JPWO2020135335A5 - - Google Patents
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- JPWO2020135335A5 JPWO2020135335A5 JP2021536788A JP2021536788A JPWO2020135335A5 JP WO2020135335 A5 JPWO2020135335 A5 JP WO2020135335A5 JP 2021536788 A JP2021536788 A JP 2021536788A JP 2021536788 A JP2021536788 A JP 2021536788A JP WO2020135335 A5 JPWO2020135335 A5 JP WO2020135335A5
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- 125000003275 alpha amino acid group Chemical group 0.000 claims description 60
- 102000025417 antigen binding proteins Human genes 0.000 claims description 55
- 108091000829 antigen binding proteins Proteins 0.000 claims description 55
- 230000035693 Fab Effects 0.000 claims description 40
- 239000000427 antigen Substances 0.000 claims description 32
- 102000038129 antigens Human genes 0.000 claims description 32
- 108091007172 antigens Proteins 0.000 claims description 32
- 229920001184 polypeptide Polymers 0.000 claims description 26
- 201000011510 cancer Diseases 0.000 claims description 8
- 102100005826 CD19 Human genes 0.000 claims description 6
- 101700087100 CD19 Proteins 0.000 claims description 6
- 201000006934 chronic myeloid leukemia Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 claims description 5
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 claims description 5
- 235000001014 amino acid Nutrition 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 210000004027 cells Anatomy 0.000 claims description 5
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 claims description 4
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 claims description 4
- 108091007229 NSP3 Papain-like protease domain Proteins 0.000 claims description 4
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 4
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 4
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims description 4
- 108020004707 nucleic acids Proteins 0.000 claims description 4
- 150000007523 nucleic acids Chemical class 0.000 claims description 4
- 239000004475 Arginine Chemical group 0.000 claims description 2
- 208000009899 Burkitt Lymphoma Diseases 0.000 claims description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical group OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 2
- 210000004443 Dendritic Cells Anatomy 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 2
- 206010020243 Hodgkin's disease Diseases 0.000 claims description 2
- 201000006743 Hodgkin's lymphoma Diseases 0.000 claims description 2
- 102000018358 Immunoglobulins Human genes 0.000 claims description 2
- 108060003951 Immunoglobulins Proteins 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical group NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 102000005632 Single-Chain Antibodies Human genes 0.000 claims description 2
- 108010070144 Single-Chain Antibodies Proteins 0.000 claims description 2
- 230000001154 acute Effects 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 201000008325 diseases of cellular proliferation Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 201000003444 follicular lymphoma Diseases 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 2
- 201000006439 lymphocytic leukemia Diseases 0.000 claims description 2
- 201000008736 systemic mastocytosis Diseases 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 4
- 206010008943 Chronic leukaemia Diseases 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 206010025310 Other lymphomas Diseases 0.000 claims 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 1
- 102000024070 binding proteins Human genes 0.000 claims 1
- 108091007650 binding proteins Proteins 0.000 claims 1
- 238000004113 cell culture Methods 0.000 claims 1
- 230000001413 cellular Effects 0.000 claims 1
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 description 3
- 206010024324 Leukaemias Diseases 0.000 description 2
- 208000004860 Blast Crisis Diseases 0.000 description 1
- 208000003747 Lymphoid Leukemia Diseases 0.000 description 1
- 201000002594 Richter's syndrome Diseases 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
Description
本発明で言及される全ての参考文献は、それらの参考文献の各々が個別に参照によって組み込まれている場合と同様に、参照によって本明細書に組み込まれる。記載は特定の実施形態に言及しているが、本発明がこれらの特定の詳細に関する変化形で実施される場合があると当業者には明らかとなる。したがって、本発明は、本明細書に示される実施形態に限定されると解釈されるべきではない。
本発明は、例えば、以下の項目を提供する。
(項目１)
多重特異性抗原結合タンパク質であって、
Ｉ．ＣＤ３に特異的に結合する抗ＣＤ３ Ｆａｂ断片であって、前記抗ＣＤ３ Ｆａｂ断片が、
（ａ）免疫グロブリン（Ｉｇ）重鎖可変領域（ＶＨ）及びＩｇ重鎖定常領域（ＣＨ１）、ならびに
（ｂ）Ｉｇ軽鎖可変領域（ＶＬ）及びＩｇ軽鎖定常領域（ＣＬ）を含む、前記抗ＣＤ３ Ｆａｂ断片と、
ＩＩ．ＣＤ１９に特異的に結合する抗ＣＤ１９抗原結合断片と、
ＩＩＩ．場合により、前記抗ＣＤ３ Ｆａｂ断片及び前記抗ＣＤ１９抗原結合断片を連結させるリンカーとを含む、前記多重特異性抗原結合タンパク質。
(項目２)
前記抗ＣＤ１９抗原結合断片が、前記抗ＣＤ３ Ｆａｂ断片の前記ＶＨのＮ末端に融合される、項目１に記載の多重特異性抗原結合タンパク質。
(項目３)
前記抗ＣＤ１９抗原結合断片が、前記抗ＣＤ３ Ｆａｂ断片の前記ＶＬのＮ末端に融合される、項目１に記載の多重特異性抗原結合タンパク質。
(項目４)
第１抗ＣＤ１９抗原結合断片及び第２抗ＣＤ１９抗原結合断片を含み、前記第１抗ＣＤ１９抗原結合断片が、前記抗ＣＤ３ Ｆａｂ断片の前記ＶＨのＮ末端に融合され、前記第２抗ＣＤ１９抗原結合断片が、前記抗ＣＤ３ Ｆａｂ断片の前記ＶＬのＮ末端に融合される、項目１に記載の多重特異性抗原結合タンパク質。
(項目５)
前記抗ＣＤ３ Ｆａｂ断片が、ＣＤ３εのＮ末端に特異的に結合する、項目１～４のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目６)
前記抗ＣＤ３ Ｆａｂ断片が、ＣＤ３εのアミノ酸１～２７内のエピトープに特異的に結合する、項目１～５のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目７)
前記抗ＣＤ３ Ｆａｂ断片の前記ＶＨが、配列番号：９のアミノ酸配列を含む重鎖超可変領域Ｈ１（ＨＶＲ－Ｈ１）、配列番号：１０のアミノ酸配列を含むＨＶＲ－Ｈ２、及び配列番号：１１のアミノ酸配列を含むＨＶＲ－Ｈ３を含み、ならびに／または前記抗ＣＤ３ Ｆａｂ断片の前記ＶＬが、配列番号：１２のアミノ酸配列を含む軽鎖超可変領域Ｌ１（ＨＶＲ－Ｌ１）、配列番号：１３のアミノ酸配列を含むＨＶＲ－Ｌ２、及び配列番号：１４のアミノ酸配列を含むＨＶＲ－Ｌ３を含む、項目５または６に記載の多重特異性抗原結合タンパク質。
(項目８)
前記抗ＣＤ３ Ｆａｂ断片の前記ＶＨが、配列番号：１５のアミノ酸配列を含み、及び／または前記抗ＣＤ３ Ｆａｂ断片の前記ＶＬが、配列番号：１６のアミノ酸配列を含む、項目５～７のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目９)
前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１及び前記ＣＬが、ジスルフィド結合によって連結されている、項目１～８のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目１０)
前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１及び前記ＣＬが、約１～約５個のジスルフィド結合によって連結されている、項目９に記載の多重特異性抗原結合タンパク質。
(項目１１)
前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１及び前記ＣＬが、約２個のジスルフィド結合によって連結されている、項目９または１０に記載の多重特異性抗原結合タンパク質。
(項目１２)
前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１が、配列番号：１８のアミノ酸配列を含み、及び／または前記抗ＣＤ３ Ｆａｂ断片の前記ＣＬが、配列番号：５２のアミノ酸配列を含む、項目１～１１のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目１３)
前記抗ＣＤ１９抗原結合断片がＶＨを含み、前記抗ＣＤ１９抗原結合断片の前記ＶＨが、配列番号：１のアミノ酸配列を含むＨＶＲ－Ｈ１、配列番号：２のアミノ酸配列を含むＨＶＲ－Ｈ２、及び配列番号：３のアミノ酸配列を含むＨＶＲ－Ｈ３を含み、ならびに／または前記抗ＣＤ１９抗原結合断片がＶＬを含み、前記抗ＣＤ１９抗原結合断片の前記ＶＬが、配列番号：４７のアミノ酸配列を含むＨＶＲ－Ｌ１、配列番号：４８のアミノ酸配列を含むＨＶＲ－Ｌ２、及び配列番号：６もしくは４９のアミノ酸配列を含むＨＶＲ－Ｌ３を含む、項目１～１２のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目１４)
前記抗ＣＤ１９抗原結合断片の前記ＶＨが、配列番号：７のアミノ酸配列を含み、及び／または前記抗ＣＤ１９抗原結合断片の前記ＶＬが、配列番号：８もしくは５０のアミノ酸配列を含む、項目１３に記載の多重特異性抗原結合タンパク質。
(項目１５)
前記抗ＣＤ１９抗原結合断片が一本鎖可変断片（ｓｃＦｖ）である、項目１～１４のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目１６)
前記抗ＣＤ１９ ｓｃＦｖが、配列番号：５１または５９のアミノ酸配列を含む、項目１５に記載の多重特異性抗原結合タンパク質。
(項目１７)
前記多重特異性抗原結合タンパク質が、第１抗ＣＤ１９ ｓｃＦｖ及び第２抗ＣＤ１９
ｓｃＦｖを含む、項目１５または１６に記載の多重特異性抗原結合タンパク質。
(項目１８)
前記第１抗ＣＤ１９ ｓｃＦｖ及び前記第２抗ＣＤ１９ ｓｃＦｖが、同じアミノ酸配列を有する、項目１７に記載の多重特異性抗原結合タンパク質。
(項目１９)
前記リンカーが、グリシン、セリン、アルギニン、及びアラニンからなる群から選択される約２～約３０個のアミノ酸残基を含む、項目１～１８のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目２０)
前記リンカーが、約２～約１５個のアミノ酸残基を含む、項目１～１９のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目２１)
前記リンカーが、配列番号：２０～２２、２９、及び３１～４４からなる群から選択される、項目１～２０のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目２２)
前記多重特異性抗原結合タンパク質が、第１ポリペプチド及び第２ポリペプチドを含み、前記第１ポリペプチドが、配列番号：５３または６０のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：５４または６１のアミノ酸配列を含む、項目１～２１のいずれか１項に記載の多重特異性抗原結合タンパク質。
(項目２３)
前記第１ポリペプチドが、配列番号：５３のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：５４のアミノ酸配列を含む、項目２２に記載の多重特異性抗原結合タンパク質。
(項目２４)
前記第１ポリペプチドが、配列番号：６０のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：６１のアミノ酸配列を含む、項目２２に記載の多重特異性抗原結合タンパク質。
(項目２５)
項目１～２４のいずれか１項に記載の多重特異性抗原結合タンパク質をコードする、単離核酸。
(項目２６)
項目１～２４のいずれか１項に記載の多重特異性抗原結合タンパク質と、場合により薬学的に許容される担体とを含む、医薬組成物。
(項目２７)
がんの処置を必要とする個体におけるがんの処置方法であって、有効量の項目２６に記載の医薬組成物を前記個体に投与することを含む、前記方法。
(項目２８)
前記医薬組成物が静脈内投与される、項目２７に記載の方法。
(項目２９)
前記個体がヒトである、項目２７または２８に記載の方法。
(項目３０)
前記がんが、急性骨髄性白血病（ＡＭＬ）、慢性骨髄性白血病（ＣＭＬ）の急性転化及びＣＭＬと関連するＡｂｅｌｓｏｎがん遺伝子（Ｂｃｒ－ＡＢＬ転座）を含む慢性骨髄性白血病、骨髄異形成症候群（ＭＤＳ）、急性Ｂリンパ芽球性白血病（Ｂ－ＡＬＬ）、びまん性大細胞型Ｂ細胞リンパ腫（ＤＬＢＣＬ）、濾胞性リンパ腫、慢性リンパ性白血病（ＣＬＬ）のリヒター症候群またはリヒター形質転換を含む慢性リンパ性白血病、有毛細胞白血病（ＨＣＬ）、芽球性形質細胞様樹状細胞腫瘍（ＢＰＤＣＮ）、マントル細胞白血病（ＭＣＬ）及び小リンパ球性リンパ腫（ＳＬＬ）を含む非ホジキンリンパ腫（ＮＨＬ）、ホジキンリンパ腫、全身性肥満細胞症、ならびにバーキットリンパ腫からなる群から選択される、項目２７～２９のいずれか１項に記載の方法。
(項目３１)
前記がんがＤＬＢＣＬまたはＡＬＬである、項目３０に記載の方法。
All references mentioned in this invention are herein incorporated by reference as if each of those references were individually incorporated by reference. Although the description refers to specific embodiments, it will be apparent to those skilled in the art that the invention may be practiced with variations to these specific details. Therefore, this invention should not be construed as limited to the embodiments set forth herein.
The present invention provides, for example, the following items.
(Item 1)
A multispecific antigen binding protein,
I. An anti-CD3 Fab fragment that specifically binds to CD3, said anti-CD3 Fab fragment comprising:
(a) an immunoglobulin (Ig) heavy chain variable region (VH) and an Ig heavy chain constant region (CH1), and
(b) said anti-CD3 Fab fragment comprising an Ig light chain variable region (VL) and an Ig light chain constant region (CL);
II. an anti-CD19 antigen-binding fragment that specifically binds to CD19;
III. optionally, said multispecific antigen binding protein comprising a linker connecting said anti-CD3 Fab fragment and said anti-CD19 antigen binding fragment.
(Item 2)
The multispecific antigen binding protein of item 1, wherein said anti-CD19 antigen binding fragment is fused to the N-terminus of said VH of said anti-CD3 Fab fragment.
(Item 3)
The multispecific antigen binding protein of item 1, wherein said anti-CD19 antigen binding fragment is fused to the N-terminus of said VL of said anti-CD3 Fab fragment.
(Item 4)
comprising a first anti-CD19 antigen-binding fragment and a second anti-CD19 antigen-binding fragment, wherein said first anti-CD19 antigen-binding fragment is fused to the N-terminus of said VH of said anti-CD3 Fab fragment; The multispecific antigen binding protein of item 1, wherein the fragment is fused to the N-terminus of said VL of said anti-CD3 Fab fragment.
(Item 5)
5. The multispecific antigen binding protein of any one of items 1-4, wherein said anti-CD3 Fab fragment specifically binds to the N-terminus of CD3ε.
(Item 6)
6. The multispecific antigen binding protein of any one of items 1-5, wherein said anti-CD3 Fab fragment specifically binds to an epitope within amino acids 1-27 of CD3ε.
(Item 7)
wherein said VH of said anti-CD3 Fab fragment comprises a heavy chain hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:9, HVR-H2 comprising the amino acid sequence of SEQ ID NO:10, and SEQ ID NO:11 a light chain hypervariable region L1 (HVR-L1) comprising an HVR-H3 comprising an amino acid sequence, and/or wherein said VL of said anti-CD3 Fab fragment comprises an amino acid sequence of SEQ ID NO: 12, an amino acid of SEQ ID NO: 13 7. The multispecific antigen binding protein of item 5 or 6, comprising HVR-L2 comprising the sequence and HVR-L3 comprising the amino acid sequence of SEQ ID NO:14.
(Item 8)
any of items 5-7, wherein said VH of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO:15 and/or said VL of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO:16 2. A multispecific antigen binding protein according to paragraph 1.
(Item 9)
9. The multispecific antigen binding protein of any one of items 1-8, wherein said CH1 and said CL of said anti-CD3 Fab fragment are linked by a disulfide bond.
(Item 10)
10. The multispecific antigen binding protein of item 9, wherein said CH1 and said CL of said anti-CD3 Fab fragment are linked by about 1 to about 5 disulfide bonds.
(Item 11)
11. The multispecific antigen binding protein of items 9 or 10, wherein said CH1 and said CL of said anti-CD3 Fab fragment are linked by about two disulfide bonds.
(Item 12)
any of items 1-11, wherein said CH1 of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO:18 and/or said CL of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO:52 2. A multispecific antigen binding protein according to paragraph 1.
(Item 13)
the anti-CD19 antigen-binding fragment comprises a VH, wherein the VH of the anti-CD19 antigen-binding fragment comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a sequence No.: HVR-H3 comprising the amino acid sequence of 3, and/or the anti-CD19 antigen-binding fragment comprises a VL, and the VL of the anti-CD19 antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 47. 13. The multispecific antigen binding of any one of items 1-12, comprising L1, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 48, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6 or 49. protein.
(Item 14)
item 13, wherein said VH of said anti-CD19 antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 7 and/or said VL of said anti-CD19 antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 8 or 50 A multispecific antigen binding protein as described.
(Item 15)
15. The multispecific antigen binding protein of any one of items 1-14, wherein said anti-CD19 antigen binding fragment is a single chain variable fragment (scFv).
(Item 16)
16. The multispecific antigen binding protein of item 15, wherein said anti-CD19 scFv comprises the amino acid sequence of SEQ ID NO:51 or 59.
(Item 17)
wherein the multispecific antigen binding protein comprises a first anti-CD19 scFv and a second anti-CD19
17. A multispecific antigen binding protein according to items 15 or 16, comprising a scFv.
(Item 18)
18. The multispecific antigen binding protein of item 17, wherein said first anti-CD19 scFv and said second anti-CD19 scFv have the same amino acid sequence.
(Item 19)
19. The multispecific antigen binding protein of any one of items 1-18, wherein said linker comprises from about 2 to about 30 amino acid residues selected from the group consisting of glycine, serine, arginine, and alanine. .
(Item 20)
20. The multispecific antigen binding protein of any one of items 1-19, wherein said linker comprises from about 2 to about 15 amino acid residues.
(Item 21)
21. The multispecific antigen binding protein of any one of items 1-20, wherein said linker is selected from the group consisting of SEQ ID NOs: 20-22, 29, and 31-44.
(Item 22)
Said multispecific antigen binding protein comprises a first polypeptide and a second polypeptide, said first polypeptide comprising the amino acid sequence of SEQ ID NO: 53 or 60, said second polypeptide comprising SEQ ID NO: 22. A multispecific antigen binding protein according to any one of items 1-21, comprising a sequence of 54 or 61 amino acids.
(Item 23)
23. The multispecific antigen binding protein of item 22, wherein said first polypeptide comprises the amino acid sequence of SEQ ID NO:53 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:54.
(Item 24)
23. The multispecific antigen binding protein of item 22, wherein said first polypeptide comprises the amino acid sequence of SEQ ID NO:60 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:61.
(Item 25)
An isolated nucleic acid encoding the multispecific antigen binding protein of any one of items 1-24.
(Item 26)
A pharmaceutical composition comprising the multispecific antigen binding protein of any one of items 1-24 and optionally a pharmaceutically acceptable carrier.
(Item 27)
27. A method of treating cancer in an individual in need of cancer treatment, comprising administering to said individual an effective amount of the pharmaceutical composition of item 26.
(Item 28)
28. The method of item 27, wherein said pharmaceutical composition is administered intravenously.
(Item 29)
29. The method of items 27 or 28, wherein said individual is a human.
(Item 30)
The cancer is acute myelogenous leukemia (AML), blast crisis of chronic myelogenous leukemia (CML) and chronic myelogenous leukemia containing the Abelson oncogene (Bcr-ABL translocation) associated with CML, myelodysplastic syndrome (MDS), acute B-lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), including Richter's syndrome or Richter's transformation non-Hodgkin's lymphomas (NHL), including lymphocytic leukemia, hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), mantle cell leukemia (MCL) and small lymphocytic lymphoma (SLL); 30. The method of any one of items 27-29, selected from the group consisting of Hodgkin's lymphoma, systemic mastocytosis, and Burkitt's lymphoma.
(Item 31)
31. The method of item 30, wherein said cancer is DLBCL or ALL.
Claims (26)
ｉ）ＣＤ３に特異的に結合する抗ＣＤ３ Ｆａｂ断片であって、前記抗ＣＤ３ Ｆａｂ断片が、
（ａ）免疫グロブリン（Ｉｇ）重鎖可変領域（ＶＨ）及びＩｇ重鎖定常領域（ＣＨ１）、ならびに
（ｂ）Ｉｇ軽鎖可変領域（ＶＬ）及びＩｇ軽鎖定常領域（ＣＬ）を含む、前記抗ＣＤ３ Ｆａｂ断片と、
ｉｉ）ＣＤ１９に特異的に結合する抗ＣＤ１９抗原結合断片と、
ｉｉｉ）前記抗ＣＤ３ Ｆａｂ断片及び前記抗ＣＤ１９抗原結合断片を連結させる、任意選択のリンカーとを含む、前記多重特異性抗原結合タンパク質。 A multispecific antigen binding protein,
i) an anti-CD3 Fab fragment that specifically binds to CD3, said anti-CD3 Fab fragment comprising:
(a) an immunoglobulin (Ig) heavy chain variable region (VH) and an Ig heavy chain constant region (CH1); and (b) an Ig light chain variable region (VL) and an Ig light chain constant region (CL). an anti-CD3 Fab fragment;
ii) an anti-CD19 antigen-binding fragment that specifically binds to CD19;
iii) an optional linker connecting said anti-CD3 Fab fragment and said anti-CD19 antigen binding fragment.
ｉｉ）前記抗ＣＤ１９抗原結合断片が、前記抗ＣＤ３ Ｆａｂ断片の前記ＶＬのＮ末端に融合される、
請求項１に記載の多重特異性抗原結合タンパク質。 i) said anti-CD19 antigen-binding fragment is fused to the N-terminus of said VH of said anti-CD3 Fab fragment, or
ii) said anti-CD19 antigen-binding fragment is fused to the N-terminus of said VL of said anti-CD3 Fab fragment;
2. The multispecific antigen binding protein of claim 1.
ｉｉ）前記抗ＣＤ３ Ｆａｂ断片が、ＣＤ３εのアミノ酸１～２７内のエピトープに特異的に結合する、
請求項１～３のいずれか１項に記載の多重特異性抗原結合タンパク質。 i) said anti-CD3 Fab fragment specifically binds to the N-terminus of CD3ε, and/or
ii) said anti-CD3 Fab fragment specifically binds to an epitope within amino acids 1-27 of CD3ε;
The multispecific antigen binding protein according to any one of claims 1-3 .
ｉｉ）前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１及び前記ＣＬが、約２個のジスルフィド結合によって連結されている、ならびに／または
ｉｉｉ）前記抗ＣＤ３ Ｆａｂ断片の前記ＣＨ１が、配列番号：１８のアミノ酸配列を含み、及び／または前記抗ＣＤ３ Ｆａｂ断片の前記ＣＬが、配列番号：５２のアミノ酸配列を含む、
請求項１～７のいずれか１項に記載の多重特異性抗原結合タンパク質。 i) said CH1 and said CL of said anti-CD3 Fab fragment are linked by about 1 to about 5 disulfide bonds, and/or
ii) said CH1 and said CL of said anti-CD3 Fab fragment are linked by about two disulfide bonds, and/or
iii) said CH1 of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO: 18 and/or said CL of said anti-CD3 Fab fragment comprises the amino acid sequence of SEQ ID NO: 52;
The multispecific antigen binding protein according to any one of claims 1-7.
ｓｃＦｖを含む、請求項１２または１３に記載の多重特異性抗原結合タンパク質。 wherein the multispecific antigen binding protein comprises a first anti-CD19 scFv and a second anti-CD19
14. The multispecific antigen binding protein of claim 12 or 13 , comprising a scFv.
ｉｉ）前記リンカーが、グリシン、セリン、アルギニン、及びアラニンからなる群から選択されるアミノ酸残基を含む、ならびに／または
ｉｉｉ）前記リンカーが、配列番号：２０～２２、２９、及び３１～４４からなる群から選択されるアミノ酸配列を含む、
請求項１～１５のいずれか１項に記載の多重特異性抗原結合タンパク質。 i) said linker comprises from about 2 to about 30 amino acid residues, and/or
ii) said linker comprises amino acid residues selected from the group consisting of glycine, serine, arginine and alanine, and/or
iii) said linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 20-22, 29, and 31-44;
A multispecific antigen binding protein according to any one of claims 1-15 .
ｉｉ）前記第１ポリペプチドが、配列番号：６０のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：６１のアミノ酸配列を含む、
ｉｉｉ）前記第１ポリペプチドが、配列番号：５３のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：５８のアミノ酸配列を含む、
ｉｖ）前記第１ポリペプチドが、配列番号：６０のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：５８のアミノ酸配列を含む、
ｖ）前記第１ポリペプチドが、配列番号：５７のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：５４のアミノ酸配列を含む、または
ｖｉ）前記第１ポリペプチドが、配列番号：５７のアミノ酸配列を含み、前記第２ポリペプチドが、配列番号：６１のアミノ酸配列を含む、
請求項１７に記載の多重特異性抗原結合タンパク質。 i) said first polypeptide comprises the amino acid sequence of SEQ ID NO:53 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:54;
ii) said first polypeptide comprises the amino acid sequence of SEQ ID NO:60 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:61;
iii) said first polypeptide comprises the amino acid sequence of SEQ ID NO:53 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:58;
iv) said first polypeptide comprises the amino acid sequence of SEQ ID NO:60 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:58;
v) said first polypeptide comprises the amino acid sequence of SEQ ID NO:57 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:54, or
vi) said first polypeptide comprises the amino acid sequence of SEQ ID NO:57 and said second polypeptide comprises the amino acid sequence of SEQ ID NO:61;
18. The multispecific antigen binding protein of claim 17 .
ｉｉ）前記個体がヒトである、
請求項２２に記載の組成物。 i) said multispecific antigen binding protein or said pharmaceutical composition is administered intravenously, and/or
ii) said individual is a human,
23. The composition of claim 22 .
ｉ）請求項１９に記載の単離核酸またはベクターを含む宿主細胞または請求項２０に記載の単離宿主細胞を、コードされる多重特異性抗原結合タンパク質の発現に好適な条件下で培養する工程、およびi) culturing the host cell comprising the isolated nucleic acid or vector of claim 19 or the isolated host cell of claim 20 under conditions suitable for expression of the encoded multispecific antigen binding protein. ,and
ｉｉ）前記発現された多重特異性抗原結合タンパク質を、細胞培養物から回収する工程ii) recovering said expressed multispecific antigen binding protein from the cell culture
を含む、方法。A method, including
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| PCT/CN2018/123108 WO2020132810A1 (en) | 2018-12-24 | 2018-12-24 | Multispecific antigen binding proteins capable of binding cd19 and cd3, and use thereof |
| PCT/CN2019/127433 WO2020135335A1 (en) | 2018-12-24 | 2019-12-23 | Multispecific antigen binding proteins capable of binding cd19 and cd3, and use thereof |
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| AU2023254191A1 (en) | 2022-04-11 | 2024-10-17 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for universal tumor cell killing |
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| EP2710042A2 (en) * | 2011-05-16 | 2014-03-26 | Fabion Pharmaceuticals, Inc. | Multi-specific fab fusion proteins and methods of use |
| HUE033245T2 (en) * | 2011-12-19 | 2017-11-28 | Synimmune Gmbh | Bispecific antibody molecule |
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