JP7239179B2 - Nk細胞および抗pdl1による癌治療法に関連する方法および組成物 - Google Patents
Nk細胞および抗pdl1による癌治療法に関連する方法および組成物 Download PDFInfo
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- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
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Description
本明細書および添付の請求項で使用される単数形「a」、「an」および「the」は、文脈上明らかに別の意味を表す場合を除き、複数形の指示対象を包含する。したがって、例えば「a pharmaceutical carrier」(医薬担体)と言う場合、それには2つ以上のこのような担体の混合物などが包含される。
既に説明した通り、大部分の腫瘍では腫瘍部位に動員されるCD8 T細胞が分泌するIFNγに応答してPD-L1の発現が誘導される。このように腫瘍にPD-L1発現が誘導されると、諸事象のカスケードが惹起され、それが最終的には免疫抑制環境を作り出すとともに、PD-1受容体との相互作用により細胞傷害性T細胞の機能を直接阻止し、細胞傷害性T細胞のアナジーおよびアポトーシスを引き起こす。次いで、これらの変化が腫瘍の進行および転移を促進する。PD-L1の誘導およびそれに続く免疫抑制カスケードによって腫瘍に対する初期免疫応答が停止した癌では、新たな抗PD-L1/抗PD-1療法により、機能が停止した免疫系を解放することが可能になった。しかし、上述の通り、抗PDL1/PD1療法は、既にPDL1が誘導された癌に限定されている。
本開示の組成物を調製するのに使用する成分および本明細書に開示される方法で使用する組成物自体が開示される。これらのおよびその他の材料が本明細書に開示され、これらの材料の組合せ、サブセット、相互作用、グループなどが開示されるとき、これらの化合物の様々な組合せおよび順列が個別に、および総体として明確に開示されずにそれぞれ具体的に言及されない場合があるが、それぞれが本明細書で具体的に企図され記載されることが理解される。例えば、特定の抗PDL1抗体、PM21粒子、EX21エキソソームまたはFC21フィーダー細胞を開示して記述し、抗PDL1抗体、PM21粒子、EX21エキソソームまたはFC21フィーダー細胞を含めた多数の分子に対して施し得る多数の修正を記述する場合、そうでないことが具体的に記載されない限り、抗PDL1抗体、PM21粒子、EX21エキソソームまたはFC21フィーダー細胞および可能な修正のあらゆる組合せおよび順列が具体的に企図される。したがって、A、BおよびCという分子のクラスのほかにも、D、EおよびFという分子のクラスならびに分子A~Dの組合せの例が開示される場合、それぞれが記載されていなくてもそれぞれが個別に、および総体として企図され、A~E、A~F、B~D、B~E、B~F、C~D、C~EおよびC~Fという組合せが開示されるとみなされることを意味する。同様に、これらの任意の部分集合または組合せも開示される。したがって、例えば、A~E、B~FおよびC~Eというサブグループが開示されるとみなされ得る。この考えは、特に限定されないが、本開示の組成物の作製法および使用法の段階を含めた本願のあらゆる態様に適用される。したがって、実施し得る様々な追加の段階が存在する場合、これらの追加の各段階を本開示の方法の任意の特定の実施形態または実施形態の組合せとともに実施し得ることが理解される。
本明細書に開示される抗癌療法および癌を治療する方法は、抗PDL1抗体の使用を含む。本開示の方法および治療法は、特に、治療効果を有することが既に示されている、特に限定されないがGenentech社のアテゾリズマブを含めた、任意の既知の抗PDL1抗体を含み、かつ/またはこれを用いるものであり得ることが理解され、本明細書で企図される。
「抗体」という用語は、本明細書では広義に使用され、ポリクローナル抗体およびモノクローナル抗体をともに包含する。インタクトの免疫グロブリン分子に加え、それらの免疫グロブリン分子のフラグメントまたはポリマーおよびヒト型またはヒト化型の免疫グロブリン分子またはそのフラグメントも、PDL1がPD1と相互作用するのを阻害するようPDL1と相互作用することが可能であるものとして選択される限り、「抗体」という用語に包含される。抗体は、既知の臨床試験法に従ってそのin vivoの治療活性および/または予防活性を試験した後、本明細書に記載されるin vitroアッセイを用いて、またはこれに類似した方法により、その所望の活性を試験することができる。ヒト免疫グロブリンには、IgA、IgD、IgE、IgGおよびIgMの5つの主要なクラスがあり、このうちのいくつかはさらに、サブクラス(アイソタイプ)、例えば、IgG-1、IgG-2、IgG-3およびIgG-4;IgA-1およびIgA-2に分けることができる。当業者には、マウスについてもこれと同等のクラスが認識されよう。免疫グロブリンの様々なクラスに対応する重鎖定常ドメインは、それぞれアルファ、デルタ、イプシロン、ガンマおよびミューと呼ばれる。
本開示のヒト抗体は、任意の技術を用いることにより調製することができる。本開示のヒト抗体は、トランスジェニック動物から得ることもできる。例えば、免疫感作に応答してヒト抗体の完全なレパートリーを産生することが可能なトランスジェニック変異マウスが記載されている(例えば、Jakobovitsら,Proc.Natl.Acad.Sci.USA,90:2551 255(1993);Jakobovitsら,Nature,362:255 258(1993);Bruggermannら,Year in Immunol.,7:33(1993)を参照されたい)。具体的には、これらのキメラ生殖系列変異マウスの抗体重鎖連結領域(J(H))にあるホモ接合性欠失によって内因性の抗体産生が完全に阻害され、このような生殖系列変異マウスへのヒト生殖系列抗体遺伝子アレイの導入に成功することによって、抗原曝露時にヒト抗体が産生される。本明細書に記載されるEnv-CD4-共受容体複合体を用いて、所望の活性を有する抗体を選択する。
抗体ヒト化技術では一般に、組換えDNA技術を用いて、抗体分子の1つまたは複数のポリペプチドをコードするDNA配列を操作する。その結果、ヒト化型の非ヒト抗体(またはそのフラグメント)は、ヒト(レシピエント)抗体のフレームワーク内に組み込まれた非ヒト(ドナー)抗体由来の抗原結合部位の一部分を含む、キメラ抗体またはキメラ抗体鎖(またはそのsFv、Fv、Fab、Fab’、F(ab’)2などのフラグメント、もしくは抗体のその他の抗原結合部分)となる。
抗体の投与は、本明細書に開示される通りに実施することができる。抗体送達を送達する核酸法も存在する。広範囲に中和する抗PDL1抗体および抗体フラグメントを、その抗体または抗体フラグメントをコードする核酸調製物(例えば、DNAまたはRNA)として患者または対象に投与して、患者または対象自身の細胞にその核酸を取り込ませ、コードされる抗体または抗体フラグメントを産生および分泌させることもできる。核酸の送達は、例えば本明細書に開示されるような任意の手段によるものであり得る。
上記の通り、組成物を薬学的に許容される担体でin vivoで投与することもできる。「薬学的に許容される」は、生物学的に、またはその他の面で望ましくないものではない材料を意味する、すなわち、望ましくない生物学的作用を引き起こすことも、それが含まれる医薬組成物のいずれの他の成分と有害な方法で相互作用することもなく、材料を核酸またはベクターとともに対象に投与し得ることを意味する。当然のことながら、担体は、当業者には周知のように、対象内での有効成分の分解を最小限に抑え有害な副作用を最小限に抑えるよう選択する。
抗体を含めた組成物を薬学的に許容される担体と組み合わせて治療に使用することができる。
組成物を投与するのに効果的な用量およびスケジュールは実験によって決定し得るものであり、このような決定は当該分野の技術の範囲内にある。組成物を投与するための用量範囲は、障害の症状がもたらされる所望の効果を得るのに十分な量のものである。用量は、望ましくない交差反応、アナフィラキシー反応などの有害な副作用を引き起こす程度の量にするべきではない。用量は一般に、患者の年齢、状態、性別および疾患の程度、投与経路、またはレジメンに他の薬物が含まれているかどうかによって異なり、当業者によって決定され得るものである。用量は、何らかの禁忌症がある場合、個々の医師が調節することができる。用量は変化し得るものであり、1日1用量または複数用量を1日または数日間投与することができる。所与のクラスの医薬品に適した用量に関する指針を文献にみることができる。例えば、抗体に適した用量を選択する際の指針については、抗体の治療的使用に関する文献、例えば、Handbook of Monoclonal Antibodies,Ferroneら編,Noges Publications,Park Ridge,N.J.,(1985)ch.22 and pp.303-357;Smithら,Antibodies in Human Diagnosis and Therapy,Haberら編,Raven Press,New York(1977)pp.365-389にみることができる。単独で使用する抗体の典型的な1日量は、上に挙げた要因に応じて1日当たり約1μg/kg体重から最大100mg/kg体重またはそれ以上までの範囲になるものと思われる。
癌を治療する方法であって、対象に本開示の組成物の1つを、治療する疾患または障害に対する既知の治療法と併用して投与することを含む、方法が開示される。例えば、癌を治療する方法であって、抗PDL1抗体および/またはPM21粒子および/またはEX21エキソソームを含む有効量の組成物を、特に限定されないが、化学療法、免疫療法、放射線療法または疼痛療法などの既知の癌治療法と併用して投与することを含む、方法が開示される。
以下の実施例は、本願で特許請求される化合物、組成物、物品、装置および/または方法を作製および評価する方法を当業者に完全に開示および説明するために記載されるものであり、単に例示することを意図するものであって、本開示を限定することを意図するものではない。数値(例えば、量、温度など)に関しては正確さを確保するようにしたが、多少の誤差および偏差を考慮に入れるべきである。特に明示されない限り、部分は重量部であり、温度は℃で表されるものであるか、周囲温度であり、圧力は大気圧またはほぼ大気圧である。
本発明は以下の態様を含みうる。
[1]
対象の癌を治療する方法であって、前記対象にNK細胞および抗PDL1抗体を投与することを含む、方法。
[2]
前記NK細胞がXM NK細胞である、上記[1]に記載の方法。
[3]
ナイーブNK細胞集団をPM21粒子、EX21エキソソームまたはFC21フィーダー細胞と接触させることにより前記NK細胞を活性化または拡大する、上記[1]に記載の方法。
[4]
PM21粒子、EX21エキソソームまたはFC21細胞によるNK細胞の活性化または拡大をex vivoで実施する、上記[3]に記載の方法。
[5]
前記対象に前記NK細胞を投与する1~21日前にPM21粒子、EX21エキソソームまたはFC21細胞によるNK細胞の拡大の活性化を実施する、上記[4]に記載の方法。
[6]
前記NK細胞が、末梢血、臍帯血または幹細胞に由来するものであり得る、上記[1]に記載の方法。
[7]
前記NK細胞が、NK92などのNK細胞様細胞系に由来するものである、上記[1]に記載の方法。
[8]
前記抗PDL1抗体を投与する1~14日前に前記NK細胞を投与する、上記[1]に記載の癌を治療する方法。
[9]
前記NK細胞および抗PDL1抗体を同時に投与する、上記[1]に記載の癌を治療する方法。
[10]
前記NK細胞が、自家NK細胞、ハプロタイプ一致NK細胞または同種NK細胞である、上記[1]に記載の癌を治療する方法。
[11]
前記対象に前記NK細胞を投与する前に、前記NK細胞をIL-12、IL-15およびIL-18のうちの1つまたは複数のものと接触させることをさらに含む、上記[1]に記載の癌を治療する方法。
[12]
前記対象にIL-12、IL-15およびIL-18のうちの1つまたは複数のものを投与することをさらに含む、上記[1]に記載の癌を治療する方法。
[13]
前記IL-12、IL-15およびIL-18を前記NK細胞と同時に投与する、上記[12]に記載の癌を治療する方法。
[14]
前記NK細胞を投与する前に前記IL-12、IL-15およびIL-18を投与する、上記[12]に記載の癌を治療する方法。
[15]
前記NK細胞を投与した後に前記IL-12、IL-15およびIL-18を投与する、上記[12]に記載の癌を治療する方法。
[16]
前記対象にPM21粒子またはEX21エキソソームを投与することをさらに含む、上記[1]に記載の癌を治療する方法。
[17]
前記PM21粒子またはEX21エキソソームを前記NK細胞と同時に投与する、上記[16]に記載の癌を治療する方法。
[18]
前記NK細胞を投与した後、前記PM21粒子またはEX21エキソソームを少なくとも1週間に1回、2回、3回投与する、上記[16]に記載の癌を治療する方法。
[19]
対象の癌を治療する方法であって、対象にPM21粒子またはEX21エキソソームおよび抗PDL1抗体を投与することを含む、方法。
[20]
前記抗PDL1抗体を投与する1~14日前に前記PM21粒子またはEX21エキソソームを投与する、上記[19]に記載の癌を治療する方法。
[21]
前記PM21粒子またはEX21エキソソームおよび前記抗PDL1抗体を同時に投与する、上記[19]に記載の癌を治療する方法。
[22]
IL-12、IL-15およびIL-18のうちの1つまたは複数のものを投与することをさらに含む、上記[19]に記載の癌を治療する方法。
[23]
前記IL-12、IL-15およびIL-18を前記PM21粒子またはEX21エキソソームと同時に投与する、上記[22]に記載の癌を治療する方法。
[24]
前記PM21粒子またはEX21エキソソームを投与する前に前記IL-12、IL-15およびIL-18を投与する、上記[22]に記載の癌を治療する方法。
[25]
前記PM21粒子またはEX21エキソソームを投与した後に前記IL-12、IL-15およびIL-18を投与する、上記[22]に記載の癌を治療する方法。
[26]
PM21粒子またはEX21エキソソームの初回投与後、前記PM21粒子またはEX21エキソソームを少なくとも1週間に1回、2回、3回投与する、上記[19]に記載の癌を治療する方法。
[27]
PM21、EX21またはFC21 NK細胞と、抗PDL1抗体とを含む、抗癌療法。
[28]
PM21粒子またはEX21エキソソームをさらに含む、上記[27]に記載の抗癌療法。
[29]
IL-12、IL-15およびIL-18のうちの1つまたは複数のものをさらに含む、上記[27]に記載の抗癌療法。
[30]
PM21粒子またはEX21エキソソームと、抗PDL1抗体とを含む、抗癌療法。
[31]
IL-12、IL-15およびIL-18のうちの1つまたは複数のものをさらに含む、上記[30]に記載の抗癌療法。
Claims (25)
- 対象の癌を治療する方法に使用するための組合せ物であって、
拡大記憶(XM)NK細胞および抗PDL1抗体を含み、
前記NK細胞は、ex vivoでナイーブNK細胞集団をIL-12、IL-15およびIL-18と接触させ、その後FC21フィーダー細胞と呼ばれる膜結合IL-21を発現するフィーダー細胞、またはそれぞれPM21粒子およびEX21エキソソームと呼ばれる、FC21フィーダー細胞から調製される細胞膜粒子(PM)もしくはエキソソーム(EX)と拡大することによって、活性化または拡大され、
前記方法が、前記対象に前記XM NK細胞および前記抗PDL1抗体を投与することを含む、組合せ物。 - 前記対象に前記NK細胞を投与する1~21日前にPM21粒子、EX21エキソソームまたはFC21細胞によるNK細胞の活性化または拡大を実施する、請求項1に記載の組合せ物。
- 前記NK細胞が、末梢血、臍帯血または幹細胞に由来するものであり得る、請求項1に記載の組合せ物。
- 前記NK細胞が、PM21粒子と拡大され、前記PM21粒子が、41BBLをさらに含む、請求項1に記載の組合せ物。
- 前記抗PDL1抗体を投与する1~14日前に前記NK細胞を投与する、請求項1に記載の組合せ物。
- 前記NK細胞および抗PDL1抗体を同時に投与する、請求項1に記載の組合せ物。
- 前記NK細胞が、自家NK細胞、ハプロタイプ一致NK細胞または同種NK細胞である、請求項1に記載の組合せ物。
- 前記対象にIL-12、IL-15およびIL-18のうちの1つまたは複数のものを投与することをさらに含む、請求項1に記載の組合せ物。
- 前記IL-12、IL-15およびIL-18を前記NK細胞と同時に投与する、請求項8に記載の組合せ物。
- 前記NK細胞を投与する前に前記IL-12、IL-15およびIL-18を投与する、請求項8に記載の組合せ物。
- 前記NK細胞を投与した後に前記IL-12、IL-15およびIL-18を投与する、請求項8に記載の組合せ物。
- 前記対象にPM21粒子またはEX21エキソソームを投与することをさらに含む、請求項1に記載の組合せ物。
- 前記PM21粒子またはEX21エキソソームを前記NK細胞と同時に投与する、請求項12に記載の組合せ物。
- 前記NK細胞を投与した後、前記PM21粒子またはEX21エキソソームを少なくとも1週間に1回、2回、3回投与する、請求項12に記載の組合せ物。
- 対象の癌を治療する方法に使用するための組合せ物であって、
前記組合せ物は、(i)IL-12、IL-15およびIL-18、(ii)それぞれPM21粒子およびEX21エキソソームと呼ばれる、膜結合IL-21を発現するフィーダー細胞から調製される細胞膜粒子(PM)またはエキソソーム(EX)、および(iii)抗PDL1抗体を含み、
前記方法は、前記対象に(i)IL-12、IL-15およびIL-18、(ii)前記PM21粒子または前記EX21エキソソーム、および(iii)前記抗PDL1抗体を投与することを含む、組合せ物。 - 前記抗PDL1抗体を投与する1~14日前に前記PM21粒子またはEX21エキソソームを投与する、請求項15に記載の組合せ物。
- 前記PM21粒子またはEX21エキソソームおよび前記抗PDL1抗体を同時に投与する、請求項15に記載の組合せ物。
- 前記IL-12、IL-15およびIL-18を前記PM21粒子またはEX21エキソソームと同時に投与する、請求項15に記載の組合せ物。
- 前記PM21粒子またはEX21エキソソームを投与する前に前記IL-12、IL-15およびIL-18を投与する、請求項15に記載の組合せ物。
- 前記PM21粒子またはEX21エキソソームを投与した後に前記IL-12、IL-15およびIL-18を投与する、請求項15に記載の組合せ物。
- PM21粒子またはEX21エキソソームの初回投与後、前記PM21粒子またはEX21エキソソームを少なくとも1週間に1回、2回、3回投与する、請求項15に記載の組合せ物。
- (i)FC21フィーダー細胞と呼ばれる膜結合IL-21を発現するフィーダー細胞、またはそれぞれPM21粒子およびEX21エキソソームと呼ばれる、FC21フィーダー細胞から調製される細胞膜粒子(PM)もしくはエキソソーム(EX)、(ii)IL-12、IL-15およびIL-18、および(iii)抗PDL1抗体を含む、抗癌療法に使用するための組合せ物。
- (i)それぞれPM21粒子およびEX21エキソソームと呼ばれる、膜結合IL-21を発現するフィーダー細胞から調製される細胞膜粒子(PM)またはエキソソーム(EX)、(ii)IL-12、IL-15およびIL-18、および(iii)抗PDL1抗体を含む、抗癌療法に使用するための組合せ物。
- 前記癌が、低PD-L1発現を有するかまたはPD-L1発現がなく、前記活性化NK細胞の投与が、前記癌においてPD-L1発現を誘導する、請求項1または15に記載の組合せ物。
- 前記抗PDL1抗体が、F(ab’)2フラグメント、Fab’フラグメント、Fabフラグメント、Fvフラグメント、またはsFvフラグメントである、請求項1、15、22、または23に記載の組合せ物。
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