JPWO2021243415A5 - - Google Patents
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- JPWO2021243415A5 JPWO2021243415A5 JP2022574600A JP2022574600A JPWO2021243415A5 JP WO2021243415 A5 JPWO2021243415 A5 JP WO2021243415A5 JP 2022574600 A JP2022574600 A JP 2022574600A JP 2022574600 A JP2022574600 A JP 2022574600A JP WO2021243415 A5 JPWO2021243415 A5 JP WO2021243415A5
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- 239000003795 chemical substances by application Substances 0.000 claims description 43
- 230000008685 targeting Effects 0.000 claims description 41
- 239000000412 dendrimer Substances 0.000 claims description 20
- 229920000736 dendritic polymer Polymers 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000000539 amino acid group Chemical group 0.000 claims description 8
- 230000000536 complexating effect Effects 0.000 claims description 8
- 125000006850 spacer group Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000002355 alkine group Chemical group 0.000 claims description 4
- 229920006187 aquazol Polymers 0.000 claims description 4
- 150000003384 small molecules Chemical group 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 229910052765 Lutetium Inorganic materials 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 3
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000427 antigen Substances 0.000 claims description 3
- 102000036639 antigens Human genes 0.000 claims description 3
- 108091007433 antigens Proteins 0.000 claims description 3
- 229910052733 gallium Inorganic materials 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims description 3
- 208000015486 malignant pancreatic 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
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 229910052726 zirconium Inorganic materials 0.000 claims description 3
- SOAPXKSPJAZNGO-WDSKDSINSA-N (2s)-2-[[(1s)-1,3-dicarboxypropyl]carbamoylamino]pentanedioic acid Chemical class OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCC(O)=O SOAPXKSPJAZNGO-WDSKDSINSA-N 0.000 claims description 2
- NEMHIKRLROONTL-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-azidophenyl)propanoate Chemical group OC(=O)[C@@H](N)CC1=CC=C(N=[N+]=[N-])C=C1 NEMHIKRLROONTL-QMMMGPOBSA-N 0.000 claims description 2
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 claims description 2
- GTACSIONMHMRPD-UHFFFAOYSA-N 2-[4-[2-(benzenesulfonamido)ethylsulfanyl]-2,6-difluorophenoxy]acetamide Chemical compound C1=C(F)C(OCC(=O)N)=C(F)C=C1SCCNS(=O)(=O)C1=CC=CC=C1 GTACSIONMHMRPD-UHFFFAOYSA-N 0.000 claims description 2
- WXFIFTYQCGZRGR-UHFFFAOYSA-N 5-hydroxy-2-methylhex-2-enamide Chemical compound CC(O)CC=C(C)C(N)=O WXFIFTYQCGZRGR-UHFFFAOYSA-N 0.000 claims description 2
- 101710130081 Aspergillopepsin-1 Proteins 0.000 claims description 2
- ZUHQCDZJPTXVCU-UHFFFAOYSA-N C1#CCCC2=CC=CC=C2C2=CC=CC=C21 Chemical group C1#CCCC2=CC=CC=C2C2=CC=CC=C21 ZUHQCDZJPTXVCU-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 102100031007 Cytosolic non-specific dipeptidase Human genes 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 2
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 claims description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052767 actinium Inorganic materials 0.000 claims description 2
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052789 astatine Inorganic materials 0.000 claims description 2
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical compound [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 claims description 2
- -1 benzyl-DOTA Chemical compound 0.000 claims description 2
- 229910052797 bismuth Inorganic materials 0.000 claims description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 2
- 230000000295 complement effect Effects 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 2
- 108010082974 polysarcosine Proteins 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910052713 technetium Inorganic materials 0.000 claims description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Description
結果
図１９及び下表に示すように、標的放射性核種デンドリマー（化合物ＳＲＳ－２－３０４）及び非標的放射性核種デンドリマー（化合物ＲＨ－３－１６０）は、いずれも腫瘍成長を抑制するのに有効であり、標的デンドリマーが最も効果的であった。図２０は、１５ｍＢｑ及び２×９ＭＢｑの１７７Ｌｕ用量での、標的（化合物ＳＲＳ－２－３０４）の６７日目の腫瘍再成長を示していない。
［１］デンドリマー－標的化剤コンジュゲートであって、
ａ）デンドリマーであって
ｉ）コアユニット（Ｃ）、及び
ｉｉ）構成ユニット（ＢＵ）を含み、
前記デンドリマーが、２～６世代の構成ユニットを有し、
前記コアユニットが、少なくとも２つの構成ユニットに共有結合により付着している、デンドリマーと、
ｂ）スペーサー基により前記デンドリマーに共有結合により連結している、標的化剤と、
ｃ）前記デンドリマーの最も外側の構成ユニットに付着している１つ以上の第１の末端基であって、前記第１の末端基が、放射性核種を錯体化するための錯体化基を含む、第１の末端基と、
ｄ）前記デンドリマーの最も外側の構成ユニットに付着している１つ以上の第２の末端基であって、前記第２の末端基が、薬物動態修飾部分を含む、第２の末端基と、を含む、コンジュゲート
又はその塩。
［２］前記標的化剤が、最大約１５０ｋＤａ、又は最大約１１０ＫＤａ、又は最大約８０ＫＤａ、又は最大約５５ＫＤａ、又は最大約１６ｋＤａの分子量を有し、抗原結合部位を含むペプチド部分である、上記［１］に記載のコンジュゲート。
［３］前記標的化剤が、最大約８０ｋＤａの分子量を有し、抗原結合部位を含むペプチド部分である、上記［２］に記載のコンジュゲート。
［４］前記標的化剤が、抗体、重鎖抗体、ＳｃＦＶ－Ｆｃ、Ｆａｂ、Ｆａｂ２、Ｆｖ、ｓｃＦｖ、又は単一ドメイン抗体から選択される、上記［１］～［３］のいずれかに記載のコンジュゲート。
［５］前記標的化剤が、重鎖可変（Ｖ
Ｈ
）ドメインを含むか、又はそれからなる、上記［１］～［４］のいずれかに記載のコンジュゲート。
［６］前記標的化剤が、軽鎖可変（Ｖ
Ｌ
）ドメインを含むか、又はそれからなる、上記［１］～［５］のいずれかに記載のコンジュゲート。
［７］前記標的化剤が、約５ｋＤａ～約３０ｋＤａの分子量を有する、上記［１］～［６］のいずれかに記載のコンジュゲート。
［８］前記標的化剤が、約３ｋＤａ～約２０ｋＤａの分子量を有する、上記［７］に記載のコンジュゲート。
［９］前記標的化剤が、１２０未満のアミノ酸残基を含む、上記［１］～［８］のいずれかに記載のコンジュゲート。
［１０］前記標的化剤が、ＨＥＲ２標的化剤である、上記［１］～［９］のいずれかに記載のコンジュゲート。
［１１］前記標的化剤が、ＨＥＲ２ナノボディである、上記［１０］に記載のコンジュゲート。
［１２］前記標的化剤が、本明細書に記載の標的化剤アミノ酸配列のいずれかを含むか、又はそれらからなる、上記［１］～［１１］のいずれかに記載のコンジュゲート。
［１３］前記標的化剤が、小分子である、上記［１］に記載のコンジュゲート。
［１４］前記標的化剤が、ＰＳＭＡと結合する小分子である、上記［１３］に記載のコンジュゲート。
［１５］前記標的化剤が、ＤＵＰＡ類似体である、上記［１４］に記載のコンジュゲート。
［１６］前記標的化剤が、ＦＡＰ結合基である、上記［１３］に記載のコンジュゲート。
［１７］前記標的化剤と前記スペーサー基との間の共有結合による連結が、前記標的化剤を含む中間体及び前記デンドリマーを含む中間体上に存在する相補的反応性官能基間の反応によって形成されている、上記［１］～［１６］のいずれかに記載のコンジュゲート。
［１８］前記標的化剤を含む前記中間体が、非天然アミノ酸残基を含み、前記非天然アミノ酸残基が、反応性官能基を含む側鎖を有する、上記［１７］に記載のコンジュゲート。
［１９］前記非天然アミノ酸残基が、４－アジドフェニルアラニン残基である、上記［１８］に記載のコンジュゲート。
［２０］前記標的化剤を含む前記中間体が、反応性システイン残基を含む、上記［１７］に記載のコンジュゲート。
［２１］前記スペーサー基が、ＰＥＧ基を含む、上記［１］～［２０］のいずれかに記載のコンジュゲート。
［２２］前記標的化剤が、前記標的化剤のＣ末端で、又はその近傍で、前記スペーサー基に共有結合により連結している、上記［１］～［２１］のいずれかに記載のコンジュゲート。
［２３］前記デンドリマーを含む前記中間体が、アルキン基である反応性官能基を含む、上記［１８］又は［１９］に記載のコンジュゲート。
［２４］前記アルキン基が、ジベンゾシクロオクチン基である、上記［２３］に記載のコンジュゲート。
［２５］前記第１の末端基が、錯体化基と錯体化した放射性核種を更に含む、上記［１］～［２４］のいずれかに記載のコンジュゲート。
［２６］前記錯体化基が、ＤＯＴＡ、ベンジル－ＤＯＴＡ、ＮＯＴＡ、ＤＴＰＡ、サルコファジン、マクロパ、ＤＦＯ、ＰＥＰＡ、又はＥＤＴＡ基である、上記［１］～［２５］のいずれかに記載のコンジュゲート。
［２７］放射性核種含有部分中の前記放射性核種が、ルテチウム、ガリウム、ジルコニウム、アクチニウム、ビスマス、アスタチン、テクネチウム、鉛、イットリウム、又は銅放射性核種である、上記［１］～［２６］のいずれかに記載のコンジュゲート。
［２８］前記放射性核種が、ガリウム、ジルコニウム、鉛、又はルテチウム放射性核種である、上記［２７］に記載のコンジュゲート。
［２９］前記放射性核種が、α放射体である、上記［１］～［２８］のいずれかに記載のコンジュゲート。
［３０］前記放射性核種が、β放射体である、上記［１］～［２８］のいずれかに記載のコンジュゲート。
［３１］前記薬物動態修飾部分が、ポリエチレングリコール（ＰＥＧ）基、又はポリエチルオキサゾリン（ＰＥＯＸ）基、又はポリ－（２）メチル－（２）－オキサゾールアミン（ＰＯＺ）、又はポリサルコシン、又はポリ（２－ヒドロキシプロピル）メタクリルアミド（ｐＨＰＭＡ）基である、上記［１］～［３０］のいずれかに記載のコンジュゲート。
［３２］前記薬物動態修飾部分が、ポリエチレングリコール（ＰＥＧ）基である、上記［３１］に記載のコンジュゲート。
［３３］前記薬物動態修飾部分が、４００～２４００ダルトンの範囲の平均分子量を有する、上記［３１］に記載のコンジュゲート。
［３４］前記デンドリマーが、２～５世代の構成ユニットを有する、上記［１］～［３３］のいずれかに記載のコンジュゲート。
［３５］前記コアユニットが、
［３６］前記構成ユニットが、リジン残基又はそれらの類似体である、上記［１］～［３５］のいずれかに記載のコンジュゲート。
［３７］前記構成ユニットが、それぞれ、
［３８］前記コンジュゲートが、例示コンジュゲートのいずれかである、上記［１］～［３７］のいずれかに記載のコンジュゲート。
［３９］上記［１］～［３８］のいずれかに記載の複数のコンジュゲートを含む組成物。
［４０］薬学的組成物であって、
ｉ）上記［１］～［３８］のいずれかに記載のコンジュゲートと、
ｉｉ）薬剤的に許容される賦形剤と、を含む、薬学的組成物。
［４１］療法若しくは画像化において使用するための、上記［１］～［３８］のいずれかに記載のコンジュゲート、又は上記［４０］に記載の薬学的組成物。
［４２］がんの治療に使用するための、上記［１］～［３８］のいずれかに記載のコンジュゲート、又は上記［４０］に記載の薬学的組成物。
［４３］がんの治療のための医薬品の製造における、上記［１］～［３８］のいずれかに記載のコンジュゲート、又は上記［３９］に記載の組成物、又は上記［４０］に記載の薬学的組成物の、使用。
［４４］対象におけるがんを治療する方法であって、治療有効量の上記［１］～［３８］のいずれかに記載のコンジュゲート、又は上記［３９］に記載の組成物、又は上記［４０］に記載の薬学的組成物を、前記対象に投与することを含む、方法。
［４５］前記がんが、前立腺がん、膵臓がん、胃腸がん、肺がん、乳がん、又は脳がんである、上記［４１］～［４４］のいずれかに記載の方法、使用、又は使用のためのコンジュゲート若しくは組成物。
［４６］前記コンジュゲートが、更なる活性剤と組み合わせて投与される、上記［４１］～［４５］のいずれかに記載の方法、使用、又は使用のためのコンジュゲート若しくは組成物。
［４７］上記［１］～［３８］のいずれかに記載の治療用コンジュゲートを生成するためのキットであって、
ａ）上記［１～２４］、［２６］、及び［３１］～［３８］のいずれかに記載のコンジュゲートと、
ｂ）放射性核種と、を含む、キット。
Results As shown in Figure 19 and the table below, both the targeted radionuclide dendrimer (compound SRS-2-304) and the non-targeted radionuclide dendrimer (compound RH-3-160) were effective in suppressing tumor growth, with the targeted dendrimer being the most effective. Figure 20 shows no tumor regrowth at 67 days for the targeted (compound SRS-2-304) at 177 Lu doses of 15 mBq and 2 x 9 MBq.
[1] A dendrimer-targeting agent conjugate comprising:
a) a dendrimer
i) a core unit (C), and
ii) comprises a building unit (BU),
The dendrimer has constitutional units of generations 2 to 6,
a dendrimer, the core unit being covalently attached to at least two constituent units;
b) a targeting agent covalently linked to said dendrimer by a spacer group;
c) one or more first end groups attached to an outermost building block of the dendrimer, the first end groups comprising a complexing group for complexing a radionuclide;
d) one or more second terminal groups attached to an outermost building block of the dendrimer, the second terminal groups comprising a pharmacokinetic-modifying moiety.
Or its salt.
[2] The conjugate according to [1] above, wherein the targeting agent is a peptide moiety having a molecular weight of up to about 150 kDa, or up to about 110 KDa, or up to about 80 KDa, or up to about 55 KDa, or up to about 16 kDa, and comprising an antigen-binding site.
[3] The conjugate according to [2] above, wherein the targeting agent is a peptide moiety having a molecular weight of up to about 80 kDa and comprising an antigen-binding site.
[4] The conjugate according to any one of the above [1] to [3], wherein the targeting agent is selected from an antibody, a heavy chain antibody, an ScFV-Fc, a Fab, a Fab2, an Fv, an scFv, or a single domain antibody.
[5] The conjugate according to any one of the above [1] to [4], wherein the targeting agent comprises or consists of a heavy chain variable (V H ) domain.
[6] The conjugate according to any one of the above [1] to [5], wherein the targeting agent comprises or consists of a light chain variable (V L ) domain.
[7] The conjugate according to any one of the above [1] to [6], wherein the targeting agent has a molecular weight of about 5 kDa to about 30 kDa.
[8] The conjugate according to [7] above, wherein the targeting agent has a molecular weight of about 3 kDa to about 20 kDa.
[9] The conjugate according to any one of [1] to [8] above, wherein the targeting agent comprises fewer than 120 amino acid residues.
[10] The conjugate according to any one of the above [1] to [9], wherein the targeting agent is a HER2 targeting agent.
[11] The conjugate described in [10] above, wherein the targeting agent is a HER2 nanobody.
[12] The conjugate according to any of the above [1] to [11], wherein the targeting agent comprises or consists of any of the targeting agent amino acid sequences described herein.
[13] The conjugate according to [1] above, wherein the targeting agent is a small molecule.
[14] The conjugate described in [13] above, wherein the targeting agent is a small molecule that binds to PSMA.
[15] The conjugate according to [14] above, wherein the targeting agent is a DUPA analogue.
[16] The conjugate according to [13] above, wherein the targeting agent is a FAP binding group.
[17] The conjugate according to any one of the above-mentioned [1] to [16], wherein the covalent linkage between the targeting agent and the spacer group is formed by a reaction between complementary reactive functional groups present on the targeting agent-containing intermediate and the dendrimer-containing intermediate.
[18] The conjugate according to [17] above, wherein the intermediate comprising the targeting agent comprises a non-natural amino acid residue, the non-natural amino acid residue having a side chain comprising a reactive functional group.
[19] The conjugate according to [18] above, wherein the unnatural amino acid residue is a 4-azidophenylalanine residue.
[20] The conjugate according to [17] above, wherein the intermediate comprising the targeting agent comprises a reactive cysteine residue.
[21] The conjugate according to any one of the above [1] to [20], wherein the spacer group comprises a PEG group.
[22] The conjugate according to any of the above-mentioned [1] to [21], wherein the targeting agent is covalently linked to the spacer group at or near the C-terminus of the targeting agent.
[23] The conjugate according to [18] or [19] above, wherein the intermediate comprising the dendrimer comprises a reactive functional group which is an alkyne group.
[24] The conjugate according to [23] above, wherein the alkyne group is a dibenzocyclooctyne group.
[25] The conjugate according to any one of [1] to [24] above, wherein the first terminal group further comprises a radionuclide complexed to a complexing group.
[26] The conjugate according to any one of the above [1] to [25], wherein the complexing group is a DOTA, benzyl-DOTA, NOTA, DTPA, sarcophadin, macropa, DFO, PEPA, or EDTA group.
[27] The conjugate according to any of the above [1] to [26], wherein the radionuclide in the radionuclide-containing moiety is a lutetium, gallium, zirconium, actinium, bismuth, astatine, technetium, lead, yttrium, or copper radionuclide.
[28] The conjugate according to [27] above, wherein the radionuclide is a gallium, zirconium, lead, or lutetium radionuclide.
[29] The conjugate according to any one of the above [1] to [28], wherein the radioactive nuclide is an alpha emitter.
[30] The conjugate according to any one of the above [1] to [28], wherein the radioactive nuclide is a β-emitter.
[31] The conjugate according to any one of the above-mentioned [1] to [30], wherein the pharmacokinetic modifying moiety is a polyethylene glycol (PEG) group, or a polyethyloxazoline (PEOX) group, or a poly-(2)methyl-(2)-oxazolamine (POZ), or a polysarcosine, or a poly(2-hydroxypropyl)methacrylamide (pHPMA) group.
[32] The conjugate according to [31] above, wherein the pharmacokinetic modifying moiety is a polyethylene glycol (PEG) group.
[33] The conjugate according to [31] above, wherein the pharmacokinetic modifying moiety has an average molecular weight in the range of 400 to 2400 daltons.
[34] The conjugate according to any one of [1] to [33] above, wherein the dendrimer has constitutional units of generations 2 to 5.
[35] The core unit is
[36] The conjugate according to any one of the above [1] to [35], wherein the constitutional unit is a lysine residue or an analog thereof.
[37] The structural units are each
[38] The conjugate according to any one of [1] to [37] above, wherein the conjugate is any one of the exemplary conjugates.
[39] A composition comprising a plurality of conjugates according to any one of [1] to [38] above.
[40] A pharmaceutical composition comprising:
i) a conjugate according to any one of the above [1] to [38];
ii) a pharma- ceutically acceptable excipient.
[41] The conjugate according to any one of [1] to [38] above, or the pharmaceutical composition according to [40] above, for use in therapy or imaging.
[42] The conjugate according to any one of [1] to [38] above, or the pharmaceutical composition according to [40] above, for use in treating cancer.
[43] Use of the conjugate according to any one of [1] to [38] above, or the composition according to [39] above, or the pharmaceutical composition according to [40] above, in the manufacture of a medicine for the treatment of cancer.
[44] A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate according to any one of [1] to [38] above, or the composition according to [39] above, or the pharmaceutical composition according to [40] above.
[45] The method, use, or conjugate or composition for use according to any one of [41] to [44] above, wherein the cancer is prostate cancer, pancreatic cancer, gastrointestinal cancer, lung cancer, breast cancer, or brain cancer.
[46] The method, use, or conjugate or composition for use according to any one of [41] to [45] above, wherein the conjugate is administered in combination with a further active agent.
[47] A kit for producing a therapeutic conjugate according to any one of [1] to [38] above, comprising:
a) a conjugate according to any one of the above [1 to 24], [26], and [31] to [38];
b) a radionuclide.
Claims (21)
ａ）デンドリマーであって
ｉ）コアユニット（Ｃ）、及び
ｉｉ）構成ユニット（ＢＵ）を含み、
前記デンドリマーが、２～６世代の構成ユニットを有し、
前記コアユニットが、少なくとも２つの構成ユニットに共有結合により付着している、デンドリマーと、
ｂ）スペーサー基により前記デンドリマーに共有結合により連結している、標的化剤と、
ｃ）前記デンドリマーの最も外側の構成ユニットに付着している１つ以上の第１の末端基であって、前記第１の末端基が、放射性核種を錯体化するための錯体化基を含む、第１の末端基と、
ｄ）前記デンドリマーの最も外側の構成ユニットに付着している１つ以上の第２の末端基であって、前記第２の末端基が、薬物動態修飾部分を含む、第２の末端基と、を含む、コンジュゲート
又はその塩。 1. A dendrimer-targeting agent conjugate comprising:
a) a dendrimer comprising: i) a core unit (C); and ii) a constitutional unit (BU);
The dendrimer has constitutional units of generations 2 to 6,
a dendrimer, the core unit being covalently attached to at least two constituent units;
b) a targeting agent covalently linked to said dendrimer by a spacer group;
c) one or more first end groups attached to an outermost building block of the dendrimer, the first end groups comprising a complexing group for complexing a radionuclide;
d) one or more second terminal groups attached to an outermost building block of the dendrimer, said second terminal groups comprising a pharmacokinetically modifying moiety; or a salt thereof.
任意選択的に前記標的化剤を含む前記中間体が、非天然アミノ酸残基を含み、前記非天然アミノ酸残基が、反応性官能基を含む側鎖を有し、任意選択的に前記非天然アミノ酸残基が、４－アジドフェニルアラニン残基であり、または
任意選択的に前記標的化剤を含む前記中間体が、反応性システイン残基を含む、請求項１～６のいずれか一項に記載のコンジュゲート。 a covalent linkage between the targeting agent and the spacer group is formed by reaction between complementary reactive functional groups present on the targeting agent-containing intermediate and the dendrimer-containing intermediate ;
wherein the intermediate, optionally comprising the targeting agent, comprises a non-natural amino acid residue, the non-natural amino acid residue having a side chain that comprises a reactive functional group, optionally the non-natural amino acid residue is a 4-azidophenylalanine residue; or
The conjugate of any one of claims 1 to 6 , wherein the intermediate, optionally including the targeting agent, comprises a reactive cysteine residue.
ｉ）請求項１～１７のいずれか一項に記載のコンジュゲートと、
ｉｉ）薬剤的に許容される賦形剤と、を含む、薬学的組成物。 1. A pharmaceutical composition comprising:
i) a conjugate according to any one of claims 1 to 17 ;
ii) a pharma- ceutically acceptable excipient.
ａ）請求項１～１０、１２、及び１６～１７のいずれか一項に記載のコンジュゲートと、
ｂ）放射性核種と、を含む、キット。 A kit for producing a therapeutic conjugate according to any one of claims 1 to 17 , comprising:
a) a conjugate according to any one of claims 1 to 10, 12 and 16 to 17 ;
b) a radionuclide.
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| PCT/AU2021/050554 WO2021243415A1 (en) | 2020-06-03 | 2021-06-03 | Therapeutic conjugates |
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