JP2018512138A - T細胞免疫グロブリン及びムチンタンパク質3(tim−3)に対する抗体 - Google Patents
T細胞免疫グロブリン及びムチンタンパク質3(tim−3)に対する抗体 Download PDFInfo
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Abstract
Description
本明細書と同時に提出され、コンピューターで読み取り可能な、以下の通り識別されるヌクレオチド/アミノ酸の配列表は、その全体が本明細書に参照により援用される:2016年3月31日付け作成の「723697_ST25.TXT」という名前の369,646バイトのASCII(テキスト)ファイル1件
本発明は、単離された免疫グロブリン重鎖ポリペプチド及び/又は単離された免疫グロブリン軽鎖ポリペプチド、又はその断片(例えば、抗原結合断片)を提供する。本明細書で使用される場合、用語「免疫グロブリン」又は「抗体」は、脊椎動物の血液又はその他の体液においてみられるタンパク質を指し、それは、例えば、細菌及びウイルス等の外来の異物を見つけ出し、中和する免疫システムによって用いられる。該ポリペプチドは、天然環境から取り出されることにおいて、「単離」される。好ましい実施形態においては、免疫グロブリン又は抗体は、少なくとも1つの相補性決定領域(CDR)を含むタンパク質である。該CDRは、抗体の抗原結合を担う「超可変領域」を形成する(更に以下において検討する)。免疫グロブリン全体は、典型的には4本のポリペプチド:2コピーの同一な重(H)鎖ポリペプチド及び2コピーの同一な軽(L)鎖ポリペプチドからなる。各重鎖は1つのN末端可変(VH)領域及び3つのC末端定常(CH1、CH2及びCH3)領域を含有し、各軽鎖は1つのN末端可変(VL)領域及び1つのC末端定常(CL)領域を含有する。抗体の軽鎖は、それらの定常ドメインのアミノ酸配列に基づいて、2つの異なる型のカッパ(κ)又はラムダ(λ)のいずれか一方に割り当てられ得る。典型的な免疫グロブリンにおいては、各軽鎖は重鎖とジスルフィド結合によって結びつき、2本の該重鎖は互いにジスルフィド結合によって結びついている。軽鎖の可変領域は、該重鎖の可変領域と整列し、軽鎖の定常領域は、重鎖の最初の定常領域と整列する。重鎖の残りの定常領域は互いに整列する。
本実施例は、進化可能ライブラリー(evolvable library)からヒトTIM−3に対する抗体を同定する方法及び同定した抗体の親和性成熟を実証する。
本実施例は、本発明の抗TIM−3モノクローナル抗体が、in vitroにおいて、単独で及び抗PD−1抗体との組合せで、TIM−3シグナル伝達を阻害できること、及びT細胞の活性化を促進できることを実証する。
本実施例は、同系マウス腫瘍モデルにおいて、抗TIM−3抗体がTIM−3活性を拮抗することを実証する。
本実施例は、同系マウス腫瘍モデルにおいて、抗TIM−3抗体単独での又は抗PD−1抗体との組合せでの抗腫瘍活性における、抗体アイソタイプの特定の効果を実証する。
Claims (57)
- 単離された免疫グロブリン重鎖ポリペプチドであって、
アミノ酸配列Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Xaa1 Ala Xaa2 Ser Gly Phe Xaa3 Xaa4 Xaa5 Thr Phe Ser Xaa6 Tyr Xaa7 Met Xaa8 Trp Val Arg Gln Ala Xaa9 Gly Lys Gly Leu Xaa10 Trp Val Ser Xaa11 Ile Ser Xaa12 Gly Gly Xaa13 Tyr Thr Tyr Tyr Gln Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Xaa14 Glu Asp Thr Ala Val Tyr Tyr Cys Xaa15 Ser Xaa16 Xaa17 Xaa18 Xaa19 Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala(配列番号1)を含み、
(a)Xaa1は欠失しているか又はアラニン(Ala)であり、
(b)Xaa2はアラニン(Ala)、プロリン(Pro)、アスパラギン酸(Asp)、グリシン(Gly)、スレオニン(Thr)又はバリン(Val)であり、
(c)内部配列Xaa3 Xaa4 Xaa5は欠失しているか又はThr−Phe−Ileであり、
(d)Xaa6はセリン(Ser)、アスパラギン(Asn)、アルギニン(Arg)又はスレオニン(Thr)であり、
(e)Xaa7はアスパラギン酸(Asp)又はアラニン(Ala)であり、
(f)Xaa8はセリン(Ser)又はスレオニン(Thr)であり、
(g)Xaa9はプロリン(Pro)又はロイシン(Leu)であり、
(h)Xaa10はアスパラギン酸(Asp)又はグルタミン酸(Glu)であり、
(i)Xaa11はスレオニン(Thr)又はアラニン(Ala)であり、
(j)Xaa12はグリシン(Gly)又はセリン(Ser)であり、
(k)Xaa13はセリン(Ser)、スレオニン(Thr)、アスパラギン酸(Asp)、グリシン(Gly)、アスパラギン(Asn)又はリジン(Lys)であり、
(l)Xaa14はアラニン(Ala)又はバリン(Val)であり、
(m)Xaa15はアラニン(Ala)又はスレオニン(Thr)であり、及び
(n)内部配列Xaa16 Xaa17 Xaa18 Xaa19は欠失しているか又はPro−Tyr−Tyr−Alaである、
ポリペプチド。 - 内部配列Xaa3 Xaa4 Xaa5が欠失している、請求項1に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号2、配列番号3、配列番号5〜配列番号8、配列番号10〜配列番号12、配列番号14〜配列番号27又は配列番号29〜配列番号44のいずれか1つのアミノ酸配列を含む、請求項2に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 内部配列Xaa3 Xaa4 Xaa5がThr−Phe−Ileである、請求項1に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号4、配列番号9、配列番号13及び配列番号28のいずれか1つのアミノ酸配列を含む、請求項4に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 内部配列Xaa16 Xaa17 Xaa18 Xaa19が欠失している、請求項1に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号3〜配列番号44のいずれか1つのアミノ酸配列を含む、請求項6に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 内部配列Xaa16 Xaa17 Xaa18 Xaa19がPro−Tyr−Tyr−Alaである、請求項1に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号2のアミノ酸配列を含む、請求項8に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 単離された免疫グロブリン軽鎖ポリペプチドであって、アミノ酸配列Asp Ile Gln Met Thr Xaa1 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Xaa2 Ser Gln Ser Ile Xaa3 Xaa4 Tyr Leu Asn Trp Tyr Xaa5 Gln Lys Xaa6 Xaa7 Lys Ala Pro Lys Leu Leu Xaa8 Tyr Xaa9 Ala Ser Xaa10 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Xaa11 Tyr Tyr Cys Gln Gln Xaa12 Xaa13 Xaa14 Xaa15 Pro Xaa16 Thr Phe Gly Xaa17 Gly Thr Lys Xaa18 Glu Ile Lys Arg(配列番号45)を含み、
(a)Xaa1はグルタミン(Gln)又はヒスチジン(His)であり、
(b)Xaa2はアラニン(Ala)又はスレオニン(Thr)であり、
(c)Xaa3はセリン(Ser)、アルギニン(Arg)、アスパラギン(Asn)又はスレオニン(Thr)であり、
(d)Xaa4はセリン(Ser)、アルギニン(Arg)、アスパラギン酸(Asp)、スレオニン(Thr)又はグリシン(Gly)であり、
(e)Xaa5はグルタミン(Gln)又はヒスチジン(His)であり、
(f)Xaa6はプロリン(Pro)又はアラニン(Ala)であり、
(g)Xaa7はグリシン(Gly)、リジン(Lys)又はアルギニン(Arg)であり、
(h)Xaa8はイソロイシン(Ile)又はメチオニン(Met)であり、
(i)Xaa9はアラニン(Ala)、グリシン(Gly)、アスパラギン酸(Asp)、スレオニン(Thr)、セリン(Ser)、バリン(Val)又はイソロイシン(Ile)であり、
(j)Xaa10はセリン(Ser)又はスレオニン(Thr)であり、
(k)Xaa11はバリン(Val)、メチオニン(Met)又はアラニン(Ala)であり、
(l)Xaa12はセリン(Ser)又はアルギニン(Arg)であり、
(m)Xaa13はチロシン(Tyr)、ヒスチジン(His)、フェニルアラニン(Phe)、アスパラギン酸(Asp)、セリン(Ser)又はアスパラギン(Asn)であり、
(n)Xaa14はセリン(Ser)又はアスパラギン(Asn)であり、
(o)Xaa15はスレオニン(Thr)、セリン(Ser)、アラニン(Ala)又はプロリン(Pro)であり、
(p)Xaa16はロイシン(Leu)又はヒスチジン(His)であり、
(q)Xaa17はグリシン(Gly)、アルギニン(Arg)又はグルタミン酸(Glu)であり、及び
(r)Xaa18はバリン(Val)又はロイシン(Leu)である、
ポリペプチド。 - 配列番号46〜配列番号125のいずれか1つのアミノ酸配列を含む、請求項10に記載の単離された免疫グロブリン軽鎖ポリペプチド。
- 単離された免疫グロブリン重鎖ポリペプチドであって、アミノ酸配列Glu Val Gln Xaa1 Leu Xaa2 Xaa3 Xaa4 Xaa5 Ser Gly Gly Xaa6 Leu Xaa7 Gln Pro Gly Gly Ser Leu Arg Leu Xaa8 Cys Xaa9 Ala Ser Gly Phe Thr Phe Xaa10 Xaa11 Ser Tyr Xaa12 Met Xa13 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Xaa14 Ile Ser Gly Ser Gly Gly Xaa15 Thr Tyr Tyr Xaa16 Asp Ser Val Lys Gly Xaa17 Phe Thr Ile Ser Xaa18 Asp Asn Ser Xaa19 Asn Thr Xaa20 Tyr Leu Gln Met Asn Xaa21 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Xaa22 Lys Lys Tyr Tyr Xaa23 Xaa24 Pro Ala Asp Tyr Trp Xaa25 Gln Gly Thr Leu Val Thr Val Ser Ser Gly(配列番号126)を含み、
(a)Xaa1はロイシン(Leu)、バリン(Val)又はメチオニン(Met)であり、
(b)内部配列Xaa2 Xaa3 Xaa4は欠失しているか又はGlu−Ser−Leuであり、
(c)Xaa5は欠失しているか又はグルタミン酸(Glu)であり、
(d)Xaa6はグリシン(Gly)又はアスパラギン酸(Asp)であり、
(d)Xaa7はバリン(Val)又はイソロイシン(Ile)であり、
(e)Xaa8はセリン(Ser)又はチロシン(Tyr)であり、
(f)Xaa9はアラニン(Ala)又はバリン(Val)であり、
(g)Xaa10はセリン(Ser)、アスパラギン(Asn)、アルギニン(Arg)、スレオニン(Thr)、アスパラギン酸(Asp)又はグリシン(Gly)であり、
(h)Xaa11は欠失しているか又はグリシン(Gly)であり、
(i)Xaa12はアラニン(Ala)又はスレオニン(Thr)であり、
(j)Xaa13はセリン(Ser)又はアスパラギン(Asn)であり、
(k)Xaa14はアラニン(Ala)、グリシン(Gly)、バリン(Val)、セリン(Ser)、フェニルアラニン(Phe)、イソロイシン(Ile)、スレオニン(Thr)又はアスパラギン酸(Asp)であり、
(l)Xaa15はセリン(Ser)又はアスパラギン(Asn)であり、
(m)Xaa16はアラニン(Ala)、バリン(Val)又はアスパラギン(Asn)であり、
(n)Xaa17はアルギニン(Arg)又はグルタミン(Gln)であり、
(o)Xaa18はアルギニン(Arg)又はリジン(Lys)であり、
(p)Xaa19はリジン(Lys)又はアスパラギン(Asn)であり、
(q)Xaa20はロイシン(Leu)、バリン(Val)、スレオニン(Thr)、メチオニン(Met)又はプロリン(Pro)であり、
(r)Xaa21はセリン(Ser)又はアスパラギン(Asn)であり、
(s)Xaa22はアラニン(Ala)又はグリシン(Gly)であり、
(t)Xaa23はグリシン(Gly)、バリン(Val)、アスパラギン酸(Asp)、アラニン(Ala)、スレオニン(Thr)又はアスパラギン(Asn)であり、
(u)Xaa24はグリシン(Gly)、セリン(Ser)、バリン(Val)、アスパラギン酸(Asp)、アスパラギン(Asn)又はスレオニン(Thr)であり、及び
(v)Xaa25はグリシン(Gly)又はアスパラギン酸(Asp)である、
ポリペプチド。 - 内部配列Xaa2 Xaa3 Xaa4が欠失している、請求項12に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号127〜配列番号227、配列番号229〜配列番号231、配列番号233〜配列番号235、配列番号237〜配列番号243又は配列番号245〜配列番号259のいずれか1つのアミノ酸配列を含む、請求項13に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 内部配列Xaa2 Xaa3 Xaa4がGlu−Ser−Leuである、請求項12に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号228、配列番号232、配列番号236又は配列番号244のアミノ酸配列を含む、請求項15に記載の単離された免疫グロブリン重鎖ポリペプチド。
- Xaa5が欠失している、請求項12に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号222、配列番号231、配列番号235又は配列番号243のいずれか1つのアミノ酸配列を含む、請求項17に記載の単離された免疫グロブリン重鎖ポリペプチド。
- Xaa5がグルタミン酸(Glu)である、請求項12に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 配列番号126〜配列番号221、配列番号223〜配列番号230、配列番号232〜配列番号234、配列番号236〜配列番号242又は配列番号244〜配列番号259のいずれか1つのアミノ酸配列を含む、請求項19に記載の単離された免疫グロブリン重鎖ポリペプチド。
- 単離された免疫グロブリン軽鎖ポリペプチドであって、アミノ酸配列Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Xaa1 Trp Tyr Xaa2 Xaa3 Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Xaa4 Gly Val Pro Asp Arg Phe Xaa5 Gly Ser Xaa6 Ser Gly Thr Asp Phe Thr Leu Xaa7 Ile Xaa8 Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Xaa Gln Tyr Tyr Xaa10 Ser Pro Xaa11 Thr Phe Gly Gly Gly Thr Lys Ile Glu Xaa12 Lys(配列番号260)を含み、
(a)Xaa1はアラニン(Ala)又はスレオニン(Thr)であり、
(b)Xaa2はグルタミン(Gln)又はヒスチジン(His)であり、
(c)Xaa3はグルタミン(Gln)又はヒスチジン(His)であり、
(d)Xaa4はセリン(Ser)、チロシン(Tyr)、アスパラギン酸(Asp)、グリシン(Gly)、スレオニン(Thr)、アスパラギン(Asn)、リジン(Lys)、グルタミン酸(Glu)、ロイシン(Leu)、プロリン(Pro)又はバリン(Val)であり、
(e)Xaa5はセリン(Ser)又はアスパラギン(Asn)であり、
(f)Xaa6はグリシン(Gly)、グルタミン酸(Glu)、アラニン(Ala)、アスパラギン酸(Asp)、アスパラギン(Asn)、セリン(Ser)、スレオニン(Thr)又はバリン(Val)であり、
(g)Xaa7はスレオニン(Thr)又はイソロイシン(Ile)であり、
(h)Xaa8はセリン(Ser)又はイソロイシン(Ile)であり、
(i)Xaa9はグルタミン(Gln)又はヒスチジン(His)であり、
(j)Xaa10はセリン(Ser)、アスパラギン(Asn)、アルギニン(Arg)、グリシン(Gly)又はスレオニン(Thr)であり、
(k)Xaa11はロイシン(Leu)又はイソロイシン(Ile)であり、及び
(l)Xaa12はロイシン(Leu)又はバリン(Val)である、
ポリペプチド。 - 配列番号261〜配列番号328のいずれか1つのアミノ酸配列を含む、請求項21に記載の単離された免疫グロブリン軽鎖ポリペプチド。
- 請求項1〜9又は12〜20のいずれか1項に記載の免疫グロブリン重鎖ポリペプチドをコードする、単離された核酸配列。
- 請求項10、11、21又は22のいずれか1項に記載の免疫グロブリン軽鎖ポリペプチドをコードする、単離された核酸配列。
- 請求項23又は請求項24に記載の単離された核酸配列を含むベクター。
- 請求項1〜9又は12〜20のいずれか1項に記載の免疫グロブリン重鎖ポリペプチド及び/又は請求項10、11、21又は22のいずれか1項に記載の免疫グロブリン軽鎖ポリペプチドを含む、T細胞免疫グロブリン及びムチンタンパク質3(TIM−3)結合剤。
- 請求項1〜9又は12〜20のいずれか1項に記載の免疫グロブリン重鎖ポリペプチド及び請求項10、11、21又は22のいずれか1項に記載の免疫グロブリン軽鎖ポリペプチドを含む、請求項26に記載のTIM−3結合剤。
- 請求項1〜9若しくは12〜20のいずれか1項に記載の免疫グロブリン重鎖ポリペプチド又は請求項10、11、21若しくは22のいずれか1項に記載の免疫グロブリン軽鎖ポリペプチドを含む、請求項26に記載のTIM−3結合剤。
- 抗体、抗体複合体又はその抗原結合断片である、請求項26〜28のいずれか1項に記載のTIM−3結合剤。
- F(ab’)2断片、Fab’断片、Fab断片、Fv断片、scFv断片、dsFv断片、dAb断片又は一本鎖結合ポリペプチドである、請求項29に記載のTIM−3結合剤。
- 請求項26〜30のいずれか1項に記載のTIM−3結合剤をコードする単離された核酸配列。
- 請求項31に記載の単離された核酸配列を含むベクター。
- 請求項32に記載のベクターを含む単離された細胞。
- (a)請求項26〜30のいずれか1項に記載のTIM−3結合剤又は請求項32に記載のベクター及び(b)医薬的に許容される担体を含む、組成物。
- TIM−3阻害に応答する、哺乳動物における病気の治療方法であって、TIM−3阻害に応答する病気を有する哺乳動物に、請求項34の組成物を有効量投与することを含み、それにより哺乳動物における病気が治療される、方法。
- 前記病気ががんである、請求項35に記載の方法。
- 前記がんが、メラノーマ、腎臓細胞がん、肺がん、膀胱がん、乳がん、子宮頸がん、結腸がん、胆嚢がん、喉頭がん、肝臓がん、甲状腺がん、胃がん、唾液腺がん、前立腺がん、膵臓がん又はメルケル細胞がんである、請求項36に記載の方法。
- 前記病気が感染症である、請求項35に記載の方法。
- 前記感染症が、ウイルス又は細菌によって引き起こされる、請求項38に記載の方法。
- 前記ウイルスが、ヒト免疫不全ウイルス(HIV)、呼吸器合胞体ウイルス(RSV)、インフルエンザウイルス、デング熱ウイルス又はB型肝炎ウイルス(HBV)である、請求項39に記載の方法。
- 前記病気が自己免疫疾患である、請求項35に記載の方法。
- 前記自己免疫疾患が、多発性硬化症、1型真性糖尿病、関節リウマチ、強皮症、クローン病、乾癬、全身性エリトマトーデス(SLE)又は潰瘍性大腸炎である、請求項41に記載の方法。
- 哺乳動物におけるTIM−3結合剤の半減期が、30分〜45日の間である、請求項35〜42のいずれか1項に記載の方法。
- 前記TIM−3結合剤が、約1ピコモーラー(pM)〜約100マイクロモーラー(μM)の間のKDでTIM−3に結合する、請求項35〜43のいずれか1項に記載の方法。
- 哺乳動物にPD−1結合剤を投与することを、更に含む、請求項35〜44のいずれか1項に記載の方法。
- 前記PD−1結合剤が、抗体、抗体複合体又はその抗原結合断片である、請求項45に記載の方法。
- 哺乳動物にLAG−3結合剤を投与することを、更に含む、請求項35〜46のいずれか1項に記載の方法。
- 前記LAG−3結合剤が、抗体、抗体複合体又はその抗原結合断片である、請求項47に記載の方法。
- 単離された免疫グロブリン重鎖ポリペプチドであって、配列番号329のアミノ酸配列からなる相補性決定領域1(CDR1)、配列番号330のアミノ酸配列からなるCDR2及び/又は配列番号331のアミノ酸配列からなるCDR3を含む、ポリペプチド。
- 単離された免疫グロブリン軽鎖ポリペプチドであって、配列番号332のアミノ酸配列からなるCDR1、配列番号333のアミノ酸配列からなるCDR2及び/又は配列番号334のアミノ酸配列からなるCDR3を含む、ポリペプチド。
- 単離された免疫グロブリン重鎖ポリペプチドであって、配列番号335のアミノ酸配列からなるCDR1、配列番号336のアミノ酸配列からなるCDR2及び/又は配列番号337のアミノ酸配列からなるCDR3を含む、ポリペプチド。
- 単離された免疫グロブリン軽鎖ポリペプチドであって、配列番号338のアミノ酸配列からなるCDR1、配列番号339のアミノ酸配列からなるCDR2及び/又は配列番号340のアミノ酸配列からなるCDR3を含む、ポリペプチド。
- 請求項49若しくは51に記載の免疫グロブリン重鎖ポリペプチド及び/又は請求項50若しくは52に記載の免疫グロブリン軽鎖ポリペプチドを含む、TIM−3結合剤。
- 請求項49又は51に記載の免疫グロブリン重鎖ポリペプチド及び請求項50又は52に記載の免疫グロブリン軽鎖ポリペプチドを含む、請求項53に記載のTIM−3結合剤。
- 請求項49に記載の免疫グロブリン重鎖ポリペプチド及び請求項50に記載の免疫グロブリン軽鎖ポリペプチド、又は請求項51に記載の免疫グロブリン重鎖ポリペプチド及び請求項52に記載の免疫グロブリン軽鎖ポリペプチドを含む、請求項53に記載のTIM−3結合剤。
- 抗体、抗体複合体又はその抗原結合断片である、請求項53〜55のいずれか1項に記載のTIM−3結合剤。
- F(ab’)2断片、Fab’断片、Fab断片、Fv断片、scFv断片、dsFv断片、dAb断片又は一本鎖結合ポリペプチドである、請求項56に記載のTIM−3結合剤。
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