JP7075125B2 - 標的としてのおよび胆嚢がんおよび胆管がんおよびその他のがんに対する免疫療法で使用するための新規ペプチド、ペプチド組み合わせ - Google Patents
標的としてのおよび胆嚢がんおよび胆管がんおよびその他のがんに対する免疫療法で使用するための新規ペプチド、ペプチド組み合わせ Download PDFInfo
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Description
a)がん精巣抗原:T細胞によって認識され得る初めて同定されたTAAはこのクラスに属し、元々はがん精巣(CT)抗原と称されたが、それは、そのメンバーが組織学的に異なるヒト腫瘍において発現し、正常組織では精巣の精母細胞/精原細胞のみに存在し、時として胎盤に存在するためであった。精巣の細胞は、クラスIおよびII HLA分子を発現しないので、これらの抗原は正常組織のT細胞によって認識され得ず、したがって免疫学的に腫瘍特異的と見なされる。CT抗原の周知の例は、MAGEファミリーメンバーおよびNY-ESO-1である。
b)分化抗原:これらのTAAは、腫瘍と、それから腫瘍が生じる正常組織との間で共有される。既知の分化抗原のほとんどは、黒色腫および正常メラノサイトに見いだされる。これらのメラノサイト系関連タンパク質の多くは、メラニン生合成に関与し、したがって腫瘍特異的でないが、それでもなおがん免疫療法のために広く利用されている。例としては、黒色腫に対するチロシナーゼとMelan-A/MART-1、または前立腺がんに対するPSAが挙げられるが、これに限定されるものではない。
c)過剰発現TAA:広範に発現されるTAAをエンコードする遺伝子は、組織学的に異なる型の腫瘍において検出され、多数の正常組織においても概してより低い発現レベルで検出されている。正常組織によってプロセスされて潜在的に提示されるエピトープの多くは、T細胞認識の閾値レベル未満であり得る一方で、腫瘍細胞におけるそれらの過剰発現は、以前確立された免疫寛容を破壊することにより、抗がん応答を始動し得る。このクラスのTAAの顕著な例は、Her-2/neu、サバイビン、テロメラーゼまたはWT1である。
d)腫瘍特異的抗原:これらのユニークなTAAは、正常な遺伝子(β-カテニン、CDK4など)の変異から生じる。これらの分子変化のいくつかは、腫瘍性形質転換および/または進行に関連する。腫瘍特異的抗原は、通常、正常組織に対する自己免疫反応のリスクなしに、強力な免疫応答を誘導できる。他方、これらのTAAは、ほとんどの場合、その上でそれらが同定されたまさにその腫瘍のみと関係があり、通常は、多くの個々の腫瘍間で共有されない。腫瘍特異的(関連)イソ型を有するタンパク質では、ペプチドの腫瘍特異性(または関連性)はまた、ペプチドが腫瘍(関連)エクソンに由来する場合に生じてもよい。
e)異常な翻訳後修飾から生じるTAA:このようなTAAは、特異的でなく腫瘍において過剰発現もされないタンパク質から生じてもよいが、それでもなお、腫瘍において主に活性である翻訳後プロセスによって腫瘍関連になる。このクラスの例は、腫瘍にMUC1のような新規エピトープをもたらす改変グリコシル化パターン、または腫瘍特異的であってもなくてもよい分解中のタンパク質スプライシングのような事象から生じる。
f)オンコウイルスタンパク質:これらのTAAはウイルスタンパク質であり、それらは発がん過程において重要な役割を果たしてもよく、外来性である(ヒト由来でない)ため、それらはT細胞応答を誘起し得る。このようなタンパク質の例は、子宮頸がんにおいて発現される、ヒト乳頭腫16型ウイルスタンパク質E6およびE7である。
同一性百分率=100[1-(C/R)]
式中、Cは、参照配列と比較される配列との間のアライメント長にわたる、参照配列と比較配列の間の差異の数であり、
(i)比較配列中に対応する整列塩基またはアミノ酸を有しない、参照配列中の各塩基またはアミノ酸、および
(ii)参照配列中の各ギャップ、および
(iii)比較配列中の整列塩基またはアミノ酸と異なる、参照配列中の各整列塩基またはアミノ酸が差異を構成して、
(iiii)アライメントは、整合配列の1位から開始しなくてはならず;
Rは、比較配列とのアライメント長にわたる参照配列中の塩基またはアミノ酸の数であり、参照配列中に生じる任意のギャップもまた、塩基またはアミノ酸として数えられる。
(a)溶液中のまたは凍結乾燥形態の上述の医薬組成物を含有する容器;
(b)任意選択的に、凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
(c)任意選択的に、(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキットをさらに目的とする。
1.悪性物質からのHLAリガンドを質量分析法によって同定した
2.ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を使用して、一連の正常器官および組織と比較して悪性組織(胆嚢がんおよび胆管がん)中の遺伝子過剰発現を同定した
3.同定されたHLAリガンドを遺伝子発現データと比較した。好ましくは、ステップ2で検出されたような選択的に発現されまたは過剰発現される遺伝子によってコードされる、腫瘍組織上で過剰提示されまたは選択的に提示されるペプチドが、多重ペプチドワクチンのための適切なTUMAP候補と見なされた。
4.同定されたペプチドのTUMAPとしての妥当性を支持する追加的な証拠を同定するために、文献調査を実施した
5.mRNAレベルでの過剰発現の関連性をステップ3からの選択されたTUMAPの腫瘍組織上における再検出と、健常組織における検出の欠如(または稀な)検出によって確認した。
6.選択されたペプチドによる生体内T細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびに胆嚢がんおよび胆管がん患者からのヒトT細胞を使用して、生体外免疫原性アッセイを実施した。
細胞表面に提示される腫瘍関連ペプチドの同定および定量化
組織サンプル
患者の腫瘍組織は、Conversant Healthcare SystemsInc.(米国アラバマ州ハンツビル)、ProteoGenex Inc.(米国カリフォルニア州カルバーシティ)、Tissue Solutions Ltd(英国グラスゴー)、University Hospital Tubingen(独国チュービンゲン)から入手された。正常組織は、Asterand(米国ミシガン州デトロイト;英国ハートフォードシャー州ロイストン)、Bio-Options Inc.(米国カリフォルニア州ブレア)、BioServe(米国メリーランド州ベルツビル)、Capital BioScience Inc.(米国メリーランド州ロックビル)、Geneticist Inc.(米国カリフォルニア州グレンデール)、京都府立医科大学(KPUM)(日本国京都)、ProteoGenex Inc.(米国カリフォルニア州カルバーシティ)、Tissue Solutions Ltd(英国グラスゴー)、University Hospital Geneva(スイス国ジュネーブ)、University Hospital Heidelberg(独国ハイデルベルク)、University Hospital Munich(独国ミュンヘン)、University Hospital Tubingen(独国チュービンゲン)から入手された。
衝撃凍結組織サンプルからのHLAペプチド貯留は、わずかに修正されたプロトコル(Falk et al.,1991;Seeger et al.,1999)に従って、HLA-A*02-特異的抗体BB7.2、HLA-A、-B、-C特異的抗体W6/32、CNBr活性化セファロース、酸処理、および限外濾過を使用して、免疫沈殿によって固形組織から得られた。
得られたHLAペプチド貯留は、逆相クロマトグラフィー(nanoAcquity UPL C system,Waters)によってそれらの疎水性に従って分離し、ESI源を装着したLTQ-velosおよびfusion hybrid質量分光計(ThermoElectron)内で溶出ペプチドを分析した。ペプチド貯留は、毎分400nLの流速を適用して、1.7μm C18逆相材料(Waters)で充填された分析用融合シリカマイクロキャピラリーカラム(75μm内径×250mm)上に直接挿入した。引き続いて、毎分300nLの流速で10%から33%へのBの二段階180分間二成分勾配を用いて、ペプチドを分離した。勾配は、溶媒A(水中の0.1%ギ酸)および溶媒B(アセトニトリル中の0.1%ギ酸)から構成された。nanoESI源への導入には、金被覆ガラス毛管(PicoTip,New Objective)を使用した。LTQ-Orbitrap質量分光計は、TOP5ストラテジーを使用してデータ依存モードで操作した。手短に述べると、Orbitrap(R=30000)内の高質量精度の完全スキャンでスキャンサイクルを開始し、これもまたOrbitrap(R=7500)内の5種の最も豊富な前駆イオンのMS/MSスキャンがそれに続き、以前選択されたイオンは動的に排除された。タンデム質量スペクトルは、SEQUESTおよび追加的な手動調節によって解釈した。同定されたペプチド配列は、生成された天然ペプチド断片化パターンと、配列が同一の合成参照ペプチドの断片化パターンとの比較によって確認した。
表は、正常組織パネルと比較して腫瘍上で非常に高度に過剰提示され(+++)、正常組織パネルと比較して腫瘍上で高度に過剰提示され(++)、正常組織パネルと比較して腫瘍上で過剰提示される(+)、ペプチドを列挙する。腫瘍との比較に適切であると見なされた正常組織のパネルは、脂肪組織、副腎、動脈、骨髄、脳、中枢神経、結腸、十二指腸、食道、眼、胆嚢、心臓、腎臓、肝臓、肺、リンパ節、単核白血球細胞、膵臓、副甲状腺、末梢神経、腹膜、下垂体、胸膜、直腸、唾液腺、骨格筋、皮膚、小腸、脾臓、胃、甲状腺、気管、尿管、膀胱、静脈からなった。
本発明のペプチドをコードする遺伝子発現プロファイリング
正常細胞と比較した腫瘍細胞上のペプチドの過剰提示または特異的提示は、免疫療法におけるその有用性にとって十分であり、いくつかのペプチドは、それらの起源タンパク質が正常組織にもまた存在するにもかかわらず、腫瘍特異的である。それでもなお、mRNA発現プロファイリングは、免疫療法のためのペプチド標的の選択において、安全性のレベルを高めることができる。特に、アフィニティ成熟TCRなどの安全性リスクが高い治療選択肢では、理想的な標的ペプチドは、腫瘍に特有で正常組織上には見いだされないタンパク質に由来する。
外科的に除去された組織標本は、告知に基づく同意書が各患者から入手された後に、上述の通り提供された(実施例1を参照されたい)。腫瘍組織標本が手術直後にスナップ凍結され、その後、液体窒素下で乳鉢と乳棒を用いて均質化された。TRI試薬(独国ダルムシュタットのAmbion)を使用して、これらのサンプルから全RNAが調製され、RNeasy(独国ヒルデンのQIAGEN)による精製がそれに続き;どちらの方法も製造業者のプロトコルに従って実施された。
腫瘍および正常組織RNAサンプルの遺伝子発現解析は、CeGaT(独国チュービンゲン)によって、次世代配列決定(RNAseq)によって実施された。簡単に述べると、配列決定ライブラリーは、RNA断片化、cDNA転換、および配列決定アダプターの付加を含む、Illumina HiSeq v4試薬キットを使用して、販売業者(米国カリフォルニア州サンディエゴのIllumina Inc.)のプロトコルに従って作成される。複数のサンプルに由来するライブラリーは等モル混合され、Illumina HiSeq 2500配列決定装置上で、製造会社の使用説明書に従って配列決定され、50bpのシングルエンドリードが生成される。処理された読み取りは、STARソフトウェアを使用して、ヒトゲノム(GRCh38)にマッピングされる。発現データは、ensembl配列データベース(Ensembl77)の注釈に基づいて、RPKM(100万個のマッピングされた読み取り当たりキロベース当たり読み取り、ソフトウェアCufflinksによって作成される)として転写物レベルで、そしてエクソンレベルで(全読み取り、ソフトウェアBedtoolsによって作成される)提供される。エクソン読み取りは、エクソン長さおよびアライメントサイズについて正規化されて、RPKM値が得られる。
表は、正常組織パネルと比較して腫瘍において非常に高度に過剰発現され(+++)、正常組織パネルと比較して腫瘍において高度に過剰発現され(++)、正常組織パネルと比較して腫瘍において過剰発現される(+)、遺伝子に由来するペプチドを列挙する。スコアのベースラインは、脂肪組織、副腎、動脈、胆管、血液細胞、骨髄、脳、軟骨、結腸、食道、眼、胆嚢、唾液腺、心臓、腎臓、肝臓、肺、リンパ節、膵臓、副甲状腺、末梢神経、腹膜、下垂体、胸膜、直腸、骨格筋、皮膚、小腸、脾臓、胃、甲状腺、気管、尿管、膀胱、および静脈の関連正常組織の測定値から計算された。同一組織型のいくつかのサンプル発現データが利用できる場合、全ての各サンプルの算術平均が、計算のために使用された。
MHCクラスI提示ペプチドの生体外免疫原性
本発明のTUMAPの免疫原性に関する情報を得るために、本発明者らは、ペプチド/MHC複合体および抗CD28抗体を負荷した人工抗原提示細胞(aAPC)によるCD8+T細胞の反復刺激に基づく、生体外T細胞プライミングアッセイを用いて研究を実施した。このようにして、本発明者らは、本発明のHLA-A*0201拘束性TUMAPの免疫原性を示し得て、これらのペプチドが、それに対するCD8+前駆T細胞がヒトに存在する、T細胞エピトープであることを実証した(表10)。
ペプチドMHC複合体(pMHC)および抗CD28抗体を負荷した、人工抗原提示細胞による生体外刺激を実施するために、本発明者らは、最初に、告知に基づく同意後に、独国のUniversity clinics Mannheimから得られた健常ドナーのCD8ミクロビーズ(独国ベルギッシュ・グラートバッハのMiltenyi Biotec)を使用した正の選択を通じて、新鮮HLA-A*02白血球除去生成物からCD8+T細胞を単離した。
HLAクラスIペプチドを試験するために、ペプチド特異的T細胞株の生成によって生体外免疫原性が実証され得た。本発明の2種のペプチドの、TUMAP特異的多量体染色後の例示的フローサイトメトリー結果は、対応する陰性対照と共に図3に示される。本発明の3種のペプチドの、TUMAP特異的多量体染色後の追加的な例示的フローサイトメトリー結果は、対応する陰性対照と共に図4に示される。本発明からの25種のペプチドの結果は、表10Aに要約される。本発明の4種のペプチドのさらなる結果は、表10Bに要約される。
出願人によって実施された本発明のペプチドの生体外免疫原性実験の例示的結果。<20%=+;20%-49%=++;50%-69%=+++;>=70%=++++
出願人によって実施された、本発明のHLA-A*02拘束性ペプチドについての生体外免疫原性実験の代表的結果である。生体外免疫原性実験の結果が示される。陽性ウェルおよびドナーの百分率(評価可能内の)は、示されるように要約される
<20%=+;20%-49%=++;50%-69%=+++;>=70%=++++
ペプチドの合成
Fmocストラテジーを使用した標準的な十分に確立された固相ペプチド合成を使用して、全てのペプチドを合成した。個々のペプチドのアイデンティティーおよび純度は、質量分析および分析用RP-HPLCによって判定された。ペプチドは、純度>50%の白色から灰白色の凍結乾燥物(lyophilizes)(トリフルオロ酢酸塩)として得られた。全てのTUMAPは、好ましくはトリフルオロ酢酸塩または酢酸塩として投与され、その他の塩形態もまた可能である。
MHC結合アッセイ
本発明によるT細胞ベースの治療法のための候補ペプチドを、それらのMHC結合能力(親和性)についてさらに試験した。個々のペプチド-MHC複合体は、UVリガンド交換によって生成され、UV感受性ペプチドはUV照射に際して切断されて、分析される目的ペプチドで交換された。ペプチド受容性MHC分子と効果的に結合して安定化し得るペプチド候補のみが、MHC複合体の分離を防止する。交換反応の収率を判定するために、安定化MHC複合体の軽鎖(β2m)の検出に基づくELISAを実施した。アッセイは、Rodenko et al.(Rodenko et al.,2006)に一般的に記載されるようにして実施した。
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Claims (18)
- 配列番号18に示されるアミノ酸配列からなるペプチドもしくはその薬学的に許容可能な塩、または
配列番号18に示されるアミノ酸配列からなるペプチドもしくはその薬学的に許容可能な塩であり、前記ペプチドがMHCクラスI分子に結合する能力を有し、前記MHCに結合した際に、CD8T細胞によって認識されることができるようになる、ペプチドもしくはその薬学的に許容可能な塩。 - 請求項1に記載のペプチドが、修飾され、および/または非ペプチド結合を含む、ペプチド。
- 請求項1または2に記載のペプチドと、HLA-DR抗原関連不変鎖(p33)の80個のN末端アミノ酸を含んでなる融合タンパク質。
- 抗体、可溶性抗体、膜結合抗体、モノクローナル抗体、または抗体、可溶性抗体、膜結合抗体およびモノクローナル抗体からなる群から選択される抗体の断片であって、
1)請求項1もしくは2に記載のペプチドを特異的に認識する、または
2)MHC分子と結合した際に、請求項1もしくは2に記載のペプチドを特異的に認識する、
抗体、可溶性抗体、膜結合抗体、モノクローナル抗体、または前記断片。 - T細胞受容体、可溶性T細胞受容体、膜結合性T細胞受容体、またはT細胞受容体、可溶性T細胞受容体および膜結合性T細胞受容体からなる群から選択されるT細胞受容体の断片であって、
1)請求項1もしくは2に記載のペプチド、または
2)MHC分子と結合している請求項1もしくは2に記載のペプチドである、
HLAリガンドと反応する、
T細胞受容体、可溶性T細胞受容体、膜結合性T細胞受容体、または前記断片。 - 前記T細胞受容体が可溶性分子として提供される、または前記T細胞受容体が可溶性分子として提供され、免疫刺激ドメインもしくは毒素によって代表されるさらなるエフェクター機能を保有する、請求項5に記載のT細胞受容体。
- 請求項1もしくは2に記載のペプチド、またはMHC分子と結合している請求項1もしくは2に記載のペプチドを特異的に認識する、アプタマー。
- 請求項1に記載のペプチド、請求項4に記載の抗体もしくは抗体の断片または請求項5に記載のT細胞受容体もしくはT細胞受容体の断片をコードする核酸または、前記核酸を発現する発現ベクターまたは、
請求項1に記載のペプチド、請求項4に記載の抗体もしくは抗体の断片または請求項5に記載のT細胞受容体もしくはT細胞受容体の断片をコードする核酸であって、異種プロモーター配列と結合する核酸または、前記核酸を発現する発現ベクター。 - 請求項8に記載の核酸または発現ベクターを含んでなる組換え宿主細胞であって、ここで該宿主細胞は、樹状細胞、T細胞、NK細胞または抗原提示細胞から選択される、組換え宿主細胞。
- T細胞を、適切な抗原提示細胞の表面に、または抗原提示細胞を模倣する人工コンストラクトの表面に発現される抗原負荷ヒトクラスIMHC分子に、前記T細胞を抗原特異的様式で活性化するのに十分な時間にわたり、生体外で接触させるステップを含んでなり、前記抗原が、請求項1に記載のペプチドである、活性化Tリンパ球を製造するインビトロ法。
- 請求項1に記載のペプチドを提示する細胞を選択的に認識する、請求項10に記載の方法によって生産される活性化Tリンパ球。
- 請求項1または2に記載のペプチド、請求項3に記載の融合タンパク質、請求項4に記載の抗体もしくは抗体の断片、請求項5に記載のT細胞受容体もしくはT細胞受容体の断片、請求項7に記載のアプタマー、請求項8に記載の核酸もしくは発現ベクター、請求項9に記載の宿主細胞、または請求項11に記載の活性化Tリンパ球からなる群から選択される少なくとも1つの活性成分、またはコンジュゲートされもしくは標識された前記活性成分と、薬学的に許容できる担体を含んでなる、医薬組成物、または
請求項1または2に記載のペプチド、請求項3に記載の融合タンパク質、請求項4に記載の抗体もしくは抗体の断片、請求項5に記載のT細胞受容体もしくはT細胞受容体の断片、請求項7に記載のアプタマー、請求項8に記載の核酸もしくは発現ベクター、請求項9に記載の宿主細胞、または請求項11に記載の活性化Tリンパ球からなる群から選択される少なくとも1つの活性成分、またはコンジュゲートされもしくは標識された前記活性成分と、薬学的に許容できる担体と、薬学的に許容可能な賦形剤および/もしくは安定剤とを含んでなる、医薬組成物。 - 請求項9に記載の宿主細胞を培養するステップと、前記宿主細胞および/またはその培養液から、ペプチド、融合タンパク質、抗体もしくは抗体の断片、またはT細胞受容体もしくはT細胞受容体の断片を単離するステップとを含んでなる、請求項1に記載のペプチド、請求項3に記載の融合タンパク質、請求項4に記載の抗体もしくは抗体の断片、または請求項5に記載のT細胞受容体もしくはT細胞受容体の断片を製造する方法。
- 請求項1または2に記載のペプチド、請求項3に記載の融合タンパク質、請求項4に記載の抗体もしくは抗体の断片、請求項5に記載のT細胞受容体もしくはT細胞受容体の断片、請求項7に記載のアプタマー、請求項8に記載の核酸もしくは発現ベクター、請求項9に記載の宿主細胞、または請求項11に記載の活性化Tリンパ球、を含む医薬品。
- 請求項11で定義される活性化Tリンパ球の有効数を患者に投与するための標的細胞死滅剤であって、その標的細胞が、請求項1に記載のペプチドを提示する患者のものである標的細胞死滅剤。
- 以下のいずれか1つを含む、がんの診断剤またはがんの治療剤、またはがんに対する薬剤の製造で使用するための薬剤;
請求項1または2に記載のペプチド、請求項3に記載の融合タンパク質、請求項4に記載の抗体もしくは抗体の断片、請求項5に記載のT細胞受容体もしくはT細胞受容体の断片、請求項7に記載のアプタマー、請求項8に記載の核酸もしくは発現ベクター、請求項9に記載の宿主細胞、または請求項11に記載の活性化Tリンパ球。 - がんが、配列番号18に示されるアミノ酸配列からなるペプチドに由来するタンパク質の過剰発現を示す、胆嚢がんおよび胆管がん、急性骨髄性白血病、黒色腫、小細胞肺がん、非小細胞肺がん、非ホジキンリンパ腫、慢性リンパ球性白血病、膵臓がん、肝臓がん、卵巣がん、頭頸部がん、膀胱がん、乳がん、および腎臓がんの群から選択される、請求項16に記載の薬剤。
- a)溶液または凍結乾燥形態にある、請求項12に記載の医薬組成物を含んでなる容器;と以下b)~d)から選択される1つ以上の要素を含んでなるキットもしくは以下b)~d)を含まないキット、
b)凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
c)配列番号1~配列番号17および配列番号19~配列番号38からなる群から選択される少なくとももう1つのペプチド、および
d)(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書、または
a)溶液または凍結乾燥形態にある、請求項12に記載の医薬組成物を含んでなる容器;と以下b)~d)から選択される1つ以上の要素を含んでなるキットもしくは以下b)~d)を含まないキットであって、
b)凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
c)配列番号1~配列番号17および配列番号19~配列番号38からなる群から選択される少なくとももう1つのペプチド、および
d)(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書、
さらに(iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針、または(v)シリンジから選択される1つまたは複数を含んでなる、キット。
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- 2021-08-27 US US17/458,670 patent/US11897936B2/en active Active
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Patent Citations (3)
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US20070237770A1 (en) | 2001-11-30 | 2007-10-11 | Albert Lai | Novel compositions and methods in cancer |
JP2014507138A (ja) | 2011-02-01 | 2014-03-27 | ゲンマブ エー/エス | Cd74に対するヒト抗体および抗体−薬物コンジュゲート |
WO2014160499A2 (en) | 2013-03-13 | 2014-10-02 | Creatics Llc | Methods and compositions for detecting pancreatic cancer |
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JP2022123887A (ja) | 2022-08-24 |
US20190284256A1 (en) | 2019-09-19 |
CL2021001525A1 (es) | 2022-02-04 |
US11897936B2 (en) | 2024-02-13 |
US10472407B2 (en) | 2019-11-12 |
US11897935B2 (en) | 2024-02-13 |
ZA201807333B (en) | 2019-08-28 |
PH12018502315A1 (en) | 2019-04-15 |
MX2022000201A (es) | 2022-01-24 |
JP2019520059A (ja) | 2019-07-18 |
US20210380662A1 (en) | 2021-12-09 |
IL263257A (en) | 2018-12-31 |
TW202304969A (zh) | 2023-02-01 |
US20210403531A1 (en) | 2021-12-30 |
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