JP5701266B2 - 感染症治療剤 - Google Patents
感染症治療剤 Download PDFInfo
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- JP5701266B2 JP5701266B2 JP2012197861A JP2012197861A JP5701266B2 JP 5701266 B2 JP5701266 B2 JP 5701266B2 JP 2012197861 A JP2012197861 A JP 2012197861A JP 2012197861 A JP2012197861 A JP 2012197861A JP 5701266 B2 JP5701266 B2 JP 5701266B2
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Description
1.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を含有してなる免疫賦活組成物、
2.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を含有してなる癌治療組成物、
3.癌転移を抑制する組成物である前項2記載の癌治療組成物、
4.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を含有してなる感染症治療組成物、
5.免疫賦活を介して作用することを特徴とする前項2または3記載の癌治療組成物、
6.免疫賦活を介して作用することを特徴とする前項4記載の感染症治療組成物、
7.PD−1とPD−L1若しくはPD−1とPD−L2の相互作用阻害物質、PD−1の細胞内シグナル阻害物質、およびPD−1、PD−L1若しくはPD−L2の産生阻害物質から選択される一以上の免疫抑制シグナル阻害物質である前項1乃至6のいずれかに記載の組成物、
8.PD−1抗体、PD−L1抗体、可溶化PD−1、および可溶化PD−L1から選択される一以上のPD−1とPD−L1の相互作用阻害物質である前項7記載の組成物、
9.国際受託番号FERM BP-8392で識別されるハイブリドーマが産生する抗ヒトPD−1抗体、非ヒト抗体をヒト化させた抗PD−1抗体、および完全ヒト型抗ヒトPD−1抗体から選択されるPD−1抗体である前項8記載の組成物、
10.遺伝子改変によりPD−1発現が阻害されたリンパ球細胞が、免疫抑制シグナル阻害物質である前項1乃至6のいずれかに記載の組成物、
11.PD−1とPD−L1若しくはPD−1とPD−L2の相互作用阻害物質、PD−1の細胞内シグナル阻害物質、またはPD−1、PD−L1若しくはPD−L2の産生阻害物質が、タンパク質、ポリペプチド若しくはペプチド、ポリヌクレオチド若しくはポリヌクレオシド、抗体若しくはそれらの誘導体、有機合成化合物、無機化合物、および天然物から選択される一以上の物質である前項7記載の組成物、
12.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を投与することからなる免疫賦活方法、
13.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を投与することからなる癌治療方法、
14.癌転移を抑制する前項13記載の癌治療方法、
15.PD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質を投与することからなる感染症治療方法、
16.免疫賦活を介して作用することを特徴とする前項13または14記載の癌治療方法、
17.免疫賦活を介して作用することを特徴とする前項15記載の感染症治療方法、
18.PD−1とPD−L1若しくはPD−1とPD−L2の相互作用阻害物質、PD−1の細胞内シグナル阻害物質、およびPD−1、PD−L1若しくはPD−L2の産生阻害物質から選択される一以上の免疫抑制シグナル阻害物質である前項12乃至17のいずれかに記載の方法、
19.PD−1抗体、PD−L1抗体、可溶化PD−1、および可溶化PD−L1から選択される一以上のPD−1とPD−L1の相互作用阻害物質である前項18記載の方法、
20.国際受託番号FERM BP-8392で識別されるハイブリドーマが産生する抗ヒトPD−1抗体、非ヒト抗体をヒト化させたPD−1抗体、および完全ヒト型抗ヒトPD−1抗体から選択されるPD−1抗体である前項19記載の方法、
21.遺伝子改変によりPD−1発現が阻害されたリンパ球細胞が、免疫抑制シグナル阻害物質である前項12乃至17のいずれかに記載の方法、
22.PD−1とPD−L1若しくはPD−1とPD−L2の相互作用阻害物質、PD−1の細胞内シグナル阻害物質、またはPD−1、PD−L1若しくはPD−L2の産生阻害物質が、タンパク質、ポリペプチド若しくはペプチド、ポリヌクレオチド若しくはポリヌクレオシド、抗体若しくはそれらの誘導体、有機合成化合物、無機化合物、および天然物から選択される1つ以上の物質である前項18記載の方法、
23.免疫賦活組成物を製造するためのPD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質の使用、
24.癌治療組成物を製造するためのPD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質の使用、
25.癌治療組成物が、癌転移抑制組成物である前項24記載の物質の使用、
26.感染症治療組成物を製造するためのPD−1、PD−L1、またはPD−L2の免疫抑制シグナル阻害物質の使用、
27.PD−L1またはPD−L2を発現するように形質転換されたスクリーニング用癌細胞株、
28.前項27記載の細胞、リンパ球細胞および被験物質を接触させて、前項27記載の細胞へのリンパ球細胞の免疫反応に対する被験物質の増強作用を評価することを特徴とする免疫賦活物質のスクリーニング方法、
29.癌細胞である前項27記載の細胞、リンパ球細胞および被験物質を接触させて、その癌細胞へのリンパ球細胞の免疫反応に対する被験物質の増強作用またはその腫瘍細胞の増殖に対する阻害作用を評価することを特徴とする癌治療物質のスクリーニング方法、
30.病原体を感染させた前項27記載の細胞またはPD−L1若しくはPD−L2を発現する細胞、リンパ球細胞および被験物質を接触させて、その感染細胞へのリンパ球細胞の免疫反応に対する被験物質の増強作用または病原体増殖に対する阻害作用を評価することを特徴とする感染症治療物質のスクリーニング方法、
31.前項27記載の癌細胞株を移植して作出した哺乳動物、
32.前項31記載の哺乳動物に被験物質を投与し、被験物質による移植癌細胞の増殖に対する抑制率またはその被移植哺乳動物の生存率を評価することを特徴とする癌治療物質の選別方法に関する。
モノクローナル抗体産生細胞の作製は、抗原で免疫された動物から抗体価の認められた個体を選択し、最終免疫の2〜5日後に脾臓またはリンパ節を採取し、それらに含まれる抗体産生細胞を同種または異種動物の骨髄腫細胞と融合させることにより、継代培養可能なモノクローナル抗体産生ハイブリドーマを作製することにより行なうことができる。抗原タンパク質の投与は、抗体産生が可能な部位にそれ自体あるいは担体、希釈剤と共に行なう。投与には、抗体産生能を高めるため、完全フロイントアジュバントや不完全フロイントアジュバントを投与するのが一般的である。また、“DNA免疫”と呼ばれる方法によっても、動物を免疫することができる。この方法は、免疫動物の後足前脛骨筋にカルジオトキシン(Cardiotoxin)を処置し、さらに抗原タンパク質を発現するベクターを導入した後、組織修復の過程でベクターが筋細胞に取りこまれ、タンパク質を発現する現象を利用した方法である(Nature Immunology,2001年,第2巻,第3号,p.261〜267)。
マウスPD−L1発現ベクターの作製は、マウスPD-L1cDNA(Journal of Experimental Medicine,2000年,第19巻,第7号,p.1027〜1034)を制限酵素EcoRIで消化して、発現ベクターpApuroXS(The EMBO Journal,1994年,第13巻,第6号,p.1341〜1349)に挿入し、連結させることによって行った。作製した発現ベクターpApuroXS-PD-L1のP815細胞への導入は、エレクトロポーレーション法(360V、500μF)で行った。P815細胞の培養は、FCS(10%)、2−メルカプトエタノール(10-5M)、各種抗生物質含RPMI-1640培地で培養できるが、さらに、抗生物質ピューロマイシン(Puromycin;3μg/ml)を含んだ培地の培養に対して耐性の同細胞株を継代培養することによって、マウスPD−L1を安定的に発現する形質転換P815細胞株を取得した。PD−L1の発現は、フローサイトメトリー解析にて確認した。図1(A)にH−2Ld特異的2C CTLクローンのPD−1発現(i)と、P815(肥満細胞種由来細胞株)のPD−L1発現安定形質転換株でのPD−L1発現(ii)を示すフローサイトメトリーを示す。
同様の方法で、PD−L1を安定的に発現する形質転換B16細胞株(B16/PD−L1)を取得した(図1(A)(iii)〜(v)参照)。ここでは発現ベクターとして同様の方法で作製したpEFBOSneo-PD-L1(Nucleic Acid Research,1990年,第18巻,第17号,p.5322)を用い、細胞株の選択培養にはG418(0.5mg/ml)を使用した。
全長マウスPD-L1cDNAの3'末端側に6個のヒスチジンがタンデムに並んだペプチドタグ(His-Tag)を連結させたタンパク質をコードするcDNAを制限酵素EcoRIおよびNotIで消化して、発現ベクターpVL1393(商品名:Clontechより購入)に挿入させた。続いて、この発現ベクターをSF9昆虫細胞(Invitrogenより購入)に導入して、封入体を回収した。この封入体ウイルスをHiFive昆虫細胞(Invitrogenより購入)に2日間、27℃下で培養することによって感染させた。溶解緩衝液(Tris-HCl(50mM,pH7,含1%TritonX-100)、EDTA(10mM)、NaCl(150mM)、各種プロテアーゼ阻害剤)で溶解させた細胞溶解液を、Ni−セファロースカラムクロマトグラフィーで処理することによって、抗原となる精製PD−L1タンパク質を取得した。
透析した同PD−L1タンパク質を完全フロイントアジュバンドと共に8週令メスWhisterラット(SLC Japanより購入)に免疫して、数日後、末梢リンパ節から回収した2×108細胞を、PEG1500(Amershamより購入)を用いて同数のSP2/0細胞と細胞融合させた。さらに、RPMI1640培地(HAT(Sigmaより購入)、Origen(10%,Igenより購入)、FCS(10%)、2−メルカプトエタノール(10-5M)、各種抗生物質)で培養することによって選択し、産生抗体の存在をフローサイトメトリー解析にて確認した。これによって樹立されたハイブリドーマ(国際受託番号:FERM BP-8396で認識されるハイブリドーマ)をBalb/C nu/nuマウスに移入して、後に腹水からの回収液をプロテインGセファロースカラムクロマトグラフィーで精製することによって、PD−L1に対するモノクローナル抗体(1−111)を取得した。フローサイトメトリー等で使用される抗体は、Sulfo-NHS-LC-biotin(商品名:Pierceより購入)を用いてビオチン化したものを用いた。
また、同様の方法に従い、抗ヒトPD−1抗体(国際受託番号:FERM BP-8392で認識されるハイブリドーマから産生されるモノクローナル抗体)を作製した。
細胞傷害性アッセイは、51Cr(クロム)遊離アッセイによって行った。
2C細胞(Journal of Immunology,1996年,第157巻,第2号,p.670〜678)は、2CトランスジェニックB6マウス由来の(H−2L)dアロ反応性の細胞傷害性T細胞である。図1(B)に、2C細胞(E:エフェクター)を51Crラベル化したP815細胞(T:ターゲット)と共に(○)または3つのPD−L1発現P815細胞株(P815/PD−L1)(□、◇、△)と共にあるいはさらに10mg/mlラットanti-PD-L1F(ab')2IgG存在下(▲)を、さまざまなE/T比で混合して、4時間で遊離される51Crを測定した結果を示す。
抗PD−L1抗体(anti-PD-L1F(ab')2)は、細胞傷害性Tリンパ球細胞の低下した細胞傷害活性を回復させた。これらの結果から、PD−L1の機能を阻害することによるPD−1およびPD−L1シグナルの阻害は、癌細胞に対する細胞傷害活性を増強させることができると考えられる。
1×106細胞のP815細胞(n=6)またはP815/PD−L1細胞(n=6)を同系DBA/2マウスの皮下にそれぞれ移入し、腫瘍増殖とマウスの生存率を評価した。その結果を図2(A)に示す。図中、○はP815細胞株移植群、□、△はPD−L1発現P815細胞株移植群である。さらにP815/PD−L1細胞を移入した群の組織学的解析を行った。移入20日後のマウスの腹壁ならびに腹膜腔の組織切片を、10%ホルムアルデヒドで固定、パラフィンで砲架して、ヘマトキシリン、エオジンで染色して得られた染色像を図2(B)に示す。図中、aは腹壁および腹膜への腫瘍細胞の浸潤を示す40倍像、bは同じく400倍像であり、cは脾臓への転移、dは肝臓への転移を示す。
P815細胞を移植した群では、P815細胞の増殖は抑えられており、6〜7週目では30%が生存したのに対して、PD−L1を発現するP815細胞(P815/PD−L1)を移植した群では、癌細胞の増殖は著しく、2〜4週目までに全例が死亡した(図2(A))。P815/PD−L1は、腹膜腔、さらに、腹腔へ浸潤しており、また、肝および脾臓への転移が認められた(図2(B)a〜d参照)。
P815細胞を移入し免疫したマウスから細胞傷害性T細胞CTLを調整し、2×106個数のCTL細胞と、5×106個数のP815細胞またはP815/PD−L1細胞のみ、あるいはanti-PD-L1F(ab')2IgG(10mg/ml)存在下でP815/PD−L1細胞をそれぞれ混合培養し、24時間後の培養上清中のIFN−γをELISAキット(Bioscienceから購入)で測定した。その結果を図3(A)に示す。
また、図3(B)に、3×106個数のP815/PD−L1細胞を皮下移入した同系DBA/2マウス(n=10)に、ラットIgG(□)あるいはanti-PD-L1F(ab')2IgG(0.1mg/一匹)(○)を、細胞移入後1、3、5、7日後にそれぞれ腹腔内投与し、腫瘍増殖とマウスの生存率を評価した結果を示す。
抗PD−L1抗体は、P815/PD−L1により抑制された細胞傷害性Tリンパ球細胞からのIFN−γ産生を回復させた(図3(A))。抗PD−L1抗体の投与は、癌細胞増殖を抑制し、明確な生存効果を示した(図3(B))。この結果は、抗PD−L1抗体の投与が癌治療に有効であることを示している。
1×106個数のB16メラノーマ(n=6)またはB16/PD−L1細胞(n=6)をB6マウスにはそれぞれ皮下移入し、同数のB16/PD−L1細胞をPD−1トランスジェニックB6マウス(n=5)およびPD−1遺伝子ホモ欠損B6マウス(PD−1-/-(n=4))(Science,2001年,291巻,5502号,p.319〜332)に移入し、以後25日までそれぞれの腫瘍増殖を測定した。その結果を図4に示す。
2.5×108個数のJ558Lミエローマ細胞を皮下移入した同系Balb/Cマウス(n=9)に、ラットIgGあるいはanti-PD-L1F(ab')2IgG(0.1mg/一匹)を細胞移入後3、5、7日後にそれぞれ腹腔内投与し、腫瘍増殖を評価した(図5(B))。また、同様にJ558Lミエローマ細胞を皮下移入したPD−1ホモ欠損マウスとBalb/C(n=4)での腫瘍増殖を比較した(図5(C))。
抗PD−L1抗体の投与は、PD−L1を発現しているJ558癌細胞(図5(A)に各種ミエローマ細胞株でのPD−L1発現を示すフローサイトメトリーを示す。)の増殖を抑制した(図5(B))。また、J558細胞を移植したPD−1欠損マウスでは移植癌細胞の増殖は完全に阻害された(図5(C))。これらの結果は、PD−L1もしくはPD−1の阻害が癌治療に有効であることを示している。
血管内皮細胞(以下、ECsと略す。)をマレリーバーグの方法(Journal Immunology Methods,2000年,第244巻,第1-2号,p.205〜215)により、マウス心臓から取得した。具体的には、心臓組織をコラゲナーゼで消化した後、マウスIgとともに前培養、さらに、FITC修飾した抗CD31抗体、同修飾抗CD105抗体、同修飾抗isolectinB4抗体、および、抗FITCビーズを添加して培養した。この血管内皮細胞をMagnetic-activated cell-sorting separation columns(商品名:Miltenyi Biotecより購入)を用いて、ポジティブ選択によって精製した。
取得した血管内皮細胞でのPD−L1、PD−L2の発現を、フローサイトメトリーで確認した。同細胞の標識には、抗PD−L1抗体(抗体名:1−111)、抗PD−L2抗体(抗体名:#122)および蛍光標識した2次抗体を用いて行った(図6(A))。解析はCellQuestソフトウェア(Dickinsonより購入)を使用したFacscalibur(機器名:Becton Dickinsonより購入)で、1万回イベントで解析した。PD−L1あるいはPD−L2の発現は、開口曲線で示され、コントロールIgは充填曲線で示される。
マウス各組織でのPD−L1発現の確認を組織染色によって行った。各組織サンプリング1時間前に100μgビオチン標識化抗PD−L1抗体(1−111)を溶解した100μlPBSをマウスに静脈投与した。続いて、5μm凍結切片を4%パラホルムアルデヒド(PFA)で固定して、Streptavidin-FITCで染色した。さらに、各切片をPhalloidinで対比染色した(図6(B)、(a)眼球、(b)顎下腺、(c)心臓、(d)肺、(e)肝臓、(f)腎臓でのPD−L1の発現を示す。図中、Chは脈絡膜、CVは中心静脈、Glは糸球体、Reは網膜を示す。各矢印は、血管内皮細胞を示す。各染色像は40倍拡大像である。)。PD−L1は、心臓、肺、腎臓、胃、小腸、顎下腺、眼球、肝臓の血管内皮で認められた。肝臓での発現は、肝臓洞様毛細血管に局在していた。
肝臓非実質細胞(以下、LNPCsと略記する。)でのPD−L1発現を組織染色(図7(A))ならびにフローサイトメトリー(図7(B))で確認した。組織染色は、3%PFAで固定した5μm肝臓凍結切片をラット血清で前処理し、ビオチン標識化抗PD−L1抗体(1−111)あるいはビオチン標識化抗ICAM−1抗体(商品名:BD Pharmingenより購入)にて1時間、室温下で抗体反応を行ない、ビオチン抗体をtyramide signal amplification(TSA)fluorescence system(機器名:PerkinElmer Life Sciencesより購入)にて視覚化した(図7(A):ICAM−1の発現、同図(B):PD−L1の発現、CV:中心静脈を示す。各染色像は40倍拡大像である。)。
LNPCsは、pronaseE法(Experimental Cell Research,1976年,第99巻,p.444〜449)によってマウス肝臓より単離した。具体的には、LNPCsは、肝臓をpronaseE溶液(Merck)にて還流、培養し、密度勾配遠心法にて分離した。その細胞懸濁液中のクップファー細胞(Kupffer Cells)(CD54+、CD11bhigh)の相対的分布は20〜25%であり、肝臓類洞周囲腔内皮細胞(以下、LSECsと略記する。)(CD54+、CD11bhigh)は、75〜80%である。
クップファー細胞とLSECsを、FITC標識化抗CD11b抗体およびICAM−1、PD−L1、B7−1、B7−2に対するそれぞれのビオチン化モノクローナル抗体、それに続くPE標識化Streptavidinにて、それぞれ二重染色した。クップファー細胞とLSECsは、それぞれCD11bhighとCD11blow細胞としてゲートされる(図8)。
PD−L1は、クップファー細胞では、ICAM−1、B7−1、B7−2を共発現しているが、LSECsではその発現は弱いものであった(図8)。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型C57BL/6マウス(wt)の脾臓ならびにリンパ組織から、T-cell enrichment column(商品名:Genzymeより購入)を用いたネガティブ選別によって、ナイーブT細胞(精製度90%以上)を精製した。同細胞を10μg/ml抗CD3モノクローナル抗体(2C11)とともに48時間培養して活性化させた。
上記方法によって活性化したナイーブT細胞を、FITC標識化抗CD4抗体あるいはAPC標識化抗CD8抗体ならびにPE標識化抗CD25抗体、PE標識化抗CD44抗体、PE標識化抗CD69抗体、PE標識化抗CTLA−4抗体、ビオチン標識化抗B7−1(CD80)抗体、ビオチン標識化抗B7−2(CD86)抗体、抗PD−1抗体(抗体名:J43、国際受託番号FERM BP-8118で認識されるハイブリドーマから産生されるモノクローナル抗体)、抗PD−L1抗体(1−111)で二重染色して、フローサイトメトリーにてそれぞれの分子の発現を解析した(図9、図10)。
なお、国際受託番号FERM BP-8118で識別されるハイブリドーマは、2001年5月30日付で日本国茨城県つくば市東1丁目1番地1 中央第6(郵便番号305-8566)、独立行政法人産業技術総合研究所特許生物寄託センターに受託番号FERM P-18356で寄託され、2002年7月16日付で国際寄託に移管されている。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)のナイーブT細胞の活性化は、上記実施例8に記載の方法で行った。活性化後の同細胞の増殖をBrdU取りこみ法によって測定した(図11(A))。BrdUを48時間の最後の6時間に添加して細胞を標識し、これをProliferation ELISA kit(商品名:Rocheより購入)を用いる測定によって細胞増殖を決定した。また、この時のIFN−γ産生量をELISA Kit(商品名:Genzymeより購入)にて測定した(図12(A))。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)由来のT細胞を上記実施例8で記載の方法であらかじめ活性化させた。続いて、既に活性化しているT細胞に対して、野生型マウスからのマイトマイシンC処理LNPCsの存在あるいは非存在下で、さらに、30μg/ml抗PD−L1抗体(1−111)(コントロールとしたラットIgG)、20μg/mlCTLA4-Ig(Genzyme)(コントロールとしたヒトIgG)の存在あるいは非存在下でそれぞれ60時間培養して、最後の12時間の同細胞の増殖をBrdU取りこみ法によって測定した(図11(B))。また、48時間時点でのIFN−γ産生量も測定した(図12(B))。
ナイーブT細胞の活性化時におけるIFN−γ産生量は、PD−1-/-と野生型マウスの違いによる有意な差異は認められなかった。一方、既に活性化されたT細胞においては、野生型マウス由来のT細胞のIFN−γ産生量は、PD−1-/-由来のものに比べ有意に低かった(図12)。このことから、既に活性化しているT細胞に対するPD−1の抑制作用の効果は、ナイーブT細胞の活性化に対する効果よりも高いことが示唆された。
野生型マウス由来の活性化したT細胞は、LNPCsとの共培養では、T細胞の細胞増殖およびIFN−γ産生量に有意な変化は認められないが、PD−1-/-由来の活性化したT細胞は、LNPCsとの共培養によって、その細胞増殖に有意な増加が認められた(図11(B)、図12(B))。また、野生型マウス由来の活性化したT細胞とLNPCsとの共培養への抗PD−L1抗体の添加によって、T細胞の細胞増殖の増加が認められた(図11(B))。これらの結果は、LNPCsのPD−1あるいはPD−L1が、活性化T細胞の抑制に関与しており、PD−1の欠如あるいはPD−1とPD−L1間の相互作用の阻害が、T細胞を活性化することを示すものである。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)の活性化T細胞を、5μM CFSE(5-(6)-carboxy-fluorescein diacetate succinimidyl diester)(商品名:Molecular probesより購入)で標識して、LNPCsとともに48時間共培養した。この時の細胞***を、FACSを用いたCFSE活性測定によって決定した(図12(C))。
活性化T細胞の細胞増殖抑制は、細胞***の停止に起因しており、PD−1シグナルがT細胞の細胞***を抑制することが示唆された(図12(C))。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)(3匹/群)に109-1010PFU(plaque-forming units)Ad-lacZを静脈内投与して、マウスをアデノウイルスに感染させた。ここで使用したAd-lacZは、E1およびE3領域に欠損を有し、さらに、lacZ遺伝子を持った5型アデノウイルスであり、293細胞で増殖させた後、塩化セシウム密度勾配遠心分離(Nucleic Acid Research,1995年,第234巻,第19号,p.3816〜3821)の記載によって精製したものである。
感染後0日日あるいは7日目に、同マウスに対して屠殺1時間前に0.5mg BrdU(商品名:Sigmaより購入)を静脈内投与して、採取した脾臓細胞および肝臓内リンパ球を抗BrdU抗体および抗CD19抗体あるいは抗CD3抗体で二重標識した(図13)。
さらに、感染後7日目の同細胞に対しては、抗BrdU抗体、抗CD19抗体、抗CD3抗体、抗CD4抗体、抗CD8抗体で二重標識した(図14(B)、それぞれの棒グラフはBrdU陽性細胞の割合を示す。)。
アデノウイルス感染したPD−1-/-マウスの肝臓では、同様に感染した野生型マウスの肝臓に比較して、増殖性(BrdU陽性)の各リンパ球(CD19陽性、CD3陽性、CD4陽性、CD8陽性)の割合が増加していた。一方、このような現象が脾臓では認められなかったことから、PD−1は、炎症を起した組織でのT細胞の増殖を阻害することが示唆された(図14(B))。
PD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)(3匹/群)に109-1010PFU Ad-lacZを静脈内投与して、マウスをアデノウイルスに感染させ、さらに、感染後0日目あるいは7日目の屠殺1時間前に0.5mg BrdU(商品名:Sigmaより購入)を静脈内投与して、採取した肝臓切片を抗BrdU抗体で標識した(図15(a)〜(d))、20倍拡大像)。感染後7日目のPD−1遺伝子ホモ欠損マウス(PD−1-/-)の肝臓切片に対しては、抗BrdU抗体および抗CD4抗体あるいは抗CD8抗体で二重標識した(図15(e)、(f)、40倍拡大像)。
感染後30日目の野生型マウスの肝臓では、洞様毛細血管および非実質領域への中程度の局所的な細胞浸潤が認められたが、PD−1-/-マウスでは、肝炎を示す症状は認められなかった(図16(h)、(i)および(j)、(n))。
感染後7日目あるいは30日目のPD−1遺伝子ホモ欠損マウス(PD−1-/-)あるいは野生型マウス(wt)の肝臓切片に対して、ヘマトキシリン&エオジン染色(図16(g)〜(j),20倍拡大像、(k)〜(n),40倍拡大像)およびX−Gal染色を行った(図16(o)〜(r),40倍拡大像)。
感染後7日目および30日目の野生型マウスの肝臓では、X−Gal染色像が示すアデノウイルスの感染が認められたが、PD−1-/-マウスでは、その感染は、30日目にはほぼ排除されていた(図16(o)、(p)および(q)、(r))。これらの結果から、PD−1シグナルが、ウイルス感染による炎症組織におけるエフェクターT細胞の細胞増殖を誘導することによるウイルスの排除に関与することが示された。
マウスPD−L1を強制発現させたP−815/PD−L1細胞は、5μg/mL puromycin(Sigmaより購入)を含む通常培地(以下、選択培地と略す。)を用いて、培養フラスコに播種し、37℃、5%CO2/95%airの条件で50%〜90%コンフルエントになるまで培養した。マウスcytotoxic T lymphocyte 2C細胞は、MMC(Mitomycin C)処理したP−815細胞およびConA刺激ラット脾細胞培養上清とともに通常培地中で数日継代培養した。回収したP−815/PD−L1細胞にDELFIA EuTDA Cytotoxicity Reagents(PerkinElmerより購入)のBATDA Reagentを3μL加え、15分間培養した。さらに、PBSで洗浄した。2C細胞は、P−815細胞を加えて継代した5〜8日目の細胞を用いた。
被検物質である抗マウスPD−1抗体(図17中、anti-mPD-1Ab(J43))、抗マウスPD−L1抗体(同図中、anti-mPD-L1Ab(1−111))、マウスPD−1Fc(同図中、mPD−1Fc)、ヒトPD−1Fc(同図中、hPD−1Fc)、マウスIgG2aκ(同図中、ControlIg)またはPBSを96well plateに20μL(10ng/mL)ずつ分注し、P−815/PD−L1細胞または通常培地を50μLずつ加えた。さらに2C細胞、通常培地または1%TritonX100を含む通常培地を50μLずつ加えた。通常培地を添加したウェルの上清50μLをバックグラウンド用として回収し、その他の上清を回収するまで、37℃で保存した。残りの細胞は4時間培養した。続いて、同96well plateを遠心し、上清を回収した。回収した上清にCytotoxicity Reagents(PerkinElmerより購入)のDELFIA Europium Solutionを200μL添加して15分間振とうした。振とう後、ARVOsxマルチラベルカウンター(WALLAC)にて時間分解蛍光測定を行った。なお、1%TritonX100を含む通常培地を添加したウェルの上清を高コントロール、通常培地を添加したウェルの上清を低コントロールとした。
評価群の組成は、被検物質、P−815/PD−L1細胞及び2C細胞、高コントロール群の組成は、PBS、P−815/PD−L1細胞および1%TritonX100を含む通常培地、低コントロール群の組成は、PBS、P−815/PD−L1細胞および通常培地、2C細胞コントロール群の組成は、PBS、通常培地および2C細胞、バックグラウンド群の組成は、PBS、P−815/PD−L1細胞及び通常培地である。CTL活性(%)は、以下の式にて算出した。すべての値は、バックグランドで得た平均値を引いたものを使用した。
B16メラノーマ細胞を脾臓に移入したC57BL/6マウスに、抗マウスPD−1モノクローナル抗体を2日おきに腹腔内に投与して、移入後18日目の肝臓重量を測定することによって、癌転移に対する抗PD−1抗体の抑制効果を評価した。
コントロールIgGのみを投与したコントロール群に比べ、抗PD−1抗体投与群では、肝臓重量増加が有意に抑制された(肝臓重量/癌細胞非移入群:1.3g、コントロール群:6.8gから抗PD−1抗体投与群:3.5gへ減少)。この重量増加の抑制は、B16メラノーマ細胞の転移を抑制することを示すものである。
Claims (7)
- 抗PD−1抗体を有効成分として含む、ウイルス性肝炎治療剤。
- ウイルスが、ヒト肝炎ウイルス、ヒト免疫不全ウイルス、ヒトT細胞白血病ウイルス、単純ヘルペスウイルス、エプスタイン・バーウイルス、サイトメガロウイルス、水痘−帯状疱疹ウイルス、ヒトヘルペスウイルス、麻疹ウイルス、風疹ウイルス、インフルエンザウイルス、アデノウイルスおよびエンテロウイルスから選択される一以上のウイルスである請求項1記載のウイルス性肝炎治療剤。
- ウイルスが、ヒト肝炎ウイルスである請求項1記載のウイルス性肝炎治療剤。
- ヒト肝炎ウイルスが、B型肝炎ウイルス、C型肝炎ウイルス、A型肝炎ウイルスまたはE型肝炎ウイルスである請求項3記載のウイルス性肝炎治療剤。
- さらに、抗HIV剤、抗ウイルス剤またはワクチンと組み合わせることを特徴とする請求項1記載のウイルス性肝炎治療剤。
- 抗HIV剤が、逆転写酵素阻害剤、プロテアーゼ阻害剤またはCCR5受容体拮抗剤であり、抗ウイルス剤が、抗ヘルペスウイルス剤、抗インフルエンザウイルス剤、インターフェロン−αもしくはβまたは免疫グロブリン製剤であり、ワクチンが麻疹ワクチン、水痘ワクチン、インフルエンザワクチン、A型肝炎ワクチンまたはB型肝炎ワクチンである請求項5記載のウイルス性肝炎治療剤。
- 抗PD−1抗体が、ヒト化抗ヒトPD−1モノクローナル抗体または完全ヒト型抗ヒトPD−1モノクローナル抗体である請求項1〜6の何れか1項に記載のウイルス性肝炎治療剤。
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