JP2018516911A - がんの処置のためのPD−1アンタゴニストとCpG−C型オリゴヌクレオチドの併用 - Google Patents
がんの処置のためのPD−1アンタゴニストとCpG−C型オリゴヌクレオチドの併用 Download PDFInfo
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Abstract
【選択図】図16
Description
略号。本発明の詳細説明および実施例全体を通して、以下の略号を使用する:
BOR 最良総合効果
BID 1回用量を1日2回
CBR 臨床的有用率
CDR 相補性決定領域
CHO チャイニーズハムスターの卵巣
CR 完全奏効
DCR 病勢コントロール率
DFS 無病生存期間
DLT 用量制限毒性
DOR 奏功期間
DSDR 長期病勢安定率
FFPE ホルマリン固定パラフィン包埋
FR フレームワーク領域
IgG 免疫グロブリンG
IHC 免疫組織化学または免疫組織化学的
irRC 免疫関連効果判定基準
IV 静脈内
MTD 最大耐用量
NCBI 米国立生物工学情報センター
NCI 米国立がん研究所
ORR 客観的奏効率
OS 全生存期間
PD 進行性疾患
PD−1 プログラム細胞死1
PD−L1 プログラム細胞死1リガンド1
PD−L2 プログラム細胞死1リガンド2
PFS 無増悪生存期間
PR 部分奏功
Q2W 1回用量を2週間毎
Q3W 1回用量を3週間毎
QD 1回用量を1日1回
RECIST 固形癌効果判定基準
SD 病勢安定
VH 免疫グロブリン重鎖可変領域
VK 免疫グロブリンκ軽鎖可変領域。
本発明がより容易に理解され得るように、一部の特定の科学技術用語を以下に具体的に定義する。本文書中の別の箇所に具体的に定義していない限り、本明細書で用いる他のすべての科学技術用語は、本発明が属する技術分野の当業者に一般的に理解されているものと同じ意味を有する。
(a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z,Nv(配列番号:38)であって、ここで、Nはヌクレオシドであり、x=0、1、2または3、y=1、2、3または4、w=0、1または2、p=0または1、q=0、1または2、v=0〜89およびz=1〜20であり、X1とX1’は自己相補型ヌクレオシドであり、X2とX2’は自己相補型ヌクレオシドであり、(TCG(Nq))y配列の5’−Tは該オリゴヌクレオチドの5’末端から0〜3塩基側である;および
(b)少なくとも8塩基長のパリンドローム配列であって、ここで、該パリンドローム配列は(X1X2CGX2’X1’(CG)p)z(配列番号:56)配列の最初の(X1X2CGX2’X1’)(配列番号:55)を含む、
を含み、該ODNは12〜100塩基長である。いくつかの実施形態では、x=0、y=1、w=0、p=0または1、q=0、1または2、v=0〜20およびz=1、2、3または4である。いくつかの実施形態では、X1とX2が各々AまたはTのいずれかである。いくつかの実施形態では、該パリンドローム配列は、3分の1より多くがAとTの塩基組成を有する。いくつかの実施形態では、CpG−C ODNは、配列番号:38〜51からなる群より選択される配列を含む。
5’−TCGTTCGAACGTTCGAACGTTCGAA−3’(配列番号:42)q=0およびs=4、
5’−TCGAACGTTCGAACGTTCGAACGTT−3’(配列番号:43)q=4およびs=0、
5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)q=4およびs=5、
5’−TCGTAACGTTCGAACGTTCGAACGTTA−3’(配列番号:46)q=5およびs=1、ならびに
5’−TCGTAACGTTCGAACGTTCGAACGTT−3’(配列番号:47)q=5およびs=0
からなる群より選択される配列からなる。
5’−TCGTCGAACGTTCGAGATGAT−3’(配列番号:41);
5’−TCGTTCGAACGTTCGAACGTTCGAA−3’(配列番号:42);
5’−TCGAACGTTCGAACGTTCGAACGTT−3’(配列番号:43);
5’−TCGAACGTTCGAACGTTCGAATTTT−3’(配列番号:44);
5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45);
5’−TCGTAACGTTCGAACGTTCGAACGTTA−3’(配列番号:46);
5’−TCGTAACGTTCGAACGTTCGAACGTT−3’(配列番号:47);
5’−TCGTAACGTTCGAACGTTCGAACGT−3’(配列番号:48);
5’−TCGTAACGTTCGAACGTTCGAACG−3’(配列番号:49);
5’−TCGTAACGTTCGAACGTTCGAAC−3’(配列番号:50);および
5’−TCGTAACGTTCGAACGTTCGAA−3’(配列番号:51)
からなる群より選択される。
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET(配列番号:25)、のアミノ酸19〜290からなる。
本発明の一態様では、本発明により、個体にPD−1アンタゴニストとCpG−C型オリゴヌクレオチドを含む併用療法を投与することを含む、個体のがんを処置するための方法を提供する。
1.個体にPD−1アンタゴニストとTLR9アゴニストを含む併用療法を投与することを含む、個体のがんを処置するための方法であって、該TLR9アゴニストがCpG−C型オリゴヌクレオチドである方法。
(a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z,Nv(配列番号:38)であって、ここで、Nはヌクレオシドであり、x=0、1、2または3、y=1、2、3または4、w=0、1または2、p=0または1、q=0、1または2、v=0〜89およびz=1〜20であり、X1とX1’は自己相補型ヌクレオシドであり、X2とX2’も自己相補型ヌクレオシドである;および
(b)少なくとも8塩基長のパリンドローム配列であって、ここで、該パリンドローム配列は(X1X2CGX2’X1’(CG)p)z配列の最初の(X1X2CGX2’X1’)を含む、
からなり、該オリゴヌクレオチドが12〜100塩基長である、実施形態1〜24のいずれか1つの方法、医薬、使用またはキット。
5’−TCGTCGAACGTTCGAGATGAT−3’(配列番号:41);
5’−TCGTTCGAACGTTCGAACGTTCGAA−3’(配列番号:42);
5’−TCGAACGTTCGAACGTTCGAACGTT−3’(配列番号:43);
5’−TCGAACGTTCGAACGTTCGAATTTT−3’(配列番号:44);
5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45);
5’−TCGTAACGTTCGAACGTTCGAACGTTA−3’(配列番号:46);
5’−TCGTAACGTTCGAACGTTCGAACGTT−3’(配列番号:47);
5’−TCGTAACGTTCGAACGTTCGAACGT−3’(配列番号:48);
5’−TCGTAACGTTCGAACGTTCGAACG−3’(配列番号:49);
5’−TCGTAACGTTCGAACGTTCGAAC−3’(配列番号:50);および
5’−TCGTAACGTTCGAACGTTCGAA−3’(配列番号:51)
からなる群より選択される、実施形態1〜24のいずれか1つの方法、医薬、使用またはキット。
(a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z,Nv(配列番号:38)であって、ここで、Nはヌクレオシドであり、x=0、1、2または3、y=1、2、3または4、w=0、1または2、p=0または1、q=0、1または2、v=0〜89およびz=1〜20であり、X1とX1’は自己相補型ヌクレオシドであり、X2とX2’も自己相補型ヌクレオシドである;および
(b)少なくとも8塩基長のパリンドローム配列であって、ここで、該パリンドローム配列は(X1X2CGX2’X1’(CG)p)z(配列番号:56)配列の最初の(X1X2CGX2’X1’)(配列番号:55)を含む、
からなるものであり、該オリゴヌクレオチドが12〜100塩基長である、実施形態1の方法。
分子生物学の標準的な方法は、Sambrook,Fritsch and Maniatis(1982 & 1989 2nd Edition,2001 3rd Edition)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Sambrook and Russell(2001)Molecular Cloning,3rd ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Wu(1993)Recombinant DNA,Vol.217,Academic Press,San Diego,CA)に記載されている。また、標準的な方法は、Ausbel,et al.(2001)Current Protocols in Molecular Biology,Vols.1−4,John Wiley and Sons,Inc.New York,NYにも示されており、これには、細菌細胞でのクローニングおよびDNA変異誘発(第1巻)、哺乳動物細胞および酵母でのクローニング(第2巻)、複合糖質およびタンパク質の発現(第3巻)ならびにバイオインフォマティクス(第4巻)が記載されている。
[実施例1]
実施例1:C59−08によるヒト細胞の免疫調節
C59−08は、ホスホロチオエート骨格を有するオリゴデオキシヌクレオチド5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)のナトリウム塩である。
実施例2:C59−08によるヒト腫瘍被検体の免疫調節
ヒト腫瘍組織培養物
患者由来のヒト腫瘍被検体を、市販の供給元(Bio−Options,Folio,Coversant Bio,and Boston BioSource)およびロチェスター大学から入手した。新鮮腫瘍組織は術後1時間以内に収集され、AQIX輸送用培地(AQIX,UK)に入れられたものであった。組織は、4℃にて一晩でMerck Research Laboratories,Palo Alto,CAに輸送された。
全RNAを、ポリトロンホモジナーザーを用いたRNA STAT−60(Tel−Test,Friendswood,TX)とのホモジネーションによって単離した。全RNAを製造業者のプロトコルに従って抽出した。イソプロパノールでの沈殿後、全RNAを、フェノール:クロロホルム:イソアミルアルコール(25:24:1)(Sigma−Aldrich,St.Louis,MO)で、Phase−Lock Lightチューブを用いて再度抽出した。
C59−08でのヒト腫瘍のエキソビボ処置により、IFNα誘導性遺伝子(IFNα2、MCP1、MCP2、OAS2、IP−10、GBP1、ISG−54、MxBおよびTRAIL)、サイトカイン(IFNβ,IL−10,IL−12,IL−6およびTNFα)ならびに免疫活性化マーカー(CD80、CD86、CD40、CD70およびOX40L)が腎細胞癌(RC)(n=5)、非小細胞肺がん(NSCLC)(n=3)ならびに膀胱(n=1)および結腸直腸(n=1)がんの組織塊培養物において誘導された。RCCドナー由来の被検体でのデータを図13:(A)IFNα誘導性遺伝子;(B)サイトカイン;および(C)免疫活性化マーカーに示す。
実施例3:動物モデルにおける抗IL−10と腫瘍内C59−08の併用の抗腫瘍活性
TC40.11D8は、マウスIL−10に対して標的化されるマウスIgG1/κモノクローナル抗体である。アデノウイルスヘキソン25に特異的なマウスモノクローナル抗体をマウスIgG1アイソタイプ対照にする。どちらの抗体も内部供給源から凍結(−80℃)ストックとして入手した。
製剤バッファーは各抗体に特異的であり、タンパク質を安定化させ、沈殿を抑制するためのものである。TC40.11D8およびマウスIgG1アイソタイプ対照のどちらの製剤も、75mM塩化ナトリウム,10mMリン酸ナトリウム,3%スクロース,pH7.3であった。
シチジンホスホ−グアノシン(CpG)ベースホスホロチオエートオリゴデオキシヌクレオチド(ODN)CpG 1826 5’−tccatgacgttcctgacgtt−3’(配列番号:53)(InvivoGen,San Diego,CA)は、マウスTLR9特異的アゴニストである。CpG 1826はCpG−B型配列を有する。CpGベースホスホロチオエートODN C59−08(Dynavax,Berkeley,CA)は、ヒトTLR9およびマウスTLR9のどちらも活性化させるアゴニストである。C59−08はCpG−C型配列:5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)を有し、5’および3’はOH基である。
CpG 1826を、0.9%塩化ナトリウム中、2mg/mLの濃度で再構成し、アリコートに分け、−20℃で保存した。C59−08を、リン酸緩衝生理食塩水(PBS)中、4.53mg/mLの濃度で再構成し、アリコートに分け、−20℃で保存した。対照ODNを、PBS中、4.47mg/mLの濃度で再構成し、アリコートに分け、−20℃で保存した。
およそ7〜8週齢の雌C57BL/6JマウスをJackson Laboratory(Sacramento,CA)から入手した。慣用的な動物飼料と水を随意に与えた。動物を試験開始前の1週間、収容した。試験開始(すなわち、腫瘍移植)時の動物の平均体重は19グラムであった。
TC−1細胞株(ジョンズ・ホプキンズ大学(Baltimore,MD)により提供)は、ヒトパピローマウイルス(HPV−16)E6およびE7とc−Ha.ras癌遺伝子で同時軽質転換されたマウス原発性肺上皮細胞に由来するものである(Lin et al.,Cancer Res.,56:21−6,1996)。TC−1細胞はC57BL6/Jマウス系統と同系である。
腫瘍を、最初の投与の前日およびそれ以降は週に2回測定した。腫瘍の長さと幅を電子カリパスを用いて測定し、式:体積(mm3)=0.5×長さ×幅2(式中、長さは最長寸法である)を用いて腫瘍体積を求めた。動物の体重を、最初の投与の前日およびそれ以降は週に2回測定した。偏りを防ぐため、重量または腫瘍体積の外れ値(あれば)を除外し、残りのマウスを右脇腹の腫瘍体積(注入腫瘍と称する)に基づいて種々の処置群に群分けした。
抗体の凍結ストックを解凍し、濡れた氷に移した。凍結解凍の反復を回避するため、各バイアルのストックの解凍は1回にし、単回使用に充分な容量のアリコートを作製した。ポリプロピレン製の低接着チューブをこの目的に使用した。アリコートを−80℃で保存した。各投与の前毎に、1つのアリコートを解凍し、適切な希釈剤で調製濃度に希釈した。
アイソタイプ対照mIgG1および抗IL−10 mIgG1を10mg/kgで0、4、8および12日目に腹腔内(IP)投与した。対照ODN(2.5mg/kg)、CpG 1826(1mg/kg)およびC59−08(2.5mg/kg)を右の腫瘍だけに0、4、8および12日目に腫瘍内(IT)投与した。
腫瘍体積を、処置間で各追跡日に比較した。個々の動物の追跡は、過剰な腫瘍量のため、または他の理由で早期に終了する場合があり得る。理由および最終測定時の腫瘍サイズによっては、最後に観測された腫瘍体積を、その動物について、以降のすべての日にちの体積の下限値として処理した(右側打ち切りデータ)。
TC−1腫瘍担持C57BL/6Jマウスを最初の投与の前日、右脇腹の平均腫瘍体積がおよそ60mm3(39mm3〜87mm3)に達している場合、5つの処置群:(1)mIgG1アイソタイプ対照+対照ODN;(2)mIgG1アイソタイプ対照+C59−08;(3)抗IL−10+CpG 1826;(4)抗IL−10+対照ODN;および(5)抗IL−10+C59−08に群分けした。左の腫瘍体積の範囲は0mm3〜113mm3であった。腫瘍の完全退縮(CR)は、腫瘍は、動物を群分けした日には測定可能であったと考えて、測定を実施した時点で測定可能な腫瘍がないことと規定した。結果を図10および11に示す。抗IL−10を腫瘍内CpG 1826(第3群)またはC59−08(第5群)のいずれかと併用すると、少なくとも3匹の動物で注入腫瘍のCRがもたらされた(図10A)。しかしながら、抗IL−10とC59−08(第5群)との併用でだけ、非注入腫瘍のCRがもたらされた(10匹中3匹の動物)(図11A)。C59−08単独療法(第2群)を含む他の処置では、注入腫瘍または非注入腫瘍のいずれにおいてもCRはもたらされなかった。対照処置、抗IL−10単独療法およびC59−08単独療法と比較すると、抗IL−10とC59−08を併用した投与(IT)では6、9および12日目で、注入腫瘍の体積の有意な低減がもたらされた(p<0.05,時間点間で多重性調整)(図10B〜D)。対照処置および抗IL−10単独療法と比較すると、抗IL−10とC59−08を併用した投与(IT)では、6、9および12日目で、非注入腫瘍の体積の有意な低減がもたらされた(p<0.05,時間点間で多重性調整)(図11B〜D)。
実施例4:全身性抗PD−1抗体と腫瘍内CpG−Cオリゴヌクレオチドの併用の抗腫瘍活性
抗体
2種類の抗PD−1ブロック抗体:最初の試験では29F.1A12および後の試験ではRMP1−14を使用した。各用量は250μgの抗体/注射を含むものにした。29F.1A12は、BioLegend(San Diego,CA)から得られる精製ラット抗マウスPD−1抗体(カタログ番号135202)である。このBioLegendの抗PD−1抗体はラットIgG2a,κモノクローナル抗体である。クローンRMP1−14は、BioXCell Inc.(West Lebanon,NH)から得られる精製ラット抗マウスPD−1抗体(カタログ番号BE0146)である。このBioXCellの抗PD−1抗体はラットIgG2aモノクローナル抗体である。
非CpG対照オリゴデオキシヌクレオチド(CTRL−ODN)は、ホスホロチオエート骨格を有する配列5’−TGA CTG TGA ACC TTA GAG ATG A−3’(配列番号:54)を有する。各用量は50μg ODN/注射を含むものにした。
6〜8週齢の雌BALB/cマウスをHarlan Laboratories(Indianapolis,IN)から入手した。CT26は、American Type Culture Collection(ATCC,Manassas,VA)から得られるマウス線維芽細胞株(CT26.WT,カタログ番号CRL−2638(商標))である。CT26は、N−ニトロソ−N−メチルウレタン誘導型未分化結腸癌細胞株であり、これは、免疫療法レジメンを試験するためのモデルとして高頻度に使用される(Wang et al.,J Immunol,154:4685−4692,1995)。
約8×104個のCT26細胞をBALB/cマウス(n=5〜6/群)の脇腹に0日目に、既報の方法(Brattain et al.,Cancer Res,40:2142−2146,1980)を用いて皮下(SC)注射した。抗PD−1ブロック抗体を5、8、11、14および18日目に腹腔内(IP)注射した。
約8×104個のCT26細胞を、BALB/cマウス(n=5〜6/群)の脇腹に−7日目に皮下(SC)注射した(Brattain et al.(上掲),1980)。処置レジメンを試験0日目(腫瘍細胞移植の7日後;平均腫瘍長さ5mm)に開始した。マウスを非処置のままにするか、または200mcgのマウス抗PD−1ブロック抗体を200μLの容量で腹腔内(IP)注射した(製造業者によって提供されたそのまま製剤)。抗PD−1注射液は0、3、7、10、14、18、21および25日目に投与した。数回の抗PD−1注射後(12日目)、マウスに50mcgのC59−08またはCTRL−ODN(150μL容量のPBS中)を腫瘍内(IT)注射した。C59−08およびCTRL−ODNの注射液は12、14、18、21、25および28日目に投与した。どちらの群も、抗PD−1処置を上記のとおりに継続した。同様のサイズの腫瘍を有する別個のマウス群(腫瘍細胞は試験0日目に注射した)に、抗PD−1前処置なしでC59−08単独を12、14、18、21、25および28日目に注射した。
約8×104個のCT−26腫瘍細胞をマウスの脇腹に0日目にSC注射した(Brattain et al.(上掲),1980)。マウスを非処置のままにするか、またはIP注射による抗PD−1で5、9、12、15、19、22、26および29日目に処置した。数回の抗PD−1注射後(15日目)、マウスをIT注射によるC59−08で15、19、22、26および29日目に処置するか、または非処置のままにした。抗CD8または抗CD4枯渇抗体をIP注射により14、15、16、19、22、26および29日目に、抗PD1/C59−08処置群のマウスに投与した。抗PD−1処置マウスに250μg/注射のBioXCell RMP1−14抗体を投与した。また、マウスには50μg/注射のC59−08も投与した。枯渇のため、マウスに250μg/注射の抗CD8 Ab(YTS 169.4)または抗CD4 Ab(GK1.5)(どちらもBioXCellから得られる)のいずれかを投与した。
約8×104個のCT−26細胞を0日目に左脇腹に、2日目に右脇腹にSC注射した。マウスを非処置のままにする(n=18)か、または抗PD−1 Abを5、7、11、14、21、23および26日目にIP注射する(n=19)かのいずれかにした。数回の抗PD−1 Ab注射後(14日目)、抗PD−1処置マウスに、C59−08を左腫瘍に14、19、21、23および26日目に注射した。抗PD−1 Ab処置マウスには250μg/注射のBioXCell RMP1−14抗体および50μg/注射のC59−08を投与した。
ピンセットを用いて腫瘍をペトリ皿に入れ、5mLの5%FCS含有RPMI培地を添加した。ハサミを用いて腫瘍を小片に切断し、腫瘍組織が50mL容ピペットでピペッティングできるようになるまで3mL容シリンジプランジャーの底を用いてすり潰した。この腫瘍組織懸濁液を50mL容チューブ内に移し、ペトリ皿を、5mLの5%FCS含有RPMI培地を用いて2回すすぎ洗いした。この組織懸濁液を、50mg/mLのコラゲナーゼ4(Clostridium histolyticum由来のSigma−Aldrich C5138−100MGコラゲナーゼ)と2mg/mLのDNase I(ウシ膵臓由来のSigma−Aldrich DN25−100MGデオキシリボヌクレアーゼI)を含有する100×腫瘍消化酵素ミックス中で消化させた。チューブを、3分毎に穏やかに振盪しながら37℃で20分間、インキュベートした。試料を70μmフィルターに通して濾過し、続いて、フィルターを5%FCS含有RPMIで洗浄した。試料を1400rpmで室温にて7分間遠心分離した。細胞を、腫瘍サイズに応じて1〜5容量の5%FCS含有RPMI中に再懸濁させた。得られた懸濁液中の細胞を、血球計算盤を用いて計数した。
全腫瘍を、Qiagen(Venlo,NL)から得られるRNAlater(カタログ番号76104)中で凍結させた。解凍後、全RNAを、30mgの完全にホモジナイズされた全腫瘍から、Qiagen製のRNeasy Mini Kit(カタログ番号74106)を製造業者の使用説明書に従って用いて単離した。簡単には、RNAlater RNA安定化試薬中で保存した全腫瘍を解凍し、重量を計り、5mmのステンレス鋼ビーズとBMEを含むRLTバッファー(700μL/30mg組織,チューブ1つあたり1mLまでのRLT)とを入れた2mL容PCRclean Safe−Lockエッペンドルフチューブ内に入れた。チューブをTissueLyser Adapter Set 2x24内に入れ、これを2回、25Hzで2分間、作動させた。ライセートを13,500rpmで3分間、遠心分離した。続いて、上清みを新たな15mL容チューブに移した。700μL/30mgの要件を満たすために、必要に応じてRLTバッファーを添加した。約700μLのライセートを使用し、残りを−80℃で保存した。1容量の70%エタノールを清澄化ライセートに添加し、700μLの試料をRNeasyスピンカラムの2mL容収集チューブに移し、13,500rpmで1分間、遠心分離した。試料が700μLを超えていた場合、逐次アリコートを同じRNeasyスピンカラム内で処理し、フロースルーを廃棄した。350μLのBuffer RW1をRNeasyスピンカラムに添加し、試料を遠心分離した。DNase Iインキュベーションミックス(80μL:10μLのDNase Iストック溶液+70μLのBuffer RDD)を直接、RNeasyスピンカラムに添加し、室温で15分間インキュベートした。350μLのBuffer RW1を添加し、チューブを遠心分離し、RNeasyスピンカラムを新たなチューブに移した。2容量の500μLのBuffer RPEをカラムに添加し、1分間、遠心分離してカラムを洗浄した。RNeasyスピンカラムを新たな2mL容収集チューブに移し、最高速で1分間、遠心分離した。RNeasyスピンカラムを新たな1.5mL容収集チューブ内に移し、45μLのRNaseフリー水(Life Technologies)をカラムに添加し、13,500rpmで1分間、遠心分離し、RNAを溶出させた。
5μgの溶出RNAを、5×第一鎖バッファー(Life Technologies)、ウシ血清アルブミン(Life Technologies)、組換えRNasinリボヌクレアーゼインヒビター(Promega,Madison,WI)、オリゴ(dT)15(Promega)、ランダムプライマー(Promega)、dNTP(Invitrogen,Carlsbad,CA)、DTT(Life Technologies)およびSuperScript III逆転写酵素(Life Technologies)を使用することにより、MyiQ Real−Time PCR Machine(Bio−Rad)を用いて逆転写した。データをユビキチン発現に対して正規化し、サイクル条件は、95℃で15分間の後、95℃で15秒と60℃で1分間を40回とした。mRNAの定量は、Power SYBR Green PCR Master Mix(Life Technologies)を用いて行なった。定量および解析はすべて、Applied Biosystems(Carlsbad,CA)StepOnePlus Real Time PCRシステムを使用し、StepOne v2.1ソフトウェアを用いて行なった。相対遺伝子発現レベルを、以下の式:1.8(平均Ctユビキチン−Ct遺伝子)*100,000を用いて計算した。
この手順を使用し、腫瘍細胞から腫瘍浸潤白血球(TIL)を分離した。腫瘍から得た細胞懸濁液を、必要に応じて5%FCS含有RPMIを添加することによって7mLにした。7mLのLympholyte(登録商標)−Mammal Cell Separation Media(Cedarlane,カタログ番号:CL5120)を15mL容の遠心分離用コニカルチューブに添加し、次いで、上面に7mLの細胞懸濁液を注意深く重層した。細胞を800×gで室温にて20分間、ブレーキングなしでスピンダウンした。形成された上層を50mL容チューブ内に移し、50mLの目盛まで5%FCS含有RPMI培地で満たした。細胞を1800rpmで室温にて7分間、最大加速および最大ブレーキング下でペレット化した。培地を吸引し、TIL含有ペレットを1mL 5%FCS含有RPMI培地中に再懸濁させた。一部の細胞(150μL)を96ウェルU字底プレートに入れ、2000rpmで3分間ペレット化し、次いで、遺伝子発現アッセイのために250μLのRLTバッファーで再懸濁させた。残りの細胞をFACS解析に使用し、各染色パネルには約100〜150μLのTIL試料を使用した。
Lymopholyte(登録商標)Mammal Cell Separation Media(Cedarlane,カタログ番号:CL5120)を用いて単離した約1.5×105個のTILを、37℃で3時間、ホルボールミリスタートアセタート(PMA)、イオノマイシンおよびブレフェルジンA(BFA)を有するBD GolgiPlug(500×)を含むLeukocyte Activation Cocktail(BD Biosciences(カタログ番号550583)から得られる)またはBFA単独(3μg/mL終濃度)で、200μLの最終容量にて刺激した。試料をサイトカイン産生について細胞内染色およびフローサイトメトリーによって解析した。
試薬はすべて4℃に維持した。洗浄はすべて、プレーティング細胞懸濁液を上下に3回ピペッティングした後、1800rpmで4℃にて3分間、遠心分離し、上清みを廃棄することを伴った。各試料について、細胞を3時間の刺激後にペレット化し、80μL/ウェルのFACSバッファー(PBS,10%FBS,0.1%アジ化ナトリウム)中に再懸濁させ、試料あたり2μLのFc Blockerと0.5μg/mLの各対象抗体を含むカクテルを作製した。試料を4℃で20分間インキュベートした後、洗浄し、200μL/ウェルのFACSバッファー中に再懸濁させた。細胞を固定するため、200μLの1%パラホルムアルデヒドを各ウェルに添加し、表面染色のためにプレートを暗所で4℃にて20分間インキュベートした。次いで細胞を洗浄し、ペレット化し、300μl/ウェルのFACSバッファー中に再懸濁させ、フローサイトメータ(BD Bioscience製のLSRII)を用いて即座にデータを取得した。
T細胞表面PD−1受容体に対する抗体は、がん細胞によってスイッチオンされる免疫阻害経路をブロックする機能を果たす(Wolchok and Chan,Nature,515:496−498,2014)。ここで本明細書において記載のように、C59−08と称するCpG−C ODNは、単独またはPD−1に対する抗体と併用して投与した場合、移植可能な結腸癌のマウスCT26モデルにおいて確立された腫瘍の増殖の抑止に有効であることが示された。具体的には、C59−08により腫瘍成長を抑止し、TILの数を増加させ、望ましい遺伝子発現パターンを誘導することができた。C59−08の単独投与では腫瘍拒絶に影響を及ぼすことができなかったが、C59−08は抗PD−1処置と相乗作用して、確立された腫瘍の拒絶および無再発生存期間の延長をもたらすことが示された。特筆すべきことには、確立された抗PD−1療法に腫瘍内C59−08を加えると、腫瘍拒絶と相関している活性化T細胞の明白な浸潤がもたらされた。したがって、抗PD1抗体とCpG−C ODNの併用は、腫瘍拒絶の誘導において、いずれかの単剤単独よりも卓越していることが示された。
実施例5 転移性黒色腫を有する患者での腫瘍内C59−08とペンブロリズマブとの併用のフェーズ1b/2治験
パート1(フェーズ1b 用量漸増)では、3つの漸増用量レベルのC59−08を転移性黒色腫を有する患者において評価し、パート2(フェーズ2 拡大)は、特異的黒色腫集団において有効性と安全性をさらに評価するための拡大コホートからなる。患者集団には:
1)抗プログラム細胞死受容体−1/リガンド−1(抗PD−1/L1)療法で治療未経験である転移性黒色腫患者;
2)抗PD−1療法を受けているが進行性疾患が確認された転移性黒色腫患者
を含める。
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本明細書において挙げた参考文献はすべて、引用により、あたかも個々の各刊行物、データベース登録(例えば、Genbank配列もしくはGeneID登録)、特許出願または特許が、引用により具体的に個々に示されて組み込まれているのと同程度に組み込まれる。米国特許仮出願第62/169,309号および同第62/168,449号は引用により本明細書に組み込まれる。この引用による組込みの記載は、本出願人らが、37 C.F.R.§1.57(b)(1)により、個々の1つ1つの刊行物、データベース登録(例えば、Genbank配列もしくはGeneID登録)、特許出願または特許(これらは各々、37 C.F.R.§1.57(b)(2)に従って明確に特定される)が、かかる引用のすぐ隣に引用による組込みの献辞記載がない場合であっても関連していることを意図するものである。本明細書内に引用による組込みの献辞記載(もし、あれば)が含まれていることは、この引用による組込みの一般記載をなんら弱めるものでない。本明細書における参考文献の引用は、該参考文献が直接関係のある先行技術であることの是認を意図するものでなく、このような刊行物または文献の内容または日付に関するなんらの是認を構成するものでもない。参考文献にクレーム用語の定義が示されており、これが本明細書に示した定義と矛盾する限りでは、本明細書に示した定義がクレーム発明の解釈に用いられるものとする。
Claims (32)
- 個体にPD−1アンタゴニストとTLR9アゴニストを含む併用療法を投与することを含む、個体のがんを処置するための方法であって、前記TLR9アゴニストがCpG−C型オリゴヌクレオチドである方法。
- 前記PD−1アンタゴニストがモノクローナル抗体またはその抗原結合断片である、請求項1に記載の方法。
- 前記個体がヒトであり、前記PD−1アンタゴニストが、ヒトPD−L1に特異的に結合してヒトPD−L1がヒトPD−1に結合するのをブロックするモノクローナル抗体またはその抗原結合断片である、請求項1に記載の方法。
- 前記個体がヒトであり、前記PD−1アンタゴニストが、ヒトPD−1に特異的に結合してヒトPD−L1がヒトPD−1に結合するのをブロックするモノクローナル抗体またはその抗原結合断片である、請求項1に記載の方法。
- 前記PD−1アンタゴニストがまた、ヒトPD−L2がヒトPD−1に結合するのもブロックする、請求項4に記載の方法。
- 前記PD−1アンタゴニストが:(a)配列番号:1、2および3の軽鎖CDRと配列番号:4、5および6の重鎖CDR;または(b)配列番号:7、8および9の軽鎖CDRと配列番号:10、11および12の重鎖CDR;を含むモノクローナル抗体またはその抗原結合断片である、請求項4に記載の方法。
- 前記PD−1アンタゴニストが、配列番号:7、8および9の軽鎖CDRと配列番号:10、11および12の重鎖CDRを含むモノクローナル抗体またはその抗原結合断片である、請求項4に記載の方法。
- 前記PD−1アンタゴニストが、重鎖と軽鎖を含む抗PD−1モノクローナル抗体であり、そしてここで、前記重鎖が配列番号:21を含み、前記軽鎖が配列番号:22を含む、請求項4に記載の方法。
- 前記PD−1アンタゴニストが、重鎖と軽鎖を含む抗PD−1モノクローナル抗体であり、そしてここで、前記重鎖が配列番号:23を含み、前記軽鎖が配列番号:24を含む、請求項4に記載の方法。
- 前記PD−1アンタゴニストが、ペンブロリズマブ、ペンブロリズマブバリアントまたはニボルマブである、請求項4に記載の方法。
- 前記CpG−C型オリゴヌクレオチドが:
(a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z,Nv(配列番号:38)であって、ここで、Nはヌクレオシドであり、x=0、1、2または3、y=1、2、3または4、w=0、1または2、p=0または1、q=0、1または2、v=0〜89およびz=1〜20であり、X1とX1’は自己相補型ヌクレオシドであり、そして、X2とX2’も自己相補型ヌクレオシドである;および
(b)少なくとも8塩基長のパリンドローム配列であって、ここで、前記パリンドローム配列は(X1X2CGX2’X1’(CG)p)z配列の最初の(X1X2CGX2’X1’)を含む、
からなるものであり、前記オリゴヌクレオチドが12〜100塩基長である、
請求項1に記載の方法。 - x=0、y=1、w=0、p=0または1、q=0、1または2、v=0〜20およびz=1、2、3または4である、請求項11に記載の方法。
- 前記CpG−C型オリゴヌクレオチドがTCGNq(X1X2CGX2’X1’CG)zNv(配列番号:39)からなり、ここで、Nはヌクレオシドであり、q=0、1、2、3、4または5、v=0〜20、z=1〜4であり、X1とX1’は自己相補型ヌクレオシドであり、そして、X2とX2’も自己相補型ヌクレオシドであり、そしてここで、前記オリゴヌクレオチドが少なくとも12塩基長である、請求項1に記載の方法。
- 前記CpG−C型オリゴヌクレオチドが5’−TCGNqTTCGAACGTTCGAACGTTNs−3’(配列番号:40)からなり、ここで、Nはヌクレオシドであり、q=0、1、2、3または4、s=0〜20であり、そしてここで、前記オリゴヌクレオチドが少なくとも12塩基長である、請求項1に記載の方法。
- 前記CpG−C型オリゴヌクレオチドが、5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)からなる配列を有する、請求項1〜10のいずれかに記載の方法。
- 前記CpG−C型オリゴヌクレオチドが、ホスホロチオエート骨格を有するオリゴデオキシヌクレオチドである、請求項15に記載の方法。
- さらに、前記個体に抗IL−10抗体またはその抗原結合断片を投与することを含む、請求項11に記載の方法。
- 前記抗IL−10抗体またはその抗原結合断片が:(a)配列番号:26、27および28の軽鎖CDRと配列番号:29、30および31の重鎖CDRを含む、請求項17に記載の方法。
- 前記抗IL−10抗体またはその抗原結合断片が、配列番号:32および配列番号:33の重鎖可変領域および軽鎖可変領域を含む、請求項17に記載の方法。
- 前記抗IL−10抗体が、重鎖と軽鎖を含む抗IL−10モノクローナル抗体であり、そしてここで、前記重鎖が配列番号:34を含み、前記軽鎖が配列番号:35を含む、請求項17に記載の方法。
- 前記抗IL−10抗体が、抗IL−10 hum 12G8であるかまたは抗IL−10 hum 12G8バリアントである、請求項17に記載の方法。
- がんと診断されたヒト個体の処置方法であって、前記個体にまずペンブロリズマブを投与した後、3週間後に、配列番号:45からなるオリゴヌクレオチドを腫瘍内投与することを含む方法。
- 前記個体に、200mgのペンブロリズマブをQ3Wで、1日目から開始して投与し、そして配列番号:45のオリゴヌクレオチドを、2.0、4.0または8.0mgの用量で、22日目から開始して週に1回を4週間にわたって、続いて2.0、4.0または8.0mgの用量で3週に1回、腫瘍内投与することを含む、請求項22に記載の方法。
- 前記個体が、抗PD−1療法もしくは抗PD−L1療法で以前に処置されたことがないかまたは抗PD−1の前治療を受けている間に進行が確認されている、請求項22または23に記載の方法。
- 前記CpG−C型オリゴヌクレオチドが、5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)からなる配列とのナトリウム塩であり、そして、前記オリゴヌクレオチドがホスホロチオエート骨格を有するオリゴデオキシヌクレオチドである、請求項22および23のいずれか1項に記載の方法。
- 前記CpG−C型オリゴヌクレオチドが、5’−TCGTTCGAACGTTCGAACGTTCGAA−3’(配列番号:42)からなる配列を有する、請求項1に記載の方法。
- 前記がんが、進行型もしくは転移性の黒色腫、腎細胞癌、非小細胞肺がん、膀胱がんまたは結腸直腸がんである、請求項1および22〜26のいずれか1項に記載の方法。
- 前記PD−1アンタゴニストがペンブロリズマブであり、そして、前記CpG−C型オリゴヌクレオチドが、5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)からなる配列を有する、請求項1に記載の方法。
- 前記PD−1アンタゴニストがペンブロリズマブであり、前記CpG−C型オリゴヌクレオチドが、5’−TCGAACGTTCGAACGTTCGAACGTTCGAAT−3’(配列番号:45)からなる配列を有し、前記オリゴヌクレオチドがホスホロチオエート骨格を有するオリゴデオキシヌクレオチドである、請求項1に記載の方法。
- 前記がんが、進行型または転移性の黒色腫、腎癌、NSCLC、膀胱がんおよび結腸直腸がんからなる群より選択される、請求項28または29に記載の方法。
- 前記PD−1アンタゴニストがペンブロリズマブであり、前記CpG−C型オリゴヌクレオチドが、5’−TCGTTCGAACGTTCGAACGTTCGAA−3’(配列番号:42)からなる配列を有する、請求項1に記載の方法。
- 前記PD−1アンタゴニストが、配列番号:7、8および9の軽鎖CDRと配列番号:10、11および12の重鎖CDRを含むモノクローナル抗体またはその抗原結合断片であり、前記CpG−C型オリゴヌクレオチドが:
(a)5’−Nx(TCG(Nq))yNw(X1X2CGX2’X1’(CG)p)z,Nv(配列番号:38)であって、ここで、Nはヌクレオシドであり、x=0、1、2または3、y=1、2、3または4、w=0、1または2、p=0または1、q=0、1または2、v=0〜89およびz=1〜20であり、X1とX1’は自己相補型ヌクレオシドであり、そして、X2とX2’も自己相補型ヌクレオシドである;および
(b)少なくとも8塩基長のパリンドローム配列であって、ここで、前記パリンドローム配列は(X1X2CGX2’X1’(CG)p)z配列の最初の(X1X2CGX2’X1’)を含む、
からなるものであり、前記オリゴヌクレオチドが12〜100塩基長である、請求項1に記載の方法。
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