JP2019509760A - 新規の免疫刺激性ベクター系 - Google Patents
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Abstract
Description
1.4−1BBリガンド(4−1BBL)、単鎖IL−12(scIL−12)、およびIL−2をコードする核酸配列を含み、少なくとも1つの調節核酸配列、好ましくは、プロモーター配列をさらに含み、scIL−12およびIL−2の発現レベルと比較した、4−1BBLの発現レベルの上昇をもたらすベクター。
2.4−1BBLの発現レベルが、ベクターIm01の発現構築物(図20)により得られる4−1BBLの発現レベルと比較して上昇している、項目1のベクター。
3.ベクターIm01の発現構築物(図20)により得られるscIL−12および/またはIL−2の発現レベルと比較して、scIL−12の発現レベルが低下し、かつ/またはIL−2の発現レベルが上昇している、項目1または2のベクター。
4.4−1BBL、scIL−12、およびIL−2をコードする核酸配列を、5’〜3’方向に、1、2、3の順序で、scIL−12をコードする核酸配列が、1位にはないことを条件として構成した、項目1〜3のうちのいずれか1つのベクター。
5.アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、単純ヘルペスウイルスベクター、ポックスウイルスベクター、RNAベクター、プラスミドベクター、ナノ粒子ベクター、およびネイキッドDNAのうちのいずれか1つである、項目1〜4のうちのいずれか1つのベクター。
6.4−1BBLをコードする核酸配列が、ヒトcDNAであり、scIL−12をコードする核酸配列が、ヒトcDNAであり、かつ/またはIL−2をコードする核酸配列が、ヒトcDNAである、項目1〜5のうちのいずれか1つのベクター。
7.4−1BBLをコードする核酸配列が、配列番号1の核酸配列に対する、少なくとも70%の配列同一性を示し、変異体の核酸配列が、活性化T細胞に特異的に結合することが可能な、4−1BBLタンパク質をコードする、項目1〜6のうちのいずれか1つのベクター。
8.IL−2をコードする核酸配列が、配列番号3の核酸配列に対する、少なくとも70%の配列同一性を示し、変異体の核酸配列が、免疫刺激活性を有するIL−2タンパク質をコードする、項目1〜6のうちのいずれか1つのベクター。
9.scIL−12をコードする核酸配列が、配列番号5の核酸配列に対する、少なくとも70%の配列同一性を示し、変異体の核酸配列が、免疫刺激活性を有するscIL−12タンパク質をコードする、項目1〜6のうちのいずれか1つのベクター。
10.scIL−12およびIL−2をコードする核酸配列を、4−1BBLをコードする核酸配列の下流に配置する、項目1〜9のうちのいずれか1つのベクター。
11.IL−2をコードする核酸配列を、4−1BBLをコードする核酸配列の下流に配置し、scIL−12をコードする核酸配列を、IL−2をコードする核酸配列の下流に配置する、項目10のベクター。
12.プロモーターを、4−1BBLをコードする核酸配列の上流に配置するが、scIL−12および/またはIL−2をコードする核酸配列の上流には配置しない、項目10または11のベクター。
13.4−1BBL、scIL−12、およびIL−2をコードする核酸配列を、内部リボソーム侵入部位(IRES)により連結した、項目1〜12のうちのいずれか1つのベクター。
14.項目1〜13のうちのいずれか1つのベクターを形質導入またはトランスフェクトされたがん細胞または免疫細胞。
15.項目1〜13のうちのいずれか1つのベクター、または項目14のがん細胞もしくは免疫細胞を含む医薬。
16.がん、ウイルス感染、および/または免疫系障害を処置する方法における使用のための、項目1〜13のうちのいずれか1つのベクター、項目14のがん細胞もしくは免疫細胞、または項目15の医薬。
17.がんが、膀胱がん、乳がん、前立腺がん、リンパ腫、皮膚がん、膵臓がん、結腸がん、黒色腫、悪性黒色腫、卵巣がん、脳がん、原発性脳癌、頭頸部がん、神経膠腫、神経膠芽腫、肝臓がん、非小細胞肺がん、頭部または頸部癌、乳癌、卵巣癌、肺癌、小細胞肺癌、ウィルムス腫瘍、子宮頸癌、精巣癌、膀胱癌、膵臓癌、胃癌、結腸癌、前立腺癌、尿生殖器癌、甲状腺癌、食道癌、骨髄腫、多発性骨髄腫、副腎癌、腎細胞癌、子宮内膜癌、副腎皮質癌、悪性膵臓膵島細胞腫、悪性カルチノイド癌、絨毛癌、菌状息肉腫、悪性高カルシウム血症、子宮頸過形成、白血病、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、慢性骨髄性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、有毛細胞白血病、神経芽細胞腫、横紋筋肉腫、カポジ肉腫、真性赤血球増加症、本態性血小板増加症、ホジキン疾患、非ホジキンリンパ腫、軟部組織肉腫、中皮腫、骨肉腫、原発マクログロブリン血症、および網膜芽細胞腫のうちのいずれか1つである、項目16による使用のためのベクター、または項目16による使用のためのがん細胞もしくは免疫細胞、または項目16による使用のための医薬。
18.がんの転移を防止または処置する方法における使用のための、項目1〜13のうちのいずれか1つのベクター、または項目14のがん細胞もしくは免疫細胞、または項目15の医薬。
1.4−1BBリガンド(4−1BBL)、単鎖IL−12(scIL−12)、およびIL−2をコードする遺伝子であって、5’〜3’方向に、1、2、3の順序で、scIL−12をコードする遺伝子が、1位にはないことを条件として構成した、遺伝子の核酸配列を含むベクター。
2.アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、レトロウイルスベクター、単純ヘルペスウイルスベクター、ポックスウイルスベクター、RNAベクター、プラスミドベクター、ナノ粒子ベクター、およびネイキッドDNAのうちのいずれか1つである、項目1のベクター。
3.RNAベクターが、修飾リボヌクレオチドの挿入を含む、項目2のベクター。
4.4−1BBLをコードする遺伝子の核酸配列が、ヒトcDNAであり、scIL−12をコードする遺伝子の核酸配列が、ヒトcDNAであり、かつ/またはIL−2をコードする遺伝子の核酸配列が、ヒトcDNAである、項目1〜3のうちのいずれか1つのベクター。
5.4−1BBLをコードする遺伝子の核酸配列が、配列番号1(図13)の核酸配列に対する、少なくとも70%の相同性または配列同一性を示し、この場合、変異体の核酸配列が、T細胞、好ましくは、活性化T細胞に特異的に結合することが可能な、4−1BBLタンパク質をコードする、項目1〜4のうちのいずれか1つのベクター。
6.IL−2をコードする遺伝子の核酸配列が、配列番号3(図14)の核酸配列に対する、少なくとも70%の相同性または配列同一性を示し、この場合、変異体の核酸配列が、免疫刺激活性を有するIL−2タンパク質をコードする、項目1〜4のうちのいずれか1つのベクター。
7.scIL−12をコードする遺伝子の核酸配列が、配列番号5(図15)の核酸配列に対する、少なくとも70%の相同性または配列同一性を示し、この場合、変異体の核酸配列が、免疫刺激活性を有するscIL−12タンパク質をコードする、項目1〜4のうちのいずれか1つのベクター。
8.scIL−12およびIL−2をコードする遺伝子の核酸配列を、4−1BBLをコードする遺伝子の核酸配列の下流に配置する、項目1〜7のうちのいずれか1つのベクター。
9.IL−2をコードする遺伝子の核酸配列を、4−1BBLをコードする遺伝子の核酸配列の下流に配置し、scIL−12をコードする遺伝子の核酸配列を、IL−2をコードする核酸配列の下流に配置する、項目8のベクター。
10.プロモーターを、4−1BBLをコードする遺伝子の核酸配列の上流に配置するが、scIL−12および/またはIL−2をコードする遺伝子の核酸配列の上流には配置しない、項目8または9のベクター。
11.4−1BBL、scIL−12、およびIL−2をコードする遺伝子の核酸配列を、内部リボソーム侵入部位(IRES)により連結した、項目8〜10のうちのいずれか1つのベクター。
12.項目1〜11のうちのいずれか1つのベクターを含むウイルス粒子。
13.項目1〜11のうちのいずれか1つのベクターをコードする核酸配列を含むポリヌクレオチド。
14.項目1〜11のうちのいずれか1つのベクター、または項目12のウイルス粒子を形質導入またはトランスフェクトされたがん細胞または免疫細胞。
15.項目1〜11のうちのいずれか1つのベクター、項目12のウイルス粒子、項目13のポリヌクレオチド、または項目14のがん細胞もしくは免疫細胞を含む組成物。
16.項目1〜11のうちのいずれか1つのベクター、項目12のウイルス粒子、項目13のポリヌクレオチド、または項目14のがん細胞もしくは免疫細胞を含む医薬。
17.がん、ウイルス感染、および/または免疫系障害を処置する方法における使用のための、項目1〜11のうちのいずれか1つのベクター、項目12のウイルス粒子、項目13のポリヌクレオチド、項目14のがん細胞もしくは免疫細胞、項目15の組成物、または項目16の医薬。
18.がんが、乳がん、前立腺がん、リンパ腫、皮膚がん、膵臓がん、結腸がん、黒色腫、悪性黒色腫、卵巣がん、脳がん、原発脳癌、頭頸部がん、神経膠腫、神経膠芽腫、肝臓がん、膀胱がん、非小細胞肺がん、頭部または頸部癌、乳癌、卵巣癌、肺癌、小細胞肺癌、ウィルムス腫瘍、子宮頸癌、精巣癌、膀胱癌、膵臓癌、胃癌、結腸癌、前立腺癌、尿生殖器癌、甲状腺癌、食道癌、骨髄腫、多発性骨髄腫、副腎癌、腎細胞癌、子宮内膜癌、副腎皮質癌、悪性膵臓膵島細胞腫、悪性カルチノイド癌、絨毛癌、菌状息肉腫、悪性高カルシウム血症、子宮頸過形成、白血病、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、慢性骨髄性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、有毛細胞白血病、神経芽細胞腫、横紋筋肉腫、カポジ肉腫、真性赤血球増加症、本態性血小板増加症、ホジキン疾患、非ホジキンリンパ腫、軟部組織肉腫、中皮腫、骨肉腫、原発マクログロブリン血症、および網膜芽細胞腫のうちのいずれか1つである、項目17による使用のためのベクター、項目17による使用のためのウイルス粒子、項目17による使用のためのポリヌクレオチド、項目17による使用のためのがん細胞もしくは免疫細胞、項目17による使用のための組成物、または項目17による使用のための医薬。
19.がんの転移を防止または処置する方法における使用のための、項目1〜11のうちのいずれか1つのベクター、項目12のウイルス粒子、項目13の組成物、または項目14の医薬。
20.ベクター系が、1用量単位当たり1×1011ivp(感染性ウイルス粒子)を超えないか、好ましくは、1×1010ivpを超えないか、より好ましくは、1×109ivpを超えないか、なおより好ましくは、1×107ivpまたは1×106ivpを超えない濃度で存在することを特徴とする、項目17〜19のうちのいずれか1つの使用のためのベクター。
21.ウイルス粒子が、1用量単位当たり1×1011ivpを超えないか、好ましくは、1×1010ivpを超えないか、より好ましくは、1×109ivpを超えないか、なおより好ましくは、1×107ivpまたは1×106ivpを超えない濃度で存在することを特徴とする、項目17〜19のうちのいずれか1つの使用のためのウイルス粒子。
22.4−1BBリガンド(4−1BBL)、IL−2、および単鎖IL−12(scIL−12)を含むタンパク質の組合せであって、4−1BBLの量が、scIL−12およびIL−2の量より高量である組合せ。
マウスIm01およびヒトIm01による、IL−12、IL−2、および4−1BBLのトランス遺伝子の発現、ならびにIFN−γ応答
Im01は、以下のスキーム:
ベクターのデザインおよび研究の概観
Im02
本開示に従うベクターは、ex vivoにおける治療シミュレーション研究のために、デザインされ、作製されている。ベクターは、アデノウイルスベクターに基づき、Im02(内部ベクターコード:「Im02」)と名付けられている。Im02は、以下のスキーム:
ヒト腫瘍生検試料のex vivo培養物を、新規のベクター系のための研究モデルとして選び出した。試料は、Clinic of Urology、Asklepios hospital、Hamburg−Barmbekにより提供された。合計で、43人の患者に由来する、244例の腫瘍試料と、270例の正常膀胱組織対照生検とについて解析した。試料は、8例の患者から、経尿道的切除術(TUR)時に回収し研究組入れ試料の大部分は、膀胱切除術に由来した。本研究では、腫瘍組織および膀胱組織を、早期〜後期と変化する広範な病期にわたり解析した。16人の女性および27人の男性に由来する試料を解析した。前立腺癌の共時的診断のために、この患者コホートにおける前処置は、連続TUR、化学療法、または抗アンドロゲン療法であった。
Im02および早期ベクターIm01による、4−1BBL、IL−2、およびscIL−12のトランス遺伝子の発現、ならびにIFN−γ応答
Im02(実施例2を参照されたい)および早期ベクターIm01(実施例1を参照されたい)による、4−1BBL、IL−2、およびIL−12のトランス遺伝子の発現、ならびにIFN−γ応答を比較した。
組織ベースのモデルにおける、単一のベクターならびにIm02およびIm01の比較
scIL−12、IL−2、または4−1BBLを発現させるアデノウイルスベクターを使用する単回投与による処置単独、ならびにIm02およびIm01(後者のさらなる詳細については、実施例1を参照されたい)について検討した。
異なる用量レベルにおける、Im02およびIm01の比較
Im02およびIm01(これらのベクターのさらなる詳細については、実施例2および3を参照されたい)を、漸増用量で、腫瘍微小環境内のトランス遺伝子の発現およびIFN−γ応答について比較した。
Im02およびIm01についての遺伝子発現プロファイリング
Im02についての治療用遺伝子発現プロファイルを示すために、トランスクリプトーム解析を実施した。特に、Im02およびIm01による、白血球活性化についての包括的プロファイルを得るために、腫瘍細胞およびPBMCによる共培養物実験の腫瘍細胞に、Im02、Im01、およびAd0(空ベクター)を形質導入し、白血球についてのmRNA遺伝子活性解析(lllumina Chip HT12全ゲノム発現解析)を実施した。この目的で、形質導入の後で、末梢白血球を、共培養物へと添加した。非形質導入腫瘍細胞に対する白血球を、対照として使用した。4、24、32、48、72、および96時間後に、白血球を回収し、RNAを単離および精製した。品質チェックの後、RNAを、相補性DNA(cDNA)へと逆転写し、ビーズチップのプロトコールに従い標識し、ビーズチップであるHT12へとロードし、走査を実施した(Life & Brain、department of human genetics at the University of Bonn)。得られたデータを、GenomeStudio Software(lllumina)へと転送した。その後、IPA(登録商標)Software(Ingenuity)を使用して、データを査定した。示差的に調節された過程を示す、コア解析を実施した。調節された過程についての概観を得、それらの重要性と、関与する分子数とを例示するために、IPA(登録商標)過程解析を実施した。表1および2を参照されたい。
主要な免疫細胞型の活性化についての遺伝子発現解析
全ての主要な免疫細胞型の存在および活性化状態について、遺伝子発現データの解析を可能とするCELLMIXソフトウェアを使用して、96時間の時間経過にわたる、主要な免疫細胞型の活性化について解析した。図6の熱プロットは、RT−4ヒト膀胱がん細胞と共培養される、4日間(96時間)の時間経過にわたる、B細胞(末梢血単核細胞、PBMC)を除く、全ての主要な血中免疫細胞亜型の活性化を例示する。図6に示す通り、Im02によるヘルパーT細胞および細胞傷害性T細胞の活性化は、Im01による同じ免疫細胞の活性化より優れている。
ex vivo組織についての研究結果
組織学による組織プロファイリング
組織の品質および細胞の組成のばらつきについて、ホルマリン固定およびパラフィン包埋の後、または組織の凍結および固定の後における組織切片内でモニタリングした。全般的な品質は、ヘマトキシリン−エオシン染色(HE)の後で査定した。
Im02を形質導入した組織についての透過電子顕微鏡法(TEM)を実施して、とりわけ、小胞膜の存在および形状、ならびに細胞1個当たりの粒子の存在度により判定される、アデノウイルス粒子の取込みの標的細胞型、取込みの経路を同定した。
正常膀胱試料中および膀胱腫瘍試料中の、示差的発現の比較
正常膀胱組織および腫瘍組織に、108ivpのIm02を形質導入した。培養は、6日目まで継続した。示差的発現は、対照としてのAd0(空アデノウイルスベクター)で処置された試料と比較して決定した。図10は、9例の膀胱組織試料および10例の腫瘍組織試料のプールについての結果を示す。全体的な刺激(すなわち、免疫応答過程の誘導)は、正常膀胱組織内より、腫瘍組織内で高度である(図10を参照されたい)。この効果は、正常組織と腫瘍組織との、微小環境の差違、例えば、免疫細胞の浸潤物の数、または腫瘍細胞の近傍における抑制のレベルの差違を指示する。
アデノウイルスを取り込むためのトランスフェクタントの検討
トランスフェクタント様ポリカチオン性化合物を添加することにより、無傷の膀胱組織へのアデノウイルスの取込みを改善することができる。Im02による、ex vivoにおける組織試料の灌流のために、細胞株のセット内の、候補化合物のスクリーンにおいて、プロタミン硫酸塩(10μg/ml)が、コックサッキー−アデノウイルス受容体(CAR)の発現に依存しない、アデノウイルス生成物の取込みを可能とすることを同定した(図11を参照されたい)。ヒト膀胱がん細胞株であるRT−4が、CARを発現するのに対し、マウス結腸がん細胞株であるCT−26は、CARを発現しないことが報告されている。図11のキャプション中に表示の通り、アデノウイルス生成物を、緩衝液中で製剤化した。ヒト膀胱がん細胞株であるRT−4、およびCAR陰性マウス結腸がん細胞株であるCT−26に、標的細胞1個当たり、異なる多重度(MOI:感染多重度)で、Ad−GFP(GFPを保有するアデノウイルスベクター)を形質導入した。結果を、形質導入の48時間後における、GFP陽性細胞の百分率であって、フローサイトメトリーにより測定される百分率として例示する。結果として、いずれの細胞株でも、10μg/mlのプロタミン硫酸塩は、最高の形質導入効率を可能とした。
異なるMOIの、Im02および単一遺伝子発現ベクターによる、4−1BBL、IL−2、およびscIL−12のトランス遺伝子の発現、ならびにIFN−γ応答
Im02と、単一遺伝子発現ベクターの組合せとによる、4−1BBL、IL−2、およびscIL−12のトランス遺伝子の発現、ならびにIFN−γ応答は、IFN−γの発現が、4−1BBLレベルの上昇に依存することを明らかにする。
Claims (18)
- 4−1BBリガンド(4−1BBL)、単鎖IL−12(scIL−12)、およびIL−2をコードする核酸配列を含み、少なくとも1つの調節核酸配列、好ましくは、プロモーター配列をさらに含み、scIL−12およびIL−2の発現レベルと比較した、4−1BBLの発現レベルの上昇をもたらすベクター。
- 前記4−1BBLの発現レベルが、ベクターIm01の発現構築物(図20)により得られる4−1BBLの発現レベルと比較して上昇している、請求項1に記載のベクター。
- ベクターIm01の発現構築物(図20)により得られるscIL−12および/またはIL−2の発現レベルと比較して、前記scIL−12の発現レベルが低下し、かつ/または前記IL−2の発現レベルが上昇している、請求項1または2に記載のベクター。
- 4−1BBL、scIL−12、およびIL−2をコードする前記核酸配列を、5’〜3’方向に、1、2、3の順序で、scIL−12をコードする前記配列が、1位にはないことを条件として構成した、請求項1から3のいずれか一項に記載のベクター。
- アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、単純ヘルペスウイルスベクター、ポックスウイルスベクター、RNAベクター、プラスミドベクター、ナノ粒子ベクター、およびネイキッドDNAのうちのいずれか1つである、請求項1から4のいずれか一項に記載のベクター。
- 4−1BBLをコードする前記核酸配列が、ヒトcDNAであり、scIL−12をコードする前記核酸配列が、ヒトcDNAであり、かつ/またはIL−2をコードする前記核酸配列が、ヒトcDNAである、請求項1から5のいずれか一項に記載のベクター。
- 4−1BBLをコードする前記核酸配列が、配列番号1の核酸配列に対する、少なくとも70%の配列同一性を示し、前記変異体の核酸配列が、活性化T細胞に特異的に結合することが可能な、4−1BBLタンパク質をコードする、請求項1から6のいずれか一項に記載のベクター。
- IL−2をコードする前記核酸配列が、配列番号3の核酸配列に対する、少なくとも70%の配列同一性を示し、前記変異体の核酸配列が、免疫刺激活性を有するIL−2タンパク質をコードする、請求項1から6のいずれか一項に記載のベクター。
- scIL−12をコードする前記核酸配列が、配列番号5の核酸配列に対する、少なくとも70%の配列同一性を示し、前記変異体の核酸配列が、免疫刺激活性を有するscIL−12タンパク質をコードする、請求項1から6のいずれか一項に記載のベクター。
- scIL−12およびIL−2をコードする前記核酸配列を、4−1BBLをコードする前記核酸配列の下流に配置する、請求項1から9のいずれか一項に記載のベクター。
- IL−2をコードする前記核酸配列を、4−1BBLをコードする前記核酸配列の下流に配置し、scIL−12をコードする前記核酸配列を、IL−2をコードする前記核酸配列の下流に配置する、請求項10に記載のベクター。
- プロモーターを、4−1BBLをコードする前記核酸配列の上流に配置するが、scIL−12および/またはIL−2をコードする前記核酸配列の上流には配置しない、請求項10または11に記載のベクター。
- 4−1BBL、scIL−12、およびIL−2をコードする前記核酸配列を、内部リボソーム侵入部位(IRES)により連結した、請求項1から12のいずれか一項に記載のベクター。
- 請求項1から13のいずれか一項に記載のベクターを形質導入またはトランスフェクトされたがん細胞または免疫細胞。
- 請求項1から13のいずれか一項に記載のベクター、または請求項14に記載のがん細胞もしくは免疫細胞を含む医薬。
- がん、ウイルス感染、および/または免疫系障害を処置する方法における使用のための、請求項1から13のいずれか一項に記載のベクター、請求項14に記載のがん細胞もしくは免疫細胞、または請求項15に記載の医薬。
- 前記がんが、膀胱がん、乳がん、前立腺がん、リンパ腫、皮膚がん、膵臓がん、結腸がん、黒色腫、悪性黒色腫、卵巣がん、脳がん、原発性脳癌、頭頸部がん、神経膠腫、神経膠芽腫、肝臓がん、非小細胞肺がん、頭部または頸部癌、乳癌、卵巣癌、肺癌、小細胞肺癌、ウィルムス腫瘍、子宮頸癌、精巣癌、膀胱癌、膵臓癌、胃癌、結腸癌、前立腺癌、尿生殖器癌、甲状腺癌、食道癌、骨髄腫、多発性骨髄腫、副腎癌、腎細胞癌、子宮内膜癌、副腎皮質癌、悪性膵臓膵島細胞腫、悪性カルチノイド癌、絨毛癌、菌状息肉腫、悪性高カルシウム血症、子宮頸過形成、白血病、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、慢性骨髄性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、有毛細胞白血病、神経芽細胞腫、横紋筋肉腫、カポジ肉腫、真性赤血球増加症、本態性血小板増加症、ホジキン疾患、非ホジキンリンパ腫、軟部組織肉腫、中皮腫、骨肉腫、原発マクログロブリン血症、および網膜芽細胞腫のうちのいずれか1つである、請求項16に記載の使用のためのベクター、または請求項16に記載の使用のためのがん細胞もしくは免疫細胞、または請求項16に記載の使用のための医薬。
- がんの転移を防止または処置する方法における使用のための、請求項1から13のいずれか一項に記載のベクター、または請求項14に記載のがん細胞もしくは免疫細胞、または請求項15に記載の医薬。
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WO2017144602A1 (en) | 2017-08-31 |
EP3211000A1 (en) | 2017-08-30 |
JP6698881B2 (ja) | 2020-05-27 |
CN109311958A (zh) | 2019-02-05 |
CA3015247C (en) | 2021-12-07 |
US20190046664A1 (en) | 2019-02-14 |
ES2718192T3 (es) | 2019-06-28 |
AU2017222226A1 (en) | 2018-09-13 |
ES2901008T3 (es) | 2022-03-21 |
MX2018010172A (es) | 2019-05-22 |
MA43676A (fr) | 2018-11-28 |
EP3211000B1 (en) | 2019-01-30 |
CA3015247A1 (en) | 2017-08-31 |
AU2017222226B2 (en) | 2020-10-08 |
US10994027B2 (en) | 2021-05-04 |
EP3419995A1 (en) | 2019-01-02 |
IL261248A (en) | 2018-10-31 |
US20210220486A1 (en) | 2021-07-22 |
KR20180135441A (ko) | 2018-12-20 |
EA201891681A1 (ru) | 2019-04-30 |
EP3419995B1 (en) | 2021-09-15 |
BR112018017194A2 (pt) | 2019-01-02 |
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