JP2021506781A - Iapアンタゴニスト及び抗pd−1分子による併用抗癌療法 - Google Patents
Iapアンタゴニスト及び抗pd−1分子による併用抗癌療法 Download PDFInfo
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Abstract
Description
本発明は、抗PD−1分子による対象の治療の前に対象の癌の微小環境の免疫原性を増強させるためのIAPアンタゴニストの使用に関する。
多くの癌のタイプには、外因性又は内因性の細胞死経路の構成要素が遺伝子改変されている症例が含まれる。これには、FAS-associated via death domain(FADD)若しくはアポトーシスタンパク質阻害剤(IAP)の過剰発現又は機能的カスパーゼの発現の欠如を含むことができる。結果として、癌の特徴である細胞死抵抗性となり得る。Hoadley et al. (2014) Cell 158: 929-44;The Cancer Genome Atlas Network (2015) Nat 517: 576-82;Eytan et al. (2016) Cancer Res 76: 5442-54;Hanahan and Weinberg (2011) Cell 144: 646-74。
本発明者らは、患者の腫瘍微小環境の免疫原性を増強させるために腫瘍を有する患者をSMACミメティックなどのようなIAPアンタゴニストにより前治療することができることを提唱する。前治療は、腫瘍に対する免疫応答を引き起こすための抗PD−1分子による治療の有効性を増強させる。
定義
用語「アンタゴニスト」及び「阻害剤」は、区別なく使用され、もう一方の生理学的作用に干渉する又はそれを阻害する物質を指す。いくつかの実施形態では、用語「アンタゴニスト」及び「阻害剤」は、最先の優先日、すなわち2017年12月21日に当業者によって理解されるものと同じ意味を有し、最先の優先日の時点での当業者の共通の一般知識を念頭に置く。
本発明者らは、患者の腫瘍微小環境の免疫原性を増強させるために腫瘍を有する患者をSMACミメティックなどのようなIAPアンタゴニストにより前治療することができることを提唱する。続いて、患者は、抗PD−1分子により治療される。前治療は、患者の腫瘍が抗PD−1分子による治療に対して応答する可能性を増加させる及び/又は抗PD−1分子に対する腫瘍の応答の有効性を増強させる。IAPアンタゴニストは、既に(2017年12月21日の時点のように)承認されている又は現在臨床開発中であるものの中から、特に以下のものの中から選択されてもよい:
Debio 1143(Debiopharm、CAS RN:1071992−99−8)、GDC−917/CUDC−427(Curis/Genentech、CAS RN:1446182−94−0)、LCL161(Novartis、CAS RN:1005342−46−0)、GDC−0152(Genentech、CAS RN:873652−48−3)、TL−32711/ビリナパント(Medivir、CAS RN:1260251−31−7)、HGS−1029/AEG−408268(Aegera、CAS RN:1107664−44−7)、BI 891065(Boehringer Ingelheim)、ASTX−660(Astex/Otsuka、CAS RN:1605584−14−2)、APG−1387(Ascentage、CAS RN:1802293−83−9)、又はそれらの医薬品の許容され得る塩のいずれか。好ましくは、IAPアンタゴニストは、SMACミメティックであり、最も好ましいIAPアンタゴニストは、Debio 1143である。
原則として、任意の適した方法が、用いられてもよい。免疫組織化学的検査及びフローサイトメトリーに基づく手順が、最もよく使用される。
IAPアンタゴニストを含む医薬組成物は、経口的に、非経口的に、吸入噴霧剤によって、局所的に、直腸に、経鼻的に、頬側に(buccally)、腟に(vaginally)、又は植込み貯蔵器を介して、好ましくは経口投与又は注射による投与によって、投与されてもよい。しかしながら、二量体のSMACミメティックは、典型的に静脈内に投与されることに注意される。医薬組成物は、任意の従来の無毒性の薬学的に許容され得るキャリヤ、補助剤、又はビヒクルを含有してもよい。ある場合には、製剤のpHは、活性剤又はその送達形態の安定性を増強させるために、薬学的に許容され得る酸、塩基、又はバッファーにより調整されてもよい。標準的な医薬キャリヤ及びそれらの製剤は、非限定的に、Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995において記載される。本明細書において使用される非経口的という用語は、皮下、皮内、静脈内、筋肉内、関節内、動脈内、滑液包内、胸骨内(intrasternal)、髄腔内、病巣内、及び頭蓋内注射又は注入技術を含む。
抗PD−1分子は、典型的に静脈内注入によって投与される。
1.抗PD−1分子によるその後の治療が抗癌応答をもたらす可能性を増強させるために又は抗PD−1分子によるその後の治療に対する対象の癌の応答性を増強させるために、癌になったヒト対象を前治療するためのIAPアンタゴニスト。
2.ヒト対象は、1から28日間、好ましくは5から28日間の前治療期の間に、IAPアンタゴニストにより前治療され、前記前治療期に続いて、前記その後の抗PD−1分子治療が開始される、項目1に記載のIAPアンタゴニスト。
3.前記前治療期は、IAPアンタゴニストが投与されない1又はそれ以上の日を含む、項目2に記載のIAPアンタゴニスト。
4.前記IAPアンタゴニスト又は異なるIAPアンタゴニストはまた、抗PD−1分子による前記その後の治療の間にも投与される、項目1から3のいずれか1項に記載のIAPアンタゴニスト。
5.前記IAPアンタゴニストの投与は、抗PD−1分子による前記その後の治療の全期間の間に継続されるか、又は抗PD−1分子による前記その後の治療の完了の前に終了する又は抗PD−1分子による前記その後の治療の完了以降、継続される、項目4に記載のIAPアンタゴニスト。
6.前記癌は、かなりの割合の治療患者において抗PD−1分子による治療に対して応答性であることが知られている種類のものである、項目1から5のいずれか1項に記載のIAPアンタゴニスト。
7.前記癌は、頭頸部癌、黒色腫、尿路上皮癌、非小細胞肺癌、原発部位がわからない高頻度マイクロサテライト不安定性(MSI)腫瘍、又は腎臓癌である、項目6に記載のIAPアンタゴニスト。
8.前記癌は、抗PD−1分子による治療に応答することが示された患者のパーセンテージが低い(たとえば5%以下)種類のものである、項目1から5のいずれか1項に記載のIAPアンタゴニスト。
9.前記癌は、膵臓癌、結腸直腸癌、多発性骨髄腫、小細胞肺癌、肝臓がん、又は卵巣癌である、項目8に記載のIAPアンタゴニスト。
10.前記前治療は、癌の免疫原性が不十分であるという判断を条件とする、項目1から9のいずれか1項に記載のIAPアンタゴニスト。
11.前記判断は、前治療の前に採取された患者の生物学的サンプルにおける免疫原性のマーカーの分析、及びマーカーの存在、発現レベル、又は導き出されたスコアが所定の閾値に到達しないという所見からなる、項目10に記載のIAPアンタゴニスト。
12.前記マーカーは、癌細胞及び/又は免疫細胞上に発現されるPD−L1である、項目11に記載のIAPアンタゴニスト。
13.前記マーカーは、腫瘍浸潤リンパ球又は腫瘍中の遺伝子変異量である、項目11に記載のIAPアンタゴニスト。
14.抗PD−1分子による前記その後の治療の開始は、癌が前治療の終了時に免疫原性であるという判断を条件とする、項目1から13のいずれか1項に記載のIAPアンタゴニスト。
15.前記判断は、IAP阻害剤による前治療の後に採取された患者の生物学的サンプルにおける免疫原性のマーカーの分析、及びマーカーの存在、発現レベル、又は導き出されたスコアが所定の閾値を超えるという所見からなる、項目14に記載のIAPアンタゴニスト。
16.前記マーカーは、癌細胞及び/又は免疫細胞上に発現されるPD−L1である、項目15に記載のIAPアンタゴニスト。
17.前記マーカーは、腫瘍浸潤リンパ球又は腫瘍中の遺伝子変異量である、項目15に記載のIAPアンタゴニスト。
18.前記患者の生物学的サンプルは、腫瘍又は液体生検材料である、項目11から13及び15から17のいずれか1項に記載のIAPアンタゴニスト。
19.前記抗PD−1分子は、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、PDR001、IBI−308、セミプリマブ、カムレリズマブ、BGB−A317、BCD−100、JS−001、JNJ−3283、MEDI0680、AGEN−2034、TSR−042、Sym−021、PF−06801591、MGD−013、MGA−012、LZM−009、GLS−010、ゲノリムズマブ、BI 754091、AK−104、CX−072、WBP3155、SHR−1316、PD−L1阻害剤ミラモレキュール、BMS−936559、M−7824、LY−3300054、KN−035、FAZ−053、CK−301、又はCA−170である、項目1から18のいずれか1項に記載のIAPアンタゴニスト。
20.抗PD−1分子は、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、PDR001、又はBI 754091である、項目19に記載のIAPアンタゴニスト。
21.前記抗PD−1分子は、PD−1又はPD−L1に対する抗体である、項目1から19のいずれか1項に記載のIAPアンタゴニスト。
22.抗PD−1分子による前記その後の治療は、別の免疫療法、放射線療法、化学療法、化学放射線療法、腫瘍溶解性ウイルス、血管新生抑制療法、標的癌療法を含む、1つ又はそれ以上の他の癌療法と組み合わせられる、項目1から21のいずれか1項に記載のIAPアンタゴニスト。
23.1つ又はそれ以上の他の癌療法は、抗PD−1分子による治療を除外して、前記前治療期の間に使用される、項目1から22のいずれか1項に記載のIAPアンタゴニスト。
24.前記IAPアンタゴニストは、Debio 1143、GDC−917/CUDC−427、LCL161、GDC−0152、TL−32711/ビリナパント、HGS−1029/AEG−40826、BI 891065、ASTX−660、又はAPG−1387である、項目1から23のいずれか1項に記載のIAPアンタゴニスト。
25.前記IAPアンタゴニストは、SMACミメティックである、項目24に記載のIAPアンタゴニスト。
26.前記IAPアンタゴニストは、Debio 1143である、項目25に記載のIAPアンタゴニスト。
実施例1:頭頸部の切除可能な扁平上皮細胞癌を有する患者におけるシスプラチン(CDDP)あり又はなしのDebio 1143の術前ウィンドウ・オブ・オポチュニティ試験(EUDRACT 2014−004655−31)
本治験のために、Debio 1143は、その遊離塩基で使用し、デンプンと共に製剤し、硬カプセル内に充填した。
5グループ(n=8)の成体雌C57BL/6Jマウス(Shanghai Lingchang Bio-Technology Co.から得た)の右下脇腹に1×106細胞の同系結腸癌細胞株MC38を接種した。平均腫瘍サイズが約50mm3に届いたら(1日目)、動物は、表1に示されるように、100mg/kgの用量のp.o.SMACミメティックDebio 1143(Debiopharm)又はビヒクルからなる前治療を受けた。投薬は、7日間(1から7日目)毎日反復した。後日(8日目)、ビヒクル治療グループ及びDebio 1143前治療グループの動物に10mg/kgのコントロール抗体rIgG2b(クローン:LTF−2、BioXcell)をi.p.で与えた。コントロール抗体は、試験の終了まで毎週2回投与した。2つのグループ(ビヒクル及びDebio 1143前治療動物)の別のセットは、10mg/kgの抗PD−L1抗体(マウスサロゲート抗体、抗マウスPD−L1、クローン:10F.9G2、BioXcell)をi.p.で受けた。投与は、コントロール抗体の場合と同様に毎週2回反復した。Debio 1143前治療動物の最終グループは、抗PD−L1抗体を受け、毎日のDebio 1143も継続した。腫瘍量及び体重は、毎週2回判断した。腫瘍サイズは、キャリパーを使用して二次元で測定し、容積は、式:V=0.5a×b2、a及びbは、それぞれ腫瘍の長径及び短径である、を使用してmm3で表現した。
72匹の成体雌C57BL/6Jマウス(Shanghai Lingchang Bio-Technology Co.から得た)の右下脇腹に0.1mlのPBS中1×106細胞の同系結腸癌細胞株MC−38を皮下接種した。腫瘍量は、キャリパーを使用して二次元で毎週3回測定し、容積は、式:V=(L×W×W)/2、Vは腫瘍量であり、Lは腫瘍長(最長の腫瘍寸法)であり、Wは腫瘍幅(Lに垂直な最長の腫瘍寸法)である、を使用してmm3で表現した。動物はすべて、「Matched distribution」ランダム化法(StudyDirector(商標)ソフトウェア、バージョン3.1.399.19)に基づいて、52mm3の平均腫瘍サイズを有する9つの異なる試験グループにランダムに割り当て、治療をスタートした(1日目とした)。投薬並びに腫瘍測定及び体重測定は、ラミナーフローキャビネットにおいて行った。
5グループ(n=8)の成体雌BALB/cマウス(Shanghai Lingchang Bio-Technology Co.から得た)の右下脇腹に0.5×106細胞の同系結腸癌細胞株CT26を接種した。平均腫瘍サイズが約50mm3に届いたら(1日目)、動物は、表3aに示されるように、100mg/kgの用量のp.o.SMACミメティックDebio 1143(Debiopharm)又はビヒクルからなる前治療を受けた。投薬は、7日間(1から7日目)毎日反復した。表3bに示されるように、後日(8日目)、ビヒクル治療グループ及びDebio 1143前治療グループの動物に試験終了まで経口ビヒクルを毎日与えた。2つのグループ(ビヒクル及びDebio 1143前治療動物)の別のセットは、10mg/kgの抗PD−1抗体(マウスサロゲート抗体、抗マウスPD−1、クローン:RMP1−14、BioXcell)をi.p.で隔週に受けた。Debio 1143前治療動物の最終グループは、抗PD−1抗体を受け、毎日のDebio 1143も継続した。腫瘍量及び体重は、毎週2回判断した。腫瘍サイズは、キャリパーを使用して二次元で測定し、容積は、式:V=0.5a×b2、a及びbは、それぞれ腫瘍の長径及び短径である、を使用してmm3で表現した。
本明細書における値の範囲の記述は、本明細書において別段の指示がない限り、範囲内にあるそれぞれの別々の値を個々に指すための省略表現の方法として果たすことが単に意図され、それぞれの別々の値は、あたかも個々に本明細書において詳述されるかのように、本明細書に組み込まれる。特に指定のない限り、本明細書において提供される厳密な値はすべて、対応する近似値の代表である(たとえば、特定の因子又は測定値に関して提供されるすべての厳密な例示的な値は、適切な場合、「約」によって修飾される、対応する近似の測定値をも提供すると考えることができる)。
Claims (25)
- ヒト対象において癌を治療するための方法における使用のためのアポトーシスタンパク質阻害剤(IAP)アンタゴニストであって、前記方法が、
(i)導入期の間に前記IAPアンタゴニストを投与することであって、前記導入期の継続時間は、抗PD−1分子の第1の投与の1から48日前の範囲から選択されることと、これに続いて
(ii)前記導入期の終了後に抗PD−1分子を投与することと、
を含む、
使用のためのアポトーシスタンパク質阻害剤(IAP)アンタゴニスト。 - 前記ヒト対象が、1から28日間の導入期の間に前記IAPアンタゴニストを投与され、これに続いて前記抗PD−1分子が投与される、請求項1に記載の使用のためのIAPアンタゴニスト。
- 前記ヒト対象が、5から28日間の導入期の間に前記IAPアンタゴニストを投与され、これに続いて前記抗PD−1分子が投与される、請求項1又は2に記載の使用のためのIAPアンタゴニスト。
- 前記IAPアンタゴニストが、前記導入期の間の1又はそれ以上の日、投与されない、請求項1から3のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記IAPアンタゴニストの投与が、前記抗PD−1分子による投与がスタートした後、継続されるか、又は
別のIAPアンタゴニストが、前記抗PD−1分子と同時に投与される、請求項1から4のいずれか1項に記載の使用のためのIAPアンタゴニスト。 - 前記癌が、10%以上の治療患者において抗PD−1分子による治療に対して応答性であることが知られている癌である、請求項1から5のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記癌が、頭頸部癌、黒色腫、尿路上皮癌、非小細胞肺癌、原発部位がわからない高頻度マイクロサテライト不安定性(MSI)腫瘍、又は腎臓癌である、請求項1から5のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記癌が、抗PD−1分子による治療に対する奏効率が10%以下、好ましくは5%以下である癌である、請求項1から5のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記癌が、膵癌、結腸直腸癌、多発性骨髄腫、小細胞肺癌、肝臓がん、又は卵巣癌である、請求項1から5のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記癌が、免疫原性が不十分であると判断されている、請求項1から9のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記判断が、前記導入期の前に採取された患者の生物学的サンプルにおける免疫原性のマーカーの分析、及びマーカーの存在、発現レベル、又は導き出されたスコアが所定の閾値に到達しないという所見からなる、請求項10に記載の使用のためのIAPアンタゴニスト。
- 前記マーカーが、癌細胞及び/又は免疫細胞上に発現されるPD−L1である、請求項11に記載の使用のためのIAPアンタゴニスト。
- 前記マーカーが、腫瘍浸潤リンパ球、好ましくはCD8+細胞又は腫瘍中の遺伝子変異量である、請求項11に記載の使用のためのIAPアンタゴニスト。
- 導入期の間の前記IAPアンタゴニストの投与が、前記癌が高免疫原性であることが判断されるまで継続される、請求項1から13のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記判断が、前記導入期の後に採取された患者の生物学的サンプルにおける免疫原性のマーカーの分析、及びマーカーの存在、発現レベル、又は導き出されたスコアが所定の閾値を超えるという所見からなる、請求項14に記載の使用のためのIAPアンタゴニスト。
- 前記マーカーが、癌細胞及び/又は免疫細胞上に発現されるPD−L1である、請求項15に記載の使用のためのIAPアンタゴニスト。
- 前記マーカーが、腫瘍浸潤リンパ球、好ましくはCD8+細胞又は腫瘍中の遺伝子変異量である、請求項15に記載の使用のためのIAPアンタゴニスト。
- 前記生物学的サンプルが、腫瘍又は液体生検材料である、請求項11から13及び15から17のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記抗PD−1分子が、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、PDR001、IBI−308、セミプリマブ、カムレリズマブ、BGB−A317、BCD−100、JS−001、JNJ−3283、MEDI0680、AGEN−2034、TSR−042、Sym−021、PF−06801591、MGD−013、MGA−012、LZM−009、GLS−010、ゲノリムズマブ、BI 754091、AK−104、CX−072、WBP3155、SHR−1316、PD−L1阻害剤ミラモレキュール、BMS−936559、M−7824、LY−3300054、KN−035、FAZ−053、CK−301、又はCA−170である、請求項1から18のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記抗PD−1分子が、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、PDR001、又はBI 754091である、請求項19に記載の使用のためのIAPアンタゴニスト。
- 前記抗PD−1分子が、PD−1又はPD−L1に対する抗体である、請求項1から19のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記抗PD−1分子の投与が、別の免疫療法、放射線療法、化学療法、化学放射線療法、腫瘍溶解性ウイルス、血管新生抑制療法、及び/又は標的癌療法を含む、1つ又はそれ以上の他の癌療法と組み合わせられる、請求項1から21のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記IAPアンタゴニストが、第2ミトコンドリア由来カスパーゼ活性化因子(SMAC)ミメティックである、請求項1から22のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記導入期の間に投与される前記IAPアンタゴニストが、Debio 1143、GDC−917/CUDC−427、LCL161、GDC−0152、TL−32711/ビリナパント、HGS−1029/AEG−40826、BI 891065、ASTX−660、又はAPG−1387であり、好ましくは、前記IAPアンタゴニストは、Debio 1143、LCL161、又はビリナパントである、請求項1から23のいずれか1項に記載の使用のためのIAPアンタゴニスト。
- 前記IAPアンタゴニストが、Debio 1143である、請求項24に記載の使用のためのIAPアンタゴニスト。
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US11813484B2 (en) | 2018-11-28 | 2023-11-14 | Histosonics, Inc. | Histotripsy systems and methods |
US20230029259A1 (en) * | 2019-12-02 | 2023-01-26 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination of iap inhibitors and parp or mek inhibitors or other chemotherapeutic agents |
US11813485B2 (en) | 2020-01-28 | 2023-11-14 | The Regents Of The University Of Michigan | Systems and methods for histotripsy immunosensitization |
CN111948395A (zh) * | 2020-08-19 | 2020-11-17 | 复旦大学附属金山医院 | 用于诊断三阴性乳腺癌免疫调节亚型的四联标志物及其应用 |
CN112194723B (zh) * | 2020-09-25 | 2021-09-21 | 广州百吉生物制药有限公司 | 一种免疫细胞在治疗癌症中应用 |
CN116963732A (zh) * | 2021-02-23 | 2023-10-27 | 苏州亚盛药业有限公司 | 药物组合物及其制备方法 |
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CN105828834A (zh) * | 2013-11-05 | 2016-08-03 | 同源生物服务股份有限公司 | 检查点抑制剂和治疗剂的组合以治疗癌症 |
EP3200775B1 (en) | 2014-10-03 | 2019-11-20 | Novartis AG | Combination therapies |
WO2016049677A1 (en) * | 2014-10-03 | 2016-04-07 | The Walter And Eliza Hall Institute Of Medical Research | Method of treating cancer |
CN108495651A (zh) * | 2015-12-17 | 2018-09-04 | 诺华股份有限公司 | 抗pd-1的抗体分子及其用途 |
EA201891904A1 (ru) * | 2016-02-24 | 2019-04-30 | Чилдрен'С Хоспитал Оф Истерн Онтарио Рисерч Инститьют Инк. | Smc комбинированная терапия для лечения злокачественного новообразования |
WO2017214706A1 (en) * | 2016-06-15 | 2017-12-21 | Tissue Regeneration Therapeutics Inc. | Anti-cancer use of genetically modified human umbilical cord perivascular cells (hucpvc) |
JOP20180040A1 (ar) | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | مثبطات pd-1/pd-l1 |
JP7504106B2 (ja) * | 2019-01-17 | 2024-06-21 | デビオファーム・インターナショナル・エス・アー | がんの処置のための組合せ物 |
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Cited By (2)
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WO2022250070A1 (ja) | 2021-05-28 | 2022-12-01 | 日本化薬株式会社 | ウベニメクスと免疫チェックポイント阻害剤の併用 |
KR20240016267A (ko) | 2021-05-28 | 2024-02-06 | 니폰 가야꾸 가부시끼가이샤 | 우베니멕스와 면역관문 저해제의 병용 |
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HRP20231358T1 (hr) | 2024-02-16 |
BR112020012250A2 (pt) | 2020-11-24 |
WO2019122337A1 (en) | 2019-06-27 |
DK3728313T3 (da) | 2023-10-30 |
PT3728313T (pt) | 2023-10-23 |
RS64738B1 (sr) | 2023-11-30 |
ES2960585T3 (es) | 2024-03-05 |
EP4285927A3 (en) | 2024-03-06 |
WO2019122941A1 (en) | 2019-06-27 |
EA202091539A1 (ru) | 2020-09-17 |
JP7438947B2 (ja) | 2024-02-27 |
LT3728313T (lt) | 2023-11-10 |
IL275389A (en) | 2020-07-30 |
FI3728313T3 (fi) | 2023-11-01 |
RS64738B9 (sr) | 2023-12-29 |
US20210093645A1 (en) | 2021-04-01 |
EP3728313B1 (en) | 2023-08-02 |
PL3728313T3 (pl) | 2024-01-22 |
MX2020006534A (es) | 2020-12-09 |
EP4285927A2 (en) | 2023-12-06 |
CA3085389A1 (en) | 2019-06-27 |
KR20200103737A (ko) | 2020-09-02 |
EP3728313A1 (en) | 2020-10-28 |
EP3728313B9 (en) | 2023-10-25 |
CN111542542A (zh) | 2020-08-14 |
JP2024059699A (ja) | 2024-05-01 |
HUE063487T2 (hu) | 2024-01-28 |
SI3728313T1 (sl) | 2023-12-29 |
AU2018386626A1 (en) | 2020-07-02 |
SG11202005759YA (en) | 2020-07-29 |
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