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- 229920001184 polypeptide Polymers 0.000 claims description 135
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Description
当業者には、上記の実施形態に対して、その広義の発明概念から逸脱することなく変更がなされ得ることは理解されよう。したがって、本発明は、開示した特定の実施形態に限定されず、本明細書によって定義されている本発明の趣旨及び範囲内の改変を網羅するものとすると理解される。
以下、本発明の実施形態を示す。
［１］キメラ抗原受容体(CAR)をコードする核酸配列を含む単離されたポリヌクレオチドであって、CARが、
(a)クローディン18.2(CLDN18.2)に特異的に結合する少なくとも1つの抗原結合性ドメインを含む細胞外ドメイン、
(b)ヒンジ領域、
(c)膜貫通領域、及び
(d)細胞内シグナル伝達ドメイン
を含む、単離されたポリヌクレオチド。
［２］抗原結合性ドメインが、
(1)それぞれ配列番号21、22、23、51、52及び53、
(2)それぞれ配列番号24、25、26、54、55及び56、
(3)それぞれ配列番号27、28、29、57、58及び59、
(4)それぞれ配列番号30、31、32、60、61及び62、
(5)それぞれ配列番号33、34、35、63、64及び65、
(6)それぞれ配列番号36、37、38、66、67及び68、
(7)それぞれ配列番号39、40、41、69、70及び71、
(8)それぞれ配列番号42、43、44、72、73及び74、
(9)それぞれ配列番号45、46、47、75、76及び77、又は
(10)それぞれ配列番号48、49、50、78、79及び80、
のポリペプチド配列を有する重鎖相補性決定領域1(HCDR1)、HCDR2、HCDR3、軽鎖相補性決定領域1(LCDR1)、LCDR2及びLCDR3を含み、その抗原結合性ドメインがCLDN18.2、好ましくはヒトCLDN18.2に特異的に結合する、［1］に記載の単離されたポリヌクレオチド。
［３］抗原結合性ドメインが、
(1)それぞれ配列番号81、82、83、111、112及び113、
(2)それぞれ配列番号84、85、86、114、115及び116、
(3)それぞれ配列番号87、88、89、117、118及び119、
(4)それぞれ配列番号90、91、92、120、121及び122、
(5)それぞれ配列番号93、94、95、123、124及び125、
(6)それぞれ配列番号96、97、98、126、127及び128、
(7)それぞれ配列番号99、100、101、129、130及び131、
(8)それぞれ配列番号102、103、104、132、133及び134、
(9)それぞれ配列番号105、106、107、135、136及び137、又は
(10)それぞれ配列番号108、109、110、138、139及び140、
のポリペプチド配列を有する重鎖相補性決定領域1(HCDR1)、HCDR2、HCDR3、軽鎖相補性決定領域1(LCDR1)、LCDR2及びLCDR3を含み、その抗原結合性ドメインがCLDN18.2、好ましくはヒトCLDN18.2に特異的に結合する、［1］に記載の単離されたポリヌクレオチド。
［４］抗原結合性ドメインが配列番号1、3、5、7、9、11、13、15、17若しくは19に少なくとも95%同一であるポリペプチド配列を有する重鎖可変領域、又は配列番号2、4、6、8、10、12、14、16、18若しくは20に少なくとも95%同一であるポリペプチド配列を有する軽鎖可変領域を含む、［1］～［3］のいずれか一に記載の単離されたポリヌクレオチド。
［５］抗原結合性ドメインが、
(1)配列番号1のポリペプチド配列を有する重鎖可変領域及び配列番号2のポリペプチド配列を有する軽鎖可変領域、
(2)配列番号3のポリペプチド配列を有する重鎖可変領域及び配列番号4のポリペプチド配列を有する軽鎖可変領域、
(3)配列番号5のポリペプチド配列を有する重鎖可変領域及び配列番号6のポリペプチド配列を有する軽鎖可変領域、
(4)配列番号7のポリペプチド配列を有する重鎖可変領域及び配列番号8のポリペプチド配列を有する軽鎖可変領域、
(5)配列番号9のポリペプチド配列を有する重鎖可変領域及び配列番号10のポリペプチド配列を有する軽鎖可変領域、
(6)配列番号11のポリペプチド配列を有する重鎖可変領域及び配列番号12のポリペプチド配列を有する軽鎖可変領域、
(7)配列番号13のポリペプチド配列を有する重鎖可変領域及び配列番号14のポリペプチド配列を有する軽鎖可変領域、
(8)配列番号15のポリペプチド配列を有する重鎖可変領域及び配列番号16のポリペプチド配列を有する軽鎖可変領域、
(9)配列番号17のポリペプチド配列を有する重鎖可変領域及び配列番号18のポリペプチド配列を有する軽鎖可変領域、
(10)配列番号19のポリペプチド配列を有する重鎖可変領域及び配列番号20のポリペプチド配列を有する軽鎖可変領域
を含む、［1］～［4］のいずれか一に記載の単離されたポリヌクレオチド。
［６］抗原結合性ドメインがヒト化され、且つ、配列番号142、143、146、147、151、152、154、155、156、159、160、161、162、166、167、170、171、172、175、176、177、178、179、180、186、187、191、192若しくは193に少なくとも95%同一であるポリペプチド配列を有する重鎖可変領域、又は配列番号144、145、148、149、150、153、157、158、163、164、165、168、169、173、174、181、182、183、184、185、188、189、190、194、195、196若しくは197に少なくとも95%同一であるポリペプチド配列を有する軽鎖可変領域を含む、［1］～［3］のいずれか一に記載の単離されたポリヌクレオチド。
［７］抗原結合性ドメインがヒト化され、且つ、
(1)配列番号142のポリペプチド配列を有する重鎖可変領域及び配列番号144のポリペプチド配列を有する軽鎖可変領域、
(2)配列番号142のポリペプチド配列を有する重鎖可変領域及び配列番号145のポリペプチド配列を有する軽鎖可変領域、
(3)配列番号143のポリペプチド配列を有する重鎖可変領域及び配列番号144のポリペプチド配列を有する軽鎖可変領域、
(4)配列番号143のポリペプチド配列を有する重鎖可変領域及び配列番号145のポリペプチド配列を有する軽鎖可変領域、
(5)配列番号146のポリペプチド配列を有する重鎖可変領域及び配列番号148のポリペプチド配列を有する軽鎖可変領域、
(6)配列番号146のポリペプチド配列を有する重鎖可変領域及び配列番号149のポリペプチド配列を有する軽鎖可変領域、
(7)配列番号146のポリペプチド配列を有する重鎖可変領域及び配列番号150のポリペプチド配列を有する軽鎖可変領域、
(8)配列番号147のポリペプチド配列を有する重鎖可変領域及び配列番号148のポリペプチド配列を有する軽鎖可変領域、
(9)配列番号147のポリペプチド配列を有する重鎖可変領域及び配列番号149のポリペプチド配列を有する軽鎖可変領域、
(10)配列番号147のポリペプチド配列を有する重鎖可変領域及び配列番号150のポリペプチド配列を有する軽鎖可変領域、
(11)配列番号151のポリペプチド配列を有する重鎖可変領域及び配列番号153のポリペプチド配列を有する軽鎖可変領域、
(12)配列番号152のポリペプチド配列を有する重鎖可変領域及び配列番号153のポリペプチド配列を有する軽鎖可変領域、
(13)配列番号154のポリペプチド配列を有する重鎖可変領域及び配列番号157のポリペプチド配列を有する軽鎖可変領域、
(14)配列番号155のポリペプチド配列を有する重鎖可変領域及び配列番号157のポリペプチド配列を有する軽鎖可変領域、
(15)配列番号156のポリペプチド配列を有する重鎖可変領域及び配列番号158のポリペプチド配列を有する軽鎖可変領域、
(16)配列番号159のポリペプチド配列を有する重鎖可変領域及び配列番号163のポリペプチド配列を有する軽鎖可変領域、
(17)配列番号159のポリペプチド配列を有する重鎖可変領域及び配列番号164のポリペプチド配列を有する軽鎖可変領域、
(18)配列番号160のポリペプチド配列を有する重鎖可変領域及び配列番号163のポリペプチド配列を有する軽鎖可変領域、
(19)配列番号160のポリペプチド配列を有する重鎖可変領域及び配列番号164のポリペプチド配列を有する軽鎖可変領域、
(20)配列番号161のポリペプチド配列を有する重鎖可変領域及び配列番号165のポリペプチド配列を有する軽鎖可変領域、又は
(21)配列番号162のポリペプチド配列を有する重鎖可変領域及び配列番号165のポリペプチド配列を有する軽鎖可変領域
を含む、［1］～［3］及び［6］のいずれか一に記載の単離されたポリヌクレオチド。
［８］抗原結合性ドメインがCLDN18.2、好ましくはヒトCLDN18.2に特異的に結合する単鎖可変断片(scFv)である、［1］～［7］のいずれか一に記載の単離されたポリヌクレオチド。
［９］単鎖可変断片(scFv)がヒト化され、且つ、配列番号198～215のいずれか1つに少なくとも95%同一であるポリペプチド配列を含む、［8］に記載の単離されたポリヌクレオチド。
［１０］キメラ抗原受容体(CAR)が1つ以上の抗原結合性ドメインを含む、［1］～［9］のいずれか一に記載の単離されたポリヌクレオチド。
［１１］細胞内シグナル伝達ドメインが1つ以上の共刺激ドメイン及び1つ以上の活性化ドメインを含む、［1］～［10］のいずれか一に記載の単離されたポリヌクレオチド。
［１２］［1］～［11］のいずれか一に記載の単離されたポリヌクレオチドによってコードされる、キメラ抗原受容体(CAR)。
［１３］［1］～［11］のいずれか一に記載の単離されたポリヌクレオチドを含むベクター。
［１４］［13］に記載のベクターを含む宿主細胞。
［１５］T細胞、好ましくはヒトT細胞である、［14］に記載の宿主細胞。
［１６］NK細胞、好ましくはヒトNK細胞である、［14］に記載の宿主細胞。
［１７］キメラ抗原受容体(CAR)を発現する宿主細胞を作製する方法であって、［13］に記載のベクターでT細胞を形質導入することを含む方法。
［１８］キメラ抗原受容体(CAR)-T細胞を産生する方法であって、［1］～［11］のいずれか一に記載のキメラ抗原受容体(CAR)をコードする核酸を含む単離されたポリヌクレオチドを含むT細胞をCAR-T細胞産生条件下で培養すること、及びCAR-T細胞を回収することを含む方法。
［１９］キメラ抗原受容体(CAR)を発現する宿主細胞を作製する方法であって、［13］に記載のベクターでNK細胞を形質導入することを含む方法。
［２０］キメラ抗原受容体(CAR)-NK細胞を産生する方法であって、［1］～［11］のいずれか一に記載のキメラ抗原受容体(CAR)をコードする核酸を含む単離されたポリヌクレオチドを含むNK細胞をCAR-NK細胞産生条件下で培養すること、及びCAR-NK細胞を回収することを含む方法。
［２１］キメラ抗原受容体(CAR)を含む細胞を生成する方法であって、［1］～［11］のいずれか一に記載のキメラ抗原受容体(CAR)をコードする核酸を含む単離されたポリヌクレオチドと細胞を接触させることを含み、単離されたポリヌクレオチドはin vitro転写RNA又は合成RNAである方法。
［２２］それを必要とする対象におけるがんを処置する方法であって、［14］～［16］のいずれか一に記載の宿主細胞を対象に投与することを含む方法。
［２３］がんが、肺がん、胃がん、食道がん、胆管がん(bile duct cancer)、胆管癌(cholangiocarcinoma)、結腸がん、肝細胞癌、腎細胞癌、膀胱尿路上皮癌、転移性黒色腫、乳がん、卵巣がん、子宮頸がん、頭頸部がん、膵がん、神経膠腫、神経膠芽腫、及び他の固形腫瘍、並びに非ホジキンリンパ腫(NHL)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、多発性骨髄腫(MM)、急性骨髄性白血病(AML)及び他の液性腫瘍から選択される、［22］に記載の方法。
［２４］それを必要とする対象における炎症性の疾患を処置する方法であって、［14］～［16］のいずれか一に記載の宿主細胞を対象に投与することを含む方法。
［２５］それを必要とする対象に、CARを発現する細胞の有効性を増加させる薬剤を投与することをさらに含む、［22］～［24］のいずれか一に記載の方法。
［２６］それを必要とする対象に、CAR分子を発現する細胞の投与と関連する1つ以上の副作用を改善する薬剤を投与することをさらに含む、［22］～［24］のいずれか一に記載の方法。
［２７］それを必要とする対象に、クローディン18.2に関連した疾患を処置する薬剤を投与することをさらに含む、［22］～［24］のいずれか一に記載の方法。
Those skilled in the art will appreciate that modifications can be made to the above embodiments without departing from the broader concept of the invention. Accordingly, it is understood that the invention is not limited to the particular embodiments disclosed, but covers modifications within the spirit and scope of the invention as defined herein.
Hereinafter, embodiments of the present invention will be shown.
[1] An isolated polynucleotide containing a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein CAR
(a) An extracellular domain containing at least one antigen-binding domain that specifically binds to claudin 18.2 (CLDN 18.2),
(b) Hinge area,
(c) Transmembrane domain and
(d) Intracellular signal transduction domain
An isolated polynucleotide comprising.
[2] The antigen-binding domain is
(1) SEQ ID NOs: 21, 22, 23, 51, 52 and 53, respectively,
(2) SEQ ID NOs: 24, 25, 26, 54, 55 and 56, respectively.
(3) SEQ ID NOs: 27, 28, 29, 57, 58 and 59, respectively.
(4) SEQ ID NOs: 30, 31, 32, 60, 61 and 62, respectively.
(5) SEQ ID NOs: 33, 34, 35, 63, 64 and 65, respectively.
(6) SEQ ID NOs: 36, 37, 38, 66, 67 and 68, respectively.
(7) SEQ ID NOs: 39, 40, 41, 69, 70 and 71, respectively.
(8) SEQ ID NOs: 42, 43, 44, 72, 73 and 74, respectively,
(9) SEQ ID NOs: 45, 46, 47, 75, 76 and 77, or
(10) SEQ ID NOs: 48, 49, 50, 78, 79 and 80, respectively.
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2 and LCDR3 with the polypeptide sequence of CLDN18.2, preferably CLDN18.2. The isolated polynucleotide according to [1], which specifically binds to human CLDN 18.2.
[3] The antigen-binding domain is
(1) SEQ ID NOs: 81, 82, 83, 111, 112 and 113, respectively.
(2) SEQ ID NOs: 84, 85, 86, 114, 115 and 116, respectively,
(3) SEQ ID NOs: 87, 88, 89, 117, 118 and 119, respectively,
(4) SEQ ID NOs: 90, 91, 92, 120, 121 and 122, respectively,
(5) SEQ ID NOs: 93, 94, 95, 123, 124 and 125, respectively,
(6) SEQ ID NOs: 96, 97, 98, 126, 127 and 128, respectively,
(7) SEQ ID NOs: 99, 100, 101, 129, 130 and 131, respectively.
(8) SEQ ID NOs: 102, 103, 104, 132, 133 and 134, respectively.
(9) SEQ ID NOs: 105, 106, 107, 135, 136 and 137, or
(10) SEQ ID NOs: 108, 109, 110, 138, 139 and 140, respectively,
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2 and LCDR3 with the polypeptide sequence of CLDN18.2, preferably CLDN18.2. The isolated polynucleotide according to [1], which specifically binds to human CLDN 18.2.
[4] A heavy chain variable region having a polypeptide sequence in which the antigen-binding domain is at least 95% identical to SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17 or 19, or SEQ ID NO: 2. , 4, 6, 8, 10, 12, 14, 16, 18 or 20, comprising a light chain variable region having a polypeptide sequence that is at least 95% identical, according to any one of [1] to [3]. Isolated polynucleotide.
[5] The antigen-binding domain is
(1) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 1 and light chain variable region having the polypeptide sequence of SEQ ID NO: 2.
(2) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 3 and light chain variable region having the polypeptide sequence of SEQ ID NO: 4.
(3) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 5 and light chain variable region having the polypeptide sequence of SEQ ID NO: 6.
(4) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 7 and light chain variable region having the polypeptide sequence of SEQ ID NO: 8.
(5) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 9 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 10.
(6) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 11 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 12.
(7) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 13 and light chain variable region having the polypeptide sequence of SEQ ID NO: 14.
(8) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 15 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 16.
(9) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 17 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 18.
(10) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 19 and light chain variable region having the polypeptide sequence of SEQ ID NO: 20
The isolated polynucleotide according to any one of [1] to [4], which comprises.
[6] The antigen-binding domain has been humanized and SEQ ID NOs: 142, 143, 146, 147, 151, 152, 154, 155, 156, 159, 160, 161, 162, 166, 167, 170, 171, Heavy chain variable regions with polypeptide sequences that are at least 95% identical to 172, 175, 176, 177, 178, 179, 180, 186, 187, 191, 192 or 193, or SEQ ID NOs: 144, 145, 148, 149. , 150, 153, 157, 158, 163, 164, 165, 168, 169, 173, 174, 181, 182, 183, 184, 185, 188, 189, 190, 194, 195, 196 or 197 at least 95% The isolated polynucleotide according to any one of [1] to [3], which comprises a light chain variable region having the same polypeptide sequence.
[7] The antigen-binding domain is humanized and
(1) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 142 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 144,
(2) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 142 and light chain variable region having the polypeptide sequence of SEQ ID NO: 145,
(3) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and light chain variable region having the polypeptide sequence of SEQ ID NO: 144,
(4) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and light chain variable region having the polypeptide sequence of SEQ ID NO: 145,
(5) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and light chain variable region having the polypeptide sequence of SEQ ID NO: 148,
(6) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 149,
(7) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and light chain variable region having the polypeptide sequence of SEQ ID NO: 150,
(8) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 147 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 148,
(9) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 147 and light chain variable region having the polypeptide sequence of SEQ ID NO: 149,
(10) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 147 and light chain variable region having the polypeptide sequence of SEQ ID NO: 150,
(11) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 151 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 153,
(12) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 152 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 153,
(13) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 154 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 157,
(14) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 155 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 157,
(15) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 156 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 158.
(16) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 159 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 163,
(17) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 159 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164,
(18) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 160 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 163,
(19) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 160 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164,
(20) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 161 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 165, or
(21) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 162 and light chain variable region having the polypeptide sequence of SEQ ID NO: 165.
The isolated polynucleotide according to any one of [1] to [3] and [6], which comprises.
[8] The isolation according to any one of [1] to [7], wherein the antigen-binding domain is a single-chain variable fragment (scFv) that specifically binds to CLDN 18.2, preferably human CLDN 18.2. Polynucleotide that has been
[9] The isolated single chain variable fragment (scFv) according to [8], wherein the single chain variable fragment (scFv) is humanized and contains a polypeptide sequence that is at least 95% identical to any one of SEQ ID NOs: 198 to 215. Polynucleotide.
[10] The isolated polynucleotide according to any one of [1] to [9], wherein the chimeric antigen receptor (CAR) comprises one or more antigen-binding domains.
[11] The isolated polynucleotide according to any one of [1] to [10], wherein the intracellular signal transduction domain comprises one or more costimulatory domains and one or more activation domains.
[12] A chimeric antigen receptor (CAR) encoded by the isolated polynucleotide according to any one of [1] to [11].
[13] A vector containing the isolated polynucleotide according to any one of [1] to [11].
[14] A host cell containing the vector according to [13].
[15] The host cell according to [14], which is a T cell, preferably a human T cell.
[16] The host cell according to [14], which is an NK cell, preferably a human NK cell.
[17] A method for producing a host cell expressing a chimeric antigen receptor (CAR), which comprises transducing T cells with the vector according to [13].
[18] A method for producing a chimeric antigen receptor (CAR) -T cell, which comprises a nucleic acid encoding the chimeric antigen receptor (CAR) according to any one of [1] to [11]. A method comprising culturing T cells containing the obtained polynucleotide under CAR-T cell production conditions and recovering CAR-T cells.
[19] A method for producing a host cell expressing a chimeric antigen receptor (CAR), which comprises transducing NK cells with the vector according to [13].
[20] A method for producing a chimeric antigen receptor (CAR) -NK cell, which comprises a nucleic acid encoding the chimeric antigen receptor (CAR) according to any one of [1] to [11]. A method comprising culturing NK cells containing the obtained polynucleotide under CAR-NK cell producing conditions and recovering CAR-NK cells.
[21] A method for producing a cell containing a chimeric antigen receptor (CAR), which comprises the nucleic acid encoding the chimeric antigen receptor (CAR) according to any one of [1] to [11]. A method comprising contacting a cell with a polynucleotide that has been isolated, wherein the isolated polynucleotide is in vitro transcribed RNA or synthetic RNA.
[22] A method for treating cancer in a subject in need thereof, the method comprising administering to the subject the host cell according to any one of [14] to [16].
[23] Cancers are lung cancer, gastric cancer, esophageal cancer, bile duct cancer, cholangiocarcinoma, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urinary tract epithelial cancer, metastatic Black tumor, breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioma, and other solid tumors, as well as non-hodgkin lymphoma (NHL), acute lymphocytic Selected from leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma (MM), acute myeloid leukemia (AML) and other humoral tumors, [22 ] The method described in.
[24] A method for treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject the host cell according to any one of [14] to [16].
[25] The method according to any one of [22] to [24], further comprising administering to a subject in need thereof an agent that increases the efficacy of cells expressing CAR.
[26] Any one of [22]-[24], further comprising administering to a subject in need thereof an agent that improves one or more side effects associated with the administration of cells expressing the CAR molecule. The method described in.
[27] The method according to any one of [22] to [24], further comprising administering to a subject in need thereof a drug for treating a disease associated with claudin 18.2.
Claims (17)
(a)クローディン18.2(CLDN18.2)に特異的に結合する少なくとも1つの抗原結合性ドメインを含む細胞外ドメイン、
(b)ヒンジ領域、
(c)膜貫通領域、及び
(d)細胞内シグナル伝達ドメイン
を含む、前記単離されたポリヌクレオチド。 An isolated polynucleotide comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR is:
(a) An extracellular domain containing at least one antigen-binding domain that specifically binds to claudin 18.2 (CLDN 18.2),
(b) Hinge area,
(c) Transmembrane domain and
(d) The isolated polynucleotide comprising an intracellular signaling domain.
(1)それぞれ配列番号３６、３７、３８、６６、６７及び６８、若しくはそれぞれ配列番号９６、９７、９８、１２６、１２７及び１２８；
(2)それぞれ配列番号２１、２２、２３、５１、５２及び５３、若しくはそれぞれ配列番号８１、８２、８３、１１１、１１２及び１１３；
(3)それぞれ配列番号２４、２５、２６、５４、５５及び５６、若しくはそれぞれ配列番号８４、８５、８６、１１４、１１５及び１１６；
(4)それぞれ配列番号２７、２８、２９、５７、５８及び５９、若しくはそれぞれ配列番号８７、８８、８９、１１７、１１８及び１１９；
(5)それぞれ配列番号３０、３１、３２、６０、６１及び６２、若しくはそれぞれ配列番号９０、９１、９２、１２０、１２１及び１２２；
(6)それぞれ配列番号３３、３４、３５、６３、６４及び６５、若しくはそれぞれ配列番号９３、９４、９５、１２３、１２４及び１２５；
(7)それぞれ配列番号３９、４０、４１、６９、７０及び７１、若しくはそれぞれ配列番号９９、１００、１０１、１２９、１３０及び１３１；
(8)それぞれ配列番号４２、４３、４４、７２、７３及び７４、若しくはそれぞれ配列番号１０２、１０３、１０４、１３２、１３３及び１３４；
(9)それぞれ配列番号４５、４６、４７、７５、７６及び７７、若しくはそれぞれ配列番号１０５、１０６、１０７、１３５、１３６及び１３７；又は
(10)それぞれ配列番号４８、４９、５０、７８、７９及び８０、若しくはそれぞれ配列番号１０８、１０９、１１０、１３８、１３９及び１４０
のポリペプチド配列を有する重鎖相補性決定領域1(HCDR1)、HCDR2、HCDR3、軽鎖相補性決定領域1(LCDR1)、LCDR2及びLCDR3を含み、その抗原結合性ドメインがCLDN18.2、好ましくはヒトCLDN18.2に特異的に結合する、請求項１記載の単離されたポリヌクレオチド。 The antigen-binding domain is
(1) SEQ ID NOs: 36, 37, 38, 66, 67 and 68, respectively, or SEQ ID NOs: 96, 97, 98, 126, 127 and 128;
(2) SEQ ID NOs: 21, 22, 23, 51, 52 and 53, respectively, or SEQ ID NOs: 81, 82, 83, 111, 112 and 113;
(3) SEQ ID NOs: 24, 25, 26, 54, 55 and 56, respectively, or SEQ ID NOs: 84, 85, 86, 114, 115 and 116;
(4) SEQ ID NOs: 27, 28, 29, 57, 58 and 59, respectively, or SEQ ID NOs: 87, 88, 89, 117, 118 and 119;
(5) SEQ ID NOs: 30, 31, 32, 60, 61 and 62, respectively, or SEQ ID NOs: 90, 91, 92, 120, 121 and 122;
(6) SEQ ID NOs: 33, 34, 35, 63, 64 and 65, respectively, or SEQ ID NOs: 93, 94, 95, 123, 124 and 125;
(7) SEQ ID NOs: 39, 40, 41, 69, 70 and 71, respectively, or SEQ ID NOs: 99, 100, 101, 129, 130 and 131;
(8) SEQ ID NOs: 42, 43, 44, 72, 73 and 74, respectively, or SEQ ID NOs: 102, 103, 104, 132, 133 and 134;
(9) SEQ ID NOs: 45, 46, 47, 75, 76 and 77, respectively, or SEQ ID NOs: 105, 106, 107, 135, 136 and 137; or
(10) SEQ ID NOs: 48, 49, 50, 78, 79 and 80, respectively, or SEQ ID NOs: 108, 109, 110, 138, 139 and 140, respectively.
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2 and LCDR3 with the polypeptide sequence of CLDN18.2, preferably CLDN18.2. The isolated polynucleotide according to claim 1, which specifically binds to human CLDN 18.2.
(1)配列番号１５１のポリペプチド配列を有する重鎖可変領域及び配列番号１５３のポリペプチド配列を有する軽鎖可変領域；
(2)配列番号１１のポリペプチド配列を有する重鎖可変領域及び配列番号１２のポリペプチド配列を有する軽鎖可変領域；
(3)配列番号１のポリペプチド配列を有する重鎖可変領域及び配列番号２のポリペプチド配列を有する軽鎖可変領域；
(4)配列番号３のポリペプチド配列を有する重鎖可変領域及び配列番号４のポリペプチド配列を有する軽鎖可変領域；
(5)配列番号５のポリペプチド配列を有する重鎖可変領域及び配列番号６のポリペプチド配列を有する軽鎖可変領域；
(6)配列番号７のポリペプチド配列を有する重鎖可変領域及び配列番号８のポリペプチド配列を有する軽鎖可変領域；
(7)配列番号９のポリペプチド配列を有する重鎖可変領域及び配列番号１０のポリペプチド配列を有する軽鎖可変領域；
(8)配列番号１３のポリペプチド配列を有する重鎖可変領域及び配列番号１４のポリペプチド配列を有する軽鎖可変領域；
(9)配列番号１５のポリペプチド配列を有する重鎖可変領域及び配列番号１６のポリペプチド配列を有する軽鎖可変領域；
(10)配列番号１７のポリペプチド配列を有する重鎖可変領域及び配列番号１８のポリペプチド配列を有する軽鎖可変領域；
(11)配列番号１９のポリペプチド配列を有する重鎖可変領域及び配列番号２０のポリペプチド配列を有する軽鎖可変領域；
(12)配列番号１４２のポリペプチド配列を有する重鎖可変領域及び配列番号１４４のポリペプチド配列を有する軽鎖可変領域；
(13)配列番号１４２のポリペプチド配列を有する重鎖可変領域及び配列番号１４５のポリペプチド配列を有する軽鎖可変領域；
(14)配列番号１４３のポリペプチド配列を有する重鎖可変領域及び配列番号１４４のポリペプチド配列を有する軽鎖可変領域；
(15)配列番号１４３のポリペプチド配列を有する重鎖可変領域及び配列番号１４５のポリペプチド配列を有する軽鎖可変領域；
(16)配列番号１４６のポリペプチド配列を有する重鎖可変領域及び配列番号１４８のポリペプチド配列を有する軽鎖可変領域；
(17)配列番号１４６のポリペプチド配列を有する重鎖可変領域及び配列番号１４９のポリペプチド配列を有する軽鎖可変領域；
(18)配列番号１４６のポリペプチド配列を有する重鎖可変領域及び配列番号１５０のポリペプチド配列を有する軽鎖可変領域；
(19)配列番号１４７のポリペプチド配列を有する重鎖可変領域及び配列番号１４８のポリペプチド配列を有する軽鎖可変領域；
(20)配列番号１４７のポリペプチド配列を有する重鎖可変領域及び配列番号１４９のポリペプチド配列を有する軽鎖可変領域；
(21)配列番号１４７のポリペプチド配列を有する重鎖可変領域及び配列番号１５０のポリペプチド配列を有する軽鎖可変領域；
(22)配列番号１５２のポリペプチド配列を有する重鎖可変領域及び配列番号１５３のポリペプチド配列を有する軽鎖可変領域；
(23)配列番号１５４のポリペプチド配列を有する重鎖可変領域及び配列番号１５７のポリペプチド配列を有する軽鎖可変領域；
(24)配列番号１５５のポリペプチド配列を有する重鎖可変領域及び配列番号１５７のポリペプチド配列を有する軽鎖可変領域；
(25)配列番号１５６のポリペプチド配列を有する重鎖可変領域及び配列番号１５８のポリペプチド配列を有する軽鎖可変領域；
(26)配列番号１５９のポリペプチド配列を有する重鎖可変領域及び配列番号１６３のポリペプチド配列を有する軽鎖可変領域；
(27)配列番号１５９のポリペプチド配列を有する重鎖可変領域及び配列番号１６４のポリペプチド配列を有する軽鎖可変領域；
(28)配列番号１６０のポリペプチド配列を有する重鎖可変領域及び配列番号１６３のポリペプチド配列を有する軽鎖可変領域；
(29)配列番号１６０のポリペプチド配列を有する重鎖可変領域及び配列番号１６４のポリペプチド配列を有する軽鎖可変領域；
(30)配列番号１６１のポリペプチド配列を有する重鎖可変領域及び配列番号１６５のポリペプチド配列を有する軽鎖可変領域；又は
(31)配列番号１６２のポリペプチド配列を有する重鎖可変領域及び配列番号１６５のポリペプチド配列を有する軽鎖可変領域
を含む、請求項１～３のいずれか１項記載の単離されたポリヌクレオチド。 The antigen-binding domain is
(1) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 151 and light chain variable region having the polypeptide sequence of SEQ ID NO: 153;
(2) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 11 and light chain variable region having the polypeptide sequence of SEQ ID NO: 12;
(3) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 1 and light chain variable region having the polypeptide sequence of SEQ ID NO: 2;
(4) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 3 and light chain variable region having the polypeptide sequence of SEQ ID NO: 4;
(5) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 5 and light chain variable region having the polypeptide sequence of SEQ ID NO: 6;
(6) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 7 and light chain variable region having the polypeptide sequence of SEQ ID NO: 8;
(7) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 9 and light chain variable region having the polypeptide sequence of SEQ ID NO: 10;
(8) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 13 and light chain variable region having the polypeptide sequence of SEQ ID NO: 14;
(9) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 15 and light chain variable region having the polypeptide sequence of SEQ ID NO: 16;
(10) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 17 and light chain variable region having the polypeptide sequence of SEQ ID NO: 18;
(11) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 19 and light chain variable region having the polypeptide sequence of SEQ ID NO: 20;
(12) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 142 and light chain variable region having the polypeptide sequence of SEQ ID NO: 144;
(13) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 142 and light chain variable region having the polypeptide sequence of SEQ ID NO: 145;
(14) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and light chain variable region having the polypeptide sequence of SEQ ID NO: 144;
(15) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and light chain variable region having the polypeptide sequence of SEQ ID NO: 145;
(16) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and light chain variable region having the polypeptide sequence of SEQ ID NO: 148;
(17) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and light chain variable region having the polypeptide sequence of SEQ ID NO: 149;
(18) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 146 and light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(19) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 147 and light chain variable region with the polypeptide sequence of SEQ ID NO: 148;
(20) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 147 and light chain variable region having the polypeptide sequence of SEQ ID NO: 149;
(21) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 147 and light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(22) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 152 and light chain variable region having the polypeptide sequence of SEQ ID NO: 153;
(23) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 154 and light chain variable region having the polypeptide sequence of SEQ ID NO: 157;
(24) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 155 and light chain variable region having the polypeptide sequence of SEQ ID NO: 157;
(25) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 156 and light chain variable region having the polypeptide sequence of SEQ ID NO: 158;
(26) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 159 and light chain variable region having the polypeptide sequence of SEQ ID NO: 163;
(27) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 159 and light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(28) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 160 and light chain variable region having the polypeptide sequence of SEQ ID NO: 163;
(29) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 160 and light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(30) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 161 and light chain variable region having the polypeptide sequence of SEQ ID NO: 165; or
(31) The isolated poly according to any one of claims 1 to 3, comprising a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 162 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 165. nucleotide.
場合により、前記癌が、肺癌、胃癌、食道癌、胆管癌(bile duct cancer)、胆管癌(cholangiocarcinoma)、結腸癌、肝細胞癌、腎細胞癌、膀胱尿路上皮癌、転移性黒色腫、乳癌、卵巣癌、子宮頸癌、頭頸部癌、膵癌、神経膠腫、神経膠芽腫、及び他の固形腫瘍、並びに非ホジキンリンパ腫(NHL)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、多発性骨髄腫(MM)、急性骨髄性白血病(AML)及び他の液性腫瘍から選択される、
前記医薬組成物。 A pharmaceutical composition comprising the host cell according to claim 10 for treating a cancer or an inflammatory disease.
In some cases, the cancer may be lung cancer, gastric cancer, esophageal cancer, bile duct cancer, cholangiocarcinoma, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urinary tract epithelial cancer, metastatic melanoma, Breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioma, and other solid tumors, as well as non-hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytes Selected from Sexual Leukemia (CLL), Chronic Myeloid Leukemia (CML), Multiple Myeloma (MM), Acute Myeloid Leukemia (AML) and Other Luminous Tumors,
The pharmaceutical composition.
場合により、前記癌が、肺癌、胃癌、食道癌、胆管癌(bile duct cancer)、胆管癌(cholangiocarcinoma)、結腸癌、肝細胞癌、腎細胞癌、膀胱尿路上皮癌、転移性黒色腫、乳癌、卵巣癌、子宮頸癌、頭頸部癌、膵癌、神経膠腫、神経膠芽腫、及び他の固形腫瘍、並びに非ホジキンリンパ腫(NHL)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、多発性骨髄腫(MM)、急性骨髄性白血病(AML)及び他の液性腫瘍から選択される、
前記医薬組成物。 Claims include agents that increase the efficacy of cells expressing CAR, agents that improve one or more side effects associated with administration of cells expressing CAR molecules, or agents that treat diseases associated with claudin 18.2. Item 5. A pharmaceutical composition for treating a cancer or an inflammatory disease for use in combination with the host cell according to Item 10.
In some cases, the cancer may be lung cancer, gastric cancer, esophageal cancer, bile duct cancer, cholangiocarcinoma, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urinary tract epithelial cancer, metastatic melanoma, Breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioma, and other solid tumors, as well as non-hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytes Selected from Sexual Leukemia (CLL), Chronic Myeloid Leukemia (CML), Multiple Myeloma (MM), Acute Myeloid Leukemia (AML) and Other Luminous Tumors,
The pharmaceutical composition.
場合により、前記癌が、肺癌、胃癌、食道癌、胆管癌(bile duct cancer)、胆管癌(cholangiocarcinoma)、結腸癌、肝細胞癌、腎細胞癌、膀胱尿路上皮癌、転移性黒色腫、乳癌、卵巣癌、子宮頸癌、頭頸部癌、膵癌、神経膠腫、神経膠芽腫、及び他の固形腫瘍、並びに非ホジキンリンパ腫(NHL)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、多発性骨髄腫(MM)、急性骨髄性白血病(AML)及び他の液性腫瘍から選択される、
前記医薬組成物。 10. A host cell according to claim 10, a drug that increases the efficacy of cells expressing CAR, a drug that improves one or more side effects associated with administration of cells expressing CAR molecules, or a claudin 18.2. A pharmaceutical composition for treating a cancer or inflammatory disease, comprising a drug for treating the disease.
In some cases, the cancer may be lung cancer, gastric cancer, esophageal cancer, bile duct cancer, cholangiocarcinoma, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urinary tract epithelial cancer, metastatic melanoma, Breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioma, and other solid tumors, as well as non-hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytes Selected from Sexual Leukemia (CLL), Chronic Myeloid Leukemia (CML), Multiple Myeloma (MM), Acute Myeloid Leukemia (AML) and Other Luminous Tumors,
The pharmaceutical composition.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962825955P | 2019-03-29 | 2019-03-29 | |
| US62/825,955 | 2019-03-29 | ||
| US201962859843P | 2019-06-11 | 2019-06-11 | |
| US62/859,843 | 2019-06-11 | ||
| US201962896758P | 2019-09-06 | 2019-09-06 | |
| US62/896,758 | 2019-09-06 | ||
| PCT/US2020/024432 WO2020205331A1 (en) | 2019-03-29 | 2020-03-24 | Humanized anti-claudin 18.2 chimeric antigen receptors and uses thereof |
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| Publication Number | Publication Date |
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| JP2022527173A JP2022527173A (en) | 2022-05-31 |
| JPWO2020205331A5 true JPWO2020205331A5 (en) | 2022-06-29 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2021557602A Pending JP2022527173A (en) | 2019-03-29 | 2020-03-24 | Humanized anti-claudin 18.2 chimeric antigen receptor and its use |
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| Country | Link |
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| US (1) | US20220184126A1 (en) |
| EP (1) | EP3947468A1 (en) |
| JP (1) | JP2022527173A (en) |
| KR (1) | KR20210144792A (en) |
| CN (1) | CN113784980B (en) |
| AU (1) | AU2020253792A1 (en) |
| BR (1) | BR112021016673A2 (en) |
| CA (1) | CA3132201A1 (en) |
| IL (1) | IL286696A (en) |
| MX (1) | MX2021011887A (en) |
| SG (1) | SG11202109052YA (en) |
| WO (1) | WO2020205331A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113645996B (en) | 2019-02-01 | 2024-04-02 | 新石生物制药有限公司 | Anti-claudin 18 antibodies and methods of use thereof |
| WO2022122709A1 (en) * | 2020-12-07 | 2022-06-16 | Sotio Biotech A.S. | Antibody-drug conjugates based on humanized cldn18.2 antibodies |
| CN113354739B (en) * | 2021-01-11 | 2022-08-23 | 上海莱馥医疗科技有限公司 | Chimeric antigen receptor for targeted expression of Claudin18.2 cell and application thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013174404A1 (en) * | 2012-05-23 | 2013-11-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
| RU2678127C2 (en) * | 2012-11-13 | 2019-01-23 | Бионтех Аг | Agents for treatment of claudin expressing cancer diseases |
| WO2014075697A1 (en) * | 2012-11-13 | 2014-05-22 | Biontech Ag | Agents for treatment of claudin expressing cancer diseases |
| WO2016165762A1 (en) * | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
| WO2016180468A1 (en) * | 2015-05-11 | 2016-11-17 | Biontech Cell & Gene Therapies Gmbh | Claudin-18.2-specific immunoreceptors and t cell epitopes |
| SG11201900171QA (en) * | 2016-07-08 | 2019-02-27 | Carsgen Therapeutics Co Ltd | Antibody for anti-claudin 18a2 and use thereof |
| WO2018054484A1 (en) * | 2016-09-23 | 2018-03-29 | Biontech Ag | Bispecific trivalent antibodies binding to claudin 6 or claudin18.2 and cd3 for treatment of claudin expressing cancer diseases |
| WO2019173420A1 (en) * | 2018-03-08 | 2019-09-12 | Phanes Therapeutics, Inc. | Anti-claudin 18.2 antibodies and uses thereof |
-
2020
- 2020-03-24 KR KR1020217034225A patent/KR20210144792A/en unknown
- 2020-03-24 JP JP2021557602A patent/JP2022527173A/en active Pending
- 2020-03-24 EP EP20784482.0A patent/EP3947468A1/en not_active Withdrawn
- 2020-03-24 US US17/593,066 patent/US20220184126A1/en active Pending
- 2020-03-24 BR BR112021016673-4A patent/BR112021016673A2/en not_active Application Discontinuation
- 2020-03-24 AU AU2020253792A patent/AU2020253792A1/en not_active Abandoned
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