JP2021534735A - ヒトTim−3に対するモノクローナル抗体 - Google Patents
ヒトTim−3に対するモノクローナル抗体 Download PDFInfo
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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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
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Abstract
Description
本出願は、米国仮出願第62/720,234号(出願日:2018年8月21日)の利益を主張し、その内容は全体が参照として本明細書に組み込まれる。
本出願は、EFS-Webを介してASCII形式で提出した配列表を含み、その全体が参照として本明細書に組み込まれる。2019年8月21日に作成したASCIIの写しはSequenceListing.txtというファイル名で、サイズは15.6KBである。
ヒトTim-3(T細胞免疫グロブリンムチンドメイン含有3)のIgVドメイン若しくはヒトTim-3のIgVムチンストークに結合し、
a) GYSFTGYTIN(配列番号1)(相補性決定領域(CDR)1(CDR1));
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3);
若しくは
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3);
の1つ以上を含む重鎖、及び
b) KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3);
若しくは
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
の1つ以上を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3);
を含む重鎖、及び
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む重鎖、及び
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3)
を含む抗体の重鎖をコードする核酸を提供する。
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む抗体の重鎖をコードする核酸を提供する。
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む抗体の軽鎖をコードする核酸を提供する。
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2)
QQYSSYPT(配列番号12)(CDR3)
を含む抗体の軽鎖をコードする核酸を提供する。
a) GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3);
若しくは
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3);
の1つ以上を含む重鎖、及び
b) KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3);
若しくは
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
の1つ以上を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3);
を含む重鎖、及び
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3);
を含む重鎖、及び
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
を含む軽鎖、を含む抗体又はその抗原結合断片を提供する。
GYSFTGYTIN(配列番号1)(CDR1)
LFNPYNGGTT(配列番号2)(CDR2)
ARRYYGYDAMDY(配列番号3)(CDR3)
の1つ以上を含む重鎖を含む。
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1)
WASTRES(配列番号5)(CDR2)
HQYLSSYT(配列番号6)(CDR3)
の1つ以上を含む軽鎖を含む。
GFNIKDYYMH(配列番号7)(CDR1)
WIDPENDNTIY(配列番号8)(CDR2)
ARDFGYVAWLVY(配列番号9)(CDR3)
の1つ以上を含む重鎖を含む。
KASQNVDTAVA(配列番号10)(CDR1)
SASNRYT(配列番号11)(CDR2)
QQYSSYPT(配列番号12)(CDR3)
の1つ以上を含む軽鎖を含む。
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3)
を含む抗体の重鎖をコードする核酸を提供する。
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む抗体の重鎖をコードする核酸を提供する。
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む抗体の軽鎖をコードする核酸を提供する。
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2)
QQYSSYPT(配列番号12)(CDR3)
を含む抗体の軽鎖をコードする核酸を提供する。
(1) 非極性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2) 電荷を有さない極性:Cys、Ser、Thr、Asn、Gln;
(3) 酸性(負電荷):Asp、Glu;
(4) 塩基性(正電荷):Lys、Arg;
(5) 鎖の配向に影響を及ぼす残基;Gly、Pro、及び
(6) 芳香族:Trp、Tyr、Phe、His。
MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAMP(配列番号13)。
SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPA(配列番号22)
を含む。
ヒトTim-3 IgVコード領域(S22−A132)にプラスミドpMT/BiPのヒトIgG1Fcタグを融合することにより、Tim-3 IgV−Ig融合タンパク質を得た(Zhao 2013)。S2系で融合タンパク質を発現し、次いで精製した。マウスをTim-3 IgV−Ig融合タンパク質で免疫し、脾細胞にNSO骨髄腫細胞を融合する標準的な方法でハイブリドーマを得た。
mAb 50B5が得られた。これは、κ鎖を有するIgG1である。ELISAアッセイでは、これは、Tim-3−IgVタンパク質及びTim-3の細胞外のタンパク質(IgVムチンストーク)に結合したが、ヒトIgGタンパク質には結合しなかった(図1)。FACSでは、50B5は、細胞上に発現したヒトTim-3に結合するが、マウスTim-3には結合しないことが確認された(図2)。
別のmAbである15B4を、上述した方法と同じ方法で得た。mAb 15B4はκ鎖を有するIgG1で、細胞上に発現したヒトTim-3に結合する(図5)。表面プラズモン共鳴法では、mAb 15B4のヒトTim-3タンパク質に対する結合親和性は、KDが0.32nMであった(図6)。mAb 50B5の阻害能を決定するために結合アッセイを行い、mAb 15B4は、デキサメタゾン処理ジャーカットT細胞に発現するホスファチジルセリンとヒトTim-3との結合を妨げることを見いだした。最後に、15B4ハイブリドーマの配列を決定し、mAbが固有のVH及びVLの配列を有することがわかった。
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Claims (33)
- ヒトTim-3(T細胞免疫グロブリンムチンドメイン含有3)のIgVドメイン若しくはヒトTim-3のIgVムチンストークに結合する抗体又はその抗原結合断片であって、
a) GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3)
若しくは
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
の1つ以上を含む重鎖、及び
b) KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3);
若しくは
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
の1つ以上を含む軽鎖
を含む抗体又はその抗原結合断片。 - ヒトTim-3のIgVドメイン又はヒトTim-3のIgVムチンストークに結合する抗体又はその抗原結合断片であって、
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3)
を含む重鎖、及び
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む軽鎖
を含む抗体又はその抗原結合断片。 - ヒトTim-3のIgVドメイン又はヒトTim-3のIgVムチンストークに結合する抗体又はその抗原結合断片であって、
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む重鎖、及び
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2);
QQYSSYPT(配列番号12)(CDR3)
を含む軽鎖
を含む抗体又はその抗原結合断片。 - 前記軽鎖及び前記重鎖のフレームワーク領域が、ヒトのフレームワーク領域と85%以上の同一性を有する、請求項1〜3のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記軽鎖及び前記重鎖のフレームワーク領域が、ヒトのフレームワーク領域である、請求項4に記載の抗体又はその抗原結合断片。
- KDが10.0nMより小さい親和性でヒトTim-3のIgVドメイン又はヒトTim-3のIgVムチンストークに結合する単離された抗体又はその抗原結合断片。
- KDが0.5nMより小さい親和性でヒトTim-3のIgVドメイン又はヒトTim-3のIgVムチンストークに結合する、請求項6に記載の単離された抗体又はその抗原結合断片。
- ヒトFc領域の配列を有する、請求項1〜7のいずれか一項に記載の単離された抗体又はその抗原結合断片。
- ヒトTim-3とデキサメタゾン処理ジャーカットT細胞に発現するホスファチジルセリンとの結合を阻害する、請求項6〜8のいずれか一項に記載の単離された抗体又はその抗原結合断片。
- 1つ以上の
GYSFTGYTIN(配列番号1)(CDR1)
LFNPYNGGTT(配列番号2)(CDR2)
ARRYYGYDAMDY(配列番号3)(CDR3)
を含む重鎖を含む、請求項6〜9のいずれか一項に記載の単離された抗体又はその抗原結合断片。 - 1つ以上の
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1)
WASTRES(配列番号5)(CDR2)
HQYLSSYT(配列番号6)(CDR3)
を含む軽鎖を含む、請求項6〜10のいずれか一項に記載の単離された抗体又はその抗原結合断片。 - 1つ以上の
GFNIKDYYMH(配列番号7)(CDR1)
WIDPENDNTIY(配列番号8)(CDR2)
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む重鎖を含む、請求項6〜9のいずれか一項に記載の単離された抗体又はその抗原結合断片。 - 1つ以上の
KASQNVDTAVA(配列番号10)(CDR1)
SASNRYT(配列番号11)(CDR2)
QQYSSYPT(配列番号12)(CDR3)
を含む軽鎖を含む、請求項6〜9又は12のいずれか一項に記載の単離された抗体又はその抗原結合断片。 - 前記抗体又はその抗原結合断片は、キメラであるか、又はヒト化されている、請求項1〜13のいずれか一項に記載の単離された抗体又はその抗原結合断片。
- 前記抗体又はその抗原結合断片は、モノクローナル抗体、scFv、Fab断片、Fab’断片及びF(ab)’断片からなる群から選択される、請求項1〜14のいずれか一項に記載の単離された抗体又はその抗原結合断片。
- 1つ以上の
GYSFTGYTIN(配列番号1)(CDR1);
LFNPYNGGTT(配列番号2)(CDR2);
ARRYYGYDAMDY(配列番号3)(CDR3)
を含む抗体の重鎖をコードする核酸。 - 1つ以上の
GFNIKDYYMH(配列番号7)(CDR1);
WIDPENDNTIY(配列番号8)(CDR2);
ARDFGYVAWLVY(配列番号9)(CDR3)
を含む抗体の重鎖をコードする核酸。 - 1つ以上の
KSSQSVLYSSNQKNHLA(配列番号4)(CDR1);
WASTRES(配列番号5)(CDR2);
HQYLSSYT(配列番号6)(CDR3)
を含む抗体の軽鎖をコードする核酸。 - 1つ以上の
KASQNVDTAVA(配列番号10)(CDR1);
SASNRYT(配列番号11)(CDR2)
QQYSSYPT(配列番号12)(CDR3)
を含む抗体の軽鎖をコードする核酸。 - 請求項14〜17のいずれか一項に記載の核酸の1つ以上を含む宿主細胞。
- 治療薬と連結又は結合した、請求項1〜15のいずれか一項に記載の抗体又はその抗原結合断片。
- 前記治療薬が、細胞障害性薬剤、放射性同位体、免疫調節剤又は二次抗体である、請求項21に記載の抗体又はその抗原結合断片。
- ヒトTim-3を阻害するのに有効な量の、請求項1〜15のいずれか一項に記載の抗体若しくはその抗原結合断片、又はそのヒトTim-3結合断片を投与することを含む、対象のヒトTim-3を阻害する方法。
- 前記対象はがんに罹患している、請求項23に記載の方法。
- Tim-3が媒介するT細胞の抑制を阻害するのに有効な量の、請求項1〜15のいずれか一項に記載の抗体若しくはその抗原結合断片、又はそのヒトTim-3結合断片を投与することを含む、対象のTim-3が媒介するT細胞の抑制を阻害する方法。
- 対象のがんを治療するのに有効な量の、請求項1〜15のいずれか一項に記載の抗体又はその抗原結合断片を投与することを含む、対象のがんを治療する方法。
- 前記がんがヒトTim-3陽性のがんである、請求項26に記載の方法。
- 対象のヒトTim-3陽性細胞を検出する方法であって、
ヒトTim-3陽性細胞を標識するのに有効な量の検出可能なマーカーが結合した請求項1〜15のいずれか一項に記載の抗体又はその抗原結合断片を投与し、
前記対象における前記標識の存在を検出し、
これにより、対象のヒトTim-3陽性細胞を検出することを含む、方法。 - 前記標識を画像化により検出する、請求項28に記載の方法。
- 前記細胞ががん細胞である、請求項28又は29に記載の方法。
- 前記がんが血液悪性腫瘍である、請求項24、26、27又は30のいずれか一項に記載の方法。
- 前記がんが固形腫瘍を含む、請求項24、26、27又は30のいずれか一項に記載の方法。
- 前記対象が、抗PD−1、抗PD−L1又は抗CTLA4療法を受けている、請求項24、26、27又は30〜32のいずれか一項に記載の方法。
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WO2023174408A1 (zh) * | 2022-03-18 | 2023-09-21 | 正大天晴药业集团南京顺欣制药有限公司 | 抗tim-3抗体与抗pd-l1抗体的药物组合 |
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