JPWO2019217145A5 - - Google Patents
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- JPWO2019217145A5 JPWO2019217145A5 JP2020562110A JP2020562110A JPWO2019217145A5 JP WO2019217145 A5 JPWO2019217145 A5 JP WO2019217145A5 JP 2020562110 A JP2020562110 A JP 2020562110A JP 2020562110 A JP2020562110 A JP 2020562110A JP WO2019217145 A5 JPWO2019217145 A5 JP WO2019217145A5
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- 229920001184 polypeptide Polymers 0.000 claims description 124
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 124
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 124
- 239000000427 antigen Substances 0.000 claims description 104
- 102000036639 antigens Human genes 0.000 claims description 104
- 108091007433 antigens Proteins 0.000 claims description 104
- 239000012634 fragment Substances 0.000 claims description 85
- 229940127276 delta-like ligand 3 Drugs 0.000 claims description 79
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 claims description 57
- 102100036466 Delta-like protein 3 Human genes 0.000 claims description 51
- 206010028980 Neoplasm Diseases 0.000 claims description 36
- 210000004027 cell Anatomy 0.000 claims description 33
- 201000011510 cancer Diseases 0.000 claims description 31
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 30
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 230000001404 mediated effect Effects 0.000 claims description 10
- 101000863873 Homo sapiens Tyrosine-protein phosphatase non-receptor type substrate 1 Proteins 0.000 claims description 9
- 102100029948 Tyrosine-protein phosphatase non-receptor type substrate 1 Human genes 0.000 claims description 9
- 206010057249 Phagocytosis Diseases 0.000 claims description 8
- 230000001939 inductive effect Effects 0.000 claims description 8
- 210000002540 macrophage Anatomy 0.000 claims description 8
- 230000008782 phagocytosis Effects 0.000 claims description 8
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 7
- 102000053255 human DLL3 Human genes 0.000 claims description 6
- 102000039446 nucleic acids Human genes 0.000 claims description 6
- 108020004707 nucleic acids Proteins 0.000 claims description 6
- 150000007523 nucleic acids Chemical class 0.000 claims description 6
- 230000000903 blocking effect Effects 0.000 claims description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 210000003743 erythrocyte Anatomy 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 102000044459 human CD47 Human genes 0.000 claims description 3
- 230000008685 targeting Effects 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000012636 effector Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 230000007115 recruitment Effects 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- 206010027480 Metastatic malignant melanoma Diseases 0.000 claims 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 1
- 230000006037 cell lysis Effects 0.000 claims 1
- 230000000295 complement effect Effects 0.000 claims 1
- 102000034356 gene-regulatory proteins Human genes 0.000 claims 1
- 108091006104 gene-regulatory proteins Proteins 0.000 claims 1
- 208000021039 metastatic melanoma Diseases 0.000 claims 1
- 230000009089 cytolysis Effects 0.000 description 1
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Description
上記の実施形態に対し、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当業者であれば認識するであろう。したがって、この発明は、開示された特定の実施形態に限定されず、本明細書によって定義した本発明の趣旨及び範囲内の改変を包含することを意図するものとして理解される。
以下、本発明の実施形態を示す。
［１］a.それぞれ、配列番号25、26、27、61、62及び63;
b.それぞれ、配列番号28、29、30、64、65及び66;
c.それぞれ、配列番号31、32、33、67、68及び69;
d.それぞれ、配列番号34、35、36、70、71及び72;
e.それぞれ、配列番号37、38、39、73、74及び75;
f.それぞれ、配列番号40、41、42、76、77及び78;
g.それぞれ、配列番号43、44、45、79、80及び81;
h.それぞれ、配列番号46、47、48、82、83及び84;
i.それぞれ、配列番号49、50、51、85、86及び87;
j.それぞれ、配列番号52、53、54、88、89及び90;
k.それぞれ、配列番号55、56、57、91、92及び93;又は
l.それぞれ、配列番号58、59、60、94、95及び96;
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、DLL3、好ましくはヒトDLL3に特異的に結合する、単離された抗DLL3モノクローナル抗体又はその抗原結合断片。
［２］a.それぞれ、配列番号97、98、99、133、134及び135;
b.それぞれ、配列番号100、101、102、136、137及び138;
c.それぞれ、配列番号103、104、105、139、140及び141;
d.それぞれ、配列番号106、107、108、142、143及び144;
e.それぞれ、配列番号109、110、111、145、146及び147;
f.それぞれ、配列番号112、113、114、148、149及び150;
g.それぞれ、配列番号115、116、117、151、152及び153;
h.それぞれ、配列番号118、119、120、154、155及び156;
i.それぞれ、配列番号121、122、123、157、158及び159;
j.それぞれ、配列番号124、125、126、160、161及び162;
k.それぞれ、配列番号127、128、129、163、164及び165;又は
l.それぞれ、配列番号130、131、132、166、167及び168;
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、DLL3、好ましくはヒトDLL3に特異的に結合する、単離された抗DLL3モノクローナル抗体又はその抗原結合断片。
［３］配列番号1、3、5、7、9、11、13、15、17、19、21若しくは23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2、4、6、8、10、12、14、16、18、20、22若しくは24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、［1］又は［2］に記載の単離された抗DLL3モノクローナル抗体又は抗原結合断片。
［４］a.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;
b.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;
c.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;
d.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;
e.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;
f.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;
g.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;
h.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;
i.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;
j.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;
k.配列番号21のポリペプチド配列を有する重鎖可変領域、及び配列番号22のポリペプチド配列を有する軽鎖可変領域;又は
l.配列番号23のポリペプチド配列を有する重鎖可変領域、及び配列番号24の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抗DLL3モノクローナル抗体又は抗原結合断片。
［５］キメラである、［1］～［4］のいずれか一に記載の単離された抗DLL3モノクローナル抗体又は抗原結合断片。
［６］ヒトの又はヒト化されたものである、［1］～［4］のいずれか一に記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片。
［７］(a)配列番号170のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(b)配列番号170のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;又は
(c)配列番号170のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域
を含む、［6］に記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片。
［８］エフェクターに媒介される腫瘍細胞の溶解を誘導し、コンジュゲートした薬物の動員を媒介することが可能であり、並びに/又はがんを殺滅する作用を有する別のモノクローナル抗体若しくは抗原結合断片と共に二重特異性抗体を形成する、［1］～［7］のいずれか一に記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片。
［９］抗CD47モノクローナル抗体のヒト化重鎖可変領域及び抗DLL3モノクローナル抗体のヒト化軽鎖可変領域を含み、
(a)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(b)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(c)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;
(d)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(e)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(f)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;
(g)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(h)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(i)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;又は
(j)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号174のポリペプチド配列を有する軽鎖可変領域
を含む、単離された抗CD47モノクローナル抗体又はその抗原結合断片。
［１０］SIRPαへのCD47の結合をブロッキングすることが可能である、［9］に記載の単離された抗CD47モノクローナル抗体又はその抗原結合断片。
［１１］がん細胞のマクロファージに媒介されるファゴサイトーシスを誘導することが可能である、［9］に記載の単離された抗CD47モノクローナル抗体又はその抗原結合断片。
［１２］CD47、好ましくはヒトCD47に特異的に結合する第1の抗原結合ドメイン、及びDLL3、好ましくはヒトDLL3に特異的に結合する第2の抗原結合ドメインを含む単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片であって、第1の抗原結合ドメインが、配列番号178、179及び180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を含み;第2の抗原結合ドメインが、配列番号181、182及び183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を含み;並びに第1の抗原結合ドメイン及び第2の抗原結合ドメインがそれぞれ、配列番号184、185及び186のポリペプチド配列を有する軽鎖相補性決定領域1(LCDR1)、LCDR2、及びLCDR3を含む、単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１３］CD47、好ましくはヒトCD47に特異的に結合する第1の抗原結合ドメイン、及びDLL3、好ましくはヒトDLL3に特異的に結合する第2の抗原結合ドメインを含む単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片であって、第1の抗原結合ドメインが、配列番号187、188及び189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を含み;第2の抗原結合ドメインが、配列番号190、191及び192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を含み;並びに第1の抗原結合ドメイン及び第2の抗原結合ドメインがそれぞれ、配列番号193、194及び195のポリペプチド配列を有する軽鎖相補性決定領域1(LCDR1)、LCDR2、及びLCDR3を含む、単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１４］第1の抗原結合ドメインが、配列番号176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、及び配列番号172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み;第2の抗原結合ドメインが、配列番号170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、及び配列番号172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、［12］又は［13］に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１５］CD47とDLL3の両方を発現するがん細胞上のSIRPαへのCD47の結合をブロッキングすることが可能である、［12］～［14］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１６］DLL3とCD47の両方を発現するがん細胞のマクロファージに媒介されるファゴサイトーシスを誘導することが可能である、［12］～［14］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１７］ヒト赤血球への最小限～検出不可能の結合を伴って、DLL3とCD47の両方を発現するがん細胞に結合することが可能である、［12］～［14］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片。
［１８］［1］～［17］のいずれか一に記載の抗DLL3モノクローナル抗体若しくはその抗原結合断片、抗CD47モノクローナル抗体若しくはその抗原結合断片、又はヒト化抗CD47/DLL3二重特異性抗体若しくはその抗原結合断片をコードする単離された核酸。
［１９］［18］に記載の単離された核酸を含むベクター。
［２０］［19］に記載のベクターを含む宿主細胞。
［２１］［1］～［17］のいずれか一に記載の単離された抗DLL3モノクローナル抗体若しくはその抗原結合断片、単離された抗CD47モノクローナル抗体若しくはその抗原結合断片、又は単離されたヒト化抗CD47/DLL3二重特異性抗体若しくはその抗原結合断片及び薬学的に許容される担体を含む医薬組成物。
［２２］それを必要とする対象におけるがん細胞表面のDLL3を標的とする方法であって、［1］～［8］のいずれか一に記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２３］それを必要とする対象におけるシグナル調節タンパク質アルファ(SIRPα)へのCD47の結合をブロッキングする方法であって、［9］～［11］のいずれか一に記載の単離された抗CD47モノクローナル抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２４］それを必要とする対象におけるがん細胞のマクロファージに媒介されるファゴサイトーシスを誘導する方法であって、［9］～［11］のいずれか一に記載の単離された抗CD47モノクローナル抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２５］それを必要とする対象におけるがん細胞表面のDLL3及びCD47を標的とする方法であって、［12］～［17］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２６］それを必要とする対象において、細胞表面にCD47とDLL3の両方を発現するがん細胞のSIRPαへのCD47の結合をブロッキングする方法であって、［12］～［17］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２７］それを必要とする対象において、細胞表面にCD47とDLL3の両方を発現するがん細胞のマクロファージに媒介されるファゴサイトーシスを誘導する方法であって、［12］～［17］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２８］それを必要とする対象におけるヒト赤血球への最小限～検出不可能の結合を伴って、DLL3とCD47の両方を発現するがん細胞に結合する方法であって、［12］～［17］のいずれか一に記載の単離されたヒト化抗CD47/DLL3二重特異性抗体又はその抗原結合断片を含む医薬組成物をそれを必要とする対象に投与するステップを含む方法。
［２９］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、［21］に記載の医薬組成物を対象に投与するステップを含む方法。
［３０］がんが、肺がん、例えば、小細胞肺がん(SCLC)、大細胞神経内分泌癌(LCNEC)、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、頭頚部がん、膵臓がん、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)、急性リンパ性白血病(ALL)、慢性リンパ性白血病(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)、及び他の液状腫瘍からなる群から選択される、［29］に記載の方法。
［３１］［1］～［17］のいずれか一に記載の抗DLL3モノクローナル抗体若しくはその抗原結合断片、抗CD47モノクローナル抗体若しくはその抗原結合断片、又はヒト化抗CD47/DLL3二重特異性抗体若しくはその抗原結合断片を生産する方法であって、前記抗体又はその抗原結合断片を産生する条件下で、前記抗体又はその抗原結合断片をコードする核酸を含む細胞を培養するステップ、及び細胞又は培養物から抗体又はその抗原結合断片を回収するステップを含む方法。
［３２］［1］～［17］のいずれか一に記載の抗DLL3モノクローナル抗体若しくはその抗原結合断片、抗CD47モノクローナル抗体若しくはその抗原結合断片、又はヒト化抗CD47/DLL3二重特異性抗体若しくはその抗原結合断片を含む医薬組成物を生産する方法であって、前記抗体又はその抗原結合断片を薬学的に許容される担体と配合して、医薬組成物を得るステップを含む方法。
［３３］対象におけるDLL3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ステップ;
b.試料を［1］～［8］のいずれか一に記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片と接触させるステップ;及び
c.対象におけるDLL3のレベルを決定するステップ
を含む方法。
［３４］試料が、組織試料である、［33］に記載の方法。
［３５］組織試料が、がん組織試料である、［34］に記載の方法。
［３６］試料が、血液試料である、［33］に記載の方法。
Those skilled in the art will recognize that changes can be made to the above embodiments without departing from the broader concept of the invention. Accordingly, the invention is not limited to the particular embodiments disclosed, and is understood to be intended to include modifications within the spirit and scope of the invention as defined herein.
Hereinafter, embodiments of the present invention will be shown.
[1] a. SEQ ID NOs: 25, 26, 27, 61, 62 and 63, respectively;
b. SEQ ID NOs: 28, 29, 30, 64, 65 and 66, respectively;
c. SEQ ID NOs: 31, 32, 33, 67, 68 and 69, respectively;
d. SEQ ID NOs: 34, 35, 36, 70, 71 and 72;
e. SEQ ID NOs: 37, 38, 39, 73, 74 and 75, respectively;
f. SEQ ID NOs: 40, 41, 42, 76, 77 and 78;
g. SEQ ID NOs: 43, 44, 45, 79, 80 and 81;
h. SEQ ID NOs: 46, 47, 48, 82, 83 and 84, respectively;
i. SEQ ID NOs: 49, 50, 51, 85, 86 and 87;
j. SEQ ID NOs: 52, 53, 54, 88, 89 and 90, respectively;
k. SEQ ID NOs: 55, 56, 57, 91, 92 and 93; or
l. SEQ ID NOs: 58, 59, 60, 94, 95 and 96, respectively;
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 with polypeptide sequences of, and specifically binds to DLL3, preferably human DLL3. An isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof.
[2] a. SEQ ID NOs: 97, 98, 99, 133, 134 and 135, respectively;
b. SEQ ID NOs: 100, 101, 102, 136, 137 and 138;
c. SEQ ID NOs: 103, 104, 105, 139, 140 and 141;
d. SEQ ID NOs: 106, 107, 108, 142, 143 and 144;
e. SEQ ID NOs: 109, 110, 111, 145, 146 and 147;
f. SEQ ID NOs: 112, 113, 114, 148, 149 and 150;
g. SEQ ID NOs: 115, 116, 117, 151, 152 and 153, respectively;
h. SEQ ID NOs: 118, 119, 120, 154, 155 and 156, respectively;
i. SEQ ID NOs: 121, 122, 123, 157, 158 and 159, respectively;
j. SEQ ID NOs: 124, 125, 126, 160, 161 and 162, respectively;
k. SEQ ID NOs: 127, 128, 129, 163, 164 and 165; or
l. SEQ ID NOs: 130, 131, 132, 166, 167 and 168, respectively;
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 with polypeptide sequences of, and specifically binds to DLL3, preferably human DLL3. An isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof.
[3] A heavy chain variable region having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 or 23, or SEQ ID NO: 2. [1] or [2], which comprises a light chain variable region having a polypeptide sequence that is at least 95% identical to 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24. An isolated anti-DLL3 monoclonal antibody or antigen binding fragment.
[4] a. 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;
b. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 3 and light chain variable region with the polypeptide sequence of SEQ ID NO: 4;
c. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 5 and light chain variable region with the polypeptide sequence of SEQ ID NO: 6;
d. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 7 and light chain variable region with the polypeptide sequence of SEQ ID NO: 8;
e. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 9 and light chain variable region with the polypeptide sequence of SEQ ID NO: 10;
f. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 11 and light chain variable region with the polypeptide sequence of SEQ ID NO: 12;
g. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 13 and light chain variable region with the polypeptide sequence of SEQ ID NO: 14;
h. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 15 and light chain variable region with the polypeptide sequence of SEQ ID NO: 16;
i. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 17 and light chain variable region with the polypeptide sequence of SEQ ID NO: 18;
j. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 19 and light chain variable region with the polypeptide sequence of SEQ ID NO: 20;
k. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 21 and light chain variable region with the polypeptide sequence of SEQ ID NO: 22; or
l. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 23 and light chain variable region with the polypeptide sequence of SEQ ID NO: 24
The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment according to any one of [1] to [3].
[5] The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment according to any one of [1] to [4], which is a chimera.
[6] The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of [1] to [4], which is human or humanized.
[7] (a) Heavy chain variable region having the polypeptide sequence of SEQ ID NO: 170, and light chain variable region having the polypeptide sequence of SEQ ID NO: 171;
(b) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 170, and light chain variable region with the polypeptide sequence of SEQ ID NO: 172; or
(c) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 170 and light chain variable region with the polypeptide sequence of SEQ ID NO: 173.
The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to [6].
[8] Another monoclonal antibody or antigen binding capable of inducing effector-mediated lysis of tumor cells, mediating the recruitment of conjugated drugs, and / or having a cancer-killing effect. The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of [1] to [7], which forms a bispecific antibody together with the fragment.
[9] Containing a humanized heavy chain variable region of an anti-CD47 monoclonal antibody and a humanized light chain variable region of an anti-DLL3 monoclonal antibody.
(a) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(b) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175 and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(c) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175, and light chain variable region with the polypeptide sequence of SEQ ID NO: 173;
(d) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(e) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176 and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(f) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176 and light chain variable region with the polypeptide sequence of SEQ ID NO: 173;
(g) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(h) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177, and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(i) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177, and light chain variable region with the polypeptide sequence of SEQ ID NO: 173; or
(j) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177 and light chain variable region with the polypeptide sequence of SEQ ID NO: 174.
An isolated anti-CD47 monoclonal antibody or antigen-binding fragment thereof.
[10] The isolated anti-CD47 monoclonal antibody or antigen-binding fragment thereof according to [9], which is capable of blocking the binding of CD47 to SIRPα.
[11] The isolated anti-CD47 monoclonal antibody or antigen-binding fragment thereof according to [9], which is capable of inducing macrophage-mediated phagocytosis of cancer cells.
[12] An isolated humanized antibody comprising a first antigen-binding domain that specifically binds to CD47, preferably human CD47, and a second antigen-binding domain that specifically binds to DLL3, preferably human DLL3. CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof, in which the first antigen-binding domain has the polypeptide sequences of SEQ ID NOs: 178, 179 and 180, heavy chain complementarity determination region 1 (HCDR1), HCDR2. , HCDR3; the second antigen-binding domain comprises heavy chain complementarity determination regions 1 (HCDR1), HCDR2, HCDR3 having the polypeptide sequences of SEQ ID NOs: 181, 182 and 183; and the first antigen-binding domain. And isolated humanized anti-CD47 / containing light chain complementarity determination regions 1 (LCDR1), LCDR2, and LCDR3, each of which has a polypeptide sequence of SEQ ID NOs: 184, 185, and 186, respectively. DLL3 bispecific antibody or antigen-binding fragment thereof.
[13] An isolated humanized antibody comprising a first antigen-binding domain that specifically binds to CD47, preferably human CD47, and a second antigen-binding domain that specifically binds to DLL3, preferably human DLL3. CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof, in which the first antigen-binding domain has the polypeptide sequences of SEQ ID NOs: 187, 188 and 189, heavy chain complementarity determination region 1 (HCDR1), HCDR2. , HCDR3; the second antigen-binding domain comprises heavy chain complementarity determination regions 1 (HCDR1), HCDR2, HCDR3 having the polypeptide sequences of SEQ ID NOs: 190, 191 and 192; and the first antigen-binding domain. And isolated humanized anti-CD47 / containing light chain complementarity determination regions 1 (LCDR1), LCDR2, and LCDR3, each of which has a polypeptide sequence of SEQ ID NO: 193, 194, and 195, respectively. DLL3 bispecific antibody or antigen-binding fragment thereof.
[14] A heavy chain variable region having a polypeptide sequence in which the first antigen-binding domain is at least 95% identical to SEQ ID NO: 176, and a light chain variable having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 172. Containing a region; a heavy chain variable region having a polypeptide sequence in which the second antigen binding domain is at least 95% identical to SEQ ID NO: 170, and a light chain having a polypeptide sequence that is at least 95% identical to SEQ ID NO: 172. The isolated humanized anti-CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof according to [12] or [13], which comprises a variable region.
[15] The isolated human according to any one of [12] to [14], wherein it is possible to block the binding of CD47 to SIRPα on cancer cells expressing both CD47 and DLL3. Anti-CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof.
[16] The isolated isolated according to any one of [12] to [14] capable of inducing macrophage-mediated phagocytosis of cancer cells expressing both DLL3 and CD47. Humanized anti-CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof.
[17] Any one of [12] to [14] capable of binding to cancer cells expressing both DLL3 and CD47 with minimal to undetectable binding to human erythrocytes. An isolated humanized anti-CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof according to.
[18] The anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of [1] to [17], the anti-CD47 monoclonal antibody or its antigen-binding fragment, or the humanized anti-CD47 / DLL3 bispecific antibody or An isolated nucleic acid encoding that antigen-binding fragment.
[19] A vector containing the isolated nucleic acid according to [18].
[20] A host cell containing the vector according to [19].
[21] The isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of [1] to [17], the isolated anti-CD47 monoclonal antibody or its antigen-binding fragment, or isolated. A pharmaceutical composition comprising a humanized anti-CD47 / DLL3 bispecific antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.
[22] A method for targeting DLL3 on the surface of cancer cells in a subject in need thereof, wherein the isolated anti-DLL3 monoclonal antibody or antigen thereof according to any one of [1] to [8]. A method comprising the step of administering a pharmaceutical composition comprising a binding fragment to a subject in need thereof.
[23] A method of blocking the binding of CD47 to the signal regulatory protein alpha (SIRPα) in a subject in need thereof, wherein the isolated anti-CD47 according to any one of [9] to [11]. A method comprising the step of administering a pharmaceutical composition comprising a monoclonal antibody or an antigen-binding fragment thereof to a subject in need thereof.
[24] A method for inducing macrophage-mediated phagocytosis of cancer cells in a subject in need thereof, wherein the isolated anti-CD47 according to any one of [9] to [11]. A method comprising the step of administering a pharmaceutical composition comprising a monoclonal antibody or an antigen-binding fragment thereof to a subject in need thereof.
[25] A method of targeting DLL3 and CD47 on the surface of cancer cells in a subject in need thereof, wherein the isolated humanized anti-CD47 / according to any one of [12] to [17]. A method comprising administering a pharmaceutical composition comprising a DLL3 bispecific antibody or antigen-binding fragment thereof to a subject in need thereof.
[26] A method of blocking the binding of CD47 to SIRPα in cancer cells expressing both CD47 and DLL3 on the cell surface in subjects requiring it, any of [12] to [17]. A method comprising administering to a subject in need thereof a pharmaceutical composition comprising the isolated humanized anti-CD47 / DLL3 bispecific antibody or antigen binding fragment thereof according to one.
[27] A method of inducing macrophage-mediated phagocytosis of cancer cells expressing both CD47 and DLL3 on the cell surface in subjects in need thereof, according to [12] to [17]. A method comprising administering to a subject in need thereof a pharmaceutical composition comprising any one of the isolated humanized anti-CD47 / DLL3 bispecific antibodies or antigen-binding fragments thereof.
[28] A method of binding to cancer cells expressing both DLL3 and CD47 with minimal to undetectable binding to human erythrocytes in subjects requiring it [12]-[ A method comprising administering to a subject in need thereof a pharmaceutical composition comprising the isolated humanized anti-CD47 / DLL3 bispecific antibody or antigen binding fragment thereof according to any one of 17].
[29] A method of treating cancer in a subject in need thereof, comprising the step of administering the pharmaceutical composition according to [21] to the subject.
[30] Cancer is lung cancer, for example, small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), gastric cancer, colon cancer, hepatocellular carcinoma, renal cell carcinoma, bladder urinary tract epithelial cancer, metastatic black color. Tumors, 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 ( Selected from the group consisting of ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma (MM), acute myeloid leukemia (AML), and other liquid tumors, [29 ] The method described in.
[31] The anti-DLL3 monoclonal antibody or its antigen-binding fragment according to any one of [1] to [17], the anti-CD47 monoclonal antibody or its antigen-binding fragment, or the humanized anti-CD47 / DLL3 bispecific antibody or A method for producing an antigen-binding fragment thereof, in which a cell containing a nucleic acid encoding the antibody or the antigen-binding fragment thereof is cultured under the conditions for producing the antibody or the antigen-binding fragment thereof, and a cell or a culture thereof. A method comprising the step of recovering an antibody or an antigen-binding fragment thereof from an antibody.
[32] The anti-DLL3 monoclonal antibody or its antigen-binding fragment according to any one of [1] to [17], the anti-CD47 monoclonal antibody or its antigen-binding fragment, or the humanized anti-CD47 / DLL3 bispecific antibody or A method for producing a pharmaceutical composition containing the antigen-binding fragment, which comprises a step of blending the antibody or the antigen-binding fragment thereof with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.
[33] A method for determining the level of DLL3 in the target.
Steps to obtain a sample from the subject;
b. The step of contacting the sample with the isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of [1] to [8]; and
c. Steps to determine the level of DLL3 in the target
How to include.
[34] The method according to [33], wherein the sample is a tissue sample.
[35] The method according to [34], wherein the tissue sample is a cancer tissue sample.
[36] The method according to [33], wherein the sample is a blood sample.
Claims (22)
b.それぞれ配列番号28、29、30、64、65及び66、若しくはそれぞれ配列番号100、101、102、136、137及び138;
c.それぞれ配列番号31、32、33、67、68及び69、若しくはそれぞれ配列番号103、104、105、139、140及び141;
d.それぞれ配列番号34、35、36、70、71及び72、若しくはそれぞれ配列番号106、107、108、142、143及び144;
e.それぞれ配列番号37、38、39、73、74及び75、若しくはそれぞれ配列番号109、110、111、145、146及び147;
f.それぞれ配列番号40、41、42、76、77及び78、若しくはそれぞれ配列番号112、113、114、148、149及び150;
g.それぞれ配列番号43、44、45、79、80及び81、若しくはそれぞれ配列番号115、116、117、151、152及び153;
h.それぞれ配列番号46、47、48、82、83及び84、若しくはそれぞれ配列番号118、119、120、154、155及び156;
i.それぞれ配列番号49、50、51、85、86及び87、若しくはそれぞれ配列番号121、122、123、157、158及び159;
j.それぞれ配列番号52、53、54、88、89及び90、若しくはそれぞれ配列番号124、125、126、160、161及び162;
k.それぞれ配列番号55、56、57、91、92及び93、若しくはそれぞれ配列番号127、128、129、163、164及び165;又は
l.それぞれ配列番号58、59、60、94、95及び96、若しくはそれぞれ配列番号130、131、132、166、167及び168
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、DLL3、好ましくはヒトDLL3に特異的に結合する、単離された抗DLL3モノクローナル抗体又はその抗原結合断片。 SEQ ID NOs: 25, 26, 27, 61, 62 and 63, respectively, or SEQ ID NOs: 97, 98, 99, 133, 134 and 135;
b. SEQ ID NOs: 28, 29, 30, 64, 65 and 66, respectively, or SEQ ID NOs: 100, 101, 102, 136, 137 and 138;
c. SEQ ID NOs: 31, 32, 33, 67, 68 and 69, respectively, or SEQ ID NOs: 103, 104, 105, 139, 140 and 141;
d. SEQ ID NOs: 34, 35, 36, 70, 71 and 72, respectively, or SEQ ID NOs: 106, 107, 108, 142, 143 and 144;
e. SEQ ID NOs: 37, 38, 39, 73, 74 and 75, respectively, or SEQ ID NOs: 109, 110, 111, 145, 146 and 147;
f. SEQ ID NOs: 40, 41, 42, 76, 77 and 78, respectively, or SEQ ID NOs: 112, 113, 114, 148, 149 and 150;
g. SEQ ID NOs: 43, 44, 45, 79, 80 and 81, respectively, or SEQ ID NOs: 115, 116, 117, 151, 152 and 153;
h. SEQ ID NOs: 46, 47, 48, 82, 83 and 84, respectively, or SEQ ID NOs: 118, 119, 120, 154, 155 and 156;
i. SEQ ID NOs: 49, 50, 51, 85, 86 and 87, respectively, or SEQ ID NOs: 121, 122, 123, 157, 158 and 159;
j. SEQ ID NOs: 52, 53, 54, 88, 89 and 90, respectively, or SEQ ID NOs: 124, 125, 126, 160, 161 and 162;
k. SEQ ID NOs: 55, 56, 57, 91, 92 and 93, respectively, or SEQ ID NOs: 127, 128, 129, 163, 164 and 165; or
l. SEQ ID NOs: 58, 59, 60, 94, 95 and 96, respectively, or SEQ ID NOs: 130, 131, 132, 166, 167 and 168, respectively.
Contains heavy chain complementarity determining regions 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining regions 1 (LCDR1), LCDR2 and LCDR3 with polypeptide sequences of, and specifically binds to DLL3, preferably human DLL3. , Isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof.
b.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;
c.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;
d.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;
e.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;
f.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;
g.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;
h.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;
i.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;
j.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;
k.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;
l.配列番号21のポリペプチド配列を有する重鎖可変領域、及び配列番号22のポリペプチド配列を有する軽鎖可変領域;
m.配列番号23のポリペプチド配列を有する重鎖可変領域、及び配列番号24のポリペプチド配列を有する軽鎖可変領域;
n.配列番号170のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;又は
o.配列番号170のポリペプチド配列を有する重鎖可変領域、及び配列番号173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又は２記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片。 Heavy chain variable region with polypeptide sequence of SEQ ID NO: 170, and light chain variable region with polypeptide sequence of SEQ ID NO: 172;
b. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 1 and light chain variable region with the polypeptide sequence of SEQ ID NO: 2;
c. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 3 and light chain variable region with the polypeptide sequence of SEQ ID NO: 4;
d. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 5 and light chain variable region with the polypeptide sequence of SEQ ID NO: 6;
e. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 7 and light chain variable region with the polypeptide sequence of SEQ ID NO: 8;
f. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 9 and light chain variable region with the polypeptide sequence of SEQ ID NO: 10;
g. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 11 and light chain variable region with the polypeptide sequence of SEQ ID NO: 12;
h. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 13 and light chain variable region with the polypeptide sequence of SEQ ID NO: 14;
i. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 15 and light chain variable region with the polypeptide sequence of SEQ ID NO: 16;
j. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 17 and light chain variable region with the polypeptide sequence of SEQ ID NO: 18;
k. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 19 and light chain variable region with the polypeptide sequence of SEQ ID NO: 20;
l. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 21 and light chain variable region with the polypeptide sequence of SEQ ID NO: 22;
m. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 23, and light chain variable region with the polypeptide sequence of SEQ ID NO: 24;
n. Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 170, and light chain variable region with the polypeptide sequence of SEQ ID NO: 171; or
o. The isolated anti-DLL3 monoclonal antibody according to claim 1 or 2, which comprises a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 170 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 173. Antigen binding fragment.
(a)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(b)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(c)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(d)配列番号175のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;
(e)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(f)配列番号176のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;
(g)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号171のポリペプチド配列を有する軽鎖可変領域;
(h)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号172のポリペプチド配列を有する軽鎖可変領域;
(i)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号173のポリペプチド配列を有する軽鎖可変領域;又は
(j)配列番号177のポリペプチド配列を有する重鎖可変領域、及び配列番号174のポリペプチド配列を有する軽鎖可変領域
を含む、単離された抗CD47モノクローナル抗体又はその抗原結合断片。 Contains the humanized heavy chain variable region of the anti-CD47 monoclonal antibody and the humanized light chain variable region of the anti-DLL3 monoclonal antibody.
(a) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176, and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(b) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(c) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175 and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(d) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 175, and light chain variable region with the polypeptide sequence of SEQ ID NO: 173;
(e) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(f) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 176 and light chain variable region with the polypeptide sequence of SEQ ID NO: 173;
(g) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177 and light chain variable region with the polypeptide sequence of SEQ ID NO: 171;
(h) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177, and light chain variable region with the polypeptide sequence of SEQ ID NO: 172;
(i) Heavy chain variable region with the polypeptide sequence of SEQ ID NO: 177, and light chain variable region with the polypeptide sequence of SEQ ID NO: 173; or
(j) An isolated anti-CD47 monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 177 and a light chain variable region having the polypeptide sequence of SEQ ID NO: 174.
a.対象からの試料を請求項１～５のいずれか１項記載の単離された抗DLL3モノクローナル抗体又はその抗原結合断片と接触させるステップ;及び
b.対象におけるDLL3のレベルを決定するステップ
を含み、場合により、前記試料が組織試料又は血液試料であり、前記組織試料が、場合により癌組織試料である、前記方法。
How to determine the level of DLL3 in the target,
The step of contacting a sample from a subject with the isolated anti-DLL3 monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-5; and
b. The method comprising: determining the level of DLL3 in a subject, optionally said the sample is a tissue sample or a blood sample, and the said tissue sample is optionally a cancer tissue sample.
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| US62/754,207 | 2018-11-01 | ||
| US201962787815P | 2019-01-03 | 2019-01-03 | |
| US62/787,815 | 2019-01-03 | ||
| PCT/US2019/029888 WO2019217145A1 (en) | 2018-05-08 | 2019-04-30 | Anti-dll3 antibodies and uses thereof |
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| JPWO2019217145A5 true JPWO2019217145A5 (en) | 2022-05-02 |
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| WO2023006084A1 (en) * | 2021-07-30 | 2023-02-02 | 上海复旦张江生物医药股份有限公司 | Anti-dll3 antibody and preparation method therefor, drug conjugate and application thereof |
| CA3231586A1 (en) * | 2021-09-17 | 2023-03-23 | Yunying CHEN | D3-binding molecules and uses thereof |
| TW202346346A (en) * | 2021-12-23 | 2023-12-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Anti-dll3 antibodies, the antibody-drug conjugates and the pharmaceutical use thereof |
| CN114292334B (en) * | 2021-12-24 | 2023-11-17 | 杭州贤至生物科技有限公司 | Anti-cotinine specific antibodies, plasmid vectors and methods |
| CN116813784B (en) * | 2023-05-17 | 2024-03-01 | 星奕昂(上海)生物科技有限公司 | Antibodies targeting DLL3 and uses thereof |
| CN116789836B (en) * | 2023-08-14 | 2024-01-05 | 浙江时迈药业有限公司 | Antibodies against DLL3 and uses thereof |
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| FR2844519A1 (en) * | 2002-09-17 | 2004-03-19 | Bio Merieux | New recombinant DNA encoding chimeric protein, useful for in vitro diagnosis of viral infections, comprises sequences encoding epitopic regions, a linker and a binding region |
| CA2754024A1 (en) * | 2009-08-24 | 2011-03-03 | Sylvia Schleker | Antibody fusion-mediated plant resistance against oomycota |
| US20120195831A1 (en) * | 2009-10-09 | 2012-08-02 | Ningyan Zhang | Generation, characterization and uses thereof of anti-her3 antibodies |
| PT2530091T (en) * | 2010-01-29 | 2018-05-17 | Chugai Pharmaceutical Co Ltd | Anti-dll3 antibody |
| AU2011256290B2 (en) * | 2010-05-17 | 2014-06-12 | The Board Of Regents Of The University Of Texas System | Rapid isolation of monoclonal antibodies from animals |
| SI2817338T1 (en) * | 2012-02-24 | 2017-11-30 | Abbvie Stemcentrx Llc | Dll3 modulators and methods of use |
| MX2015010682A (en) * | 2013-02-22 | 2016-05-31 | Stemcentrx Inc | Novel antibody conjugates and uses thereof. |
| CN105873612A (en) * | 2013-08-28 | 2016-08-17 | 施特姆森特克斯股份有限公司 | Engineered anti-DLL3 conjugates and methods of use |
| US9879087B2 (en) * | 2014-11-12 | 2018-01-30 | Siamab Therapeutics, Inc. | Glycan-interacting compounds and methods of use |
| MA41613A (en) * | 2015-02-23 | 2018-01-02 | Abbvie Stemcentrx Llc | ANTI-DLL3 CHEMERICAL ANTIGENIC RECEPTORS AND METHODS FOR USING SUCH RECEIVERS |
| CN106699888B (en) * | 2015-07-28 | 2020-11-06 | 上海昀怡健康科技发展有限公司 | PD-1 antibody and preparation method and application thereof |
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| JOP20190009A1 (en) * | 2016-09-21 | 2019-01-27 | Alx Oncology Inc | Antibodies against signal-regulatory protein alpha and methods of use |
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