JP2019500327A - 抗huLRRC15抗体薬物コンジュゲート及びその使用方法 - Google Patents
抗huLRRC15抗体薬物コンジュゲート及びその使用方法 Download PDFInfo
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Abstract
Description
本出願は、2015年11月30日に出願された米国仮出願第62/261,092号、及び2016年11月4日に出願された米国仮出願第62/417,480号の、35U.S.C.119(e)下の利益を主張し、両者の内容は、参照によりそれらの全体が本明細書に組み込まれる。
本出願は、ASCII形式で電子的に提出された配列表を含み、参照によりその全体が本明細書に組み込まれる。2016年11月11日に作成されたこのASCIIコピーは、381493−259WO(144357)_SL.txtという名称であり、サイズは106,484バイトである。
本出願は、とりわけ、抗huLRRC15抗体、抗体薬物コンジュゲート(「ADC」)、ADCを含む組成物、ADCを作製する方法、及びADCを用いてがんを治療する方法に関する。
がん療法は、手術、放射線、及び化学療法を含む広範な治療アプローチを含む。しばしば相補的なアプローチが、がんを治療するために医師に利用可能である幅広い選択を可能にするが、既存の治療剤は、正常な健康細胞よりもがん細胞を標的とする選択性の欠如、治療に対してがんにより耐性が生じることなどの、多数の不利益を与える。
5.要旨
ヒトLRRC15(ロイシンリッチリピート含有タンパク質15)は、587個のアミノ酸(配列番号1;NP_001128529.2)を含有するアイソフォーム、及び配列番号1の長いアイソフォームと比較して、N末端が短縮されている581個のアミノ酸(配列番号3;NP_570843.2)を含有する別のアイソフォームの、2つのアイソフォームで存在することが報告されている、細胞表面タンパク質である。両方のアイソフォームのアミノ酸配列を、図1A〜1Dに示す。検討を容易にするために、ヒトLRRC15を本明細書において「huLRRC15」と略記する。この略語は、いずれかのアイソフォームを指すことが意図される。特定のアイソフォームが意図される場合、配列番号1の長いアイソフォーム及び配列番号3の短いアイソフォームについてそれぞれ、略語「huLRRC15l」及び「huLRRC15s」が使用される。
(I) [D−L−XY]n−Ab
による化合物又はその塩であって、各々の「D」は、他とは独立して、細胞毒性剤及び/又は細胞増殖抑制剤を表し;各々の「L」は、他とは独立して、リンカーを表し;「Ab」は、抗huLRRC15抗体又は結合断片のような抗huLRRC15抗原結合部分を表し;各々の「XY」は、リンカー上の官能基Rxと抗原結合部分上の「相補的な」官能基Ryの間に形成される連結を表し;nは、抗huLRRC15 ADCのDARを表す。具体的な例示的な実施形態において、抗huLRRC15 ADCは、構造式(I)による化合物であって、各「D」は同一であり、細胞透過性オーリスタチン(例えば、ドラスタチン−10若しくはMMAE)又は細胞透過性副溝結合DNA架橋剤(例えば、PBD又はPBD二量体)のいずれかであり;各「L」は同一であり、リソソーム酵素によって切断可能なリンカーであり;各「XY」は、マレイミドとスルフヒドリル(sulfydryl)基との間に形成される連結であり;「Ab」は、抗体huM25、huAD208.4.1、huAD208.12.1、huAD208.14.1、hu139.10、muAD210.40.9又はmuAD209.9.1の6つのCDRに対応する6つのCDRを含む抗体、又はこのような抗体によるhuLRRC15への結合に対して競合する抗体であり;nは2,3、又は4である。この例示的な実施形態又は構造式(I)の抗huLRRC15 ADCの具体的な実施形態において、「Ab」は、ヒト化抗体、例えば、抗体huM25、huAD208.4.1、huAD208.12.1、huAD208.14.1、又はhu139.10のVH鎖及びVL鎖に対応するVH及びVL鎖を含むヒト化抗体である。この例示的な実施形態及び構造式(I)の抗huLRRC15 ADCの別の具体的な実施形態において、Abは、huM25、huM25−S239C、huAD208.4.1、huAD208.4.1−S239C、huAD208.12.1、huAD208.14.1及びhu139.10から選択されるヒト化抗体である。
本開示は、ヒトLRRC15に特異的に結合する抗体薬物コンジュゲート、ADCを含む組成物、ADCを含むことができる抗huLRRC15抗体及び/又は結合断片、抗huLRRC15抗体をコードするポリヌクレオチド及び/又はADCを含む結合断片、抗体及び/又は結合断片を産生することができる宿主細胞、抗体、結合断片及びADCを作製するために有用な方法及び組成物、並びにADCを使用する様々な方法に関する。
本明細書に記載されている抗体、結合断片、ADC及びポリヌクレオチドは、多数の実施形態において、それぞれのポリペプチド配列又はポリヌクレオチド配列によって記載されている。別段に示されない限り、ポリペプチド配列はN→C配向で提供されている;ポリヌクレオチド配列は5’→3’配向で提供されている。ポリペプチド配列について、以下の表1に示すように、遺伝的にコードされたアミノ酸の通常の3文字略語又は1文字略語を使用することができる。
本明細書において別段に定義されない限り、本開示に関連して使用される科学用語及び技術用語は、当業者によって一般的に理解される意味を有するものとする。
一態様において、本開示は、ヒトLRRC15アイソフォーム1(配列番号1)又はアイソフォーム2(配列番号3)に特異的に結合する抗体薬物コンジュゲート(「ADC」)に関する。抗huLRRC15 ADCは、一般的に、抗huLRRC15抗原結合部分、例えば、抗huLRRC15抗体又は結合断片を含み、1つ以上のリンカーを介してそれに連結された1つ以上の細胞毒性剤及び/又は細胞増殖抑制剤を有する。
具体的な例示的な実施形態において、抗原結合部分は、抗体又は抗体抗原結合断片である。抗huLRRC15 ADCを構成する抗体及び/又は結合断片は、細胞表面から血中に放出される細胞外ドメインの領域(配列番号3の残基22〜527)(「脱落ECD」又は「sECD」)でhuLRRC15に特異的に結合し、続いて配列番号3のArg527とSer528の間のタンパク質分解切断部位で切断される。
VHCDR#1は配列番号10の配列に対応し、VHCDR#2は配列番号11の配列に対応し、VHCDR#3は配列番号12の配列に対応し;又は
VHCDR#1は配列番号20の配列に対応し、VHCDR#2は配列番号21の配列に対応し、VHCDR#3は配列番号22の配列に対応し;又は
VHCDR#1は配列番号30の配列に対応し、VHCDR#2は配列番号31の配列に対応し、VHCDR#3は配列番号32の配列に対応し;又は
VHCDR#1は配列番号40の配列に対応し、VHCDR#2は配列番号41の配列に対応し、VHCDR#3は配列番号42の配列に対応し;又は
VHCDR#1は配列番号50の配列に対応し、VHCDR#2は配列番号51の配列に対応し、VHCDR#3は配列番号52の配列に対応し;又は
VHCDR#1は配列番号60の配列に対応し、VHCDR#2は配列番号61の配列に対応し、VHCDR#3は配列番号62の配列に対応し;又は
VHCDR#1は配列番号70の配列に対応し、VHCDR#2は配列番号71の配列に対応し、VHCDR#3は配列番号72の配列に対応する。
VLCDR#1は配列番号13の配列に対応し、VLCDR#2は配列番号14の配列に対応し、VLCDR#3は配列番号15の配列に対応し;又は
VLCDR#1は配列番号23の配列に対応し、VLCDR#2は配列番号24の配列に対応し、VLCDR#3は配列番号25の配列に対応し;又は
VLCDR#1は配列番号33の配列に対応し、VLCDR#2は配列番号34の配列に対応し、VLCDR#3は配列番号35の配列に対応し;又は
VLCDR#1は配列番号43の配列に対応し、VLCDR#2は配列番号44の配列に対応し、VLCDR#3は配列番号45の配列に対応し;又は
VLCDR#1は配列番号53の配列に対応し、VLCDR#2は配列番号54の配列に対応し、VLCDR#3は配列番号55の配列に対応し;又は
VLCDR#1は配列番号63の配列に対応し、VLCDR#2は配列番号64の配列に対応し、VLCDR#3は配列番号65の配列に対応し;又は
VLCDR#1は配列番号73の配列に対応し、VLCDR#2は配列番号74の配列に対応し、VLCDR#3は配列番号75の配列に対応する。
VHCDR#1は配列番号10の配列に対応し、VHCDR#2は配列番号11の配列に対応し、VHCDR#3は配列番号12の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号13の配列に対応し、VLCDR#2は配列番号14の配列に対応し、VLCDR#3は配列番号15の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号20の配列に対応し、VHCDR#2は配列番号21の配列に対応し、VHCDR#3は配列番号22の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号23の配列に対応し、VLCDR#2は配列番号24の配列に対応し、VLCDR#3は配列番号25の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号30の配列に対応し、VHCDR#2は配列番号31の配列に対応し、VHCDR#3は配列番号32の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号33の配列に対応し、VLCDR#2は配列番号34の配列に対応し、VLCDR#3は配列番号35の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号40の配列に対応し、VHCDR#2は配列番号41の配列に対応し、VHCDR#3は配列番号42の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号43の配列に対応し、VLCDR#2は配列番号44の配列に対応し、VLCDR#3は配列番号45の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号50の配列に対応し、VHCDR#2は配列番号51の配列に対応し、VHCDR#3は配列番号52の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号53の配列に対応し、VLCDR#2は配列番号54の配列に対応し、VLCDR#3は配列番号55の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号60の配列に対応し、VHCDR#2は配列番号61の配列に対応し、VHCDR#3は配列番号62の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号63の配列に対応し、VLCDR#2は配列番号64の配列に対応し、VLCDR#3は配列番号65の配列に対応する3つのCDRを有するVL鎖;又は
VHCDR#1は配列番号70の配列に対応し、VHCDR#2は配列番号71の配列に対応し、VHCDR#3は配列番号72の配列に対応する3つのCDRを有するVH鎖、並びにVLCDR#1は配列番号73の配列に対応し、VLCDR#2は配列番号74の配列に対応し、VLCDR#3は配列番号75の配列に対応する3つのCDRを有するVL鎖を含む。
配列番号16に対応する配列を有するVH鎖及び配列番号17の配列に対応するVL鎖;又は
配列番号26に対応する配列を有するVH鎖及び配列番号27の配列に対応するVL鎖;又は
配列番号36に対応する配列を有するVH鎖及び配列番号37の配列に対応するVL鎖;又は
配列番号46に対応する配列を有するVH鎖及び配列番号47の配列に対応するVL鎖;又は
配列番号56に対応する配列を有するVH鎖及び配列番号57の配列に対応するVL鎖;又は
配列番号66に対応する配列を有するVH鎖及び配列番号67の配列に対応するVL鎖;又は
配列番号76に対応する配列を有するVH鎖及び配列番号77の配列に対応するVL鎖
を含む。
Ki=IC50/(1+[参照Ab濃度]/Kd)
に従って計算され、IC50は、参照抗体の結合の50%減少をもたらす試験抗体の濃度であり、Kdは、huLRRC15に対するその親和性の尺度である、参照抗体の解離定数である。参照抗huLRRC15抗体と競合する抗体は、本明細書に記載されるアッセイ条件下で10pM〜10nMのKiを有することができる。
抗huLRRC15抗体は、宿主細胞中の免疫グロブリン軽鎖遺伝子及び重鎖遺伝子の組換え発現によって調製することができる。抗体を組換え的に発現させるために、宿主細胞は、抗体の免疫グロブリン軽鎖及び重鎖をコードするDNA断片を有する1つ以上の組換え発現ベクターを用いてトランスフェクトされ、それにより、軽鎖及び重鎖が宿主細胞中で発現され、任意選択的に、宿主細胞を培養する培地中に分泌され、その培地から抗体を回収することができる。Molecular Cloning;A Laboratory Manual、第二版(Sambrook、Fritsch及びManiatis(編集)、Cold Spring Harbor、N.Y.、1989年)、Current Protocols in Molecular Biology(Ausubel、F.M.ら、編集、Greene Publishing Associates、1989年)及び米国特許第4,816,397号に記載されている方法論のように、標準的な組換えDNA方法論を用いて、抗体重鎖遺伝子及び軽鎖遺伝子を得、これらの遺伝子を組換え発現ベクターに組み込み、宿主細胞にベクターを導入する。
上記のように、抗huLRRC15 ADCは、一般的に、同一であってもよく又は異なってもよい1つ以上の細胞毒性剤及び/又は細胞増殖抑制剤を有し、それに、また同一であってもよく又は異なってもよい1つ以上のリンカーを介して連結された、抗huLRRC15抗体及び/又は結合断片のような抗huLRRC15抗原結合部分を含む。特定の実施形態において、抗huLRRC15 ADCは、構造式(I):
(I) [D−L−XY]n−Ab
による化合物又はその塩であって、各々の「D」は、他とは独立して、細胞毒性剤及び/又は細胞増殖抑制剤(「薬物」)を表し;各々の「L」は、他とは独立して、リンカーを表し;「Ab」は、抗huLRRC15抗体又は結合断片のような抗huLRRC15抗原結合部分を表し;各々の「XY」は、リンカー上の官能基Rxと抗原結合部分上の「相補的な」官能基Ryの間に形成される連結を表し;nは、Abに連結された薬物の数、又はADCの薬物対抗体比(DAR)を表す。
細胞毒性剤及び/又は細胞増殖抑制剤は、細胞、特にがん細胞及び/又は腫瘍細胞の増殖及び/若しくは複製を阻害し、並びに/又はそれらの細胞を死滅させることが知られている任意の薬剤であり得る。細胞毒性及び/又は細胞増殖抑制性を有する多数の薬剤が文献に知られている。細胞毒性剤及び/又は細胞増殖抑制剤のクラスの非限定的な例には、例として及び限定されないが、放射性核種、アルキル化剤、DNA架橋剤、DNAインターカレート剤(例えば、副溝結合剤のようなグルーブ結合剤)、細胞周期調節剤、アポトーシス制御剤、キナーゼ阻害剤、タンパク質合成阻害剤、ミトコンドリア阻害剤、核外輸送阻害剤、トポイソメラーゼI阻害剤、トポイソメラーゼII阻害剤、RNA/DNA代謝拮抗剤及び抗有糸分裂剤が含まれる。
本明細書に記載されている抗huLRRC15 ADCにおいて、細胞毒性剤及び/又は細胞増殖抑制剤は、リンカーを介して抗原結合部分に連結される。リンカーは、短鎖、長鎖、疎水性、親水性、可撓性若しくは剛性であってもよく、又はリンカーが様々な特性を有するセグメントを含み得るように、上記した特性の1つ以上をそれぞれ独立して有するセグメントから構成されてもよい。リンカーは、抗体上の単一の部位に1を超える薬剤を共有結合的に連結させるように多価であってもよく、又は共有結合的に抗体上の単一の部位に単一の薬剤を連結するように一価であってもよい。
特定の実施形態において、選択されたリンカーは、インビボで切断可能である。切断可能なリンカーは、化学的若しくは酵素的に不安定な連結又は分解可能な連結を含み得る。切断可能なリンカーは、一般的に、細胞質の減少、リソソーム中の酸性条件への曝露、又は細胞内の特定のプロテアーゼ若しくは他の酵素による切断のような、薬物を遊離させるための細胞内部のプロセスに依存する。切断可能なリンカーは、一般的に、化学的又は酵素的に切断可能である1つ以上の化学結合を組み込み、一方、リンカーの残りの部分は切断不能である。特定の実施形態において、リンカーは、ヒドラゾン基及び/又はジスルフィド基のような化学的に不安定な基を含む。化学的に不安定な基を含むリンカーは、血漿といくつかの細胞質コンパートメントとの間で異なる特性を利用する。ヒドラゾン含有リンカーの薬物放出を促進する細胞内条件は、エンドソーム及びリソソームの酸性環境であり、一方、ジスルフィド含有リンカーは、高いチオール濃度を含むサイトゾル中で還元されるリンカーであり、例えばグルタチオンが挙げられる。特定の実施形態において、化学的に不安定な基を含むリンカーの血漿安定性は、化学的に不安定な基の近傍の置換基を用いて立体障害を導入することによって増加させることができる。
ペプチドは、リソソーム酵素によって切断可能なペプチド(C→Nを示すが、カルボキシ及びアミノ「末端」を示さない)を表し;
Tは、1つ以上のエチレングリコール単位若しくはアルキレン鎖、又はそれらの組合せを含むポリマーを表し;
Raは、水素、アルキル、スルホネート及びメチルスルホネートから選択され;
pは、0〜5の範囲の整数であり;
qは、0又は1であり;
xは、0又は1であり;
yは、0又は1であり;
切断可能なリンカーは特定の利点を提供し得るが、本明細書に記載されているADCを構成するリンカーは切断性である必要はない。切断不能なリンカーについて、薬物の放出は、血漿となんらかの細胞質コンパートメントとの間の差異特性に依存しない。薬物の放出は、抗原媒介性エンドサイトーシス及びリソソームコンパートメントへの送達によるADCの内在化後に起こると仮定され、この場合、抗体は、細胞内のタンパク質分解によりアミノ酸レベルまで分解される。このプロセスは、薬物、リンカー、及びリンカーが共有結合したアミノ酸残基によって形成される薬物誘導体を放出する。切断不能なリンカーとのコンジュゲートからのアミノ酸薬物代謝産物はより親水性であり、一般的に、膜透過性が低く、切断可能なリンカーを有するコンジュゲートと比較してバイスタンダー効果が少なく、非特異的な毒性が少ない。一般的に、切断不能なリンカーを有するADCは、切断可能なリンカーを有するADCよりも循環中の安定性が高い。切断不能なリンカーは、アルキレン鎖であってもよく、又は、例えば、ポリアルキレングリコールポリマー、アミドポリマーに基づくもののような、本質的にポリマー性であってもよく、又はアルキレン鎖、ポリアルキレングリコール及び/若しくはアミドポリマーのセグメントを含んでもよい。
Raは、水素、アルキル、スルホネート及びメチルスルホネートから選択され;
Rxは、リンカーを抗体に共有結合的に連結させることができる官能基を含む部分であり;並びに
種々の基を用いてリンカー−薬物シントンを抗体に結合させて、ADCを生成することができる。結合基は、本質的に求電子性であり得、マレイミド基、活性化ジスルフィド、NHSエステル及びHOBtエステルのような活性エステル、ハロホルメート、酸ハライド、ハロアセトアミドのようなアルキルハライド及びベンジルハライドを含む。以下で検討するように、本開示に従って使用することができる「自己安定化する」マレイミド及び「架橋ジスルフィド」に関連する新たな技術もまた存在する。使用される特定の基は、部分的には、抗体への結合部位に依存する。
当業者に知られているように、特定のADCについて選択されるリンカーは、様々な因子、例えば、限定されないが、抗体への結合部位(例えば、Lys、Cys又は他のアミノ酸残基)、薬物ファーマコフォアの構造的制約及び薬物の親油性によって影響を受ける場合がある。ADCについて選択される特定のリンカーは、特異的な抗体/薬物の組合せに関して、これらの異なる因子のバランスをとるよう努める必要がある。ADCにおけるリンカーの選択によって影響される因子の概説については、Nolting、第5章、「Linker Technology in Antibody−Drug Conjugates」In:Antibody−Drug Conjugates:Methods in Molecular Biology、1045巻、71〜100頁、Laurent Ducry(編集)、Springer Science & Business Medica、LLC、2013年を参照されたい。
上記のように、抗huLRRC15 ADCの実施形態は、式(I):[D−L−XY]n−Ab(I)による構造を有する化合物又はその塩を含み、式中、Dは細胞毒性剤及び/又は細胞増殖抑制剤であり;Lはリンカーであり;Abは抗体であり;XYは、リンカーLを抗体Abに連結する共有結合的連結を表し;nは2〜8の範囲の整数である。
本明細書に記載されているADCは、周知である化学を用いて合成することができる。選択される化学は、とりわけ、細胞毒性剤及び/又は細胞増殖抑制剤(単数又は複数)、並びにリンカー及びリンカーを抗体に結合させるために使用される基の固有性に依存する。一般的に、式(I)によるADCは、以下のスキーム:
D−L−Rx+Ab−Ry → (I) [D−L−XY]n−Ab
に従って調製することができ、式中、D、L、Ab、XY及びnは、先に定義した通りであり、Rx及びRyは、上記で検討したように互いに共有結合的連結を形成し得る相補的な基を表す。
本明細書に記載されているADCは、ADC、並びに1つ以上の担体、賦形剤及び/又は希釈剤を含む組成物の形態であってもよい。組成物は、獣医学的使用又はヒトにおける薬学的使用のような特定の使用のために製剤化され得る。組成物の形態(例えば、乾燥粉末、液体製剤など)、並びに使用される賦形剤、希釈剤及び/又は担体は、抗体及び/又はADCの意図された使用、及び治療的使用については投与様式に依存する。
前述したように、様々な固形腫瘍について、huLRRC15は、腫瘍間質微小環境において発現されるが、がん細胞自体には発現されない。本明細書において提供されるデータは、抗huLRRC15 ADCが、インビボでこれらの間質(+)/がん(−)腫瘍に対して強力な抗腫瘍活性を発揮することを実証する。したがって、ADC及び/又はADCを含む医薬組成物は、間質(+)/がん(−)腫瘍の処置に治療的に使用され得る。
抗huLRRC15 ADCは、抗がん特性を有する他の薬剤若しくは治療に対して補助的に又はそれとともに使用することができる。補助的に使用される場合、抗huLRRC15及び他の薬剤(単数又は複数)は、単一の組合せ医薬製剤に一緒に製剤化されてもよく、又は単一の協調された投与レジメン若しくは異なる投薬レジメンのいずれかで個別に製剤化及び投与されてもよい。抗huLRRC15 ADCとともに補助的に投与される薬剤は、典型的には、抗huLRRC15 ADCに対して相補的な活性を有し、そのため、ADC及び他の薬剤が互いに悪影響を及ぼさない。
投与される抗huLRRC15 ADCの量は、様々な因子に依存し、例えば、限定されないが、治療される間質(+)/がん(−)腫瘍の特定のタイプ、治療される間質(+)/がん(−)腫瘍の段階、投与様式、投与頻度、所望の治療上の利益、並びに患者の年齢、体重及び他の特徴など他のパラメータなどが挙げられる。特定の投与様式及び投与頻度について治療上の利益を与えるのに有効な投薬量の決定は、当業者の能力の範囲内である。
huLRRC15に対する抗体を、標準的技法を使用して、huLRRC15を発現する細胞株(U118MGグリオブラストーマ細胞)に対して調製した。特異的アフィニティー、及び他の望ましい特徴、例えばカニクイザルLRRC15(「cynoLRRC15」)との交差反応性を有する例示的抗体を単離し、特定のこれらの抗体をヒト化した。例示的ヒト化抗体にはhuM25、huAD208.4.1、huAD208.12.1、huAD208.14.1、hu139.1があり、例示的ネズミ抗体にはmuAD209.9.1及びmuAD210.40.9がある。これらの例示的抗体のVH及びVL鎖の配列は、それぞれ図2A及び2B中に与える。例示的抗体huM25の重鎖及び軽鎖の配列は、それぞれ図3A及び3B中に与える。huM25のコード重鎖は配列番号18であってCHO細胞中での発現時にC末端が切断されて配列番号102となる場合があり、配列番号19であるhuM25のコード軽鎖を伴う。
細胞表面から脱落したhuLRRC15の細胞外ドメインの一部と例示的抗huLRRC15の結合を、ELISAアッセイにおいて実証した。huLRRC15−Fc融合タンパク質を、切断部位に対するhuLRRC15細胞外タンパク質ドメインの一部に対応する配列番号3のアミノ酸残基22〜526を使用して作製した。96ウエルImmulon4HBXプレート(Thermo、カタログ番号3855)を、カルボネート−バイカルボネートバッファー(Thermo、カタログ番号28382)pH9.4中2μg/mLで、100μL/ウエルのこのhuLRRC15融合ECDタンパク質でコーティングし、4℃において一晩結合させた。プレートはPBSTで3回洗浄し、次いで室温において1時間PBST+0.3%BSA中で様々な濃度の抗体とインキュベートした。プレートはPBSTで3回洗浄し、次いで室温において30分間100μLのヤギ抗ヒトカッパ軽鎖HRP(Bethyl、カタログ番号A80−115P)とインキュベートした。プレートはPBSTで3回洗浄し、100μLのTMB(Surmodics BioFxカタログ番号TMBW−1000−01)をそれぞれのウエルに加え、発色するまで室温においてインキュベートした(約10分間)。650nmのStop Reagent for TMB(Surmodics BioFxカタログ番号BSTP−0100−01)の添加によって反応を停止させ、光学濃度(OD)を650nmで読み取った(Molecular Devices Versamax PLUS)。特定の例示的抗huLRRC15抗体に関するELISAの結合データは図5中に示す。様々な抗huLRRC15抗体に関するEC50値は以下の表8中に与える。
huLRRC15発現細胞との結合に関してmuM25と競合する様々な例示的抗huLRRC15抗体の能力を、すなわち抗体が同一であるエピトープ又は異なるエピトープと結合するかどうかを、「参照抗体」として蛍光標識muM25(「muM25−AF488」)及び「試験抗体」として非標識抗huLRRC15抗体を使用して、フローサイトメトリー競合アッセイにおいて評価した。このアッセイ用に、U118MG細胞のアリコート(ウエルあたり200,000細胞)を1μg/mLの標識muM25及び0.0001、0.001、0.01、0.1、1、10又は100μg/mLいずれかの非標識試験抗体と同時にインキュベートし、(1μg/mLの標識muM25のみとインキュベートした対照アリコートに標準化した)結合した抗体の量をフローサイトメトリーにより決定した。アイソタイプ対照抗体(ヒト又はマウス)を陰性対照として使用し、非標識muM25は陽性対照として使用した。
様々な固形腫瘍型の間質におけるhuLRRC15の発現を、ホルマリン固定パラフィン包埋(FFPE)組織での免疫組織化学(IHC)染色を使用して評価した。異なる腫瘍型由来の生検材料を使用して組織マイクロアレイ(TMA)を作製し、これらをhuLRRC15の発現に関して評価した。組織切片(4μm)を切断し、脱パラフィン処理し、125℃で1分間BORG Decloaker抗原賦活バッファーを使用して抗原賦活を実施した。Leica自動染色装置を使用してスライドをブロッキング処理し、抗huLRRC15抗体(muAD210.40.9、1μg/mLで60分間)及びHRP抗マウス二次抗体(Dako)並びに検出用DAB試薬(Dako)とインキュベートした。実験の結果は表9及び図7中に示す。
正常、健常組織におけるhuLRRC15の発現を、正常組織のタンパク質免疫組織化学染色を使用して評価した。結果は図8中に示す。huLRRC15は大部分の正常組織中で限られた発現があり、発現は胃中の噴門/幽門、脾臓小柱周囲、骨芽細胞、及び毛包(「ECM」は細胞外マトリックスを指す)を含めた特定組織に局在していた。限られた発現は扁桃及び胎盤においても観察された(データ示さず)。主要器官(例えば心臓、肝臓、膵臓、肺)ではhuLRRC15の発現は観察されなかった。
huLRRC15の発現を、図9A中に示すようにビオチニル化抗huLRRC15抗体muAD210.40.9を使用し、ウエスタンブロットによる乳がん患者由来のがん関連線維芽細胞(CAF)のタンパク質又は市販の間葉系幹細胞(MSC)溶解物の分析によって測定した。huLRRC15はTGFβを用いた処理で乳がんCAF溶解物試料において上方制御されることを観察し、TGFβの不在下で低発現であるか又はごくわずかに検出可能な発現があった。対照的に、全3個のMSC溶解物試料においてTGFβの不在下ではhuLRRC15発現は高度であり、この発現はTGFβ処理により有意に上方制御された。以前に論じられたように、MSCは腫瘍間質中のがん関連線維芽細胞集団の大部分を構成すると考えられている(Cirri、P and Chiarugi P.American Journal of Cancer Research2011;1(4):482〜497頁)。
上皮間葉系移行(EMT)は、がん細胞において細胞可塑性をもたらすと考えられる細胞のメカニズムである。さらに間葉系の表現型へのこの移行によって初代がん細胞の運動性と侵襲性が増大すると考えられ、おそらくがんの転移、薬物耐性、又は免疫系の逸脱につながる。例えば、Ye、X and Weinberg、R.A.Trends in Cell Biology、2015、25(11)、675〜686頁を参照。この実施例中に与えるデータは、EMTを起こしたがん細胞は、それらの親上皮がん細胞と比較してhuLRRC15の発現が増大したことを実証する。
DARが異種であるhuM25−val−cit−MMAEADC組成物を、以下に説明する2ステップの化学的プロセス、huM25のジスルフィド還元、次にマレイミドカプロイルバリン−シトルリン(「val−cit」)パラ−アミノベンジルアルコール(「PABA」)モノメチルアウリスタチンE(本明細書では「vcMMAE」と呼ぶ)とのアルキル化(コンジュゲーション)によって調製した。
DAR2が富化されたhuM25−vcMMAEADC(本明細書では「huM25−vcMMAE−E2」と呼ぶ)の調製物を、疎水性相互作用クロマトグラフィー(「HIC」)による実施例8の異種DARADC組成物の解析によって得た。HICを介して異種ADC混合物を分離しDAR2及びDAR4ピークのような特異的均質種を単離するための一般的な方法は、Hamblett et al.、2004、Clin Cancer Res10:7063〜7070頁によって記載される。
huLRRC15間質(+)/がん(−)腫瘍に対する例示的抗huLRRC15ADC、huM25−vcMMAE−E2の強力な抗腫瘍活性を、EBC−1(ヒト扁平上皮NSCLC)細胞を用いて異種移植片モデルにおいて実証した。実験用に、インビトロで増殖した500万個の細胞(EBC−1)を、メスSCID−Beigeマウスの右脇腹にマウスごとに皮下接種した。腫瘍は約200mm3でサイズマッチし、図13A中に示すようにQ4D×6腹腔内(IP)投与した(4日ごとに1投与施し合計6投与)。腫瘍の長さ(L)及び幅(W)の測定は電動キャリパーにより行い、体積は以下の等式:V=L×W2/2に従い計算した。6mg/kgで処理したマウスでは、97%の最大腫瘍増殖阻害(TGImax)及び305%の腫瘍増殖遅延(TGD)がhuM25−vcMMAE−E2処理で示され、同じレジメンで投与したアイソタイプ対照抗体又は対応するアイソタイプ対照コンジュゲートでの処理と比較して、それは有意に改善された(p<0.001)(図13A)。
抗huLRRC15ADCを用いた処理後に再成長する腫瘍は、抗huLRRC15ADCに対して感受性があることを実証するため、抗huLRRC15ADCを用いて腫瘍を処理し、再増殖させ再処理した。実験用に、(初代ヒトER陰性及びPR陰性乳がん腫瘍から開発された)SUM190PTヒト乳がん細胞を増殖させ、インビトロで3回継代した。マウスあたり500万個の細胞を、メスSCIDマウスの右脇腹に皮下接種した。腫瘍は約250mm3でサイズマッチし、抗体とイムノコンジュゲートを、それぞれ10mg/kgと3mg/kg、Q4D×4IP投与した(4日ごとに1投与施し合計4投与)。サイズマッチ後第70日、腫瘍が約650mm3まで再成長したとき、6mg/kg、huM25−vcMMAE−DAR4IPQ4D×6(4日ごとに1投与施し合計6投与)で動物を再処理した。再処理時のいくつかの巨大腫瘍を、免疫組織化学法によりhuLRRC15の発現を評価するため採取した。
細胞透過性の細胞増殖抑制剤及び/又は細胞毒性剤を含む抗huLRRC15ADCがバイスタンダー死滅効果により抗腫瘍活性に影響を与える事実を、EBC−1扁平上皮肺がん異種移植片、及び2つの抗huLRRC15ADC、huM25−vcMMAE−E2とhuM25−mcMMAE−E2において実証した。MMAEは細胞膜を横断することができる。近親種であるモノメチルアウリスタチンF(「MMAF」)はそれができない。
huM25−vcMMAE−E2のE2、E4及びE2/E4調製物の安全性プロファイルをラットの耐性試験において評価した(図18A〜18B)。アッセイ用に、Sprague Dawley野生型ラットに、各抗体薬物コンジュゲートのMMAE当量レベルで1回IV用量を投与した。huM25−vcMMAE−E4を用いると、huM25−vcMMAE−E2に関して見られたもの(第8日、25%)より、初期(第3/4日)に高い割合(50%)で死亡が発生した。2倍のタンパク質抗体用量を等量のMMAEと共に送達し、E4に優るE2の生存率の改善が見られた。E4ADCよりE2を投与した動物において死亡はあまり発生せず、第8日後に死亡が偶然発生した。広域薬物分布DAR4は20mg/kgのMTDを有する。60mg/kgで投与するとhuM25−vcMMAE−E2に関して体重減少は有意ではなかったが、MMAE当量レベルの30mg/kg及びhuM25−vcMMAE−E4を投与したラットに関して体重減少が増大した(図18B)。この観察結果は、抗体あたり2細胞増殖抑制剤及び/又は細胞毒性剤(E2)のような低いMMAE薬物抗体比で多量タンパク質用量を送達するときほど、より多く薬物をロードした抗huLRRC15ADCには充分に耐容しないことを実証する。
現行の標準的ケア物質と比較した抗huLRRC15ADCの効力を、異種移植片モデル、及びNCI−H1650(腺がんNSCLC)、HN5(頭頸部)、EBC−1(扁平上皮NSCLC)、NW231(乳房)及びPANC1(膵臓)がん細胞において評価した。抗huLRRC15ADChuM25−vcMMAE−E2を、エルロチニブ、カルボプラチン、セツキシマブ、ドキソルビシン及びゲムシタビンと比較した。標準的ケア薬剤を、最大有効又は最大耐容用量レベルで投与した。図20Aに関しては、NCI−H1650細胞(500万個の細胞)をSCID/Beigeマウスに皮下移植し、それらが約200mm3に達したとき腫瘍を無作為に分類し、Q4D×6(4日ごとに1投与施し合計6投与)において6又は12mg/kgで生物学的製剤を腹腔内投与し、一方エルロチニブを100mg/kgで10日間毎日経口投与し、カルボプラチンをQ4D×4(4日ごとに1投与施し合計4投与)において50mg/kgで腹腔内投与した。huM25−vcMMAE−E2に関する抗腫瘍効果(92%のTGImax、450%のTGD)は、エルロチニブ(90%のTGImax、77%のTGD)又はカルボプラチン(56%のTGImax、77%のTGD)のいずれかに関して見られたものより優れていた。
放射線及び他の非標的化化学療法剤(例えばゲムシタビン、ドセタキセル、カルボプラチン)を補助して投与する抗huLRRC15ADCの抗腫瘍効果を、異種移植片モデル、及びHPAF−II(膵臓)、EBC−1(扁平上皮NSCLC)及びSCC−15(頭頸部)細胞において実証した。これらの細胞毒性抗がん治療剤を補助して抗huLRRC15ADC(例えばhuM25−vcMMAE−E2)を投与すると、抗腫瘍活性の改善が見られた。補助治療剤の効果は、いずれかの薬物のみに関して見られた効果より優れていた。
他の標的型化学療法剤(例えばエルロチニブ、セツキシマブ、抗PD−1抗体)を補助して投与する抗huLRRC15ADCの抗腫瘍効果を、異種移植片モデル、及びNCI−H1650(腺がんNSCLC)、HN5(頭頸部)、SCC−15(頭頸部)及びMC38(マウス同系結腸直腸)がん細胞において実証した。これらの標的化抗がん治療剤を補助して抗huLRRC15ADC(例えばhuM25−vcMMAE−E2)を投与すると、抗腫瘍活性の改善が見られた。その補助効果は、いずれかの薬物単独の効果より優れていた。
いくつかの型のhuLRRC15間質(+)/がん(−)腫瘍に対する、DNA損傷性細胞増殖抑制剤及び/又は細胞毒性剤を含む抗huLRRC15ADCの強力な抗腫瘍活性を、異種移植片モデル、及びEBC−1(扁平上皮NSCLC)、NCI−H1650(腺がんNSCLC)、HN−5(頭頸部)、HPAF−II(膵臓)及びPANC−1(膵臓)がん細胞において異なる例示的ADCで実証した。
実施例7中で前に記載したように、EMTを起こしたがん細胞は、EMTを起こさなかった細胞と比較してhuLRRC15の発現が増大していた。本発明の実施例において提供するデータは、この増大したレベルのhuLRRC15発現は、huLRRC15を標的化したADCに対する増大した感受性と相関関係があったことを示す。図23B及び23C中に示したように、ヒト及びマウスLRRC15と交差反応性があった抗LRRC15ADChuAD208.4.1−PBD−DAR2は、インビトロでLRRC15発現間葉系幹細胞に対して細胞殺傷効果を実証した。10ng/mLのTGFβで処理したヒトBM−MSC(Lonza)において、huAD208.4.1−PBD−DAR2は、同じ用量でアイソタイプ−PBD−DAR2より高度な細胞殺傷効果を示した(図23B)。同様のインビトロ細胞殺傷効果プロファイルを、TGFβ(10ng/mL)及びそれぞれのADCで処理したネズミBalb/cBM−MSC(Cyagen)においても観察した(図23C)。
前述の実施例は、EMTを起こした特定がん細胞においてhuLRRC15発現が増大し、これらの細胞はインビトロでhuLRRC15ADCに対してより感受性があったことを示す。本発明の実施例において提供するデータは、同じhuLRRC15ADCが有意なインビボ効果を示すことを実証する。図24Aは、EBC−1扁平上皮NSCLC腫瘍でSCIDマウスを処理する効果を示す。EBC−1扁平上皮NSCLC細胞(500万個)をSCIDマウスに皮下移植し、腫瘍が約175mm3に達したときマウスを無作為に分類し、第0日にADC又はアイソタイプ抗体を0.6mg/kg腹腔内投与した。1回用量のADCで、huM25−S239C−PBD−E2は、同じ用量のアイソタイプ−S239C−PBD−E2と比較して13日後に有意な抗腫瘍効果を実証した(p<0.01)。
1.huLRRC15細胞外ドメインに特異的に結合する抗体又はその結合断片であって、上記細胞外ドメインが、配列番号3のArg527及びSer528によって規定されるタンパク質分解切断部位を含む、抗体又はその結合断片。
VHCDR#1が配列番号20の配列に対応し、VHCDR#2が配列番号21の配列に対応し、VHCDR#3が配列番号22の配列に対応し;
VHCDR#1が配列番号30の配列に対応し、VHCDR#2が配列番号31の配列に対応し、VHCDR#3が配列番号32の配列に対応し;
VHCDR#1が配列番号40の配列に対応し、VHCDR#2が配列番号41の配列に対応し、VHCDR#3が配列番号42の配列に対応し;
VHCDR#1が配列番号50の配列に対応し、VHCDR#2が配列番号51の配列に対応し、VHCDR#3が配列番号52の配列に対応し;
VHCDR#1が配列番号60の配列に対応し、VHCDR#2が配列番号61の配列に対応し、VHCDR#3が配列番号62の配列に対応し;又は
VHCDR#1が配列番号70の配列に対応し、VHCDR#2が配列番号71の配列に対応し、VHCDR#3が配列番号72の配列に対応する、3つのCDRを有するVH鎖を含む、実施形態1に記載の抗体又は結合断片。
VLCDR#1が配列番号23の配列に対応し、VLCDR#2が配列番号24の配列に対応し、VLCDR#3が配列番号25の配列に対応し;
VLCDR#1が配列番号33の配列に対応し、VLCDR#2が配列番号34の配列に対応し、VLCDR#3が配列番号35の配列に対応し;
VLCDR#1が配列番号43の配列に対応し、VLCDR#2が配列番号44の配列に対応し、VLCDR#3が配列番号45の配列に対応し;
VLCDR#1が配列番号53の配列に対応し、VLCDR#2が配列番号54の配列に対応し、VLCDR#3が配列番号55の配列に対応し;
VLCDR#1が配列番号63の配列に対応し、VLCDR#2が配列番号64の配列に対応し、VLCDR#3が配列番号65の配列に対応し;
VLCDR#1が配列番号73の配列に対応し、VLCDR#2が配列番号74の配列に対応し、VLCDR#3が配列番号75の配列に対応する、3つのCDRを有するVL鎖を含む、実施形態1に記載の抗体又は結合断片。
ペプチドは、リソソーム酵素によって切断可能なペプチド(C→Nを示すが、カルボキシ及びアミノ「末端」を示さない)を表し;
Tは、1つ以上のエチレングリコール単位若しくはアルキレン鎖、又はそれらの組合せを含むポリマーを表し;
Raは、水素、アルキル、スルホネート及びメチルスルホネートから選択され;
pは、0〜5の範囲の整数であり;
qは、0又は1であり;
xは、0又は1であり;
yは、0又は1であり;
(I) [D−L−XY−]n−Ab
による化合物又はその塩であって、
Dは、細胞毒性剤及び/又は細胞増殖抑制剤であり;
Lは、リンカーであり;
Abは、抗体であり;
XYは、リンカーLを抗体Abに連結する共有結合的連結を表し;
nは、2〜8の範囲の整数である、実施形態12に記載のADC。
Claims (34)
- リンカーを介して抗huLRRC15抗体に連結された抗有糸分裂剤を含む抗huLRRC15抗体薬物コンジュゲート(「ADC」)であって、ADCは、式(I):
(I) [D−L−XY−]n−Ab
又はその塩の構造を有し、式中、
Dは、抗有糸分裂剤であり;
Lは、リンカーであり;
Abは、抗huLRRC15抗体であり;
XYは、抗体AbにリンカーLを連結している共有結合的連結を表し;
nは、2〜8の範囲の整数であり;
ADは、
配列番号16の配列に対応するVH鎖及び配列番号17の配列に対応するVL鎖、
配列番号26の配列に対応するVH鎖及び配列番号27の配列に対応するVL鎖、
配列番号36の配列に対応するVH鎖及び配列番号37の配列に対応するVL鎖、
配列番号46の配列に対応するVH鎖及び配列番号47の配列に対応するVL鎖、
配列番号56の配列に対応するVH鎖及び配列番号57の配列に対応するVL鎖、
配列番号66の配列に対応するVH鎖及び配列番号67の配列に対応するVL鎖、又は
配列番号76の配列に対応するVH鎖及び配列番号77の配列に対応するVL鎖
を含むADC。 - nが2、3又は4である、請求項1に記載のADC。
- XYが、抗体Ab上のスルフヒドリル基を用いて形成されるチオエーテル結合である、請求項1に記載のADC。
- Lが、Val−Cit又はVal−Alaを含む、請求項1に記載のADC。
- Dがアウリスタチンである、請求項1に記載のADC。
- AbがIgG1である、請求項1に記載のADC。
- nが2、3又は4である、請求項7に記載のADC。
- Abが、
(a)配列番号18、100、102、若しくは103のアミノ酸配列を有する重鎖;及び配列番号19の軽鎖;又は
(b)配列番号28、101、104、若しくは105のアミノ酸配列を有する重鎖;及び配列番号29の軽鎖
を含む、請求項7に記載のADC。 - nが2又は4である、請求項10に記載のADC。
- Abが、
(a)配列番号18、100、102、若しくは103のアミノ酸配列を有する重鎖;及び配列番号19の軽鎖;又は
(b)配列番号28、101、104、若しくは105のアミノ酸配列を有する重鎖;及び配列番号29の軽鎖
を含む、請求項10に記載のADC。 - リンカーを介して抗huLRRC15抗体に連結されたDNAインターカレート剤を含む抗huLRRC15抗体薬物コンジュゲート(「ADC」)であって、ADCは、式(I):
(I) [D−L−XY−]n−Ab
又はその塩の構造を有し、式中、
Dは、DNAインターカレート剤であり;
Lは、リンカーであり;
Abは、抗huLRRC15抗体であり;
XYは、抗体AbにリンカーLを連結している共有結合的連結を表し;
nは、2〜8の範囲の整数であり;
ADは、
配列番号16の配列に対応するVH鎖及び配列番号17の配列に対応するVL鎖、
配列番号26の配列に対応するVH鎖及び配列番号27の配列に対応するVL鎖、
配列番号36の配列に対応するVH鎖及び配列番号37の配列に対応するVL鎖、
配列番号46の配列に対応するVH鎖及び配列番号47の配列に対応するVL鎖、
配列番号56の配列に対応するVH鎖及び配列番号57の配列に対応するVL鎖、
配列番号66の配列に対応するVH鎖及び配列番号67の配列に対応するVL鎖、又は
配列番号76の配列に対応するVH鎖及び配列番号77の配列に対応するVL鎖
を含むADC。 - nが2、3又は4である、請求項13に記載のADC。
- XYが、抗体Ab上のスルフヒドリル基を用いて形成されるチオエーテル結合である、請求項13に記載のADC。
- Lが、Val−Cit又はVal−Alaを含む、請求項13に記載のADC。
- Dがピロロベンゾジアゼピンである、請求項13に記載のADC。
- AbがIgG1である、請求項13に記載のADC。
- nが2、3又は4である、請求項19に記載のADC。
- Abが、
(a)配列番号18、100、102、若しくは103のアミノ酸配列を有する重鎖;及び配列番号19の軽鎖;又は
(b)配列番号28、101、104、若しくは105のアミノ酸配列を有する重鎖;及び配列番号29の軽鎖
を含む、請求項19に記載のADC。 - nが2又は4である、請求項22に記載のADC。
- Abが、
(a)配列番号18、100、102、若しくは103のアミノ酸配列を有する重鎖;及び配列番号19の軽鎖;又は
(b)配列番号28、101、104、若しくは105のアミノ酸配列を有する重鎖;及び配列番号29の軽鎖
を含む、請求項22に記載のADC。 - 請求項1に記載のADC及び薬学的に許容される担体を含む医薬組成物。
- 請求項13に記載のADC及び薬学的に許容される担体を含む医薬組成物。
- 配列番号16の配列に対応するVH鎖及び配列番号17の配列に対応するVL鎖、
配列番号26の配列に対応するVH鎖及び配列番号27の配列に対応するVL鎖、
配列番号36の配列に対応するVH鎖及び配列番号37の配列に対応するVL鎖、
配列番号46の配列に対応するVH鎖及び配列番号47の配列に対応するVL鎖、
配列番号56の配列に対応するVH鎖及び配列番号57の配列に対応するVL鎖、
配列番号66の配列に対応するVH鎖及び配列番号67の配列に対応するVL鎖、又は
配列番号76の配列に対応するVH鎖及び配列番号77の配列に対応するVL鎖
を含む抗huLRRC15抗体又はその抗huLRRC15結合断片。 - 請求項27に記載の抗huLRRC15抗体又はその抗huLRRC15結合断片をコードするヌクレオチド配列を含む核酸。
- 請求項28に記載の核酸を含むベクター。
- 請求項29に記載のベクターで形質転換された原核宿主細胞。
- 請求項29に記載のベクターで形質転換された真核宿主細胞。
- 請求項28に記載の核酸を発現するように遺伝子操作された真核宿主細胞。
- 請求項1に記載の抗huLRRC15 ADCを作製する方法であって、抗huLRRC15抗体を構造式(III)D−L−Rxによるシントンと接触させることを含み、Dは、細胞膜を横切ることができる細胞毒性剤及び/又は細胞増殖抑制剤であり、Lは、リソソーム酵素によって切断され得るリンカーであり、Rxは、シントンが抗体と共有結合的に連結する条件下で、シントンを抗体に共有結合的に連結させることができる官能基を含む、方法。
- huLRRC15間質(+)/がん(−)腫瘍を治療する方法であって、huLRRC15間質(+)/がん(−)腫瘍を有するヒトに、治療上の利益を提供するのに十分な、請求項1に記載の抗huLRRC15 ADCの量を投与することを含む、方法。
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WO2017095805A1 (en) | 2017-06-08 |
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CA3006596A1 (en) | 2017-06-08 |
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EP3383909A1 (en) | 2018-10-10 |
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