JP7026613B2 - 標的分子に対する抗原結合コンストラクト - Google Patents
標的分子に対する抗原結合コンストラクト Download PDFInfo
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Description
本出願は、本明細書にその全体が参照により援用される2015年8月7日付けで出願された米国仮出願第62/202,665号の利益を主張する。
本出願は、電子フォーマットで配列リストと共に出願されている。配列リストは、IGNAB030WOSEQUENCE.TXTというタイトルのファイルとして提供され、これは2016年8月3日に作成され最終更新され、そのサイズは、270,446バイトである。電子配列リスト中の情報は、本明細書にその全体が参照により援用される。
本明細書に記載される実施形態は、一般的に、抗原結合コンストラクト(例えば、あらゆるscFv融合タンパク質、例えばミニボディ等)におけるヒンジ構造、及び抗原結合コンストラクトそれ自体、及びそれらを使用するための方法に関する。
a)SEQ ID NO:1(Xn1CXn2Xn3CXn4Xn5C)の配列を含むアミノ酸ヒンジ領域であって、式中、Xn1は、共有結合による架橋結合を天然に形成しない任意のアミノ酸であってよく、Xn2は、A、R、N、D、E、Q、G、H、I、L、K、M、F、P、S、T、W、Y、又はVの1つであり、Xn3は、任意のアミノ酸であってよく、Xn4は、任意のアミノ酸であってよく、Xn5は、任意のアミノ酸であってよい、アミノ酸ヒンジ領域;
b)SEQ ID NO:2(Xn1Xn2Xn3Xn4Xn5Xn6CXn7Xn8CXn9Xn10C)の配列を含むアミノ酸ヒンジ領域であって、式中、Xn1は、任意のm個のアミノ酸であってよく(ここでmは、任意のタイプのアミノ酸の任意の数である)、Xn2は、任意のアミノ酸であってよく、Xn3は、任意のアミノ酸であってよく、Xn4は、任意のアミノ酸であってよく、Xn5は、任意のアミノ酸であってよく、Xn6は、システイン以外の任意のアミノ酸であってよく、Xn7は、任意のアミノ酸であってよく、Xn8は、任意のアミノ酸であってよく、Xn9は、任意のアミノ酸であってよく、Xn10は、任意のアミノ酸であってよい、アミノ酸ヒンジ領域;
c)ELKTPLGDTTHT(SEQ ID NO:48)又はEPKSSDKTHT(SEQ ID NO:46)の上部ヒンジ配列に連結された、CVECPPCP(SEQ ID NO:57)、CPPCPPC(SEQ ID NO:52)、又はCPPCPPCPPC(SEQ ID NO:54)、又はCPPCVECPPC(SEQ ID NO:53)のうちの少なくとも1つのコアヒンジ配列;
d)対応するアミノ酸と架橋を形成することが可能なアミノ酸を含まない上部ヒンジ領域;及び上部ヒンジ領域のC末端に接続された、鎖1本当たり少なくとも3つのシステインを含むコアヒンジ領域;
e)コアヒンジ領域を含む抗体及び/又はミニボディであって、コアヒンジ領域は、鎖1本当たり少なくとも3つのシステインを含み、コアヒンジ領域内に少なくとも3つのジスルフィド結合を形成する、抗体及び/又はミニボディ;又は
f)第1の変更されたアミノ酸位置であって、天然抗体のヒンジ中ではシステインと予想されるアミノ酸であり、そのアミノ酸がジスルフィド結合を形成しないように、第1の変更された位置で変更されている、アミノ酸位置;及び第1の変更されたアミノ酸位置のC末端における、鎖1本当たり少なくとも3つのシステイン
のうちの少なくとも1つを含む。
用語「ヒンジ」は、抗原結合コンストラクト、例えば抗体又はミニボディのためのヒンジ領域の少なくとも一部を意味する。ヒンジ領域は、上部ヒンジ、コア(又は中央)ヒンジ及び下部ヒンジ領域の組合せを包含していてもよい。一部の実施形態において、ヒンジは、抗体のヒンジの定義のいずれかに従って定義される。自然のIgG1、IgG2、及びIgG4抗体は、12~15アミノ酸を有するヒンジ領域を有する。IgG3は、21個のプロリン及び11個のシステインを包含する62アミノ酸を有する伸長したヒンジ領域を有する。結晶学的な研究から推測された天然に存在する抗体の機能的なヒンジ領域は、IgG1のH鎖のアミノ酸残基216~237(EU番号付け;参照番号12)から伸長しており、下部ヒンジにCH2ドメインのN末端の小さいセグメントを包含し、ここで下部ヒンジは、CH2ドメインのN末端である。ヒンジは、3つの領域;「上部ヒンジ」、「コア」、及び「下部ヒンジ」に分割することができる。
ng high affinity human antibodies by chain shuffling」、Biotechnology (N. Y.)、10巻、7号、779~783頁、1992を参照)。
本明細書では、ヒンジ領域内の配列が様々な抗原結合コンストラクトと特別な関連性を有していてもよいと認識されている。一部の実施形態において、ヒンジ領域の価値は、例えばミニボディのアレンジメント等において特に高い可能性がある。ヒンジ内の配列は、ヒンジの機能に有用なジスルフィド結合を包含していてもよいが、変更される場合、様々な結果をもたらす可能性がある。本明細書で開示されるように、更に以下の実施例に示されるように、一部の実施形態において、ヒンジ領域配列は、タンパク質の他の領域中に存在するシステイン残基との望ましくないジスルフィドの混乱を防止及び/又は低減する、及び/又はインビボで二量体の完全性を維持するのに十分な数のシステイン対を含有する、コンカテマーが形成されないようにする、及び/又は対合したシステインの1つへの部位特異的なコンジュゲーションを可能にするように設計されていてもよい。
ことを示す。
一部の実施形態において、本明細書で提供されるヒンジは、あらゆるミニボディ又は他の抗原結合コンストラクト組成物を形成する及び/又はそれらの中に存在する半分の分子の百分率を低減することを可能にする。例えば、組成物の7%未満が半分の分子であってもよく、例えば、組成物の6、5、4、3、2、1、及び/又は0.5%未満等の範囲が、半分の分子である。
標的に結合する抗原結合コンストラクトが本明細書に記載される。抗原結合コンストラクトは、標的分子に特異的に結合するか、又は標的分子と免疫学的に反応性を有する、免疫グロブリン又は免疫グロブリン関連分子の1つ又は複数の部分を包含する分子である。一部の実施形態において、本明細書で提供されるヒンジの実施形態のいずれかは、あらゆる所望の抗原結合コンストラクトに適用することができる。一部の実施形態において、本明細書で提供されるヒンジの実施形態のいずれかは、ミニボディに適用することができる。一部の実施形態において、本明細書で提供されるヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。PSMA抗原の非限定的な実施形態は、図70に示される。PSCA抗原の非限定的な実施形態は、図71に示される。5T4抗原の非限定的な実施形態は、図72に示される。CD8抗原の一部の非限定的な実施形態は、図73及び図74に示される。CD3抗原の一部の非限定的な実施形態は、図75~図78に示される。一部の実施形態において、本明細書で提供されるヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに特異的及び/又は選択的に結合するミニボディに適用することができる。一部の実施形態において、Table 0.1(表1)又は3に示されるヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、全ヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、上部ヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、コアヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、下部ヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、上部及びコアヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、コア及び下部ヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。一部の実施形態において、上部及び下部ヒンジの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。
NO:98におけるLCDR3の軽鎖CDR3(LCDR3)を包含する。一部の実施形態において、CD3に対する抗原結合コンストラクトは、図65B又は図65CにおけるHCDR1の重鎖CDR1(HCDR1);図65B又は図65CにおけるHCDR2の重鎖CDR2(HCDR2);図65B又は図65CにおけるHCDR3の重鎖CDR3(HCDR3);図65B又は図65CにおけるLCDR1の軽鎖CDR1(LCDR1);図65B又は図65CにおけるLCDR2の軽鎖CDR2(LCDR2);及び/又は図65B又は図65CにおけるLCDR3の軽鎖CDR3(LCDR3)を包含する。Table 8(表4)に、本明細書で提供されるヒンジ配列のいずれか1つ又は複数と共に使用することができるCDR配列の一部の実施形態を示す。
部の実施形態において、これらの実施形態のいずれかは、CD8、CD3、5T4、PSCA、又はPSMAに結合するミニボディに適用することができる。
とができる。
一部の実施形態において、重鎖及び軽鎖可変ドメインは、個々の抗原結合コンストラクトにつき異なる方法で会合していてもよい。この理由のために、VH及びVLドメイン間の異なるリンカー長さの使用が、ジスルフィド結合が確実に形成されるような立体配座のフレキシビリティー及び可動域をもたらすことができる。
一部の実施形態において、抗原結合コンストラクトのポリペプチドは、核酸によってコードされ、インビボ又はインビトロで発現されてもよく、又はこれらのペプチドは、化学的に合成されてもよい。したがって、一部の実施形態において、抗原結合コンストラクトをコードする核酸が提供される。一部の実施形態において、核酸は、ミニボディ又は他の抗原結合コンストラクトの一部分又は単量体をコードする。一部の実施形態において、核酸は、2つ以上の単量体、例えば、少なくとも2つの単量体をコードする。複数の単量体をコードする核酸は、少なくとも2つの単量体の間の核酸切断部位を包含していてもよく、2つ以上の単量体の間に転写又は翻訳開始部位をコードしていてもよく、及び/又は2つ以上の単量体の間にタンパク質分解の標的部位をコードしていてもよい。
一部の実施形態において、本明細書に記載される抗原結合コンストラクト(本明細書で提供されるヒンジの少なくとも下位部分を包含し得る)のうちの少なくとも1つを発現する細胞株が提供される。一部の実施形態において、本明細書に記載されるミニボディ、scFv、又は他の抗体を産生するための発現系は、哺乳類細胞株(例えば、CHO-K1細胞株)である。一部の実施形態において、本明細書に記載されるミニボディ、scFv、及び他の抗体又は抗体フラグメントは、非グリコシル化型であり、そのような翻訳後修飾を要しないため、哺乳類発現系は必要ではない。したがって、一部の実施形態において、多種多様の哺乳類又は非哺乳類発現系の1つ又は複数を使用して、本明細書で開示された抗原結合コンストラクト(例えば、ミニボディ)を産生することができ、このような発現系としては、これらに限定されないが、哺乳類発現系(例えば、CHO-K1細胞)、細菌発現系(例えば、大腸菌(E. coli)、枯草菌(B. subtilis))、酵母発現系(例えば、ピチア属(Pichia)、サッカロミセス・セレビシエ(S. cerevisiae))又はあらゆる他の公知の発現系等が挙げられる。他の系としては、昆虫細胞及び/又は植物細胞を挙げることができる。
一部の実施形態において、抗原結合コンストラクトは、少なくとも1つの改変を包含する。例示的な改変としては、これらに限定されないが、糖付加、アセチル化、ペグ化、リン酸化、アミド化、公知の保護/ブロッキング基による誘導体化、タンパク質分解による切断、及び細胞性リガンド又は他のタンパク質への連結によって改変された抗原結合コンストラクトが挙げられる。多数の化学修飾のいずれも、これらに限定されないが、特異的な化学的切断、アセチル化、及びツニカマイシンの代謝合成等の公知の技術によって行うことができる。一部の実施形態において、誘導体は、1つ又は複数の非天然アミノ酸を含有していてもよい。
一部の実施形態において、改変された抗原結合コンストラクトは、検出可能なマーカーにコンジュゲートされている。本明細書で使用される場合、「検出可能なマーカー」は、標的分子、細胞、組織、臓器等の配置及び/又は量を診断、検出又は可視化することにおいて有用な原子、分子、又は化合物を包含する。本明細書に記載の実施形態に従って使用され得る検出可能なマーカーとしては、これらに限定されないが、放射活性物質(例えば、放射性同位体、放射性核種、放射標識又は放射性トレーサー)、色素、造影剤、蛍光化合物又は分子、生物発光化合物又は分子、酵素及び増強剤(例えば、常磁性イオン)が挙げられる。加えて、一部のナノ粒子、例えば量子ドット及び金属ナノ粒子(後述される)が、検出剤として使用するのに好適であり得る。一部の実施形態において、検出可能なマーカーは、インドシアニングリーン(ICG)、ジルコニウム-89、IR800、及び/又は別の近赤外色素である。
一部の実施形態において、医薬組成物はまた、医薬的に許容される担体を包含していてもよい。医薬的に許容される担体は、1つの組織、臓器、又は体の一部から別の組織、臓器、又は体の一部に目的の化合物を運搬又は輸送することに関与する、医薬的に許容される材料、組成物、又はビヒクルであってもよい。例えば、担体は、液体又は固体の増量剤、希釈剤、賦形剤、溶媒、若しくは封入材料、又はそれらのいくつかの組合せであってもよい。担体の各成分は、配合物の他の成分に適合するという点で「医薬的に許容される」。担体はまた、それが遭遇する可能性があるあらゆる組織、臓器、又は体の一部との接触にとって好適でもあり、これは、理想的には、その治療的利益を過剰に上回る毒性、炎症、アレルギー性反応、免疫原性、又は他のあらゆる合併症の有意なリスクをもたらさないと予想されることを意味する。
ンターフェロンアルファ、インターロイキン-2、インターロイキン-11、イソトレチノイン、イキサベピロン、イダルビシン、メシル酸イマチニブ、イフォスファミド、イリノテカン、ラパチニブ、レナリドマイド、レトロゾール、ロイコボリン、ロイプロリド、リポソームAra-C、ロムスチン、メクロレタミン、メゲストロール、メルファラン、メルカプトプリン、メスナ、メトトレキセート、メチルプレドニゾロン、マイトマイシンC、ミトタン、ミトキサントロン、ネララビン、ニルタミド、オクトレオチド、オプレルベキン、オキサリプラチン、パクリタキセル、パミドロネート、ペメトレキセド、パニツムマブ、PEGインターフェロン、ペグアスパルガーゼ、ペグフィルグラスチム、PEG-L-アスパラギナーゼ、ペントスタチン、プリカマイシン、プレドニゾロン、プレドニゾン、プロカルバジン、ラロキシフェン、リツキシマブ、ロミプロスチム、ラルチトレキセド(ralitrexed)、サパシタビン(sapacitabine)、サルグラモスチム、サトラプラチン、ソラフェニブ、スニチニブ、セムスチン、ストレプトゾシン、タモキシフェン、テガフール、テガフール-ウラシル、テムシロリムス、テモゾロミド(temozolamide)、テニポシド、サリドマイド、チオグアニン、チオテパ、トポテカン、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン、トリメトレキサート(trimitrexate)、アムルビシン(alrubicin)、ビンクリスチン、ビンブラスチン、ビンデシン(vindestine)、ビノレルビン、ボリノスタット、又はゾレドロン酸が挙げられる。
一部の実施形態において、キットが提供される。一部の実施形態において、キットは、本明細書に記載される抗原結合コンストラクトを包含する。一部の実施形態において、キットは、本明細書に記載される抗原結合コンストラクトをコードする核酸を包含する。一部の実施形態において、キットは、本明細書に記載される抗原結合コンストラクトを産生する細胞株を包含する。一部の実施形態において、キットは、本明細書に記載される検出可能なマーカーを包含する。一部の実施形態において、キットは、本明細書に記載される治療剤を包含する。一部の実施形態において、キットは、緩衝液を包含する。一部の実施形態において、キットは、陽性対照、例えば標的特異的な細胞、又はそのフラグメントを包含する。一部の実施形態において、キットは、陰性対照、例えば標的を実質的に含まない表面又は溶液を包含する。一部の実施形態において、キットは、パッケージングを包含する。一部の実施形態において、キットは、説明書を包含する。
抗原結合コンストラクトは、インビボ及び/又はインビトロで標的分子の有無を検出するのに使用することができる。したがって、一部の実施形態は、標的の有無を検出する方法を包含する。本方法は、試料に抗原結合コンストラクトを適用することを包含していてもよい。本方法は、抗原結合コンストラクトが標的分子に結合すること又は結合しないことを検出することを包含していてもよい。一部の実施形態において、本明細書で提供される選択肢を介して、あらゆる標的分子を検出することができる。一部の実施形態において、検出しようとする標的分子は、5T4、CD8、CD3、PSCA、又はPSMAの1つ又は複数である。一部の実施形態において、標的分子は、図面及び/又は例えばTable 0.2(表2)等の表に示されるミニボディのアレンジメントの1つ又は複数を使用して(又は少なくともTable 0.1(表1)で概説したヒンジアレンジメントを採用して)検出される。
抗原結合コンストラクトは、治療用分子、例えば細胞毒素を、標的陽性細胞、例えば標的分子を発現する細胞等に標的化するのに使用することができる。したがって、一部の実施形態は、治療剤を標的陽性細胞に標的化する方法を包含する。本方法は、本明細書に記載される抗原結合コンストラクトを対象に投与することを包含していてもよい。対象は、それを必要とする対象、例えば、少なくとも一部の標的陽性細胞の排除又は中和を必要とする対象であってもよい。一部の実施形態において、抗原結合コンストラクトは、少なくとも1つの本明細書に記載される治療剤を包含する。一部の実施形態において、治療剤は、共有結合、例えばジスルフィド結合等を介して抗原結合コンストラクトに直接コンジュゲートしていてもよい。一部の実施形態において、対象は、標的分子陽性細胞を別の細胞又は薬剤に局在化させることによって利益を得ることができる。
一部の実施形態において、本明細書で提供される組成物、方法(例えば、処置方法、作製方法、検出方法等)、キット、薬剤、抗原結合コンストラクトの改変、細胞株、核酸等のいずれも、あらゆる標的分子のために使用することができる。一部の実施形態において、標的分子は、がん免疫療法に関連するものであってもよい。一部の実施形態において、標的分子は、CD8、CD3、5T4、PSCA、又はPSMAの1つ又は複数、加えてそれらのバリアントであってもよい。
前立腺幹細胞抗原(PSCA)は、正常なヒト前立腺及び膀胱で発現される細胞表面糖タンパク質であり、前立腺がん(原発性腫瘍の40%、並びにリンパ節及び骨髄転移の60~100%)で過剰発現される。これはまた、膀胱及び膵臓癌の移行性癌でも高度に発現される。PSCAタンパク質の例は、SEQ ID NO:132で示される。IG8は、PSCAに特異的な抗PSCAマウスモノクローナル抗体であり、これは、インビボで抗腫瘍標的化活性を有することが実証された(Gu, Z.ら、「Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism」、Cancer Res.、65巻、20号、9495~9500頁、2005)。この抗体は、ヒトフレームワークにグラフト化することによってヒト化され(トラスツズマブ)、2B3と命名された(Olafsen, T.ら、「Targeting, imaging, and therapy using a humanized antiprostate stem cell antigen (PSCA) antibody」、Immunotherapy、30巻、4号、396~405頁、2007)。
PSMAを標的化する全長抗体が開発されており、その一部は前臨床及び臨床開発の様々な段階にある。PSMAは元々、マウス抗体(mAb)の7E11によって定義され、これは、PSMAの細胞内エピトープを認識するものであった(Olson, W. C.ら、「Clinical trials of cancer therapies targeting prostate-specific membrane antigen」、Rev. Recent Clin. Trials、2巻、3号、182~190頁、2007)。7E11 mAbをその後、FDAによって承認された、軟部組織における前立腺がんの検出及び画像化のためのプロスタシント(Prostascint)と称されるSPECT造影剤に発展させた。しかしながら、7E11は細胞内エピトープを認識するため、壊死した腫瘍組織を検出することに限定されるプロスタシントは、比較的不良な造影剤である(Olson, W. C.ら、2007)。プロスタシントはまた、全長抗体の薬物動態学的特性を有するため、注射と画像化との間に長い期間も要する。更に、プロスタシントは強い免疫反応を惹起するマウス抗体であるため、複数回の投与が妨げられる(Olson, W. C.ら、2007)。
c membrane antigen, in patients with androgen-independent prostate cancer」、J. Clin. Oncol.、23巻、21号、4591~4601頁、2005; Olson, W. C.ら、2007)。前立腺がん以外にも、111In-DOTA huJ591を用いた第I相の研究は、進行中の固形腫瘍の腫瘍新生血管の特異的な標的化を実証した(Milowsky, M. I.ら、「Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors」、J. Clin. Oncol.、25巻、5号、540~547頁、2007)。
CD8(表面抗原分類8)は、膜貫通糖タンパク質であり、細胞傷害性T細胞等のT細胞のサブクラスに特異的なマーカーである。CD8発現はまた、一部のナチュラルキラー及び樹状細胞に加えて、T細胞リンパ腫のサブセットにも存在する。CD8は、CD8アルファ及びCD8ベータサブユニットのヘテロ二量体又はCD8アルファのホモ二量体のいずれかとしてアセンブルする。アセンブルした二量体のCD8複合体は、T細胞受容体(TCR)と共に補助受容体として作用して、MHCクラスI細胞による抗原提示を認識する。CD8は、T細胞の発達及び成熟T細胞の活性化において役割を果たす。T細胞局在化の変化は、免疫反応の進行を反映する可能性があり、経時的に起こる可能性がある。CD8サブユニットの例は、SEQ ID NO:134及び135で示される。
5T4は、腫瘍胎児性糖タンパク質であり、これは、選択された成人組織では弱く発現されるが、結腸直腸がん、腎臓がん、乳がん、卵巣がん、胃がん、肺がん、及び前立腺がん等の様々な種類の癌腫では強く発現される。5T4発現は、原発性がんと転移がんの両方に見出され、発現レベルは、疾患の進行と互いに関係があることから、5T4は非常に有望なバイオマーカーになる。5T4タンパク質の例は、SEQ ID NO:133で示される。
CD3(表面抗原分類3)は、モノクローナル抗体OKT3と同時に発見された。最初のうちは、OKT3は、全ての成熟末梢T細胞に結合することが見出され、後になってTCR-CD3複合体の一部としてのCD3イプシロンサブユニットが、OKT3と結合する細胞表面抗原であることが決定された(Kung, P.ら、「Monoclonal antibodies defining distinctive human T cell surface antigens」、Science、206巻、4416号、347~349頁、1979)。CD3サブユニットの例は、SEQ ID NO:136~139で示される。続いてOKT3は、移植による拒絶反応のための免疫抑制剤として試験され、初期の試験では急性腎同種移植片拒絶反応が研究された(Cosimi, A. B.ら、「Treatment of acute renal allograft rejection with OKT3 monoclonal antibody」、Transplantation、32巻、6号、535~539頁、1981)。
一部の実施形態において、scFv又はミニボディは、画像診断にとって優れた薬物動態学的特性を有する。現在の技術は、インタクトな抗体を用いた画像化を利用しているが、これは、全長抗体の遅い血清クリアランスのために、高コントラストの画像をもたらすには相当長い時間(注射後約7日)を要する。ミニボディは、同じ日の又は次の日に画像化するための機会を提供する。進行が速い疾患を有する患者にとっては1日1日が生死にかかわることから、初期の時点で適した治療アプローチを同定することができれば、患者の生存率が改善される可能性がある。全長抗体に対してミニボディを用いて画像化する場合、移動滞在の期間又は1週間後に戻る必要性がなくなると予想されるため、同じ日の又は次の日の画像化は、処置/診断を受けるために長い距離を移動する多くの患者が直面する問題に対してロジスティックな解決法も提供する。一部の実施形態において、より低い放射線量への曝露は、複数回の画像化と経時的な疾患進行の追跡を可能にする。
原を発現する細胞に架橋することができる。
ミニボディは、2価の共有結合で結合した約80kDaのホモ二量体である。各単量体(半分の分子)は、およそ15~18アミノ酸のGly-Serリッチリンカー配列によって対応する可変軽鎖(VL)ドメインに連結された可変重鎖(VH)ドメインで構成される。各単鎖可変フラグメント(scFv)は、ヒンジ配列によりヒトIgGのCH3ドメインに連結されている。
これまでのヒンジ(例えば、γ1EH1)では、ヒンジ中の第1のシステイン(図2、上)は、LC/MSを使用したインタクトな質量分析の結果によって実証される、タンパク質の不均質性を生じる問題を引き起こした。ヒンジ領域中のシステインの重要性は明確であるにもかかわらず、このシステインをセリンに突然変異させると、結果としてγ1EH2ヒンジ(図2、下)が生じることが決定された。しかしながら、このヒンジコンストラクトは、コアヒンジ中の2つの残りのシステイン残基間で形成された2つのジスルフィド結合(図2、下)は、インビボでの二量体の安定性を維持するには不十分なようであったため、所定の所望の態様を達成しないことが決定された。
新たに導入された上記の態様に対処するため、ミニボディを更に操作した。伸長配列を有するhuIgG2をベースとした操作されたミニボディは、コアヒンジ中に第3のシステイン(IgG1の自然のコアヒンジに対する追加のシステイン)を提供することから、ジスルフィド結合を増加させ、タンパク質の安定性を増加させた。IAB2M及びIAB22MのhuIgG2ミニボディを、huIgG2のCH3ドメインに連結されたヒトIgG2(huIgG2)ヒンジ配列を使用して操作した。
Table 1(表6)は、IAB2Mバリアントの概説を示す(SEQ ID NO:は図5B~図5Eに示される)。図47~図53に、IAB2Mバリアントの追加の実施形態を示す。
89Zr-Df-IAB2M-γ1EH1のPET/CT及び生体内分布(図5B)をヌードマウスで実行した。図11Aに、24時間及び48時間における89Zr-Df-IAB2M-γ1-EH1投与後の右肩にPSMA陽性22Rv1異種移植片を有するヌードマウスのMIP PET/CT画像を示す。48時間における3匹のマウスからの組織中の平均の放射性物質取り込みを、1グラム当たりの注射された用量の百分率(ID/g)として示す(図11B)。腫瘍での取り込みは、相対的に低く(6.1±1.2%ID/g)、腎臓での取り込みは高かった(23.3±6.2%ID/g)。これは、肝臓での取り込み(14.1±1.6%ID/g)のほぼ2倍多い。ミニボディがインビボで二量体のままでいる場合、タンパク質クリアランスが肝臓を介して起こることが予測される。腎臓のシグナルが肝臓のシグナルより大きいことから、インビボにおける不安定及び半分の分子の形成が示唆された。
IgG1のヒンジ領域由来のヒンジ配列で作製されたミニボディは、腎臓を介した高いクリアランスを示したことから、インビボにおけるタンパク質の不安定及び半分の分子への解離が示唆される(図11)。
IAB22M-γ2EH1バリアント(図14B)のインタクトな質量分析(図14A)を質量分析によって実行した。γ2EH1ヒンジを有するIAB22Mは、半分の分子の約9.2%を生じる可能性のある対合していない第1のヒンジのシステインを有していた(図20B)。IAB22Mγ2EH1のインタクトな質量分析のために、試料を、逆相クロマトグラフィーカラム(TSKゲルフェニル-5PW(Tosoh社、2×75mm)によって60℃で分離し、Agilent社のESI-QTOF質量分析計によって分析した。図14Aは、上のパネルにおいて、分離した半分の分子及びフルサイズの分子の全イオンのクロマトグラムを示す。UV280のトレース(示されていない)を、ミニボディバリアント中に存在する半分の分子のパーセントのピーク統合による定量のために使用した。デコンボリューションされた質量を割り当てのために使用し、半分の分子の質量(中央のパネル)及びフルサイズの質量(下のパネル)の同一性を確認した。
IAB22M MbとhuIgG1及びhuIgG2由来のヒンジ配列との比較を、89Zr-Df-IAB22MバリアントのPET/CTによって実行した。図16A に、89Zr-Df-IAB22M-γ1-EH1(図16B)、-γ2NH1(図16C)及び-γ2EH2(図15B)バリアント投与後の左肩にCD8陽性HPB-ALL異種移植片を有するNOD-SCIDマウスのMIP PET/CT画像を示す。γ2ヒンジバリアントは、より低い腎臓での取り込みをもたらした。
上記の結果から、システインの誤った対合を防ぐためには第1のヒンジのシステインを突然変異させることが重要であることが示された。しかしながら、タンパク質の構造的な完全性を維持するために、ヒンジ領域中の2つより多くのシステイン残基が有益である。IgG2ヒンジを採用することは、インビボでの安定性を増加させる解決法を提供する。Mbコンストラクト中の末端のリジン(K)の突然変異は、タンパク質発現に影響を与えなかったが、より均一な電荷を有するタンパク質を生成した。
IAB2M(図20A)ヒンジバリアント(図5B、図5C、図7C、図5E、図5D)でインタクトな質量分析を実行した。IAB22M(図20B)ヒンジバリアント(図14B、図15B、図20C、図20D、図20E、図20F、図20G)でもインタクトな質量分析を実行した。緩衝液として水中0.1%ギ酸及びアセトニトリル中0.1%ギ酸を用いて3μl/分で作動させた、Waters nanoAcquity UPLC Waters C4 nanotileカラムと組み合わせたTrizaic nanoESIソースを備えたWaters Synapt G2 HDMS(内径150μm×長さ50mm)を使用したLC/MSによって、操作されたヒンジ(EH)を有する発現されたミニボディを半分の分子のインタクトな質量及び量について分析した(図20A及び図20B)。一部の分子について、試料を、逆相クロマトグラフィーカラム(TSKゲルフェニル-5PW(Tosoh社、2×75mm)によって分離し、Agilent社のESI-QTOF質量分析計によって分析した。
異なるヒンジ配列を有する89Zr放射標識IAB22Mb(図15B、図20C、図20D、図20F、図20G)のPET/CT分析をNOD-SCIDマウスで実行した。図30に、24時間における89Zr-標識Df-IAB22Mヒンジバリアント投与後の左肩にCD8陽性HPB-ALL異種移植片を有するNOD-SCIDマウスのMIP PET/CT画像を示す。全ての新しいヒンジバリアントは、より低い腎臓での取り込みをもたらした。全てのヒンジバリアントで17~28%ID/gの範囲の優れた腫瘍標的化が達成された。全体的に、肝臓のシグナルは腎臓のシグナルと類似していた。
Claims (37)
- EPKSSDKTHTCXn2Xn3CXn4Xn5C
(式中、Xn2、Xn3、Xn4及びXn5は、独立してC以外の任意のアミノ酸であってよい)
を含む、アミノ酸配列を含むヒンジ領域を含む、ミニボディ内のポリペプチド。 - Xn2が、P、V、又はEである、請求項1に記載のポリペプチド。
- Xn2が、P又はVである、請求項1又は2に記載のポリペプチド。
- Xn4が、P、V、又はEである、請求項1から3のいずれか一項に記載のポリペプチド。
- Xn4が、P又はVである、請求項1から4のいずれか一項に記載のポリペプチド。
- Xn3が、P又はEである、請求項1から5のいずれか一項に記載のポリペプチド。
- Xn5が、P又はEである、請求項1から6のいずれか一項に記載のポリペプチド。
- Xn3が、P又はEである、請求項7に記載のポリペプチド。
- Xn2Xn3が、VEである、請求項1から8のいずれか一項に記載のポリペプチド。
- Xn2Xn3が、PPである、請求項1から9のいずれか一項に記載のポリペプチド。
- Xn4Xn5が、VEである、請求項1から10のいずれか一項に記載のポリペプチド。
- Xn4Xn5が、PPである、請求項1から10のいずれか一項に記載のポリペプチド。
- Xn2Xn3が、VEであり、Xn4Xn5が、PPである、請求項1から9のいずれか一項に記載のポリペプチド。
- Xn2Xn3が、PPであり、Xn4Xn5が、PP又はVEである、請求項1から8のいずれか一項に記載のポリペプチド。
- Xn2Xn3が、VEであり、Xn4Xn5が、VE又はPPである、請求項1から8のいずれか一項に記載のポリペプチド。
- 各Xn2、Xn3、Xn4及びXn5はPである、請求項1に記載のポリペプチド。
- 前記アミノ酸配列が、EPKSSDKTHTCPPCVECPPC(SEQ ID NO:169)、又はEPKSSDKTHTCPPCPPCPPC(SEQ ID NO:170)の部分としてEPKSSDKTHTCXn2Xn3CXn4Xn5Cを含む、請求項1に記載のポリペプチド。
- 前記アミノ酸配列が、EPKSSDKTHTCXn2Xn3CXn4Xn5Cにおける最後のシステインのC末端に伸長又は下部配列を更に含む、請求項1から17のいずれか一項に記載のポリペプチド。
- 伸長又は下部配列が、S、G、A、P、又はVの少なくとも1つを含む、請求項18に記載のポリペプチド。
- 伸長配列が、少なくともGGGSSGGGSG(SEQ ID NO:59)を含む、請求項18又は19に記載のポリペプチド。
- 前記アミノ酸配列が、EPKSSDKTHTCXn2Xn3CXn4Xn5Cの配列のC末端に、APPVAGP(SEQ ID NO:60)、APELLGGP(SEQ ID NO:58)、又はGGGSSGGGSG(SEQ ID NO:59)の配列をさらに含む、請求項1から19のいずれか一項に記載のポリペプチド。
- 前記アミノ酸配列が、EPKSSDKTHTCXn2Xn3CXn4Xn5Cの配列のC末端に、GGGSSGGGSG(SEQ ID NO:59)の配列をさらに含む、請求項1から19のいずれか一項に記載のポリペプチド。
- 前記アミノ酸配列が、以下の配列:EPKSSDKTHTCPPCPPCGGGSSGGGSG(SEQ ID NO:26)、EPKSSDKTHTCPPCPPCAPELLGGP(SEQ ID NO:25)、又は、EPKSSDKTHTCPPCVECPPCGGGSSGGGSG(SEQ ID NO:28)、又は、EPKSSDKTHTCPPCPPCPPCGGGSSGGGSG(SEQ ID NO:30)の少なくとも1つの一部としてEPKSSDKTHTCXn2Xn3CXn4Xn5Cを含む、請求項1に記載のポリペプチド。
- 前記アミノ酸配列が単一特異性ミニボディ内にある、請求項1から23のいずれか一項に記載のポリペプチド。
- 前記アミノ酸配列が鎖1本当たり少なくとも4つのシステインを含む、請求項1から24のいずれか一項に記載のポリペプチド。
- 前記アミノ酸配列が鎖1本当たり少なくとも5つのシステインを含む、請求項1から24のいずれか一項に記載のポリペプチド。
- システインが、繰り返しのCXXモチーフとして前記アミノ酸配列にわたり分布しており、各Xは、P、V、又はEである、請求項1から23のいずれか一項に記載のポリペプチド。
- 前記アミノ酸配列が二重特異性ミニボディ内にある、請求項1から23のいずれか一項に記載のポリペプチド。
- 二重特異性ミニボディが、1:1の比でアセンブルしている2つの異なるモノマーを含む、請求項28に記載のポリペプチド。
- 請求項1から29のいずれか一項に記載のポリペプチドを含む医薬組成物であって、前記ポリペプチドを含むミニボディの5%未満の凝集が組成物中に存在する、医薬組成物。
- 請求項1から29のいずれか一項に記載のポリペプチドを含む抗原結合コンストラクトを含む医薬組成物。
- 前記ポリペプチドを含む、少なくとも1マイクログラムから100mgのミニボディが存在する、請求項30又は31に記載の医薬組成物。
- EPKSSDKTHTCPPCPPC(SEQ ID NO:168)を含むアミノ酸配列を含むヒンジ領域を含むミニボディ。
- EPKSSDKTHTCXn2Xn3CXn4Xn5Cを含むヒンジ領域を含むミニボディであって、Xn2、Xn3、Xn4及びXn5は、独立してC以外の任意のアミノ酸であってよい、ミニボディ。
- 各Xn2、Xn3、Xn4及びXn5は、Pである、請求項34に記載のミニボディ。
- ヒンジ領域が、EPKSSDKTHTCPPCPPCGGGSSGGGSG(SEQ ID NO:26)の一部としてEPKSSDKTHTCXn2Xn3CXn4Xn5Cを含む、請求項35に記載のミニボディ。
- EPKSSDKTHTCPPCPPCGGGSSGGGSG(SEQ ID NO:26)を含むアミノ酸配列を含むヒンジ領域を含むミニボディ。
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