JPWO2021226321A5 - - Google Patents
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- JPWO2021226321A5 JPWO2021226321A5 JP2022567223A JP2022567223A JPWO2021226321A5 JP WO2021226321 A5 JPWO2021226321 A5 JP WO2021226321A5 JP 2022567223 A JP2022567223 A JP 2022567223A JP 2022567223 A JP2022567223 A JP 2022567223A JP WO2021226321 A5 JPWO2021226321 A5 JP WO2021226321A5
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- 229920001184 polypeptide Polymers 0.000 claims description 512
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 512
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 512
- 239000000427 antigen Substances 0.000 claims description 99
- 102000036639 antigens Human genes 0.000 claims description 99
- 108091007433 antigens Proteins 0.000 claims description 99
- 239000012634 fragment Substances 0.000 claims description 66
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 30
- 210000004027 cell Anatomy 0.000 claims description 27
- 108091033319 polynucleotide Proteins 0.000 claims description 23
- 102000040430 polynucleotide Human genes 0.000 claims description 23
- 239000002157 polynucleotide Substances 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 12
- 150000007523 nucleic acids Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 10
- 108020004707 nucleic acids Proteins 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 claims description 7
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 6
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
- 102100032530 Glypican-3 Human genes 0.000 claims description 6
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 6
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 6
- 210000000822 natural killer cell Anatomy 0.000 claims description 6
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims description 4
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 230000004540 complement-dependent cytotoxicity Effects 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010027480 Metastatic malignant melanoma Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 claims description 3
- 201000001528 bladder urothelial carcinoma Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 3
- 230000004068 intracellular signaling Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000021039 metastatic melanoma Diseases 0.000 claims description 3
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 230000006037 cell lysis Effects 0.000 claims description 2
- 239000012636 effector Substances 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 230000007115 recruitment Effects 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002463 transducing effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 102000048373 human GPC3 Human genes 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
Description
前述の概要、並びに本出願の好ましい実施形態の以下の詳細な説明は、添付の図面と併せて読むことによりより深く理解されよう。しかし、本出願は、図面に示した正確な実施形態に限定されるものではないことを理解されたい。
本発明はまた、以下に関する。
［項目１］
(1)それぞれ配列番号87、88、89、90、91及び92、
(2)それぞれ配列番号108、109、110、111、112及び113、
(3)それぞれ配列番号17、18、19、20、21及び22、
(4)それぞれ配列番号31、32、33、34、35及び36、
(5)それぞれ配列番号45、46、47、48、49及び50、
(6)それぞれ配列番号59、60、61、62、63及び64、又は
(7)それぞれ配列番号73、74、75、76、77及び78、
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を含む、単離されたモノクローナル抗体又はその抗原結合性断片であって、抗体又はその抗原結合性断片がGPC3、好ましくはヒトGPC3に特異的に結合する、単離されたモノクローナル抗体又はその抗原結合性断片。
［項目２］
(1)それぞれ配列番号93、94、95、96、97及び98、
(2)それぞれ配列番号114、115、116、117、118及び119、
(3)それぞれ配列番号23、24、25、26、27及び28、
(4)それぞれ配列番号37、38、39、40、41及び42、
(5)それぞれ配列番号51、52、53、54、55及び56、
(6)それぞれ配列番号65、66、67、68、69及び70、又は
(7)それぞれ配列番号79、80、81、82、83及び84、
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を含む、単離されたモノクローナル抗体又はその抗原結合性断片であって、該抗体又はその抗原結合性断片がGPC3、好ましくはヒトGPC3に特異的に結合する、単離されたモノクローナル抗体又はその抗原結合性断片。
［項目３］
(1)それぞれ配列番号3、4、5、6、7及び8
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を含む、単離されたモノクローナル抗体又はその抗原結合性断片であって、抗体又はその抗原結合性断片がTIP-1、好ましくはヒトTIP-1に特異的に結合する、単離されたモノクローナル抗体又はその抗原結合性断片。
［項目４］
(1)それぞれ配列番号9、10、11、12、13及び14
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を含む、単離されたモノクローナル抗体又はその抗原結合性断片であって、抗体又はその抗原結合性断片がTIP-1、好ましくはヒトTIP-1に特異的に結合する、単離されたモノクローナル抗体又はその抗原結合性断片。
［項目５］
配列番号85、106、15、29、43、57、71若しくは1と少なくとも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86、107、16、30、44、58、72若しくは2と少なくとも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、項目1～4のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目６］
a.配列番号85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86のポリペプチド配列を有する軽鎖可変領域、
b.配列番号106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107のポリペプチド配列を有する軽鎖可変領域、
c.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、
d.配列番号29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30のポリペプチド配列を有する軽鎖可変領域、
e.配列番号43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44のポリペプチド配列を有する軽鎖可変領域、
f.配列番号57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58のポリペプチド配列を有する軽鎖可変領域、
g.配列番号71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72のポリペプチド配列を有する軽鎖可変領域、又は
h.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
を含む、項目1～5のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目７］
抗体又はその抗原結合性断片がキメラであり、及び/又はヒトであるか若しくはヒト化される、項目1～6のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目８］
ヒト化モノクローナル抗体又はその抗原結合性断片が、配列番号99～102、120～123、126～132、139～140、143～149、153～156、160～163、183～197、若しくは202～205のいずれか1つと少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、又は少なくとも99%同一であるポリペプチド配列を有する重鎖可変領域、或いは配列番号103～105、124～125、133～138、141～142、150～152、157～159、164～166、若しくは198～201のいずれか1つと少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、又は少なくとも99%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、項目7に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目９］
ヒト化モノクローナル抗体又はその抗原結合性断片が、
(1)配列番号99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103のポリペプチド配列を有する軽鎖可変領域、
(2)配列番号99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104のポリペプチド配列を有する軽鎖可変領域、
(3)配列番号100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103のポリペプチド配列を有する軽鎖可変領域、
(4)配列番号100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104のポリペプチド配列を有する軽鎖可変領域、
(5)配列番号101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103のポリペプチド配列を有する軽鎖可変領域、
(6)配列番号101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104のポリペプチド配列を有する軽鎖可変領域、
(7)配列番号102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105のポリペプチド配列を有する軽鎖可変領域、
(8)配列番号120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124のポリペプチド配列を有する軽鎖可変領域、
(9)配列番号120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125のポリペプチド配列を有する軽鎖可変領域、
(10)配列番号121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124のポリペプチド配列を有する軽鎖可変領域、
(11)配列番号121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125のポリペプチド配列を有する軽鎖可変領域、
(12)配列番号122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124のポリペプチド配列を有する軽鎖可変領域、
(13)配列番号122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125のポリペプチド配列を有する軽鎖可変領域、
(14)配列番号123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124のポリペプチド配列を有する軽鎖可変領域、
(15)配列番号139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141のポリペプチド配列を有する軽鎖可変領域、
(16)配列番号139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142のポリペプチド配列を有する軽鎖可変領域、
(17)配列番号140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141のポリペプチド配列を有する軽鎖可変領域、
(18)配列番号140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142のポリペプチド配列を有する軽鎖可変領域、
(19)配列番号153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、
(20)配列番号153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、
(21)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、
(22)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158のポリペプチド配列を有する軽鎖可変領域、
(23)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150のポリペプチド配列を有する軽鎖可変領域、
(24)配列番号144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、
(25)配列番号145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、
(26)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151のポリペプチド配列を有する軽鎖可変領域、
(27)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152のポリペプチド配列を有する軽鎖可変領域、
(28)配列番号148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151のポリペプチド配列を有する軽鎖可変領域、
(29)配列番号148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152のポリペプチド配列を有する軽鎖可変領域、
(30)配列番号149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151のポリペプチド配列を有する軽鎖可変領域、
(31)配列番号149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152のポリペプチド配列を有する軽鎖可変領域、
(32)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、
(33)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164のポリペプチド配列を有する軽鎖可変領域、
(34)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164のポリペプチド配列を有する軽鎖可変領域、
(35)配列番号163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、
(36)配列番号205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、
(37)配列番号202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、
(38)配列番号203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、
(39)配列番号204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、
(40)配列番号100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198のポリペプチド配列を有する軽鎖可変領域、
(41)配列番号183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104のポリペプチド配列を有する軽鎖可変領域、
(42)配列番号183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198のポリペプチド配列を有する軽鎖可変領域、
(43)配列番号185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104のポリペプチド配列を有する軽鎖可変領域、
(44)配列番号186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104のポリペプチド配列を有する軽鎖可変領域、
(45)配列番号185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199のポリペプチド配列を有する軽鎖可変領域、
(46)配列番号186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199のポリペプチド配列を有する軽鎖可変領域、
(47)配列番号189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104のポリペプチド配列を有する軽鎖可変領域、
(48)配列番号188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103のポリペプチド配列を有する軽鎖可変領域、
(49)配列番号190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104のポリペプチド配列を有する軽鎖可変領域、
(50)配列番号191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104のポリペプチド配列を有する軽鎖可変領域、
(51)配列番号192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104のポリペプチド配列を有する軽鎖可変領域、
(52)配列番号193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104のポリペプチド配列を有する軽鎖可変領域、
(53)配列番号194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104のポリペプチド配列を有する軽鎖可変領域、
(54)配列番号189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199のポリペプチド配列を有する軽鎖可変領域、
(55)配列番号190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199のポリペプチド配列を有する軽鎖可変領域、
(56)配列番号191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199のポリペプチド配列を有する軽鎖可変領域、
(57)配列番号192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199のポリペプチド配列を有する軽鎖可変領域、
(58)配列番号193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199のポリペプチド配列を有する軽鎖可変領域、
(59)配列番号194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199のポリペプチド配列を有する軽鎖可変領域、
(60)配列番号189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200のポリペプチド配列を有する軽鎖可変領域、
(61)配列番号190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200のポリペプチド配列を有する軽鎖可変領域、
(62)配列番号191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200のポリペプチド配列を有する軽鎖可変領域、
(63)配列番号192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200のポリペプチド配列を有する軽鎖可変領域、
(64)配列番号193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200のポリペプチド配列を有する軽鎖可変領域、
(65)配列番号186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200のポリペプチド配列を有する軽鎖可変領域、
(66)配列番号195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104のポリペプチド配列を有する軽鎖可変領域、
(67)配列番号195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199のポリペプチド配列を有する軽鎖可変領域、
(68)配列番号195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200のポリペプチド配列を有する軽鎖可変領域、
(69)配列番号194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200のポリペプチド配列を有する軽鎖可変領域、
(70)配列番号185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200のポリペプチド配列を有する軽鎖可変領域、
(71)配列番号187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104のポリペプチド配列を有する軽鎖可変領域、
(72)配列番号187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200のポリペプチド配列を有する軽鎖可変領域、
(73)配列番号187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199のポリペプチド配列を有する軽鎖可変領域、
(74)配列番号196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201のポリペプチド配列を有する軽鎖可変領域、又は
(75)配列番号197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201のポリペプチド配列を有する軽鎖可変領域
を含む、項目8に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目１０］
抗体又はその抗原結合性断片が、抗体依存性細胞傷害性(ADCC)、抗体依存性細胞食作用(ADCP)、及び/若しくは補体依存性細胞傷害性(CDC)を介して、エフェクター媒介性腫瘍細胞溶解を誘導することができ、及び/又は結合体化薬剤の動員を媒介することができ、並びに/又は殺がん作用を有する別のmAb若しくはその抗原結合性断片と二重特異性抗体を形成することができる、項目1～9のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片。
［項目１１］
項目1～10のいずれか一項に記載のモノクローナル抗体又はその抗原結合性断片を含む、二重特異性抗体又はその抗原結合性断片。
［項目１２］
項目1～10のいずれか一項に記載のモノクローナル抗体又はその抗原結合性断片をコードする単離された核酸。
［項目１３］
項目11に記載の二重特異性抗体又はその抗原結合性断片をコードする単離された核酸。
［項目１４］
項目12又は13に記載の単離された核酸を含むベクター。
［項目１５］
項目14に記載のベクターを含む宿主細胞。
［項目１６］
項目1～10のいずれか一項に記載の単離されたモノクローナル抗体若しくはその抗原結合性断片、又は項目11に記載の二重特異性抗体若しくはその抗原結合性断片、及び薬学的に許容される担体を含む医薬組成物。
［項目１７］
項目16に記載の医薬組成物を対象に投与することを含む、それを必要とする対象における、がん細胞表面上のTAAを標的化し、及び/又はがんを処置し、及び/又は炎症性疾患を処置する方法であって、必要に応じて、がんは、肺がん、胃がん、食道がん、胆管がん、胆管細胞癌、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なる群から選択される、方法。
［項目１８］
項目1～10のいずれか一項に記載のモノクローナル抗体若しくはその抗原結合性断片、又は項目11に記載の二重特異性抗体若しくはその抗原結合性断片を産生する方法であって、モノクローナル抗体若しくはその抗原結合性断片、又は二重特異性抗体若しくはその抗原結合性断片をコードする核酸を含む細胞を、モノクローナル抗体若しくはその抗原結合性断片、又は二重特異性抗体若しくはその抗原結合性断片を産生する条件下で培養し、モノクローナル抗体若しくはその抗原結合性断片、又は二重特異性抗体若しくはその抗原結合性断片を細胞又は培養物から回収することを含む方法。
［項目１９］
項目1～10のいずれか一項に記載のモノクローナル抗体若しくは抗原結合性断片、又は項目11に記載の二重特異性抗体若しくはその抗原結合性断片を含む医薬組成物を産生する方法であって、モノクローナル抗体若しくはその抗原結合性断片、又は二重特異性抗体若しくはその抗原結合性断片を薬学的に許容される担体と組み合わせて医薬組成物を得ることを含む方法。
［項目２０］
対象におけるTAAのレベルを決定する方法であって、
a.対象から試料を得ること、
b.試料を、項目1～10のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片と接触させること、及び
c.対象におけるTAAのレベルを決定すること
を含む方法。
［項目２１］
試料が、組織試料又は血液試料であり、必要に応じて、組織試料ががん組織試料である、項目20に記載の方法。
［項目２２］
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)GPC3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。
［項目２３］
抗原結合性ドメインが、
(1)それぞれ配列番号87、88、89、90、91及び92、
(2)それぞれ配列番号108、109、110、111、112及び113、
(3)それぞれ配列番号17、18、19、20、21及び22、
(4)それぞれ配列番号31、32、33、34、35及び36、
(5)それぞれ配列番号45、46、47、48、49及び50、
(6)それぞれ配列番号59、60、61、62、63及び64、又は
(7)それぞれ配列番号73、74、75、76、77及び78
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、抗原結合性ドメインがGPC3、好ましくはヒトGPC3に特異的に結合する、項目22に記載の単離されたポリヌクレオチド。
［項目２４］
抗原結合性ドメインが、
(1)それぞれ配列番号93、94、95、96、97及び98、
(2)それぞれ配列番号114、115、116、117、118及び119、
(3)それぞれ配列番号23、24、25、26、27及び28、
(4)それぞれ配列番号37、38、39、40、41及び42、
(5)それぞれ配列番号51、52、53、54、55及び56、又は
(6)それぞれ配列番号65、66、67、68、69及び70、
(7)それぞれ配列番号79、80、81、82、83及び84
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、抗原結合性ドメインがGPC3、好ましくはヒトGPC3に特異的に結合する、項目22に記載の単離されたポリヌクレオチド。
［項目２５］
抗原結合性ドメインが配列番号85、106、15、29、43、57若しくは71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86、107、16、30、44、58若しくは72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、項目22～24のいずれか一項に記載の単離されたポリヌクレオチド。
［項目２６］
抗原結合性ドメインが、
a.配列番号85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86のポリペプチド配列を有する軽鎖可変領域、
b.配列番号106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107のポリペプチド配列を有する軽鎖可変領域、
c.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、
d.配列番号29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30のポリペプチド配列を有する軽鎖可変領域、
e.配列番号43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44のポリペプチド配列を有する軽鎖可変領域、
f.配列番号57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58のポリペプチド配列を有する軽鎖可変領域、又は
g.配列番号71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72のポリペプチド配列を有する軽鎖可変領域
を含む、項目25に記載の単離されたポリヌクレオチド。
［項目２７］
抗原結合性ドメインがヒト化され、配列番号99～102、120～123、126～132、139～140、143～149、153～156、160～163、183～197、若しくは202～205と少なくとも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103～105、124～125、133～138、141～142、150～152、157～159、164～166、若しくは198～201と少なくとも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、項目22～24のいずれか一項に記載の単離されたポリヌクレオチド。
［項目２８］
抗原結合性ドメインがヒト化され、
(1)配列番号99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103のポリペプチド配列を有する軽鎖可変領域、
(2)配列番号99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104のポリペプチド配列を有する軽鎖可変領域、
(3)配列番号100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103のポリペプチド配列を有する軽鎖可変領域、
(4)配列番号100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104のポリペプチド配列を有する軽鎖可変領域、
(5)配列番号101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103のポリペプチド配列を有する軽鎖可変領域、
(6)配列番号101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104のポリペプチド配列を有する軽鎖可変領域、
(7)配列番号102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105のポリペプチド配列を有する軽鎖可変領域、
(8)配列番号120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124のポリペプチド配列を有する軽鎖可変領域、
(9)配列番号120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125のポリペプチド配列を有する軽鎖可変領域、
(10)配列番号121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124のポリペプチド配列を有する軽鎖可変領域、
(11)配列番号121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125のポリペプチド配列を有する軽鎖可変領域、
(12)配列番号122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124のポリペプチド配列を有する軽鎖可変領域、
(13)配列番号122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125のポリペプチド配列を有する軽鎖可変領域、
(14)配列番号123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124のポリペプチド配列を有する軽鎖可変領域、
(15)配列番号139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141のポリペプチド配列を有する軽鎖可変領域、
(16)配列番号139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142のポリペプチド配列を有する軽鎖可変領域、
(17)配列番号140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141のポリペプチド配列を有する軽鎖可変領域、
(18)配列番号140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142のポリペプチド配列を有する軽鎖可変領域、
(19)配列番号153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、
(20)配列番号153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、
(21)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、
(22)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158のポリペプチド配列を有する軽鎖可変領域、
(23)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150のポリペプチド配列を有する軽鎖可変領域、
(24)配列番号144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、
(25)配列番号145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、
(26)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151のポリペプチド配列を有する軽鎖可変領域、
(27)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152のポリペプチド配列を有する軽鎖可変領域、
(28)配列番号148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151のポリペプチド配列を有する軽鎖可変領域、
(29)配列番号148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152のポリペプチド配列を有する軽鎖可変領域、
(30)配列番号149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151のポリペプチド配列を有する軽鎖可変領域、
(31)配列番号149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152のポリペプチド配列を有する軽鎖可変領域、
(32)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、
(33)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164のポリペプチド配列を有する軽鎖可変領域、
(34)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164のポリペプチド配列を有する軽鎖可変領域、
(35)配列番号163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、
(36)配列番号205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、
(37)配列番号202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、
(38)配列番号203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、
(39)配列番号204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、
(40)配列番号100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198のポリペプチド配列を有する軽鎖可変領域、
(41)配列番号183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104のポリペプチド配列を有する軽鎖可変領域、
(42)配列番号183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198のポリペプチド配列を有する軽鎖可変領域、
(43)配列番号185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104のポリペプチド配列を有する軽鎖可変領域、
(44)配列番号186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104のポリペプチド配列を有する軽鎖可変領域、
(45)配列番号185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199のポリペプチド配列を有する軽鎖可変領域、
(46)配列番号186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199のポリペプチド配列を有する軽鎖可変領域、
(47)配列番号189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104のポリペプチド配列を有する軽鎖可変領域、
(48)配列番号188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103のポリペプチド配列を有する軽鎖可変領域、
(49)配列番号190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104のポリペプチド配列を有する軽鎖可変領域、
(50)配列番号191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104のポリペプチド配列を有する軽鎖可変領域、
(51)配列番号192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104のポリペプチド配列を有する軽鎖可変領域、
(52)配列番号193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104のポリペプチド配列を有する軽鎖可変領域、
(53)配列番号194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104のポリペプチド配列を有する軽鎖可変領域、
(54)配列番号189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199のポリペプチド配列を有する軽鎖可変領域、
(55)配列番号190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199のポリペプチド配列を有する軽鎖可変領域、
(56)配列番号191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199のポリペプチド配列を有する軽鎖可変領域、
(57)配列番号192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199のポリペプチド配列を有する軽鎖可変領域、
(58)配列番号193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199のポリペプチド配列を有する軽鎖可変領域、
(59)配列番号194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199のポリペプチド配列を有する軽鎖可変領域、
(60)配列番号189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200のポリペプチド配列を有する軽鎖可変領域、
(61)配列番号190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200のポリペプチド配列を有する軽鎖可変領域、
(62)配列番号191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200のポリペプチド配列を有する軽鎖可変領域、
(63)配列番号192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200のポリペプチド配列を有する軽鎖可変領域、
(64)配列番号193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200のポリペプチド配列を有する軽鎖可変領域、
(65)配列番号186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200のポリペプチド配列を有する軽鎖可変領域、
(66)配列番号195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104のポリペプチド配列を有する軽鎖可変領域、
(67)配列番号195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199のポリペプチド配列を有する軽鎖可変領域、
(68)配列番号195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200のポリペプチド配列を有する軽鎖可変領域、
(69)配列番号194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200のポリペプチド配列を有する軽鎖可変領域、
(70)配列番号185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200のポリペプチド配列を有する軽鎖可変領域、
(71)配列番号187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104のポリペプチド配列を有する軽鎖可変領域、
(72)配列番号187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200のポリペプチド配列を有する軽鎖可変領域、
(73)配列番号187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199のポリペプチド配列を有する軽鎖可変領域、
(74)配列番号196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201のポリペプチド配列を有する軽鎖可変領域、又は
(75)配列番号197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201のポリペプチド配列を有する軽鎖可変領域
を含む、項目27に記載の単離されたポリヌクレオチド。
［項目２９］
抗原結合性ドメインがGPC3、好ましくはヒトGPC3に特異的に結合する単鎖可変断片(scFv)である、項目22～28のいずれか一項に記載の単離されたポリヌクレオチド。
［項目３０］
単鎖可変断片(scFv)がヒト化される、項目29に記載の単離されたポリヌクレオチド。
［項目３１］
単鎖可変断片(scFv)が配列番号167～182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、項目29又は30に記載の単離されたポリヌクレオチド。
［項目３２］
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、項目22～31のいずれか一項に記載の単離されたポリヌクレオチド。
［項目３３］
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、項目22～32のいずれか一項に記載の単離されたポリヌクレオチド。
［項目３４］
項目22～33のいずれか一項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)。
［項目３５］
項目22～33のいずれか一項に記載の単離されたポリヌクレオチドを含むベクター。
［項目３６］
項目35に記載のベクターを含む宿主細胞。
［項目３７］
宿主細胞がT細胞、好ましくはヒトT細胞である、項目36に記載の宿主細胞。
［項目３８］
宿主細胞がNK細胞、好ましくはヒトNK細胞である、項目36に記載の宿主細胞。
［項目３９］
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、項目35に記載のベクターをT細胞に形質導入することを含む方法。
［項目４０］
キメラ抗原受容体(CAR)-T細胞を産生する方法であって、項目22～33のいずれか一項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。
［項目４１］
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、項目35に記載のベクターをNK細胞に形質導入することを含む方法。
［項目４２］
キメラ抗原受容体(CAR)-NK細胞を産生する方法であって、項目22～33のいずれか一項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。
［項目４３］
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、項目22～33のいずれか一項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。
［項目４４］
項目36～38のいずれか一項に記載の宿主細胞を、それを必要とする対象に投与することを含む、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、必要に応じて、がんは、肺がん、胃がん、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、方法。
［項目４５］
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、項目44に記載の方法。
［項目４６］
それを必要とする対象にCAR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、項目44に記載の方法。
［項目４７］
それを必要とする対象にGPC3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、項目44に記載の方法。
The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It is to be understood, however, that the present application is not limited to the precise embodiments shown in the drawings.
The present invention also relates to the following:
[Item 1]
(1) SEQ ID NOs: 87, 88, 89, 90, 91 and 92, respectively;
(2) SEQ ID NOs: 108, 109, 110, 111, 112 and 113, respectively;
(3) SEQ ID NOs: 17, 18, 19, 20, 21 and 22, respectively;
(4) SEQ ID NOs: 31, 32, 33, 34, 35 and 36, respectively;
(5) SEQ ID NOs: 45, 46, 47, 48, 49 and 50, respectively;
(6) SEQ ID NOs: 59, 60, 61, 62, 63, and 64, respectively; or
(7) SEQ ID NOs: 73, 74, 75, 76, 77 and 78, respectively;
An isolated monoclonal antibody or an antigen-binding fragment thereof, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the polypeptide sequence of:
[Item 2]
(1) SEQ ID NOs: 93, 94, 95, 96, 97 and 98, respectively;
(2) SEQ ID NOs: 114, 115, 116, 117, 118 and 119, respectively;
(3) SEQ ID NOs: 23, 24, 25, 26, 27 and 28, respectively;
(4) SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively;
(5) SEQ ID NOs: 51, 52, 53, 54, 55 and 56, respectively;
(6) SEQ ID NOs: 65, 66, 67, 68, 69, and 70, respectively; or
(7) SEQ ID NOs: 79, 80, 81, 82, 83 and 84, respectively;
An isolated monoclonal antibody or an antigen-binding fragment thereof, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the polypeptide sequence of:
[Item 3]
(1) SEQ ID NOs: 3, 4, 5, 6, 7 and 8, respectively
An isolated monoclonal antibody or antigen-binding fragment thereof, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the polypeptide sequence of:
[Item 4]
(1) SEQ ID NOs: 9, 10, 11, 12, 13 and 14, respectively
An isolated monoclonal antibody or antigen-binding fragment thereof, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the polypeptide sequence of:
[Item 5]
5. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 4, comprising a heavy chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 85, 106, 15, 29, 43, 57, 71 or 1, or a light chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 86, 107, 16, 30, 44, 58, 72 or 2.
[Item 6]
a. a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 85 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 86;
b. a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 106 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 107;
c. 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;
d. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:29 and a light chain variable region having the polypeptide sequence of SEQ ID NO:30;
e. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:43 and a light chain variable region having the polypeptide sequence of SEQ ID NO:44;
f. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:57 and a light chain variable region having the polypeptide sequence of SEQ ID NO:58;
g. a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 71 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 72; or
h. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:1 and a light chain variable region having the polypeptide sequence of SEQ ID NO:2
6. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 5, comprising:
[Item 7]
7. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 6, wherein the antibody or antigen-binding fragment thereof is chimeric and/or human or humanized.
[Item 8]
8. The isolated monoclonal antibody or antigen-binding fragment thereof according to item 7, wherein the humanized monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region having a polypeptide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 99-102, 120-123, 126-132, 139-140, 143-149, 153-156, 160-163, 183-197, or 202-205, or a light chain variable region having a polypeptide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 103-105, 124-125, 133-138, 141-142, 150-152, 157-159, 164-166, or 198-201.
[Item 9]
The humanized monoclonal antibody or antigen-binding fragment thereof,
(1) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(2) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(3) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(4) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(5) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(6) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(7) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 102 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 105;
(8) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(9) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(10) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(11) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(12) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(13) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(14) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 123 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(15) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(16) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(17) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(18) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(19) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 157;
(20) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 158;
(21) 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;
(22) 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: 158;
(23) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(24) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 144 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(25) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 145 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(26) 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: 151;
(27) 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: 152;
(28) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(29) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(30) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(31) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(32) 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;
(33) 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: 164;
(34) 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: 164;
(35) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 163 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(36) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 205 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(37) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 202 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(38) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 203 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(39) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 204 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(40) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(41) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(42) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(43) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(44) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(45) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(46) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(47) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(48) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 188 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(49) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(50) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(51) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(52) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(53) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(54) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(55) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(56) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(57) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(58) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(59) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(60) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(61) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(62) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(63) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(64) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(65) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(66) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(67) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(68) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(69) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(70) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(71) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(72) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(73) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(74) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 196 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201; or
(75) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 197 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201.
9. The isolated monoclonal antibody or antigen-binding fragment thereof according to item 8, comprising:
[Item 10]
10. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 9, wherein the antibody or antigen-binding fragment thereof is capable of inducing effector-mediated tumor cell lysis via antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC), and/or mediating the recruitment of conjugated drugs, and/or forming a bispecific antibody with another mAb or antigen-binding fragment thereof that has cancer-killing activity.
[Item 11]
11. A bispecific antibody or an antigen-binding fragment thereof comprising the monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10.
[Item 12]
11. An isolated nucleic acid encoding the monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10.
[Item 13]
12. An isolated nucleic acid encoding the bispecific antibody or antigen-binding fragment thereof according to item 11.
[Item 14]
14. A vector comprising the isolated nucleic acid according to item 12 or 13.
[Item 15]
A host cell comprising the vector according to item 14.
[Item 16]
A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10, or the bispecific antibody or antigen-binding fragment thereof according to item 11, and a pharma- ceutically acceptable carrier.
[Item 17]
17. A method for targeting a TAA on a cancer cell surface and/or treating cancer and/or treating an inflammatory disease in a subject in need thereof, comprising administering to the subject the pharmaceutical composition according to item 16, wherein, optionally, the cancer is selected from the group consisting of lung cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, cholangiocarcinoma, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urothelial carcinoma, metastatic melanoma, breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioblastoma and other solid tumors, as well as non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), acute myelogenous leukemia (AML) and other liquid tumors.
[Item 18]
A method for producing the monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10, or the bispecific antibody or antigen-binding fragment thereof according to item 11, comprising culturing a cell containing a nucleic acid encoding the monoclonal antibody or antigen-binding fragment thereof, or the bispecific antibody or antigen-binding fragment thereof, under conditions for producing the monoclonal antibody or antigen-binding fragment thereof, or the bispecific antibody or antigen-binding fragment thereof, and recovering the monoclonal antibody or antigen-binding fragment thereof, or the bispecific antibody or antigen-binding fragment thereof from the cell or culture.
[Item 19]
A method for producing a pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10, or the bispecific antibody or antigen-binding fragment thereof according to item 11, comprising combining the monoclonal antibody or antigen-binding fragment thereof, or the bispecific antibody or antigen-binding fragment thereof with a pharma- ceutically acceptable carrier to obtain a pharmaceutical composition.
[Item 20]
1. A method for determining a level of a TAA in a subject, comprising:
a. obtaining a sample from a subject;
b. contacting the sample with the isolated monoclonal antibody or antigen-binding fragment thereof according to any one of items 1 to 10; and
c. Determining the level of TAA in a subject
The method includes:
[Item 21]
21. The method according to item 20, wherein the sample is a tissue sample or a blood sample, optionally wherein the tissue sample is a cancer tissue sample.
[Item 22]
An isolated polynucleotide comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), the CAR comprising:
(a) an extracellular domain comprising at least one antigen-binding domain that specifically binds to GPC3;
(b) hinge region;
(c) a transmembrane domain, and
(d) Intracellular signaling domain
2. An isolated polynucleotide comprising:
[Item 23]
The antigen-binding domain comprises:
(1) SEQ ID NOs: 87, 88, 89, 90, 91 and 92, respectively;
(2) SEQ ID NOs: 108, 109, 110, 111, 112 and 113, respectively;
(3) SEQ ID NOs: 17, 18, 19, 20, 21 and 22, respectively;
(4) SEQ ID NOs: 31, 32, 33, 34, 35 and 36, respectively;
(5) SEQ ID NOs: 45, 46, 47, 48, 49 and 50, respectively;
(6) SEQ ID NOs: 59, 60, 61, 62, 63, and 64, respectively; or
(7) SEQ ID NOs: 73, 74, 75, 76, 77 and 78, respectively
23. The isolated polynucleotide according to item 22, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the polypeptide sequence of:
[Item 24]
The antigen-binding domain comprises:
(1) SEQ ID NOs: 93, 94, 95, 96, 97 and 98, respectively;
(2) SEQ ID NOs: 114, 115, 116, 117, 118 and 119, respectively;
(3) SEQ ID NOs: 23, 24, 25, 26, 27 and 28, respectively;
(4) SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively;
(5) SEQ ID NOs: 51, 52, 53, 54, 55, and 56, respectively; or
(6) SEQ ID NOs: 65, 66, 67, 68, 69 and 70, respectively;
(7) SEQ ID NOs: 79, 80, 81, 82, 83 and 84, respectively
23. The isolated polynucleotide according to item 22, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the polypeptide sequence of:
[Item 25]
25. The isolated polynucleotide of any one of items 22 to 24, wherein the antigen-binding domain comprises a heavy chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 85, 106, 15, 29, 43, 57, or 71, or a light chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 86, 107, 16, 30, 44, 58, or 72.
[Item 26]
The antigen-binding domain comprises:
a. a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 85 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 86;
b. a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 106 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 107;
c. 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;
d. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:29 and a light chain variable region having the polypeptide sequence of SEQ ID NO:30;
e. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:43 and a light chain variable region having the polypeptide sequence of SEQ ID NO:44;
f. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:57 and a light chain variable region having the polypeptide sequence of SEQ ID NO:58; or
g. A heavy chain variable region having the polypeptide sequence of SEQ ID NO:71 and a light chain variable region having the polypeptide sequence of SEQ ID NO:72
26. The isolated polynucleotide according to item 25, comprising:
[Item 27]
25. The isolated polynucleotide of any one of items 22 to 24, wherein the antigen-binding domain is humanized and comprises a heavy chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 99-102, 120-123, 126-132, 139-140, 143-149, 153-156, 160-163, 183-197, or 202-205, or a light chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 103-105, 124-125, 133-138, 141-142, 150-152, 157-159, 164-166, or 198-201.
[Item 28]
The antigen-binding domain is humanized,
(1) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(2) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(3) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(4) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(5) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(6) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(7) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 102 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 105;
(8) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(9) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(10) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(11) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(12) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(13) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(14) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 123 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(15) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(16) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(17) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(18) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(19) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 157;
(20) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 158;
(21) 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;
(22) 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: 158;
(23) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(24) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 144 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(25) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 145 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(26) 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: 151;
(27) 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: 152;
(28) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(29) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(30) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(31) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(32) 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;
(33) 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: 164;
(34) 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: 164;
(35) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 163 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(36) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 205 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(37) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 202 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(38) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 203 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(39) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 204 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(40) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(41) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(42) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(43) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(44) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(45) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(46) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(47) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(48) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 188 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(49) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(50) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(51) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(52) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(53) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(54) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(55) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(56) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(57) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(58) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(59) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(60) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(61) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(62) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(63) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(64) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(65) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(66) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(67) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(68) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(69) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(70) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(71) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(72) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(73) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(74) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 196 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201; or
(75) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 197 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201.
28. The isolated polynucleotide according to Item 27, comprising:
[Item 29]
29. The isolated polynucleotide of any one of items 22 to 28, wherein the antigen-binding domain is a single-chain variable fragment (scFv) that specifically binds to GPC3, preferably human GPC3.
[Item 30]
30. The isolated polynucleotide of item 29, wherein the single chain variable fragment (scFv) is humanized.
[Item 31]
31. The isolated polynucleotide according to item 29 or 30, wherein the single chain variable fragment (scFv) comprises a polypeptide sequence at least 95% identical to any one of SEQ ID NOs: 167 to 182.
[Item 32]
32. The isolated polynucleotide of any one of items 22 to 31, wherein the chimeric antigen receptor (CAR) comprises one or more antigen-binding domains.
[Item 33]
33. The isolated polynucleotide of any one of paragraphs 22 to 32, wherein the intracellular signaling domain comprises one or more costimulatory domains and one or more activation domains.
[Item 34]
A chimeric antigen receptor (CAR) encoded by the isolated polynucleotide of any one of items 22 to 33.
[Item 35]
A vector comprising the isolated polynucleotide of any one of items 22 to 33.
[Item 36]
A host cell comprising the vector according to item 35.
[Item 37]
37. The host cell according to item 36, wherein the host cell is a T cell, preferably a human T cell.
[Item 38]
37. The host cell according to item 36, wherein the host cell is a NK cell, preferably a human NK cell.
[Item 39]
A method for producing a host cell expressing a chimeric antigen receptor (CAR), comprising transducing a T cell with the vector of item 35.
[Item 40]
34. A method for producing chimeric antigen receptor (CAR)-T cells, comprising culturing T cells comprising an isolated polynucleotide comprising a nucleic acid encoding the chimeric antigen receptor (CAR) of any one of items 22 to 33 under CAR-T cell production conditions, and recovering the CAR-T cells.
[Item 41]
A method for producing a host cell expressing a chimeric antigen receptor (CAR), comprising transducing an NK cell with the vector described in item 35.
[Item 42]
34. A method for producing chimeric antigen receptor (CAR)-NK cells, comprising culturing NK cells comprising an isolated polynucleotide comprising a nucleic acid encoding the chimeric antigen receptor (CAR) of any one of items 22 to 33 under CAR-NK cell producing conditions, and recovering the CAR-NK cells.
[Item 43]
34. A method for generating a cell comprising a chimeric antigen receptor (CAR), comprising contacting a cell with an isolated polynucleotide comprising a nucleic acid encoding the chimeric antigen receptor (CAR) of any one of items 22 to 33, wherein the isolated polynucleotide is an in vitro transcribed RNA or a synthetic RNA.
[Item 44]
39. A method of treating cancer in a subject in need thereof comprising administering to a subject in need thereof the host cell of any one of items 36 to 38, optionally wherein the cancer is selected from lung cancer, gastric cancer, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urothelial carcinoma, metastatic melanoma, breast cancer, ovarian cancer, cervical cancer, head and neck cancer, pancreatic cancer, glioma, glioblastoma and other solid tumors, as well as non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), acute myelogenous leukemia (AML) and other liquid tumors.
[Item 45]
45. The method of item 44, further comprising administering to a subject in need thereof an agent that increases efficacy of the cell expressing a CAR.
[Item 46]
45. The method of item 44, further comprising administering to a subject in need thereof an agent that ameliorates one or more side effects associated with administration of the cells expressing a CAR.
[Item 47]
45. The method according to item 44, further comprising administering to a subject in need thereof a drug for treating a disease associated with GPC3.
Claims (17)
(2)それぞれ配列番号108、109、110、111、112及び113、又はそれぞれ配列番号114、115、116、117、118及び119、
(3)それぞれ配列番号17、18、19、20、21及び22、又はそれぞれ配列番号23、24、25、26、27及び28、
(4)それぞれ配列番号31、32、33、34、35及び36、又はそれぞれ配列番号37、38、39、40、41及び42、
(5)それぞれ配列番号45、46、47、48、49及び50、又はそれぞれ配列番号51、52、53、54、55及び56、
(6)それぞれ配列番号59、60、61、62、63及び64、又はそれぞれ配列番号65、66、67、68、69及び70、又は
(7)それぞれ配列番号73、74、75、76、77及び78、又はそれぞれ配列番号79、80、81、82、83及び84、
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を含む、単離されたモノクローナル抗体又はその抗原結合性断片又は抗原結合性ドメインであって、GPC3、好ましくはヒトGPC3に特異的に結合する、単離されたモノクローナル抗体又はその抗原結合性断片又は抗原結合性ドメイン。 (1) SEQ ID NOs: 87, 88, 89, 90, 91 and 92, or 93, 94, 95, 96, 97 and 98, respectively;
(2) SEQ ID NOs: 108, 109, 110, 111, 112, and 113, respectively, or SEQ ID NOs: 114, 115, 116, 117, 118, and 119, respectively;
(3) SEQ ID NOs: 17, 18, 19, 20, 21, and 22, or SEQ ID NOs: 23, 24, 25, 26, 27, and 28, respectively;
(4) SEQ ID NOs: 31, 32, 33, 34, 35, and 36, or SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively;
(5) SEQ ID NOs: 45, 46, 47, 48, 49, and 50, or SEQ ID NOs: 51, 52, 53, 54, 55, and 56, respectively;
(6) SEQ ID NOs: 59, 60, 61, 62, 63, and 64, respectively, or SEQ ID NOs: 65, 66, 67, 68, 69, and 70, respectively; or
(7) SEQ ID NOs: 73, 74, 75, 76, 77, and 78, or SEQ ID NOs: 79, 80, 81, 82, 83, and 84, respectively;
An isolated monoclonal antibody or an antigen-binding fragment or domain thereof, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the polypeptide sequence of:
(2)配列番号106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107のポリペプチド配列を有する軽鎖可変領域、
(3)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、
(4)配列番号29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30のポリペプチド配列を有する軽鎖可変領域、
(5)配列番号43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44のポリペプチド配列を有する軽鎖可変領域、
(6)配列番号57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58のポリペプチド配列を有する軽鎖可変領域、
(7)配列番号71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72のポリペプチド配列を有する軽鎖可変領域、
(8)配列番号99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103のポリペプチド配列を有する軽鎖可変領域、
(9)配列番号99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104のポリペプチド配列を有する軽鎖可変領域、
(10)配列番号100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103のポリペプチド配列を有する軽鎖可変領域、
(11)配列番号100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104のポリペプチド配列を有する軽鎖可変領域、
(12)配列番号101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103のポリペプチド配列を有する軽鎖可変領域、
(13)配列番号101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104のポリペプチド配列を有する軽鎖可変領域、
(14)配列番号102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105のポリペプチド配列を有する軽鎖可変領域、
(15)配列番号120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124のポリペプチド配列を有する軽鎖可変領域、
(16)配列番号120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125のポリペプチド配列を有する軽鎖可変領域、
(17)配列番号121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124のポリペプチド配列を有する軽鎖可変領域、
(18)配列番号121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125のポリペプチド配列を有する軽鎖可変領域、
(19)配列番号122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124のポリペプチド配列を有する軽鎖可変領域、
(20)配列番号122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125のポリペプチド配列を有する軽鎖可変領域、
(21)配列番号123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124のポリペプチド配列を有する軽鎖可変領域、
(22)配列番号139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141のポリペプチド配列を有する軽鎖可変領域、
(23)配列番号139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142のポリペプチド配列を有する軽鎖可変領域、
(24)配列番号140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141のポリペプチド配列を有する軽鎖可変領域、
(25)配列番号140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142のポリペプチド配列を有する軽鎖可変領域、
(26)配列番号153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、
(27)配列番号153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、
(28)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、
(29)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158のポリペプチド配列を有する軽鎖可変領域、
(30)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150のポリペプチド配列を有する軽鎖可変領域、
(31)配列番号144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、
(32)配列番号145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、
(33)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151のポリペプチド配列を有する軽鎖可変領域、
(34)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152のポリペプチド配列を有する軽鎖可変領域、
(35)配列番号148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151のポリペプチド配列を有する軽鎖可変領域、
(36)配列番号148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152のポリペプチド配列を有する軽鎖可変領域、
(37)配列番号149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151のポリペプチド配列を有する軽鎖可変領域、
(38)配列番号149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152のポリペプチド配列を有する軽鎖可変領域、
(39)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、
(40)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164のポリペプチド配列を有する軽鎖可変領域、
(41)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164のポリペプチド配列を有する軽鎖可変領域、
(42)配列番号163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、
(43)配列番号205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、
(44)配列番号202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、
(45)配列番号203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、
(46)配列番号204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、
(47)配列番号100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198のポリペプチド配列を有する軽鎖可変領域、
(48)配列番号183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104のポリペプチド配列を有する軽鎖可変領域、
(49)配列番号183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198のポリペプチド配列を有する軽鎖可変領域、
(50)配列番号185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104のポリペプチド配列を有する軽鎖可変領域、
(51)配列番号186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104のポリペプチド配列を有する軽鎖可変領域、
(52)配列番号185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199のポリペプチド配列を有する軽鎖可変領域、
(53)配列番号186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199のポリペプチド配列を有する軽鎖可変領域、
(54)配列番号189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104のポリペプチド配列を有する軽鎖可変領域、
(55)配列番号188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103のポリペプチド配列を有する軽鎖可変領域、
(56)配列番号190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104のポリペプチド配列を有する軽鎖可変領域、
(57)配列番号191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104のポリペプチド配列を有する軽鎖可変領域、
(58)配列番号192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104のポリペプチド配列を有する軽鎖可変領域、
(59)配列番号193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104のポリペプチド配列を有する軽鎖可変領域、
(60)配列番号194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104のポリペプチド配列を有する軽鎖可変領域、
(61)配列番号189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199のポリペプチド配列を有する軽鎖可変領域、
(62)配列番号190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199のポリペプチド配列を有する軽鎖可変領域、
(63)配列番号191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199のポリペプチド配列を有する軽鎖可変領域、
(64)配列番号192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199のポリペプチド配列を有する軽鎖可変領域、
(65)配列番号193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199のポリペプチド配列を有する軽鎖可変領域、
(66)配列番号194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199のポリペプチド配列を有する軽鎖可変領域、
(67)配列番号189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200のポリペプチド配列を有する軽鎖可変領域、
(68)配列番号190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200のポリペプチド配列を有する軽鎖可変領域、
(69)配列番号191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200のポリペプチド配列を有する軽鎖可変領域、
(70)配列番号192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200のポリペプチド配列を有する軽鎖可変領域、
(71)配列番号193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200のポリペプチド配列を有する軽鎖可変領域、
(72)配列番号186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200のポリペプチド配列を有する軽鎖可変領域、
(73)配列番号195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104のポリペプチド配列を有する軽鎖可変領域、
(74)配列番号195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199のポリペプチド配列を有する軽鎖可変領域、
(75)配列番号195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200のポリペプチド配列を有する軽鎖可変領域、
(76)配列番号194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200のポリペプチド配列を有する軽鎖可変領域、
(77)配列番号185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200のポリペプチド配列を有する軽鎖可変領域、
(78)配列番号187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104のポリペプチド配列を有する軽鎖可変領域、
(79)配列番号187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200のポリペプチド配列を有する軽鎖可変領域、
(80)配列番号187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199のポリペプチド配列を有する軽鎖可変領域、
(81)配列番号196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201のポリペプチド配列を有する軽鎖可変領域、又は
(82)配列番号197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201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に記載の単離されたモノクローナル抗体又はその抗原結合性断片又は抗原結合性ドメイン。 (1) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 85 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 86;
(2) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 106 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 107;
(3) 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;
(4) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 29 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 30;
(5) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 43 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 44;
(6) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 57 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 58;
(7) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 71 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 72;
(8) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(9) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 99 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(10) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(11) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(12) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(13) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 101 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(14) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 102 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 105;
(15) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(16) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 120 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(17) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(18) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 121 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(19) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(20) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 122 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 125;
(21) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 123 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 124;
(22) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(23) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 139 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(24) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 141;
(25) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 140 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 142;
(26) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 157;
(27) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 153 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 158;
(28) 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;
(29) 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: 158;
(30) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 143 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(31) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 144 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(32) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 145 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 150;
(33) 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: 151;
(34) 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: 152;
(35) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(36) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 148 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(37) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 151;
(38) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 149 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 152;
(39) 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;
(40) 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: 164;
(41) 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: 164;
(42) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 163 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(43) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 205 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(44) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 202 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(45) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 203 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(46) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 204 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 164;
(47) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 100 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(48) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(49) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 183 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 198;
(50) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(51) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(52) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(53) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(54) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(55) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 188 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 103;
(56) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(57) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(58) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(59) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(60) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(61) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(62) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(63) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(64) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(65) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(66) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(67) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 189 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(68) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 190 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(69) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 191 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(70) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 192 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(71) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 193 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(72) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 186 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(73) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(74) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(75) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 195 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(76) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 194 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(77) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 185 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(78) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 104;
(79) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 200;
(80) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 187 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 199;
(81) A heavy chain variable region having the polypeptide sequence of SEQ ID NO: 196 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201; or
(82) The isolated monoclonal antibody or antigen-binding fragment or domain thereof of claim 1, comprising a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 197 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 201.
a.対象から試料を得ること、
b.試料を、請求項1～5のいずれか一項に記載の単離されたモノクローナル抗体又はその抗原結合性断片と接触させること、及び
c.対象におけるGPC3のレベルを決定すること
を含み、必要に応じて試料が、組織試料又は血液試料であり、必要に応じて、組織試料ががん組織試料である、方法。 1. A method for determining the level of GPC3 in a subject, comprising:
a. obtaining a sample from a subject;
b. contacting the sample with the isolated monoclonal antibody or antigen-binding fragment thereof of any one of claims 1 to 5; and
c. A method comprising determining the level of GPC3 in a subject, optionally wherein the sample is a tissue sample or a blood sample, optionally wherein the tissue sample is a cancer tissue sample.
(a)請求項1～5のいずれか一項に記載の抗原結合性ドメイン又は請求項6に記載の二重特異性抗原結合ドメインを少なくとも１つ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。 An isolated polynucleotide comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), the CAR comprising:
(a) an extracellular domain comprising at least one antigen-binding domain according to any one of claims 1 to 5 or a bispecific antigen-binding domain according to claim 6;
(b) hinge region;
(c) a transmembrane domain, and
(d) An isolated polynucleotide comprising an intracellular signaling domain.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202063021215P | 2020-05-07 | 2020-05-07 | |
| US63/021,215 | 2020-05-07 | ||
| US202062706131P | 2020-08-03 | 2020-08-03 | |
| US62/706,131 | 2020-08-03 | ||
| US202063198420P | 2020-10-16 | 2020-10-16 | |
| US63/198,420 | 2020-10-16 | ||
| US202063131394P | 2020-12-29 | 2020-12-29 | |
| US63/131,394 | 2020-12-29 | ||
| PCT/US2021/031055 WO2021226321A2 (en) | 2020-05-07 | 2021-05-06 | Anti-tumor associated antigen antibodies and uses thereof |
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| JP2023525991A JP2023525991A (en) | 2023-06-20 |
| JPWO2021226321A5 true JPWO2021226321A5 (en) | 2024-05-20 |
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| EP (1) | EP4146702A2 (en) |
| JP (1) | JP2023525991A (en) |
| KR (1) | KR20230007452A (en) |
| CN (1) | CN115515981A (en) |
| AU (1) | AU2021267893A1 (en) |
| BR (1) | BR112022020716A2 (en) |
| CA (1) | CA3173176A1 (en) |
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| AR114112A1 (en) * | 2018-02-15 | 2020-07-22 | Seattle Genetics Inc | GLIPICAN 3 ANTIBODIES AND CONJUGATES THEREOF |
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