAまたはsMICB上昇によって特徴付けられる造血悪性腫瘍より選択される、態様33の方法。
[態様35]
上皮細胞腫瘍が、肺、乳房、胃、結腸、卵巣、腎細胞、または前立腺癌腫、あるいは黒色腫を含む、態様34の方法。
[態様36]
造血悪性腫瘍が、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、急性単球性白血病(AMol);リンパ腫、例えばホジキンリンパ腫、および非ホジキンリンパ腫;または多発性骨髄腫を含む、態様34の方法。
[態様37]
sMICAおよび/またはsMICBレベル上昇によって特徴付けられるウイルス感染に罹患した被験体を治療する方法であって、必要な被験体に、態様1〜29のいずれか一項の抗体の療法的有効量を投与する工程を含む、前記方法。
[態様38]
ウイルス感染が、呼吸器合胞体ウイルス(RSV)または1型ヒト免疫不全ウイルス(HIV−1)での感染である、態様37の方法。
Claims (27)
- (a)MICAの細胞外ドメインに特異的に結合するが、MICAの膜結合型の細胞外ドメインに特異的に結合しない;または
(b)MICBの細胞外ドメインに特異的に結合するが、MICBの膜結合型の細胞外ドメインに特異的に結合しない
単離抗体。 - アルファ−3ドメインを含むMICBの可溶性細胞外ドメイン(sMICB)に特異的に結合し、そしてMICBの膜結合型の細胞外ドメインに特異的に結合しない、請求項1の単離抗体。
- MICBのアルファ−3ドメイン上のエピトープに特異的に結合する、請求項2の単離抗体。
- sMICBアルファ−3ドメインのアミノ酸残基243−274内のエピトープに特異的に結合する、請求項3の単離抗体。
- アルファ−3ドメインを含むMICAの可溶性細胞外ドメイン(sMICA)に特異的に結合し、そしてMICAの膜結合型の細胞外ドメインに特異的に結合しない、請求項1の単離抗体。
- MICAのアルファ−3ドメイン上のエピトープに特異的に結合する、請求項5の単離抗体。
- sMICAアルファ−3ドメインのアミノ酸残基243−274内のエピトープに特異的に結合する、請求項6の単離抗体。
- ポリクローナル抗体を含む、請求項1〜7のいずれか一項の単離抗体。
- 配列番号23の軽鎖可変領域アミノ酸配列中のCDR L1、CDR L2、およびCDR L3、並びに、配列番号27の重鎖可変領域アミノ酸配列中のCDR H1、CDR H2、およびCDR H3を含む、請求項1の単離抗体。
- アミノ酸配列RASKSVSTSGYSYMH(配列番号83)を含むCDR L1;アミノ酸配列RASNLES(配列番号84)を含むCDR L2;アミノ酸配列QHSRELPLT(配列番号85)を含むCDR L3;アミノ酸配列DYSVH(配列番号89)、GYTFTDY(配列番号95)、またはGYTFTDYSVH(配列番号99)を含むCDR H1;アミノ酸配列WINTETGEPTYADDFKG(配列番号90)、NTETG(配列番号96)、またはWINTETGEP(配列番号100)を含むCDR H2;およびアミノ酸配列AGGNAFAY(配列番号91)を含むCDR H3を含む、請求項9の単離抗体。
- 配列番号23のアミノ酸配列を含む軽鎖可変領域VL、および配列番号27のアミノ酸配列を含む重鎖可変領域VHを含む、請求項1の単離抗体。
- 配列番号31の軽鎖可変領域アミノ酸配列中のCDR L1、CDR L2、およびCDR L3、並びに、配列番号35の重鎖可変領域アミノ酸配列中のCDR H1、CDR H2、およびCDR H3を含む、請求項1の単離抗体。
- アミノ酸配列RSSKSLLQSNGNTFLY(配列番号86)を含むCDR L1;アミノ酸配列RMSNLAS(配列番号87)を含むCDR L2;アミノ酸配列MQHLEYPFT(配列番号88)を含むCDR L3;アミノ酸配列NYGMN(配列番号92)、GYTFTNY(配列番号97)、またはGYTFTNYGMN(配列番号101)を含むCDR H1;アミノ酸配列WINTNTGEPTYAEEFKG(配列番号93)、NTNTG(配列番号98)、またはWINTNTGEP(配列番号102)を含むCDR H2;およびアミノ酸配列SGGSSPFAY(配列番号94)を含むCDR H3を含む、請求項12の単離抗体。
- 配列番号31のアミノ酸配列を含む軽鎖可変領域VL、および配列番号35のアミノ酸配列を含む重鎖可変領域VHを含む、請求項1の単離抗体。
- 配列番号23のアミノ酸配列を含む軽鎖可変領域VLおよび配列番号27のアミノ酸配列を含む重鎖可変領域VHを有する抗体によって結合されるエピトープへのの結合に関して競合する、請求項1〜7のいずれか一項の単離抗体。
- 配列番号31のアミノ酸配列を含む軽鎖可変領域VLおよび配列番号35のアミノ酸配列を含む重鎖可変領域VHを有する抗体によって結合されるエピトープへのの結合に関して競合する、請求項1〜7のいずれか一項の単離抗体。
- モノクローナル抗体を含む、請求項1〜7および9〜16のいずれか一項の単離抗体。
- キメラ抗体を含む、請求項1〜17のいずれか一項の単離抗体。
- ヒト化抗体を含む、請求項1〜17のいずれか一項の単離抗体。
- 全長ヒト抗体を含む、請求項1〜17のいずれか一項の単離抗体。
- 抗体断片を含む、請求項1〜17のいずれか一項の単離抗体。
- 請求項1〜21のいずれか一項の単離抗体、および薬学的に許容されうるキャリアーを含む、薬学的組成物。
- 被験体中のsMICAおよび/またはsMICBの上昇したレベルを減少させるために使用される、請求項22の薬学的組成物。
- 上昇したレベルのsMICAおよび/またはsMICBによって特徴付けられる疾患または障害を治療するために使用される、請求項22の薬学的組成物。
- 疾患または障害が、MIC + 癌、あるいはsMICAまたはsMICB上昇によって特徴付けられる造血悪性腫瘍より選択される、請求項24の薬学的組成物。
- 癌が、肺癌、乳癌、胃癌、結腸癌、卵巣癌、腎癌、または前立腺癌、あるいは黒色腫を含む、請求項25の薬学的組成物。
- 造血悪性腫瘍が、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、急性単球性白血病(AMol);リンパ腫、例えばホジキンリンパ腫、および非ホジキンリンパ腫;または多発性骨髄腫を含む、請求項25の薬学的組成物。
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ES2460899T3 (es) | 2008-03-03 | 2014-05-14 | The University Of Miami | Inmunoterapia basada en células cancerosas alógenas |
CA2945822A1 (en) * | 2014-05-21 | 2015-11-26 | Dana-Farber Cancer Institute, Inc. | Methods for treating cancer with anti bip or anti mica antibodies |
RU2714157C2 (ru) | 2015-02-06 | 2020-02-12 | Хит Байолоджикс, Инк. | Вектор, коэкспрессирующий молекулы для вакцинации и костимулирующие молекулы |
CR20230116A (es) * | 2015-12-04 | 2023-05-05 | Dana Farber Cancer Inst Inc | Composición de vacuna que comprende el dominio alfa 3 de mica/b (div. 2018-350) |
WO2018071405A1 (en) | 2016-10-11 | 2018-04-19 | University Of Miami | Vectors and vaccine cells for immunity against zika virus |
CN110088137A (zh) * | 2016-10-19 | 2019-08-02 | 诺瓦罗技科斯生物科技有限公司 | 针对mica和micb蛋白的抗体 |
CN107964041B (zh) * | 2016-10-20 | 2023-08-01 | 中国科学院广州生物医药与健康研究院 | 高稳定性和高亲和力的dmic及其制法 |
EP3532091A2 (en) * | 2016-10-29 | 2019-09-04 | H. Hoffnabb-La Roche Ag | Anti-mic antibidies and methods of use |
CN108204958A (zh) * | 2016-12-19 | 2018-06-26 | 伊缪泰普有限公司 | 结合测定 |
WO2018141959A1 (en) | 2017-02-06 | 2018-08-09 | Innate Pharma | Immunomodulatory antibody drug conjugates binding to a human mica polypeptide |
WO2018187260A1 (en) | 2017-04-04 | 2018-10-11 | Heat Biologics, Inc. | Intratumoral vaccination |
EP3743109A4 (en) * | 2018-01-25 | 2021-11-10 | Cullinan Mica Corp. | ANTI-MICA / B ANTIBODIES AND THEIR METHODS OF USE |
TW202003565A (zh) | 2018-03-23 | 2020-01-16 | 美商必治妥美雅史谷比公司 | 抗mica及/或micb抗體及其用途 |
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CA3108022A1 (en) * | 2018-07-31 | 2020-02-06 | Cullinan Mica Corp. | Anti-mica/b antibodies that block mica/b shedding and methods of use |
WO2020035345A1 (en) | 2018-08-14 | 2020-02-20 | Innate Pharma | Treatment of colorectal cancer by a combination of an anti-mica antibody and an anti-nkg2a antibody |
BR112021012066A2 (pt) | 2018-12-21 | 2021-11-03 | Onxeo | Novas moléculas de ácido nucleico conjugadas e seus usos |
WO2020214957A1 (en) * | 2019-04-19 | 2020-10-22 | Tcrcure Biopharma Corp. | Anti-pd-1 antibodies and uses thereof |
AU2020336023A1 (en) * | 2019-08-23 | 2022-03-03 | Northwestern University | Materials and methods for activating antigen-specific T cell responses |
TW202214857A (zh) | 2020-06-19 | 2022-04-16 | 法商昂席歐公司 | 新型結合核酸分子及其用途 |
CN112574311B (zh) * | 2020-12-14 | 2022-03-25 | 广州康盛生物科技股份有限公司 | 双mic结合活性的抗体及其应用 |
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JP6518199B6 (ja) | 2019-06-12 |
EP2970490A2 (en) | 2016-01-20 |
WO2014140904A2 (en) | 2014-09-18 |
CA2906356A1 (en) | 2014-09-18 |
JP2016512223A (ja) | 2016-04-25 |
US10851148B2 (en) | 2020-12-01 |
US20160046689A1 (en) | 2016-02-18 |
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US20210040173A1 (en) | 2021-02-11 |
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