JP2017031156A - 慢性免疫病に対する免疫治療のためのtim−3およびpd−1に対する二重特異性抗体 - Google Patents
慢性免疫病に対する免疫治療のためのtim−3およびpd−1に対する二重特異性抗体 Download PDFInfo
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Abstract
【解決手段】PD-1分子と特異的に結合する少なくとも1つの結合部位、およびTIM-3分子と特異的に結合する少なくとも1つの結合部位を含む、多重特異性ポリペプチド剤。前記ポリペプチド剤を、阻害性受容体PD-1及びTIM-3を同時発現している機能的に疲弊しているか又は非応答性の免疫細胞のような細胞を標的化するために使用する方法。前記組成物及び方法は、持続感染又は癌のような慢性免疫病の処置のために有用である。
【選択図】図11
Description
本願は、2010年7月20日出願の米国仮出願第61/365,910号、および2010年6月18日出願の米国仮出願第61/356,354号(各々の内容は、参照によりその全体が本明細書に組み入れられる)の35U.S.C.§119(e)の下での恩典を主張するものである。
本発明は、慢性免疫病の処置においてPD-1およびTim-3を標的化するための組成物および方法に関する。
本発明は、National Institutes of Healthにより授与されたグラントNIH P01AI073748およびNIH R01NS045937の下で政府の支援を受けて作成された。政府は、本発明における一定の権利を有する。
本明細書において使用されるように、「二重特異性ポリペプチド剤」という用語は、第一の標的に対する結合特異性を有する結合部位を有する第一のポリペプチドドメインと、第二の標的に対する結合特異性を有する結合部位を有する第二のポリペプチドドメインとを含むポリペプチドをさし、即ち、その剤は、2種の標的に対する特異性を有する。第一の標的および第二の標的は、同一でない(即ち、異なる標的(例えば、タンパク質)である)が、両方とも、本明細書に記載される細胞傷害性T細胞のような細胞に存在する(例えば、同時発現されている)。本明細書に記載される二重特異性ポリペプチド剤は、1種の標的のみを発現している細胞より強く(例えば、より大きなアビディティで)、第一の細胞表面標的および第二の細胞表面標的の両方を発現している細胞と結合する。従って、本明細書に記載される二重特異性ポリペプチド剤は、第一の標的および第二の標的を発現している細胞と選択的にかつ特異的に結合することができる。二重特異性ポリペプチド剤の非限定的な例は、二重特異性抗体またはその抗原結合断片である。
[本発明1001]
PD-1分子と特異的に結合する少なくとも1つの結合部位、およびTIM-3分子と特異的に結合する少なくとも1つの結合部位を含む、多重特異性ポリペプチド剤。
[本発明1002]
PD-1分子と特異的に結合する1つの結合部位、およびTIM-3分子と特異的に結合する1つの結合部位を含む、二重特異性ポリペプチド剤。
[本発明1003]
多重特異性抗体またはその多重特異性抗体断片である、本発明1001のポリペプチド剤。
[本発明1004]
二重特異性抗体またはその二重特異性抗体断片である、本発明1002のポリペプチド剤。
[本発明1005]
PD-1分子が、SEQ ID NO:1に示された配列を有するか、またはSEQ ID NO:1の対立遺伝子バリアントもしくはスプライスバリアントである、前記本発明のいずれかのポリペプチド剤。
[本発明1006]
TIM-3分子が、SEQ ID NO:2に示された配列を有するか、またはSEQ ID NO:2の対立遺伝子バリアントもしくはスプライスバリアントである、前記本発明のいずれかのポリペプチド剤。
[本発明1007]
PD-1分子と特異的に結合する結合部位が、PD-1のリガンド相互作用部位に指向する、前記本発明のいずれかのポリペプチド剤。
[本発明1008]
TIM-3分子と特異的に結合する結合部位が、TIM-3のリガンド相互作用部位に指向する、前記本発明のいずれかのポリペプチド剤。
[本発明1009]
PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L1との相互作用をモジュレートする、本発明1007のポリペプチド剤。
[本発明1010]
PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L2との相互作用をモジュレートする、本発明1007のポリペプチド剤。
[本発明1011]
PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L1およびPD-L2との相互作用をモジュレートする、本発明1007のポリペプチド剤。
[本発明1012]
PD-1のリガンド相互作用部位が、SEQ ID NO:1のアミノ酸残基41〜136を含む、本発明1007または本発明1009〜1011のいずれかのポリペプチド剤。
[本発明1013]
PD-1におけるリガンド相互作用部位が、SEQ ID NO:1のアミノ酸64、66、68、73、74、75、76、78、90、122、124、126、128、130、131、132、134、および136からなる群より選択されるアミノ酸残基のいずれかを含む、本発明1007または本発明1009〜1012のいずれかのポリペプチド剤。
[本発明1014]
PD-1におけるリガンド相互作用部位が、SEQ ID NO:1のアミノ酸78、126、および136からなる群より選択されるアミノ酸残基のいずれかを含む、本発明1007または本発明1009〜1013のいずれかのポリペプチド剤。
[本発明1015]
TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とガレクチン-9との相互作用をモジュレートする、本発明1008のポリペプチド剤。
[本発明1016]
TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とホスファチジルセリンとの相互作用をモジュレートする、本発明1008のポリペプチド剤。
[本発明1017]
TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とガレクチン-9およびホスファチジルセリンとの相互作用をモジュレートする、本発明1008のポリペプチド剤。
[本発明1018]
TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸残基24〜131を含む、本発明1008または本発明1015〜1017のいずれかのポリペプチド剤。
[本発明1019]
TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸50、62、69、112、および121からなる群より選択されるアミノ酸残基のいずれかを含む、本発明1008または本発明1015〜1018のいずれかのポリペプチド剤。
[本発明1020]
TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸44、74、および100からなる群より選択されるアミノ酸残基のいずれかを含む、本発明1008または本発明1015〜1019のいずれかのポリペプチド剤。
[本発明1021]
本発明1001〜1020のいずれかのポリペプチド剤の有効量を、慢性免疫病を有する対象へ投与する工程を含む、慢性免疫病を有する対象を処置する方法。
[本発明1022]
本発明1001〜1020のいずれかのポリペプチド剤の有効量を、慢性免疫病を有する対象へ投与する工程を含む、慢性免疫病を有する対象において免疫応答を活性化する方法。
[本発明1023]
慢性免疫病が持続感染である、本発明1021または1022の方法。
[本発明1024]
慢性免疫病が癌または腫瘍である、本発明1021または1022の方法。
[本発明1025]
慢性免疫病が、機能的に疲弊したT細胞の集団を含む、本発明1021〜1024のいずれかの方法。
[本発明1026]
機能的に疲弊したT細胞の集団が、CD8+T細胞集団を含む、本発明1025の方法。
阻害性受容体PD-1およびTim-3の両方を同時発現している細胞を標的化するための組成物および方法が、本明細書に記載される。これらの組成物および方法は、Tim-3経路およびPD-1経路の阻害の組み合わせが、疲弊したまたは非応答性のT細胞のような免疫細胞の免疫学的な活性および機能を回復させること、そしてこれらの2種の経路のそのような阻害の組み合わせが、癌または持続感染のような、特異的な免疫応答の不足または阻害を特徴とする慢性免疫病のコントロールおよび処置において、いずれかの経路のみの標的化より有効であることの新規の発見に、一部、基づく。
PD-1(またはCD279)は、免疫グロブリン(Ig)スーパーファミリードメイン、20アミノ酸スターク、膜貫通ドメイン、およびITIM(immunoreceptor tyrosine-based inhibitory motif)とITSM(immunoreceptor tyrosine-based switch motif)とを含有しているおよそ95残基の細胞内ドメインから構成される、288アミノ酸のI型膜貫通型タンパク質である。PD-1は、マウスにおいては第一染色体上のPdcd1遺伝子、ヒトにおいては第二染色体上のPDCD1遺伝子によりコードされる。両方の種において、Pdcd1は5つのエキソンからなる。エキソン1は、短いシグナル配列をコードし、エキソン2はIgドメインをコードする。スタークおよび膜貫通ドメインがエキソン3を構成し、エキソン4は、細胞質ドメインの始めを特徴付ける短い12アミノ酸配列をコードする。エキソン5は、C末端細胞内残基および長い3'UTRを含有している(Keir ME et al.,2008.Annu Rev Immunol.26:677-704)。PD-1は受容体のB7ファミリーのメンバーである。
のアミノ酸配列を有する288アミノ酸ポリペプチドをさし、さらに、天然に存在するその対立遺伝子バリアント、スプライスバリアント、およびプロセシングされた型もさす。典型的には、PD-1とは、ヒトPD-1をさす。「PD-1」という用語は、PD-1ポリペプチドの短縮型または断片をさすためにも使用される。PD-1のそのような型の言及は、本願において、例えば、「PD-1(42-136)」により同定され得る。例えば、成熟PD-1ペプチドは、本明細書において、PD-1(21-288)と呼ばれ、PD-1 IgVドメインはPD-1(42-136)と呼ばれる。PD-1の特定の残基は、例えば、「PD-1(68)」と呼ばれ得る。
TIM-3は、N末端免疫グロブリン(Ig)様ドメイン、O結合型グリコシル化を有し、膜付近にN結合型グリコシル化を有するムチンドメイン、単一の膜貫通ドメイン、およびチロシンリン酸化モチーフを有する細胞質領域を含むI型細胞表面糖タンパク質である。TIM-3は、TIM(T cell/transmembrane,immunoglobulin,and mucin)遺伝子ファミリーのメンバーである。
のアミノ酸配列を有する301アミノ酸ポリペプチドをさし、さらに、天然に存在するその対立遺伝子バリアント、スプライスバリアント、およびプロセシングされた型もさす。典型的には、TIM-3とは、ヒトTIM-3をさす。「TIM-3」という用語は、TIM-3ポリペプチドの短縮型または断片をさすためにも使用される。TIM-3のそのような型または断片に対する言及は、本願において、例えば、「TIM-3(24-131)」により同定され得る。TIM-3の特定の残基は、例えば、「TIM-3(62)」と呼ばれ得る。
機能的に疲弊した免疫細胞のような細胞の表面においてPD-1およびTIM-3が同時発現されている時、これらの分子と特異的に結合する二重特異性ポリペプチド剤および多重特異性ポリペプチド剤が、本明細書に記載される。ポリペプチド剤は、PD-1標的に対する結合特異性を有する結合部位を有する少なくとも1つのポリペプチドドメインと、TIM-3標的に対する結合特異性を有する結合部位を有する少なくとも1つのポリペプチドドメインとを含み得る。本明細書に記載されるように、そのようなポリペプチド剤は、PD-1およびTIM-3の両方を同時発現しているダブルポジティブ細胞と選択的に結合することができる。従って、抗体およびその抗原結合断片のような、細胞表面抗原と特異的に結合するポリペプチドは、PD-1およびTIM-3を同時発現している細胞と選択的に結合することができる剤を提供するため、本明細書に記載されるポリペプチド剤へとフォーマットされ得る。これらの二重特異性ポリペプチド剤および多重特異性ポリペプチド剤は、PD-1およびTIM-3を同時発現している細胞と選択的に結合するため、本明細書に記載されたポリペプチド剤を使用すれば、シングルポジティブ細胞への治療剤の送達に起因し得る望ましくない効果(例えば、疲弊していないまたは病原性の(例えば、自己特異的な)T細胞の活性化)を回避することができる。
本明細書に記載されたある種の局面は、腫瘍部位に浸潤していることが見出されたもののような、機能的疲弊の状態にあるCD8+T細胞が、阻害性受容体PD-1およびTIM-3を同時発現していることの、本発明者らによる発見に、一部、基づく。本発明者らは、TIM-3発現免疫細胞を、TIM-3低発現細胞およびTIM-3高発現細胞にさらに細分し得ることを見出した。本発明者らは、CD8 T細胞のような免疫細胞におけるPD-1およびTIM-3の同時発現が、その他のリンパ組織コンパートメントに比べて、腫瘍微小環境のような特異的な微小環境に制限されているか、またはそのような微小環境において増加している可能性があることも見出した。さらに、本発明者らは、ダブルポジティブPD-1+TIM-3+細胞が、PD-1のみまたはTIM-3のみのいずれかを発現しているシングルポジティブCD8+T細胞と比較した時、最も高度の機能障害、即ち、最小の増殖およびサイトカイン産生を有することを見出した。実際、腫瘍部位に浸潤しているPD-1シングルポジティブ(即ち、PD-1+TIM-3-)CD8細胞が、IFNγを産生する機能的に疲弊していない真のエフェクターT細胞を含んでおり、PD-1-TIM-3-TILよりはるかに高い、最も高頻度のIFNγ産生細胞を含有していることが見出されたため、本明細書に記載されたデータは、PD-1が単独では免疫細胞機能的疲弊の不完全なマーカーであることを証明している。
本明細書に記載された二重特異性ポリペプチド剤または多重特異性ポリペプチド剤は、対象における有効な処置をもたらす適切な経路により、その必要のある対象へ投与され得る。本明細書において使用されるように、「投与」および「導入」という用語は、交換可能に使用され、所望の効果が生じるよう、炎症の部位のような所望の部位におけるそのような剤の少なくとも部分的な局在をもたらす方法または経路により、二重特異性ポリペプチド剤または多重特異性ポリペプチド剤を対象へ配置することをさす。
本明細書に記載された方法のある種の局面は、腫瘍部位に浸潤していることが見出されたもののような、機能的疲弊の状態にあるCD8+T細胞により同時発現されている阻害性受容体PD-1およびTIM-3の同時標的化が、機能的疲弊の状態を逆転させ、有効な免疫応答をもたらし得るという本発明者らによる発見に、一部、基づく。従って、本明細書に記載された二重特異性ポリペプチド剤および多重特異性ポリペプチド剤を使用する方法は、CD8+T細胞のような免疫細胞の集団の機能的疲弊により、免疫応答が抑制されているか、不十分であるか、阻害されているか、または排除されている、持続感染または癌のような慢性免疫病を有する対象の処置において有用である。これらの方法は、活性化すべき細胞、即ち、TIM-3およびPD-1の両方を同時発現している細胞のみの特異的な標的化を提供し、シングルポジティブ細胞、機能的に疲弊していない細胞、および活性化により病原性となる細胞、例えば、自己反応性細胞の不要なまたは望まれない活性化を妨害する。
癌におけるT細胞疲弊におけるTim-3の可能性のある役割を調査するため、固形腫瘍CT26結腸を保持しているマウスに由来するT細胞におけるTim-3およびPD-1の発現を、最初に調査した。CD8+癌腫瘍浸潤リンパ球(TIL)の中で、Tim-3およびPD-1を同時発現している細胞は、主要な集団(およそ50%)を構成し、PD-1のみを発現している細胞、またはTim-3もPD-1も発現していない細胞は、より小さな集団(それぞれおよそ30%およびおよそ20%)を構成することが観察された(図1Aおよび1B)。その他の癌にこれらの観察を拡張するため、その他の固形腫瘍:4T1乳腺癌およびB16F10黒色腫を保持しているマウスにおいて、CD8+TILを調査した。CT26を保持しているマウスにおける観察と一致して、Tim-3およびPD-1を同時発現している細胞は、4T1腫瘍を保持しているマウスにおいても、CD8 TILのおよそ50%を構成し、PD-1のみを発現している細胞、またはTim-3もPD-1も発現していない細胞は、より小さな集団(それぞれおよそ25%およびおよそ15%)を構成する(図1B)。B16F10黒色腫を保持しているマウスにおいては、CD8+TILの3種の集団(Tim-3-PD-1-、Tim-3+PD-1+、およびTim-3+PD-1+)が、全て、ほぼ等しい頻度で存在する。興味深いことに、調査された3種の腫瘍モデルの全てにおいて、Tim-3+PD-1-TILは観察されなかった(図1A)。CD4+TILも調査した;しかしながら、これらはより少量であり、これらのうちの過半数がTim3-PD-1-であり、Tim3+PD-1+集団およびTim-3-PD-1+集団がほぼ等しいことが見出された(図1A)。総合すると、これらのデータは、Tim-3およびPD-1を同時発現しているCD8+TILが、異なる固形腫瘍に浸潤しているTILに存在するT細胞の主要な集団を構成することを示している。
CD8+ TILの異なるサブセットをさらに特徴決定するため、CD44およびCD62Lの発現を最初に調査した。CD62LおよびCD44の発現パターンは、Tim-3-PD-1-TIL、Tim-3-PD-1+TIL、およびTim-3+PD-1+TILの間で極めて異なっていることが見出された。TILの3種の集団は、全て、高レベルのCD44を発現していた(図2Aおよび2B)。しかしながら、Tim-3-PD1-TILおよびTim-3-PD-1+TILのみが、ナイーブ(CD44低CD62L高)T細胞を含有しており、Tim-3-PD-1-TILが、最も高い割合でナイーブT細胞を含有していた(およそ35%)。Tim-3+PD-1+TILのうち過半数がCD62L低であり、この集団においてはセントラルメモリー(CD44高CD62L高)細胞の画分が最低であった。これらのデータは、Tim-3およびPD-1のディファレンシャルな発現を特徴とするTILの3種の集団が、異なる機能的状態にある細胞を含有していることを初めて示すものであった。
PD-1またはTim-3のいずれかのシグナル伝達経路の遮断(Jones et al.2008;Golden-Mason et al.2009)が、慢性感染の情況においてT細胞機能を改善し得るという以前の観察と共に、これらの証明は、これらの2種の経路の標的化の組み合わせが、インビボの抗腫瘍免疫を回復させるための最も効果的な手段であると判明する可能性を与えた。インビボ処理を始める前に、CT26腫瘍におけるPD-1およびTim-3のリガンド(それぞれPD-L1およびガレクチン-9)の発現(図7)を最初に確認した。次いで、インビボで遮断機能を有することが以前に記載された(Monney et al.2002)抗Tim-3抗体、抗PD-L1抗体、抗Tim-3抗体+抗PD-L1抗体、または対照免疫グロブリンにより、CT26腫瘍保持マウスを処理した。抗Tim-3単独による処理には、ほとんどまたは全く効果がなく、抗PD-L1単独による処理は、腫瘍成長の遅延の傾向を示すことが見出された;しかしながら、これは実験間で変動し、統計的有意性には達しなかった(図5)。しかしながら、抗Tim-3および抗PD-L1による処理の組み合わせは、腫瘍成長の劇的な低下をもたらし、マウスの50%が完全な腫瘍退縮を示した。CT26腫瘍はPD-L1を発現しているがTim-3は発現していないため(図7)、抗PD-L1抗体が腫瘍成長に対する直接の阻害効果を有する可能性を考慮した。CT26腫瘍を、抗PD-L1または対照免疫グロブリンの存在下で培養したところ、腫瘍増殖は影響を受けないことが見出された(図8)。B16黒色腫を保持しているマウスにおいても抗Tim-3+抗PD-L1処理の効果を試験したところ、対照免疫グロブリン、抗Tim-3、または抗PD-L1により処理されたマウスに比べて、処理の組み合わせを受容したマウスは、増強された生存を示すことが見出された。
腫瘍浸潤リンパ球の単離。20分間、コラゲナーゼD(25mg/ml)の存在下で腫瘍組織を解離させた後、不連続パーコール勾配(GE Healthcare)上で遠心分離することにより、腫瘍浸潤リンパ球を単離した。次いで、単離された細胞を、T細胞機能の様々なアッセイにおいて使用した。
Claims (26)
- PD-1分子と特異的に結合する少なくとも1つの結合部位、およびTIM-3分子と特異的に結合する少なくとも1つの結合部位を含む、多重特異性ポリペプチド剤。
- PD-1分子と特異的に結合する1つの結合部位、およびTIM-3分子と特異的に結合する1つの結合部位を含む、二重特異性ポリペプチド剤。
- 多重特異性抗体またはその多重特異性抗体断片である、請求項1記載のポリペプチド剤。
- 二重特異性抗体またはその二重特異性抗体断片である、請求項2記載のポリペプチド剤。
- PD-1分子が、SEQ ID NO:1に示された配列を有するか、またはSEQ ID NO:1の対立遺伝子バリアントもしくはスプライスバリアントである、前記請求項のいずれか一項記載のポリペプチド剤。
- TIM-3分子が、SEQ ID NO:2に示された配列を有するか、またはSEQ ID NO:2の対立遺伝子バリアントもしくはスプライスバリアントである、前記請求項のいずれか一項記載のポリペプチド剤。
- PD-1分子と特異的に結合する結合部位が、PD-1のリガンド相互作用部位に指向する、前記請求項のいずれか一項記載のポリペプチド剤。
- TIM-3分子と特異的に結合する結合部位が、TIM-3のリガンド相互作用部位に指向する、前記請求項のいずれか一項記載のポリペプチド剤。
- PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L1との相互作用をモジュレートする、請求項7記載のポリペプチド剤。
- PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L2との相互作用をモジュレートする、請求項7記載のポリペプチド剤。
- PD-1のリガンド相互作用部位との特異的結合が、PD-1とPD-L1およびPD-L2との相互作用をモジュレートする、請求項7記載のポリペプチド剤。
- PD-1のリガンド相互作用部位が、SEQ ID NO:1のアミノ酸残基41〜136を含む、請求項7または請求項9〜11のいずれか一項記載のポリペプチド剤。
- PD-1におけるリガンド相互作用部位が、SEQ ID NO:1のアミノ酸64、66、68、73、74、75、76、78、90、122、124、126、128、130、131、132、134、および136からなる群より選択されるアミノ酸残基のいずれかを含む、請求項7または請求項9〜12のいずれか一項記載のポリペプチド剤。
- PD-1におけるリガンド相互作用部位が、SEQ ID NO:1のアミノ酸78、126、および136からなる群より選択されるアミノ酸残基のいずれかを含む、請求項7または請求項9〜13のいずれか一項記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とガレクチン-9との相互作用をモジュレートする、請求項8記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とホスファチジルセリンとの相互作用をモジュレートする、請求項8記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位との特異的結合が、TIM-3とガレクチン-9およびホスファチジルセリンとの相互作用をモジュレートする、請求項8記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸残基24〜131を含む、請求項8または請求項15〜17のいずれか一項記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸50、62、69、112、および121からなる群より選択されるアミノ酸残基のいずれかを含む、請求項8または請求項15〜18のいずれか一項記載のポリペプチド剤。
- TIM-3のリガンド相互作用部位が、SEQ ID NO:2のアミノ酸44、74、および100からなる群より選択されるアミノ酸残基のいずれかを含む、請求項8または請求項15〜19のいずれか一項記載のポリペプチド剤。
- 請求項1〜20のいずれか一項記載のポリペプチド剤の有効量を、慢性免疫病を有する対象へ投与する工程を含む、慢性免疫病を有する対象を処置する方法。
- 請求項1〜20のいずれか一項記載のポリペプチド剤の有効量を、慢性免疫病を有する対象へ投与する工程を含む、慢性免疫病を有する対象において免疫応答を活性化する方法。
- 慢性免疫病が持続感染である、請求項21または22記載の方法。
- 慢性免疫病が癌または腫瘍である、請求項21または22記載の方法。
- 慢性免疫病が、機能的に疲弊したT細胞の集団を含む、請求項21〜24のいずれか一項記載の方法。
- 機能的に疲弊したT細胞の集団が、CD8+T細胞集団を含む、請求項25記載の方法。
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US9163087B2 (en) | 2015-10-20 |
JP2019031579A (ja) | 2019-02-28 |
US9834607B2 (en) | 2017-12-05 |
JP6652897B2 (ja) | 2020-02-26 |
US10934352B2 (en) | 2021-03-02 |
US20180051083A1 (en) | 2018-02-22 |
CA2802344C (en) | 2023-06-13 |
JP7074796B2 (ja) | 2022-05-24 |
US20160002334A1 (en) | 2016-01-07 |
WO2011159877A3 (en) | 2012-04-19 |
JP2022110068A (ja) | 2022-07-28 |
CA2802344A1 (en) | 2011-12-22 |
WO2011159877A2 (en) | 2011-12-22 |
JP2020122006A (ja) | 2020-08-13 |
JP2013532153A (ja) | 2013-08-15 |
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