JP2017502695A - 抗体及び使用方法 - Google Patents
抗体及び使用方法 Download PDFInfo
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- JP2017502695A JP2017502695A JP2016560886A JP2016560886A JP2017502695A JP 2017502695 A JP2017502695 A JP 2017502695A JP 2016560886 A JP2016560886 A JP 2016560886A JP 2016560886 A JP2016560886 A JP 2016560886A JP 2017502695 A JP2017502695 A JP 2017502695A
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Abstract
Description
この出願は、2013年12月23日に出願された米国仮特許出願シリアル番号61/920396及び2014年11月18日出願された米国仮特許出願シリアル番号62/081435に対する優先権を主張し、それらは両方ともその全体が参照により本明細書に援用される。
本出願は、ASCIIフォーマットで電子的に提出された配列表を含み、その全体が本明細書中で参照することにより援用される。2014年12月22日に作成された前記ASCIIコピーは、00B206.0170_SL.txtと命名され、大きさは155,738バイトである。
本発明は、β−クロトー(KLB)、線維芽細胞増殖因子受容体1(FGFR1)、又はその両方に結合する抗体、及びその使用方法に関する。
明確にするためにかつ限定するものではないが、本開示の主題の詳細な説明は、以下のサブセクションに分けられる:
I.定義;
II.抗体:
III.使用方法;
IV.薬学的製剤;及び
V.製造品
本明細書における目的のための「アクセプターヒトフレームワーク」とは、下記に定義されるように、ヒト免疫グロブリンフレームワーク又はヒトコンセンサスフレームワークから得られる軽鎖可変ドメイン(VL)フレームワーク又は重鎖可変ドメイン(VH)フレームワークのアミノ酸配列を含有するフレームワークである。ヒト免疫グロブリンのフレームワーク又はヒトコンセンサスフレームワーク「に由来する」アクセプターヒトフレームワークは、その同一のアミノ酸配列を含んでもよく、又はそれはアミノ酸配列の変化を含み得る。ある実施態様では、アミノ酸変化の数は10以下、9以下、8以下、7以下、6以下、5以下、4以下、3以下、又は2以下である。ある実施態様では、VLアクセプターヒトフレームワークは、VLヒト免疫グロブリンフレームワーク配列又はヒトコンセンサスフレームワーク配列と配列が同一である。
FSGDGRAIWSKNPNFTPVNESQLFLYDTFPKNFFWGIGTGALQVEGSWKKDGKGPSIWDHFIHTHLKNVSSTNGSSDSYIFLEKDLSALDFIGVSFYQFSISWPRLFPDGIVTVANAKGLQYYSTLLDALVLRNIEPIVTLYHWDLPLALQEKYGGWKNDTIIDIFNDYATYCFQMFGDRVKYWITIHNPYLVAWHGYGTGMHAPGEKGNLAAVYTVGHNLIKAHSKVWHNYNTHFRPHQKGWLSITLGSHWIEPNRSENTMDIFKCQQSMVSVLGWFANPIHGDGDYPEGMRKKLFSVLPIFSEAEKHEMRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLREALNWIKLEYNNPRILIAENGWFTDSRVKTEDTTAIYMMKNFLSQVLQAIRLDEIRVFGYTAWSLLDGFEWQDAYTIRRGLFYVDFNSKQKERKPKSSAHYYKQIIRENGFSLKESTPDVQGQFPCDFSWGVTESVLKPESVASSPQFSDPHLYVWNATGNRLLHRVEGVRLKTRPAQCTDFVNIKKQLEMLARMKVTHYRFALDWASVLPTGNLSAVNRQALRYYRCVVSEGLKLGISAMVTLYYPTHAHLGLPEPLLHADGWLNPSTAEAFQAYAGLCFQELGDLVKLWITINEPNRLSDIYNRSGNDTYGAAHNLLVAHALAWRLYDRQFRPSQRGAVSLSLHADWAEPANPYADSHWRAAERFLQFEIAWFAEPLFKTGDYPAAMREYIASKHRRGLSSSALPRLTEAERRLLKGTVDFCALNHFTTRFVMHEQLAGSRYDSDRDIQFLQDITRLSSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITASGIDDQALEDDRLRKYYLGKYLQEVLKAYLIDKVRIKGYYAFKLAEEKSKPRFGFFTSDFKAKSSIQFYNKVISSRGFPFENSSSRCSQTQENTECTVCLFLVQKKPLIFLGCCFFSTLVLLLSIAIFQRQKRRKFWKAKNLQHIPLKKGKRVVS(配列番号145)。
MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAVHKLAKSIPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWELPRDRLVLGKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNPEEQLSSKDLVSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHHIDYYKKTTNGRLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMDKPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLDLSMPLDQYSPSFPDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR(配列番号146)。
(a)アミノ酸残基26−32(L1)、50−52(L2)、91−96(L3)、26−32(H1)、53−55(H2)、及び96−101(H3)で生じる超可変ループ(Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));
(b)アミノ酸残基24−34(L1)、50−56(L2)、89−97(L3)、31−35b(H1)、50−65(H2)、及び95−102(H3)で生じるCDR(Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));
(c)アミノ酸残基27c−36(L1)、46−55(L2)、89−96(L3)、30−35b(H1)、47−58(H2)、及び93−101(H3)で生じる抗原接触(MacCallum et al. J. Mol. Biol. 262: 732-745 (1996));及び
(d)HVRのアミノ酸残基46−56(L2)、47−56(L2)、48−56(L2)、49−56(L2)、26−35(H1)、26−35b(H1)、49−65(H2)、93−102(H3)、及び94−102(H3)を含む、(a)、(b)、及び/又は(c)の組み合わせ。
分率X/Yの100倍
ここで、Xは、A及びBのプログラムアラインメントにおいて、配列アラインメントプログラムALIGN−2によって同一であると一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基の全数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと一致しない場合、AのBに対する%アミノ酸配列同一性は、BのAに対する%アミノ酸配列同一性とは一致しないと評価されるであろう。特に断らない限りは、ここで使用される全ての%アミノ酸配列同一性値は、直前のパラグラフに記載したように、ALIGN−2コンピュータプログラムを用いて得られる。
一態様において、本発明は、KLB及びFGFR1cの両方に結合し、FGFR1c/KLB受容体複合体を選択的に活性化し、肝臓に重大な影響を与えることなくかつ骨量の損失を伴わない体重減少並びにグルコース及び脂質代謝の改善を含む、FGF21様活性から予想される有益な代謝変化を誘発する二重特異性抗体の発見に一部基づいている。
一態様において、本開示は、KLBタンパク質に結合する単離された抗体を提供する。ある実施態様において、本開示の抗KLB抗体はKLBのC末端ドメインに結合する。ある実施態様において、本開示の抗KLB抗体は、アミノ酸配列SSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITAS(配列番号142)を含むKLBの断片に結合する。ある実施態様において、抗体は、本明細書に記載された抗KLB抗体、例えば、8C5と同じエピトープに結合する。
一態様において、本開示は、FGFR1タンパク質に結合する単離された抗体を提供する。ある実施態様において、本開示の抗FGFR1抗体はFGFR1cに結合する。ある実施態様において、本開示は、(a)配列番号136を含むHVR−H1;(b)配列番号137を含むHVR−H2;(c)配列番号138を含むHVR−H3;(d)配列番号139を含むHVR−L1;(e)配列番号140を含むHVR−L2;及び(f)配列番号141を含むHVR−L3から選択される少なくとも一、二、三、四、五、又は六のHVRを含む抗FGFR1抗体を提供する。
本開示は更にKLB及びFGFR1の両方に結合する二重特異性抗体(すなわち、抗KLB/抗FGFR1二重特異性抗体)を提供する。二重特異性抗体は、2つの異なる結合特異性を有しており、例えば、米国特許第5,922,845号及び第5,837,243号;Zeilder (1999) J. Immunol. 163:1246-1252; Somasundaram (1999) Hum. Antibodies 9:47-54; Keler (1997) Cancer Res. 57:4008-4014を参照。例えば、限定するものではないが、本開示の主題は、KLB上に存在する第一のエピトープに対する一つの結合部位(例えば、抗原結合部位)を有する二重特異性抗体及びFGFR1上に存在する第二のエピトープに対する第二の結合部位を提供する。例えば、限定するものではないが、本発明は、一つのアームがKLBに結合し、かつ本明細書に記載の抗KLB抗体配列の何れかを含み、第二のアームがFGFR1に結合し、かつ本明細書に記載の抗FGFR1抗体配列の何れかを含む抗体を提供する。ある実施態様において、本開示の抗KLB/抗FGFR1二重特異性抗体は、KLB上に存在する第一のエピトープに対する一つの結合部位及びFGFR1c上に存在する第二のエピトープに対する第二の結合部位を有する。
ある実施態様において、本開示の抗体は、解離定数(Kd)が、1M、≦100mM、≦10mM、≦1mM、≦100μM、≦10μM、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、又は≦0.001nMを有する。ある実施態様において、本開示の抗体は、約10−3以下、又は10−8M以下、例えば、10−8Mから10−13M、例えば、10−9Mから10−13MのKdを有することができる。
ある実施態様において、本開示の抗体は、抗体断片である。抗体断片には、Fab、Fab’、Fab’−SH、F(ab’)2、Fv及びscFv断片ならびに下に記載される他の断片が含まれるが、これらに限定されない。ある種の抗体断片の概説については、Hudsonら、Nat.Med.9:129〜134(2003)を参照されたい。scFv断片の総説については、例えば、Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994)を参照;また、国際公開第93/16185号;及び米国特許第5,571,894号及び第5,587,458号も参照。サルベージ受容体結合エピトープ残基を含み、かつインビボ半減期を増加させたFab及びF(ab’)2断片の議論については、米国特許第5869046号を参照のこと。
ある実施態様において、本開示の抗体は、キメラ抗体である。特定のキメラ抗体は、例えば、米国特許第4816567号;及びMorrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)に記載されている。ある実施態様において、本開示のキメラ抗体は非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、又はサルなどの非ヒト霊長類由来の可変領域)及びヒト定常領域を含む。更なる例では、キメラ抗体は、クラス又はサブクラスが親抗体のクラス又はサブクラスから変えられている「クラス転換された」抗体であることができる。キメラ抗体にはその抗原結合断片が含まれる。
ある実施態様において、本開示の抗体は、ヒト抗体であることができる。ヒト抗体は当技術分野で公知の種々の技術を使用して産生することができる。ヒト抗体は一般的には、van Dijk及びvan de Winkel、Curr.Opin.Pharmacol.5:368~74(2001)ならびにLonberg、Curr.Opin.Immunol.20:450~459(2008)に記載されている。
本開示の抗体は、1種又は複数の所望の活性を有する抗体を求めてコンビナトリアルライブラリーをスクリーニングすることにより単離しうる。例えば、ファージディスプレイライブラリーを作製し所望の結合特徴を有する抗体を求めてそのようなライブラリーをスクリーニングするための種々の方法は当技術分野では公知である。そのような方法は、例えば、Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001)に総説され、更に、例えば、McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004);及びLee et al., J. Immunol. Methods 284(1-2): 119-132(2004)に概説されている。
ある実施態様において、本開示の抗体は、多重特異性抗体、例えば、二重特異性抗体であることができる。多特異的抗体は、少なくとも2つの異なるエピトープに対する結合特異性を有するモノクローナル抗体である。ある実施態様において、結合特異性の一つはKLB上に存在するエピトープに対してであり、他は、任意の他の抗原に対してである。ある実施態様において、結合特異性の一つはFGFR1上に存在するエピトープに対してであり、他は、任意の他の抗原に対してである。ある実施態様において、本開示の二重特異性抗体は、KLB上のエピトープに結合することができ、かつ、FGFR1上のエピトープに結合することができる。ある実施態様において、本開示の二重特異性抗体は、KLB上のエピトープに結合することができ、かつ、FGFR1c上のエピトープに結合することができる。二重特異的抗体は、完全長抗体又は抗体断片として調製することができる。
本開示の主題は、開示された抗体のアミノ酸配列変異体を更に提供する。例えば、抗体の結合親和性及び/又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体は、抗体をコードするヌクレオチド配列に適切な改変を導入することにより、又はペプチド合成によって調製することができる。そのような修飾は、限定されないが、抗体のアミノ酸配列内の残基の欠失、及び/又は挿入及び/又は置換を含む。すなわち、改変された最終抗体が所望の特性、例えば、抗原結合を有していることを条件として、欠失、挿入、及び置換の任意の組み合わせが、最終構築物に到達させるために作成されることができる。
ある実施態様において、抗体変異体は一以上のアミノ酸置換を有することができる。置換型変異誘発の対象となる部位は、HVR及びFRを含む。保存的置換の非限定的な例は、表1の「望ましい置換」の見出しの下に示されている。より実質的な変更の非限定的な例が、表1の「例示的置換」の見出しの下に与えられ、アミノ酸側鎖のクラスを参照して以下に更に説明される。アミノ酸置換は対象の抗体に導入され、生成物は、所望の活性、例えば、保持された/改善された抗原結合性、減少した免疫原性、又は改善された補体依存性細胞傷害(CDC)もしくは抗体依存性細胞媒介性細胞傷害(ADCC)についてスクリーニングされることができる。
アミノ酸は共通の側鎖特性に基づいてグループに分けることができる:
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性の親水性Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖配向に影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
ある実施態様では、本開示の抗体は、抗体がグリコシル化される程度を高める又は減じるために改変されることができる。抗体へのグリコシル化部位の付加又は削除は、1つ又は複数のグリコシル化部位が作り出される又は取り除かれるようにアミノ酸配列を変化させることにより都合よく実現しうる。
ある特定の実施態様では、1つ又は複数のアミノ酸改変を本明細書に提供される抗体のFc領域に導入し、それによりFc領域変異体を産生することができる。Fc領域の変異体は、1つ又は複数のアミノ酸位置においてアミノ酸修飾(例えば置換)を含むヒトFc領域の配列(例えば、ヒトIgG1、IgG2、IgG3又はIgG4のFc領域)を含んでもよい。
ある特定の実施態様では、抗体の1つ又は複数の残基がシステイン残基で置換されているシステイン操作抗体、例えば、「チオMAb」を作り出すのが望ましいことがある。特定の実施態様では、置換される残基は抗体の接触可能部位に存在する。更に本明細書で説明されるように、それらの残基をシステインで置換することにより、反応性チオール基はそれにより抗体の接触可能部位に置かれ、この基を使用して抗体を、薬物部分又はリンカー薬物部分などの他の部分にコンジュゲートさせて、免疫コンジュゲートを作り出しうる。ある実施態様において、以下の残基の何れか又は複数がシステインに置換され得る:軽鎖のV205(Kabat番号付け);重鎖のA118(EU番号付け);及び重鎖Fc領域のS400(EU番号付け)。システイン操作抗体は、例えば、米国特許第7521541号に記載される通りに産生することができる。
ある実施態様において、本開示の抗体は当該分野において知られており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更に改変され得る。抗体の誘導体化に適した部分としては、限定されないが、水溶性ポリマーを含む。水溶性ポリマーの非限定的な例は、限定されないが、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共重合体、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/無水マレイン酸共重合体、ポリアミノ酸(単独重合体又はランダム共重合体の何れか)及びデキストラン又はポリ(n−ビニルピロリドン)ポリエチレングリコール、プロピレングリコール単独重合体、プロピレンオキシド/エチレンオキシド共重合体、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及びこれらの混合物を包含する。ポリエチレングリコールプロピオンアルデヒドはその水中での安定性のために製造上の利点を有し得る。ポリマーは任意の分子量のものであってよく、分枝鎖又は非分枝鎖であってよい。抗体に結合するポリマーの数は変化してもよく、一を超えるポリマーが結合する場合、それらは同じ分子でも異なる分子でもよい。一般に、誘導体化に使用されるポリマーの数及び/又は型は、限定されるものではないが、向上されるべき抗体の特定の特性又は機能、その抗体誘導体が定まった条件下で治療に使用されるかどうかを含む考慮事項に基づいて決定され得る。
本明細書中に開示される抗体は、当技術分野における任意の利用可能な又は既知の技術を用いて産生することができる。例えば、限定するものではないが、抗体は、例えば、米国特許第4816567号に記載されている組換え法及び組成物を使用して産生することができる。抗体を生成する詳細な手順は、以下の実施例に記載される。
本明細書で提供される本開示の抗体は、当技術分野で公知でありかつ本明細書に提供される様々なアッセイによってその物理的/化学的性質及び/又は生物学的活性について同定され、スクリーニングされ、又は特徴づけることができる。
ある実施態様において、本開示の抗体は、酵素結合免疫吸着アッセイ(ELISA)、ラジオイムノアッセイ(RIA)、又はウエスタンブロットアッセイなどの周知の方法により、その抗原結合活性について試験することができる。これらのアッセイの各々は、一般に、目的の複合体に特異的な標識試薬(例えば、抗体)を用いることによって、特に興味深いタンパク質−抗体複合体の存在を検出する。例えば、KLB−抗体複合体は、例えば、抗体−KLB複合体を認識して特異的に結合する酵素結合抗体又は抗体断片を用いて検出することができる。あるいは、複合体は、種々の他のイムノアッセイの何れかを用いて検出することができる。例えば、抗体を放射性標識し、ラジオイムノアッセイ(RIA)で使用することができる(例えば、本明細書中に参考として援用される、Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986を参照)。放射性同位元素は、ガイガーカウンターもしくはシンチレーションカウンターの使用のような手段によって、又はオートラジオグラフィーによって検出することができる。
本開示は、生物学的活性を有するそれらの抗KLB抗体を同定するためのアッセイを提供する。生物学的活性は、例えばKLB/FGFR1cの受容体複合体を活性化することを含むことができる。インビボ及び/又はインビトロでこのような生物学的活性を有する抗体もまた提供される。ある実施態様において、アッセイは、本開示の抗体を、細胞、例えば、KLBを発現する293T細胞に結合させ、及びKLB−FGFR1c受容体複合体、例えばERKの一以上の下流の標的の活性及び/又はリン酸化状態を分析することを含むことができる。ある実施態様において、アッセイは、被験体、例えば、非ヒト動物に対する本開示の抗体を投与すること及び抗体が被験体におけるグルコースレベルに関して有する影響を分析することを含むことができる。
本開示の主題は更に、化学療法剤又は薬物、成長抑制剤、毒素(例えば、タンパク質毒素、細菌、真菌、植物、又は動物起源の酵素活性毒素、又はそれらの断片)、又は放射性同位元素など、1つ以上の細胞傷害性薬物にコンジュゲートした本明細書に開示された抗体を含むイムノコンジュゲートを提供する。例えば、開示された主題の抗体又は抗原結合部分は(例えば、化学的カップリング、遺伝子融合、非共有結合又はその他によって)、別の抗体、抗体断片、ペプチド又は結合模倣物などの一以上の他の結合分子に機能的に連結することができる。
本開示の主題は更に、開示される抗体、例えば、抗KLBは/抗FGFR1c二重特異性抗体を使用する方法を提供する。ある実施態様において、本方法は、本開示の抗体の治療的使用を対象とする。ある実施態様において、本方法は、診断方法における開示された抗体の使用を対象とする。
ある実施態様において、KLBに対する特異性を有する本明細書に開示される何れかの抗体、例えば、上記に開示される抗KLB抗体及び/又は抗KLB/抗FGFR1二重特異性抗体は、生物学的試料中においてKLBの存在を検出するために有用であり得る。更なる態様では、本開示の主題は、本明細書に開示される抗KLB抗体又は抗KLB/抗FGFR1二重特異性抗体を用いて疾患を診断する及び/又は検出するための方法を提供する。本明細書で使用する「検出」という用語は、定量的及び/又は定性的検出を包含する。
ある実施態様において、本開示の主題の一以上の抗体は、被験体における疾患及び/又は障害を治療するために使用することができる。例えば、限定するものではないが、疾患は代謝障害であり得る。代謝障害の非限定的な例としては、代謝障害、例えば、多嚢胞性卵巣症候群(PCOS)、メタボリックシンドローム(MetS)、肥満症、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪肝疾患(NAFLD)、高脂血症、高血圧、2型糖尿病、非2型糖尿病、1型糖尿病、潜在性自己免疫性糖尿病(LAD)、及び若年発症成人型糖尿病(MODY)を含む。ある実施態様において、代謝障害は2型糖尿病である。ある実施態様において、代謝障害は肥満症である。
現在開示された主題は、更に、本明細書に記載されるような一以上の抗体を薬学的に許容可能な担体とともに含有する薬学的製剤を提供する。ある実施態様において、薬学的組成物は、現在開示された主題の複数(例えば、二以上)の抗体及び/又はその抗原結合部分の組み合わせを含むことができる。ある実施態様において、本開示の薬学的組成物は、一以上の抗KLB/抗FGFR1二重特異性抗体を含むことができる。
本開示の主題は、更に、上述した障害の治療、予防、及び/又は診断に有用な物質を含む製造品に関する。
3つのファージ由来抗FGFR1抗体、YW182.2(本明細書では「R1MAb1」とも称す)YW182.3(本明細書では「R1MAb2」とも称す)及びYW182.5(本明細書では「R1MAb3」とも称す)は以前に記載された(参照により本明細書に組み込まれる国際公開第2012/158704号)。3つの抗体の各々は、強力なFGFR1選択的アゴニストとして作用し、マウスにおいてインスリン感作特性を示した。
FGFR1 ECDはD1からD3と称され3つのIg様ドメインからなる。図1Cに示すように、二つの非重複ペプチド(P26:KLHAVPAAKTVKFKCP(配列番号143)及びP28:FKPDHRIGGYKVRY(配列番号144)は、FGFR1のD2ドメイン内に存在し、以前にYW182.2及びYW182.3の両方に結合することが同定されました(参照により本明細書に援用される国際公開第2012/158704号)。
Balb/cマウスを、安定的にhFGFR1c及びhKLBタンパク質を発現するHEK293細胞で免疫した。脾臓を12週間後に回収し、ハイブリドーマを生成した。抗hKLB抗体産生ハイブリドーマは、免疫化に使用されるHEK293細胞を用いたFACS分析によって同定された。簡潔には、hFGFR1単独、hKLB単独、又はその両方を発現する293細胞を、希釈したハイブリドーマ上清及びPE結合ヤギ抗マウスIgG抗体(Jackson Labs)を用いてFACS緩衝液(PBS中0.5%BSA)中で染色した。同じFACS緩衝液が染色した細胞を洗浄するために使用された。染色された細胞を、FACScan(Becton Dickinson)及びFlowJo FACS解析ソフトウェア(Tree Star)により分析した。IgG重鎖及び軽鎖をコードするcDNAを、発現ベクターにクローニングした。全ての組換えモノクローナル抗体分子は、一過性にトランスフェクトしたチャイニーズハムスター卵巣(CHO)細胞で産生され、通常のカラムクロマトグラフィーを用いて精製された。
様々な抗KLB抗体間の競合を試験するために、ELISAを使用した。幾つかの実施態様において、6D12、8C5、及び11F1に対応するハイブリドーマ上清から精製されたIgG抗体は、EZ−リンクNHS−PEO固相ビオチン化キット(Pierce)を用いてビオチン化された。KLB−ECD−Hisタンパク質jへの結合は、様々な濃度のハイブリドーマ由来抗KLBの存在下で、HRP結合ストレプトアビジンを用いて試験された。幾つかの実施態様において、組換えヒトIgGのKLB−ECD−Hisタンパク質への結合は、様々な濃度のハイブリドーマ由来抗KLBの存在下で、HRP結合抗ヒトIgG(Jackson ImmunoResearch Inc.)を用いて試験された。11F1、11D4、8E1及び46C3のいずれもが結合について6D12と競合しないことが観察された(他は6D12に対して試験されなかった)。抗KLB抗体14E6及び12A11は、結合について8C5と競合するが、11D4及び14C10は競合せず(他は8C5に対して試験されなかった)、11D4は、結合について11F1と競合するが、6D12、8E1、及び46C3は競合しない(他は11F1に対して試験されなかった)。
開示される抗KLB抗体の種交差反応性は、HEK293T細胞に一過性にトランスフェクトされたpRK哺乳動物発現ベクターにクローニングされたマウス、ラット、ウサギ、カニクイザル及びアカゲザルからのKLB cDNAを用いてFACS分析により分析された。発現されたKLB細胞外ドメインのポリペプチド配列は以下のとおりである:
マウス:
FSGDGKAIWDKKQYVSPVNPSQLFLYDTFPKNFSWGVGTGAFQVEGSWKTDGRGPSIWDRYVYSHLRGVNGTDRSTDSYIFLEKDLLALDFLGVSFYQFSISWPRLFPNGTVAAVNAQGLRYYRALLDSLVLRNIEPIVTLYHWDLPLTLQEEYGGWKNATMIDLFNDYATYCFQTFGDRVKYWITIHNPYLVAWHGFGTGMHAPGEKGNLTAVYTVGHNLIKAHSKVWHNYDKNFRPHQKGWLSITLGSHWIEPNRTDNMEDVINCQHSMSSVLGWFANPIHGDGDYPEFMKTGAMIPEFSEAEKEEVRGTADFFAFSFGPNNFRPSNTVVKMGQNVSLNLRQVLNWIKLEYDDPQILISENGWFTDSYIKTEDTTAIYMMKNFLNQVLQAIKFDEIRVFGYTAWTLLDGFEWQDAYTTRRGLFYVDFNSEQKERKPKSSAHYYKQIIQDNGFPLKESTPDMKGRFPCDFSWGVTESVLKPEFTVSSPQFTDPHLYVWNVTGNRLLYRVEGVRLKTRPSQCTDYVSIKKRVEMLAKMKVTHYQFALDWTSILPTGNLSKVNRQVLRYYRCVVSEGLKLGVFPMVTLYHPTHSHLGLPLPLLSSGGWLNMNTAKAFQDYAELCFRELGDLVKLWITINEPNRLSDMYNRTSNDTYRAAHNLMIAHAQVWHLYDRQYRPVQHGAVSLSLHCDWAEPANPFVDSHWKAAERFLQFEIAWFADPLFKTGDYPSVMKEYIASKNQRGLSSSVLPRFTAKESRLVKGTVDFYALNHFTTRFVIHKQLNTNRSVADRDVQFLQDITRLSSPSRLAVTPWGVRKLLAWIRRNYRDRDIYITANGIDDLALEDDQIRKYYLEKYVQEALKAYLIDKVKIKGYYAFKLTEEKSKPRFGFFTSDFRAKSSVQFYSKLISSSGLPAENRSPACGQPAEDTDCTICSFLV(配列番号158)。
ラット(+N−ter FLAG):
DYKDDDDKLEFSGDGKAIWDKKQYVSPVNPGQLFLYDTFPKNFSWGVGTGAFQVEGSWKADGRGPSIWDRYVDSHLRGVNSTDRSTDSYVFLEKDLLALDFLGVSFYQFSISWPRLFPNGTVAAVNAKGLQYYRALLDSLVLRNIEPIVTLYHWDLPLTLQEEYGGWKNATMIDLFNDYATYCFQTFGDRVKYWITIHNPYLVAWHGFGTGMHAPGEKGNLTAVYTVGHNLIKAHSKVWHNYDKNFRPHQKGWLSITLGSHWIEPNRTENMEDVINCQHSMSSVLGWFANPIHGDGDYPEFMKTSSVIPEFSEAEKEEVRGTADFFAFSFGPNNFRPSNTVVKMGQNVSLNLRQVLNWIKLEYDNPRILISENGWFTDSYIKTEDTTAIYMMKNFLNQVLQAIKFDEIQVFGYTAWTLLDGFEWQDAYTTRRGLFYVDFNSEQKERKPKSSAHYYKQIIQDNGFPLQESTPDMKGQFPCDFSWGVTESVLKPEFTVSSPQFTDPHLYVWNVTGNRLLYRVEGVRLKTRPSQCTDYVSIKKRVEMLAKMKVTHYQFALDWTSILPTGNLSKINRQVLRYYRCVVSEGLKLGISPMVTLYHPTHSHLGLPMPLLSSGGWLNTNTAKAFQDYAGLCFKELGDLVKLWITINEPNRLSDMYNRTSNDTYRAAHNLMIAHAQVWHLYDRQYRPVQHGAVSLSLHSDWAEPANPYVESHWKAAERFLQFEIAWFADPLFKTGDYPLAMKEYIASKKQRGLSSSVLPRFTLKESRLVKGTIDFYALNHFTTRFVIHKQLNTNCSVADRDVQFLQDITRLSSPSRLAVTPWGMRKLLGWIRRNYRDMDIYVTANGIDDLALEDDQIRKYYLEKYVQEALKAYLIDKVKIKGYYAFKLTEEKSKPRFGFFTSDFKAKSSVQFYSKLISSSGFSSENRSPACGQPPEDTECAICSFLT(配列番号147)。
ウサギ(+N−ter FLAG):
DYKDDDDKLDFPGDGRAVWSQNPNLSPVNESQLFLYDTFPKNFFWGVGTGAFQVEGSWKKDGKGLSVWDHFIATHLNVSSRDGSSDSYIFLEKDLSALDFLGVSFYQFSISWPRLFPDGTVAVANAKGLQYYNRLLDSLLLRNIEPVVTLYHWDLPWALQEKYGGWKNETLIDLFNDYATYCFQTFGDRVKYWITIHNPYLVAWHGYGTGLHAPGEKGNVAAVYTVGHNLLKAHSKVWHNYNRNFRPHQKGWLSITLGSHWIEPNRAESIVDILKCQQSMVSVLGWFANPIHGDGDYPEVMTKKLLSVLPAFSEAEKNEVRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLRQVLNWIKLEYGNPRILIAENGWFTDSYVQTEDTTAIYMMKNFLNQVLQAIRLDGVRVFGYTAWSLLDGFEWQDAYNTRRGLFYVDFNSEQRERRPKSSAHYYKQVIGENGFTLREATPDLQGQFPCDFSWGVTESVLKPESVASSPQFSDPHLYVWNATGNRMLHRVEGVRLKTRPAQCTDFITIKKQLEMLARMKVTHFRFALDWASVLPTGNLSEVNRQALRYYRCVVTEGLKLNISPMVTLYYPTHAHLGLPAPLLHSGGWLDPSTAKAFRDYAGLCFRELGDLVKLWITINEPNRLSDVYNRTSNDTYQAAHNLLIAHAIVWHLYDRQYRPSQRGALSLSLHSDWAEPANPYVASHWQAAERFLQFEIAWFAEPLFKTGDYPVAMREYIASKTRRGLSSSVLPRFSDAERRLVKGAADFYALNHFTTRFVMHEQQNGSRYDSDRDVQFLQDITRLASPSRLAVMPWGEGKLLRWMRNNYGDLDVYITANGIDDQALQNDQLRQYYLEKYVQEALKAYLIDKIKIKGYYAFKLTEEKSKPRFGFFTSDFKAKSSIQFYNKLITSNGFPSENGGPRCNQTQGNPECTVCLLLL(配列番号148)。
カニクイザル(+N−ter FLAG):
DYKDDDDKLEFSGDGRAVWSKNPNFTPVNESQLFLYDTFPKNFFWGVGTGALQVEGSWKKDGKGPSIWDHFVHTHLKNVSSTNGSSDSYIFLEKDLSALDFIGVSFYQFSISWPRLFPDGIVTVANAKGLQYYNTLLDSLVLRNIEPIVTLYHWDLPLALQEKYGGWKNDTIIDIFNDYATYCFQTFGDRVKYWITIHNPYLVAWHGYGTGMHAPGEKGNLAAVYTVGHNLIKAHSKVWHNYNTHFRPHQKGWLSITLGSHWIEPNRSENTMDILKCQQSMVSVLGWFASPIHGDGDYPEGMKKKLLSILPLFSEAEKNEVRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLREALNWIKLEYNNPRILIAENGWFTDSHVKTEDTTAIYMMKNFLSQVLQAIRLDEIRVFGYTAWSLLDGFEWQDAYTIRRGLFYVDFNSKQKERKPKSSAHYYKQIIRENGFSLKEATPDVQGQFPCDFSWGVTESVLKPESVASSPQFSDPYLYVWNATGNRLLHRVEGVRLKTRPAQCTDFVNIKKQLEMLARMKVTHYRFALDWASVLPTGNLSAVNRQALRYYRCVVSEGLKLGISAMVTLYYPTHAHLGLPEPLLHAGGWLNPSTVEAFQAYAGLCFQELGDLVKLWITINEPNRLSDIYNRSGNDTYGAAHNLLVAHALAWRLYDRQFRPSQRGAVSLSLHADWAEPANPYADSHWRAAERFLQFEIAWFAEPLFKTGDYPAAMREYIASKHRRGLSSSALPRLTEAERRLLKGTVDFCALNHFTTRFVMHEQLAGSRYDSDRDIQFLQDITRLSSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITASGIDDQALEDDRLRKYYLEKYLQEVLKAYLIDKVRIKGYYAFKLAEEKSKPRFGFFTSDFKAKSSIQFYNKMISSSGFPSENSSSRCSQTQKNTECTVCLFLA(配列番号149)。アカゲザル(+N−ter FLAG):
DYKDDDDKLEFSGDGRAVWSKNPNFTPVNESQLFLYDTFPKNFFWGVGTGALQVEGSWKKDGKGPSIWDHFVHTHLKNVSSTNGSSDSYIFLEKDLSALDFIGVSFYQFSISWPRLFPDGIVTVANAKGLQYYNALLDSLVLRNIEPIVTLYHWDLPLALQEKYGGWKNDTIIDIFNDYATYCFQTFGDRVKYWITIHNPYLVAWHGYGTGMHAPGEKGNLAAVYTVGHNLIKAHSKVWHNYNTHFRPHQKGWLSITLGSHWIEPNRSENTMDILKCQQSMVSVLGWFANPIHGDGDYPEGMKKKLLSILPLFSEAEKNEVRGTADFFAFSFGPNNFKPLNTMAKMGQNVSLNLREALNWIKLEYNNPQILIAENGWFTDSHVKTEDTTAIYMMKNFLSQVLQAIRLDEIRVFGYTAWSLLDGFEWQDAYTIRRGLFYVDFNSKQKERKPKSSAHYYKQIIRENGFSLKEATPDVQGQFPCDFSWGVTESVLKPESVASSPQFSDPYLYVWNATGNRLLHRVEGVRLKTRPAQCTDFVNIKKQLEMLARMKVTHYRFALDWASVLPTGNLSAVNRQALRYYRCVVSEGLKLGISAMVTLYYPTHAHLGLPEPLLHAGGWLNPSTVEAFQAYAGLCFQELGDLVKLWITINEPNRLSDIYNRSGNDTYGAAHNLLVAHALAWRLYDRQFRPSQRGAVSLSLHADWAEPANPYADSHWRAAERFLQFEIAWFAEPLFKTGDYPAAMREYIASKHRRGLSSSALPRLTEAERRLLKGTVDFCALNHFTTRFVMHEQLAGSRYDSDRDIQFLQDITRLSSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITASGIDDQALEDDRLRKYYLEKYLQEVLKAYLIDKVRIKGYYAFKLAEEKSKPRFGFFTSDFKAKSSIQFYNKMISSSGFPSENSSSRCSQTQKNTECTVCLFLV(配列番号150)。
抗KLB抗体がヒトα−クロトー(hKLA)の細胞外ドメイン(ECD)に結合しないかどうかを決定するために、以下の配列を有する構築物が使用された:
(C末端(細胞内)FLAGで)発現された予測されるポリペプチド配列:
EPGDGAQTWARFSRPPAPEAAGLFQGTFPDGFLWAVGSAAYQTEGGWQQHGKGASIWDTFTHHPLAPPGDSRNASLPLGAPSPLQPATGDVASDSYNNVFRDTEALRELGVTHYRFSISWARVLPNGSAGVPNREGLRYYRRLLERLRELGVQPVVTLYHWDLPQRLQDAYGGWANRALADHFRDYAELCFRHFGGQVKYWITIDNPYVVAWHGYATGRLAPGIRGSPRLGYLVAHNLLLAHAKVWHLYNTSFRPTQGGQVSIALSSHWINPRRMTDHSIKECQKSLDFVLGWFAKPVFIDGDYPESMKNNLSSILPDFTESEKKFIKGTADFFALCFGPTLSFQLLDPHMKFRQLESPNLRQLLSWIDLEFNHPQIFIVENGWFVSGTTKRDDAKYMYYLKKFIMETLKAIKLDGVDVIGYTAWSLMDGFEWHRGYSIRRGLFYVDFLSQDKMLLPKSSALFYQKLIEKNGFPPLPENQPLEGTFPCDFAWGVVDNYIQVDTTLSQFTDLNVYLWDVHHSKRLIKVDGVVTKKRKSYCVDFAAIQPQIALLQEMHVTHFRFSLDWALILPLGNQSQVNHTILQYYRCMASELVRVNITPVVALWQPMAPNQGLPRLLARQGAWENPYTALAFAEYARLCFQELGHHVKLWITMNEPYTRNMTYSAGHNLLKAHALAWHVYNEKFRHAQNGKISIALQADWIEPACPFSQKDKEVAERVLEFDIGWLAEPIFGSGDYPWVMRDWLNQRNNFLLPYFTEDEKKLIQGTFDFLALSHYTTILVDSEKEDPIKYNDYLEVQEMTDITWLNSPSQVAVVPWGLRKVLNWLKFKYGDLPMYIISNGIDDGLHAEDDQLRVYYMQNYINEALKAHILDGINLCGYFAYSFNDRTAPRFGLYRYAADQFEPKASMKHYRKIIDSNGFPGPETLERFCPEEFTVCTECSFFHTRKSLLAFIAFLFFASIISLSLIFYYSKKGRRSYKLEDYKDDDDK(配列番号151)。
FabとしてFGFR1を活性化するR1MAbsの能力に基づいて、より低い親和性のR1MAbのより高い親和性の抗KLB抗体への連結を組み込んだ分子が、抗KLB/抗FGFR1二重特異性抗体を生成するために産生された(図6A;国際公開第2012/158704号)。
BsAb10及びその誘導体(BsAb11−20)並びにFGF21の更なる特徴付けは、幾つかの類似点と相違点を明らかにした。MAPKシグナル伝達中間体のリン酸化レベルを決定するために、細胞はFBS、L−グルタミン及びGA−1000を含有する前脂肪細胞基本培地−2中で増殖させた。コンフルエント後、(Lonzaから取得した)皮下前脂肪細胞は、デキサメタゾン、インドメタシン、3−イソブチル−1−メチルキサンチン(IBMX)を含有する増殖培地中で分化させた。遺伝子発現解析のために、細胞を14日間分化させ、次いで指示されたアゴニストとともに更に48時間培養した。MAPKシグナル伝達解析のために、細胞を10日間分化させ、3時間無血清培地中で増殖させ、次いで、指示されたアゴニストとともに更なる時間培養した。
アクセプター結合ベンジルグアニンSNAPAlexa647(NEB)の1μMにより37℃、5%CO2で1時間標識された。3回洗浄した後、Lumi4−Tbの発光とTR−FRETシグナルは、リガンド添加後、T=0及びt=15分でSafire2プレートリーダー(Tecan)を使用して、343nmでのレーザー励起後60μs遅れて400μsの間、それぞれ620nm及び665nmで記録された。Alexa647の発光シグナルは、同じプレートリーダーを用いて640nmでの励起後682nmで検出された。FRET強度は次のように計算された:(SNAP−ドナー及びSNAPアクセプターにより標識された細胞からの665nmでのシグナル)−(SNAPドナーにより標識され及びSNAPにより標識されないトランスフェクト細胞の同じバッチからの665nmでのシグナル)。
上記のように、マウス受容体複合体とBsAb10及びその誘導体の交差反応性(例えば、図6C及び図10Bを参照)は、マウスモデルにおけるそのインビボ活性の試験を可能にした。IgGのエフェクター機能の潜在的な毒性を回避するために、デュアル変異[D265A/N297G]がBsAb20に対してそのFc領域において導入され、FcgRsへの結合及び免疫エフェクター細胞の動員を消失させた。更に、IgGのエフェクター機能の潜在的な毒性を回避するために、N297GがBsAb17に対してそのFc領域において導入され、FcgRsへの結合及び免疫エフェクター細胞の動員を消失させた。
8C5のマウス軽鎖CDRがヒトKappa2及びKappa4軽鎖フレームワークに移植された。ヒトKappa2及びKappa4軽鎖フレームワークに移植された。一次移植に加えて、軽鎖の位置4がロイシンに変換されるように(「M4L」と命名)点変異もまたそれぞれで生成された。分析は、最高に発現されかつ有意な凝集を示さなかったものを同定するために実施された。同様に、重鎖CDRは、ヒトH1、H2、H3及びH4 IgG1重鎖フレームワークに移植された。重鎖バックボーンにおける様々な残基が次のように変異された:H1に対しては以下の変更が導入された:K71R、N73T及びV78A(親では「KNV」と命名され、構築物は「RTA」と命名);H2に対しては以下の変更が導入された:N73T(親では「KNV」と命名され、構築物は「KTV」と命名);H3に対しては以下の変更が導入された:K71R及びV78L(親では「KNV」と命名され、構築物は「RNL」と命名);及びH4に対しては以下の変更が導入された:K71V、N73T、及びV78F(親では「KNV」と命名され、構築物は「VTF」と命名)。
8C5.K4.M4L.H3.KNV 重鎖可変領域
EVQLVESGGGLVQPGGSLRLSCAASDFSLTTYGVHWVRQAPGKGLEWLGVIWSGGSTDYNAAFISRLTISKDNSKNTVYLQMNSLRAEDTAVYYCARDYGSTYVDAIDYWGQGTLVTVSS(配列番号128)
8C5.K4.M4L.H3.KNV 完全重鎖
EVQLVESGGGLVQPGGSLRLSCAASDFSLTTYGVHWVRQAPGKGLEWLGVIWSGGSTDYNAAFISRLTISKDNSKNTVYLQMNSLRAEDTAVYYCARDYGSTYVDAIDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号129)
8C5.K4.M4L.H3.KNV 軽鎖可変領域
DIVLTQSPDSLAVSLGERATINCRASESVESYGNRYMTWYQQKPGQPPKLLIYRAANLQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSNEDPWTFGQGTKVEIK(配列番号130)
8C5.K4.M4L.H3.KNV 完全軽鎖
DIVLTQSPDSLAVSLGERATINCRASESVESYGNRYMTWYQQKPGQPPKLLIYRAANLQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSNEDPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号131)
抗FGFR1アームの非存在下においてKLB/FGFR1c複合体を活性化しない抗FGFR1アームであるYW182.5は、8C5と組み合わされる場合に良好な結果を与えることが見いだされており、酸化を受けやすい重鎖の位置33としてトリプトファンを有する。YW182.5と同じエピトープに結合するように思われるYW182.2もまた、重鎖の位置33にトリプトファンを有する。この問題を解消するために、幾つかの変異がこの位置に導入された:YW182.5については、W33Y、W33H、W33F及びW33Lが導入され、YW182.2についてはW33Y及びW33Fが導入された。驚くべきことに、導入された変異は、二つの抗体で異なる作用を有する。YW182.2の場合には、変異はFGFR1に対する親和性又はアゴニスト活性に認識できるほどには影響を及ぼさなかったが、一方YW182.5においては、変異はFGFR1に対する親和性及びアゴニスト活性を大きく減少させることが観察された(例えば、図31参照)。従って、W33Y変異を有するが、YW182.5抗体の親和性と近い親和性を有する抗体を同定するために実験が2つのアプローチを使用して実施された。
YW182.5_YGDY 重鎖可変領域
EVQLVESGGGLVQPGGSLRLSCAASGFTFTSNYISWVRQAPGKGLEWVGEIDPYDGDTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCATGTDVMDYWGQGTLVTVSS(配列番号132)。
YW182.5_YGDY 完全重鎖
EVQLVESGGGLVQPGGSLRLSCAASGFTFTSNYISWVRQAPGKGLEWVGEIDPYDGDTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCATGTDVMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号133)。
YW182.5_YGDY 軽鎖可変領域
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK(配列番号134)。
YW182.5_YGDY 完全軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号135)
8C5.K4H3.M4L.KNVと異なる抗FGFR1アームの種々の二重特異性抗体の組み合わせが、KLBの有無にかかわらずFGFR1cを発現しているHEK293細胞におけるGAL−ELK1ベースルシフェラーゼアッセイで試験された。以前に観察されたように、各二重特異性抗体の組み合わせは、KLBを発現しない細胞においてでなく、組換えhFGFR1cとhKLBを発現する細胞中で用量依存的にルシフェラーゼ活性を誘導した(図30)。これらのデータは、これらの修飾された変異体は、親抗体、例えばBsAb13の利点を保持することを確認する。HEK293細胞の表面上のヒト、カニクイザル及びマウスKLB/FGFR1c複合体への、ヒト化8C5アーム(8C5.K4.M4L.H3.KNV)及びYW182.5_YGDYアームを有する抗KLB/抗FGFR1抗体の結合親和性が表10に示される。
Claims (53)
- β−クロトー(KLB)及び線維芽細胞増殖因子受容体1(FGFR1)に結合する単離された二重特異性抗体又はその抗原結合部分。
- 抗体又はその抗原結合部分が、KLBのC末端ドメインに結合する、請求項1に記載の抗体。
- 抗体又はその抗原結合部分が、配列番号142に記載のアミノ酸配列を含むKLBの断片に特異的に結合する、請求項1に記載の抗体。
- 抗体又はその抗原結合部分が、配列番号143又は配列番号144に記載のアミノ酸配列を含むFGFR1cの断片内のFGFR1エピトープに結合する、請求項1−3の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、インビボで血中グルコースレベルを低下させる、請求項1−4の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、骨密度に有意に影響を与えない、請求項1−5の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、肝臓に有意に影響を与えない、請求項1−6の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、肝臓においてERK及びMEKのリン酸化を、FGF21が誘導するよりも有意に低いレベルで誘導する、請求項1−7の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、10−8Mから10−13MのKdでKLBと結合する、請求項1−8の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、約10nMから約10μMのKdでFGFR1cに結合する、請求項1−9の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、モノクローナル抗体である、請求項1−10の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、ヒト、ヒト化、又はキメラ抗体である、請求項1−11の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、重鎖可変領域及び軽鎖可変領域を含み、重鎖可変領域が、配列番号128に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み、軽鎖可変領域が、配列番号130に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含む、請求項1−12の何れか一項に記載の抗体。
- 抗体又はその抗原結合部分が、
(a)配列番号1−15からなる群から選択されるアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR1;
(b)配列番号16−31からなる群から選択されるアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR2ドメイン;
(c)配列番号32−47からなる群から選択されるアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR3ドメイン;
(d)配列番号48−62からなる群から選択されるアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR1ドメイン;
(e)配列番号63−78からなる群から選択されるアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR2ドメイン;及び
(f)配列番号79−93からなる群から選択されるアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR3ドメイン
を含む、請求項1−12の何れか一項に記載の抗体。 - 抗体又はその抗原結合部分が、
(a)配列番号15に記載のアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR1ドメイン;
(b)配列番号31に記載のアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR2ドメイン;
(c)配列番号47に記載のアミノ酸配列及びその保存的置換を含む重鎖可変領域CDR3ドメイン;
(d)配列番号62に記載のアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR1ドメイン;
(e)配列番号78に記載のアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR2ドメイン;
(f)配列番号93に記載のアミノ酸配列及びその保存的置換を含む軽鎖可変領域CDR3ドメイン
を含む、請求項1−12の何れか一項に記載の抗体。 - (a)配列番号1−15からなる群から選択されるアミノ酸配列を含むHVR−H3、(b)配列番号79−93からなる群から選択されるアミノ酸配列を含むHVR−L3、及び(c)配列番号16−31からなる群から選択されるアミノ酸配列を含むHVR−H2を含む、抗β−クロトー抗体又はその抗原結合部分。
- 抗体又はその抗原結合部分が、(a)配列番号1−15からなる群から選択されるアミノ酸配列を含むHVR−H1、(b)配列番号16−31からなる群から選択されるアミノ酸配列を含むHVR−H2、及び(c)配列番号32−47からなる群から選択されるアミノ酸配列を含むHVR−H3を含む、請求項16に記載の抗体。
- (a)配列番号48−62からなる群から選択されるアミノ酸配列を含むHVR−L1、(b)配列番号63−78からなる群から選択されるアミノ酸配列を含むHVR−L2、及び(c)配列番号79−93からなる群から選択されるアミノ酸配列を含むHVR−L3を更に含む、請求項17に記載の抗体。
- 抗体又はその抗原結合部分が、(a)配列番号12のアミノ酸配列を含むHVR−H1、(b)配列番号28のアミノ酸配列を含むHVR−H2、(c)配列番号44のアミノ酸配列を含むHVR−H3、(d)配列番号59のアミノ酸配列を含むHVR−L1、(e)配列番号75のアミノ酸配列を含むHVR−L2、及び(f)配列番号90のアミノ酸配列を含むHVR−L3を含む、請求項18に記載の抗体。
- 抗体又はその抗原結合部分が、(a)配列番号15のアミノ酸配列を含むHVR−H1、(b)配列番号31のアミノ酸配列を含むHVR−H2、(c)配列番号47のアミノ酸配列を含むHVR−H3、(d)配列番号62のアミノ酸配列を含むHVR−L1、(e)配列番号78のアミノ酸配列を含むHVR−L2、及び(f)配列番号93のアミノ酸配列を含むHVR−L3を含む、請求項18に記載の抗体。
- 抗体又はその抗原結合部分が、(a)配列番号128のアミノ酸配列を含む重鎖可変領域及び(b)配列番号130のアミノ酸配列を含む軽鎖可変領域を含む、請求項20に記載の抗体。
- 抗体又はその抗原結合部分が、(a)配列番号129のアミノ酸配列を含む重鎖、及び(b)配列番号131のアミノ酸配列を含む軽鎖を含む、請求項20に記載の抗体。
- 請求項16−21に記載の任意の抗体の結合を競合的に阻害する、抗KLB抗体又はその抗原結合部分。
- 抗体又はその抗原結合部分が、12A11又は8C5抗体と同じエピトープに結合する、請求項23に記載の抗体。
- 抗体又はその抗原結合部分が、KLBのC末端ドメイン内のエピトープに結合する、請求項23に記載の抗体。
- 抗体が、アミノ酸配列SSPTRLAVIPWGVRKLLRWVRRNYGDMDIYITAS(配列番号142)からなるKLBの断片内のKLBエピトープに結合する、請求項25に記載の抗体。
- (a)配列番号128のアミノ酸配列に少なくとも95%の配列同一性を有する重鎖可変領域;(b)配列番号130のアミノ酸配列に少なくとも95%の配列同一性を有する軽鎖可変領域;及び(c)(a)に記載の重鎖可変領域及び(b)に記載の軽鎖可変領域を含む抗KLB抗体又はその抗原結合部分。
- 抗体が二重特異性抗体である、請求項16−27の何れか一項に記載の抗体。
- 抗体が、FGFR1に結合する可変ドメインを含む、請求項28に記載の抗体。
- FGFR1がFGFR1cである、請求項28に記載の抗体。
- 抗体が、アミノ酸配列KLHAVPAAKTVKFKCP(配列番号143)又はFKPDHRIGGYKVRY(配列番号144)からなるFGFR1cの断片に結合する、請求項30に記載の抗体。
- 抗体が、(a)配列番号136のアミノ酸配列を含むHVR−H1、(b)配列番号137のアミノ酸配列を含むHVR−H2、(c)配列番号138のアミノ酸配列を含むHVR−H3、(d)配列番号139のアミノ酸配列を含むHVR−L1、(e)配列番号140のアミノ酸配列を含むHVR−L2、及び(f)配列番号141のアミノ酸配列を含むHVR−L3を含む、請求項30に記載の抗体。
- 抗体が、(a)配列番号132のアミノ酸配列を含む重鎖可変領域及び(b)配列番号134のアミノ酸配列を含む軽鎖可変領域を含む、請求項30に記載の抗体。
- 抗体が、(a)配列番号133のアミノ酸配列を含む重鎖及び(b)配列番号135のアミノ酸配列を含む軽鎖を含む、請求項30に記載の抗体。
- (a)重鎖可変領域及び軽鎖可変領域を含む第一抗体又はその抗原結合部分を含み、ここで、重鎖可変領域は、配列番号128に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み、軽鎖可変領域は、配列番号130に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み;且つ
(b)重鎖可変領域及び軽鎖可変領域を含む第二抗体又はその抗原結合部分を含み、ここで、重鎖可変領域は、配列番号132に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み、軽鎖可変領域は、配列番号134に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含む、単離された抗KLB/抗FGFR1二重特異性抗体。 - (a)重鎖領域及び軽鎖領域を含む第一抗体又はその抗原結合部分を含み、ここで、重鎖領域は、配列番号129に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み、軽鎖領域は、配列番号131に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み;且つ
(b)重鎖領域及び軽鎖領域を含む第二抗体又はその抗原結合部分を含み、ここで、重鎖領域は、配列番号133に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含み、軽鎖領域は、配列番号135に記載の配列に対して少なくとも95%同一である配列を有するアミノ酸を含む、単離された抗KLB/抗FGFR1二重特異性抗体。 - 請求項1−36の何れか一項に記載の抗体をコードする単離された核酸。
- 請求項37に記載の核酸を含む宿主細胞。
- 抗体が産生されるように、請求項38に記載の宿主細胞を培養することを含む、抗体を産生する方法。
- 宿主細胞から抗体を回収することを更に含む、請求項39に記載の方法。
- 請求項1−36の何れか一項に記載の一以上の抗体及び薬学的に許容可能な担体を含む、薬学的製剤。
- 付加的治療剤を更に含む、請求項41に記載の薬学的製剤。
- 医薬としての使用のための、請求項1−36の何れか一項に記載の抗体。
- 多嚢胞性卵巣症候群(PCOS)、メタボリックシンドローム(MetS)、肥満症、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪肝疾患(NAFLD)、高脂血症、高血圧、2型糖尿病、非2型糖尿病、1型糖尿病、潜在性自己免疫性糖尿病(LAD)、及び若年発症成人型糖尿病(MODY)、並びに老化及びアルツハイマー病、パーキンソン病及びALSなどの関連疾患からなる群から選択される障害を治療することにおける使用のための、請求項1−36の何れか一項に記載の抗体。
- KLB/FGFR1受容体複合体を活性化することにおける使用のための、請求項1−36の何れか一項に記載の抗体。
- 代謝障害の治療のための医薬の製造における、請求項1−36の何れか一項に記載の抗体の使用。
- KLB/FGFR1受容体複合体を活性化するための医薬の製造における、請求項1−36の何れか一項に記載の抗体の使用。
- 代謝障害が糖尿病である、請求項46に記載の使用。
- 多嚢胞性卵巣症候群(PCOS)、メタボリックシンドローム(MetS)、肥満症、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪肝疾患(NAFLD)、高脂血症、高血圧、2型糖尿病、非2型糖尿病、1型糖尿病、潜在性自己免疫性糖尿病(LAD)、及び若年発症成人型糖尿病(MODY)、並びに老化及びアルツハイマー病、パーキンソン病及びALSなどの関連疾患、バルデ−ビードル症候群、プラダー・ウィリー症候群、アルストレーム症候群、コーエン症候群、オルブライト遺伝性骨異栄養症(偽性副甲状腺機能低下)、カーペンター症候群、MOMO症候群、ルービンスタイン−テービ症候群、脆弱X症候群及びBorjeson−フォルスマン・リーマン症候群からなる群から選択される疾患を有する個体を治療する方法であって、請求項1−36の何れか一項に記載の一以上の抗体の有効量を個体に投与することを含む方法。
- 疾患が糖尿病である、請求項49に記載の方法。
- 付加的治療剤を個体へ投与することを更に含む、請求項49に記載の方法。
- 請求項1−36の何れか一項に記載の抗体の有効量を個体に投与することを含む、個体においてKLB−FGFR1受容体複合体を活性化する方法。
- 抗体又はその抗原結合部分が、KLB−FGFR1c複合体を活性化する、請求項1−36の何れか一項に記載の抗体。
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2014
- 2014-12-22 TW TW103144843A patent/TWI670283B/zh active
- 2014-12-22 TW TW108119185A patent/TWI728373B/zh active
- 2014-12-23 ES ES14827379T patent/ES2926375T3/es active Active
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