JP2020518673A - 二官能性キレートの薬物動態増強及びその使用 - Google Patents
二官能性キレートの薬物動態増強及びその使用 Download PDFInfo
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- 229940069328 povidone Drugs 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
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- 239000004208 shellac Substances 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
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- 239000008109 sodium starch glycolate Substances 0.000 description 1
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- 230000009870 specific binding Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006169 tetracyclic group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical group C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 229930004006 tropane Natural products 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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Abstract
Description
本出願は、2017年5月5日に出願された「二官能性キレートの薬物動態増強及びその使用」という表題の米国仮特許出願第62/502,260号に対する優先権及びその利益を主張し、その内容全体があらゆる目的で参照により本明細書に組み込まれる。
A-L1-(L2)n-B
式I
[式中、Aはキレート化部分又はその金属錯体であり;
L1は、置換されていてもよいC1〜C6アルキル、置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール又はヘテロアリールであり;
Bは、治療的部分、標的化部分、若しくは架橋基、又はその薬学的に許容される塩であり;
nは1〜5であり;
L2はそれぞれ独立に、構造:
(-X1-L3-Z1-)
式II
(式中、X1は、C=O(NR1)、C=S(NR1)、OC=O(NR1)、NR1C=O(O)、NR1C=O(NR1)、-CH2PhC=O(NR1)、-CH2Ph(NH)C=S(NR1)、O、NR1であり、R1は、H又は置換されていてもよいC1〜C6アルキル若しくは置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール若しくはヘテロアリールであり;L3は、置換されていてもよいC1〜C50アルキル又は置換されていてもよいC1〜C50ヘテロアルキル又はC5〜C20ポリエチレングリコールであり;Z1は、CH2、C=O、C=S、OC=O、NR1C=O、NR1であり、R1は水素又は置換されていてもよいC1〜C6アルキル、ピロリジン-2,5-ジオンである)
を有する]
を有する化合物を特徴とする。
式中、Y1は、Hであり、Y2は、L1-(L2)n-Bである)
を有する。
を有する。
本明細書で使用される用語「アシル」は、本明細書で定義されるカルボニル基を介して、親分子基に結合される、水素又は本明細書で定義されるアルキル基(例えば、ハロアルキル基)を表し、ホルミル(すなわち、カルボキシアルデヒド基)、アセチル、トリフルオロアセチル、プロピオニル、ブタノイル等によって例示される。例示的な非置換アシル基は、1〜7個、1〜11個、又は1〜21個の炭素を含む。一部の実施形態では、アルキル基は、1、2、3、又は4個の本明細書に記載の置換基で更に置換される。
テトラヒドロチエニル、ジヒドロチエニル、ジヒドロインドリル、ジヒドロキノリル、テトラヒドロキノリル、テトラヒドロイソキノリル、ジヒドロイソキノリル、ピラニル、ジヒドロピラニル、ジチアゾリル、ベンゾフラニル、イソベンゾフラニル、ベンゾチエニル等が挙げられる。更に他の例示的なヘテロシクリルとしては、2,3,4,5-テトラヒドロ-2-オキソ-オキサゾリル; 2,3-ジヒドロ-2-オキソ-1H-イミダゾリル; 2,3,4,5-テトラヒドロ-5-オキソ-1H-ピラゾリル(例えば、2,3,4,5-テトラヒドロ-2-フェニル-5-オキソ-1H-ピラゾリル); 2,3,4,5-テトラヒドロ-2,4-ジオキソ-1H-イミダゾリル(例えば、2,3,4,5-テトラヒドロ-2,4-ジオキソ-5-メチル-5-フェニル-1H-イミダゾリル); 2,3-ジヒドロ-2-チオキソ-1,3,4-オキサジアゾリル(例えば、2,3-ジヒドロ-2-チオキソ-5-フェニル-1,3,4-オキサジアゾリル); 4,5-ジヒドロ-5-オキソ-1H-トリアゾリル(例えば、4,5-ジヒドロ-3-メチル-4-アミノ5-オキソ-1H-トリアゾリル); 1,2,3,4-テトラヒドロ-2,4-ジオキソピリジニル(例えば、1,2,3,4-テトラヒドロ-2,4-ジオキソ-3,3-ジエチルピリジニル); 2,6-ジオキソ-ピペリジニル(例えば、2,6-ジオキソ-3-エチル-3-フェニルピペリジニル); 1,6-ジヒドロ-6-オキソピリジミニル; 1,6-ジヒドロ-4-オキソピリミジニル(例えば、2-(メチルチオ)-1,6-ジヒドロ-4-オキソ-5-メチルピリミジン-1-イル); 1,2,3,4-テトラヒドロ-2,4-ジオキソピリミジニル(例えば、1,2,3,4-テトラヒドロ-2,4-ジオキソ-3-エチルピリミジニル); 1,6-ジヒドロ-6-オキソ-ピリダジニル(例えば、1,6-ジヒドロ-6-オキソ-3-エチルピリダジニル); 1,6-ジヒドロ-6-オキソ-1,2,4-トリアジニル(例えば、1,6-ジヒドロ-5-イソプロピル-6-オキソ-1,2,4-トリアジニル); 2,3-ジヒドロ-2-オキソ-1H-インドリル(例えば、3,3-ジメチル-2,3-ジヒドロ-2-オキソ-1H-インドリル及び2,3-ジヒドロ-2-オキソ-3,3'-スピロプロパン-1H-インドール-1-イル); 1,3-ジヒドロ-1-オキソ-2H-イソ-インドリル; 1,3-ジヒドロ-1,3-ジオキソ-2H-イソ-インドリル; 1H-ベンゾピラゾリル(例えば、1-(エトキシカルボニル)-1H-ベンゾピラゾリル); 2,3-ジヒドロ-2-オキソ-1H-ベンズイミダゾリル(例えば、3-エチル-2,3-ジヒドロ-2-オキソ-1H-ベンズイミダゾリル); 2,3-ジヒドロ-2-オキソ-ベンゾオキサゾリル(例えば、5-クロロ-2,3-ジヒドロ-2-オキソ-ベンゾオキサゾリル); 2,3-ジヒドロ-2-オキソ-ベンゾオキサゾリル;2-オキソ-2H-ベンゾピラニル; 1,4-ベンゾジオキサニル; 1,3-ベンゾジオキサニル; 2,3-ジヒドロ-3-オキソ,4H-1,3-ベンゾチアジニル; 3,4-ジヒドロ-4-オキソ-3H-キナゾリニル(例えば、2-メチル-3,4-ジヒドロ-4-オキソ-3H-キナゾリニル); 1,2,3,4-テトラヒドロ-2,4-ジオキソ-3H-キナゾリル(例えば、1-エチル-1,2,3,4-テトラヒドロ-2,4-ジオキソ-3H-キナゾリル); 1,2,3,6-テトラヒドロ-2,6-ジオキソ-7H-プリニル(例えば、1,2,3,6-テトラヒドロ-1,3-ジメチル-2,6-ジオキソ-7H-プリニル); 1,2,3,6-テトラヒドロ-2,6-ジオキソ-1H-プリニル(例えば、1,2,3,6-テトラヒドロ-3,7-ジメチル-2,6-ジオキソ-1H-プリニル); 2-オキソベンゾ[c,d]インドリル; 1,1-ジオキソ-2H-ナフタ[1,8-c,d]イソチアゾリル;及び1,8-ナフチレンジカルボキサミドが挙げられる。更なる複素環としては、3,3a,4,5,6,6a-ヘキサヒドロ-ピロロ[3,4-b]ピロール-(2H)-イル及び2,5-ジアザビシクロ[2.2.1 ]ヘプタン-2-イル、ホモピペラジニル(又はジアゼパニル)、テトラヒドロピラニル、ジチアゾリル、ベンゾフラニル、ベンゾチエニル、オキセパニル、チエパニル、アゾカニル、オキセカニル、及びチオカニルが挙げられる。複素環基はまた、式
の基を含む。本明細書に記載のヘテロシクリル基のいずれかを、(1)C1〜7アシル(例えば、カルボキシアルデヒド);(2)C1〜20アルキル(例えば、C1〜6アルキル、C1〜6アルコキシ-C1〜6アルキル、C1〜6アルキルスルフィニル-C1〜6アルキル、アミノ-C1〜6アルキル、アジド-C1〜6アルキル、(カルボキシアルデヒド)-C1〜6アルキル、ハロ-C1〜6アルキル(例えば、ペルフルオロアルキル)、ヒドロキシ-C1〜6アルキル、ニトロ-C1〜6アルキル、又はC1〜6チオアルコキシ-C1〜6アルキル);(3)C1〜20アルコキシ(例えば、ペルフルオロアルコキシ等のC1〜6アルコキシ);(4)C1〜6アルキルスルフィニル;(5)C6〜10アリール;(6)アミノ;(7)C1〜6アルク-C6〜10アリール;(8)アジド;(9)C3〜8シクロアルキル;(10)C1〜6アルク-C3〜8シクロアルキル;(11)ハロ;(12)C1〜12ヘテロシクリル(例えば、C2〜12ヘテロアリール);(13)(C1〜12ヘテロシクリル)オキシ;(14)ヒドロキシ;(15)ニトロ;(16)C1〜20チオアルコキシ(例えば、C1〜6チオアルコキシ);(17)-(CH2)qCO2RA'(式中、qは0〜4の整数であり、RA'は、(a)C1〜6アルキル、(b)C6〜10アリール、(c)水素、及び(d)C1〜6アルク-C6〜10アリールからなる群から選択される);(18)-(CH2)qCONRB'RC'(式中、qは0〜4の整数であり、RB'及びRC'は、(a)水素、(b)C1〜6アルキル、(c)C6〜10アリール、及び(d)C1〜6アルク-C6〜10アリールからなる群から独立に選択される);(19)-(CH2)qSO2RD'(式中、qは0〜4の整数であり、RD'は、(a)C1〜6アルキル、(b)C6〜10アリール、及び(c)C1〜6アルク-C6〜10アリールからなる群から選択される);(20)-(CH2)qSO2NRE'RF'(式中、qは0〜4の整数であり、RE'及びRF'はそれぞれ独立に、(a)水素、(b)C1〜6アルキル、(c)C6〜10アリール、及び(d)C1〜6アルク-C6〜10アリールからなる群から選択される);(21)チオール;(22)C6〜10アリールオキシ;(23)C3〜8シクロアルコキシ;(24)アリールアルコキシ;(25)C1〜6アルク-C1〜12ヘテロシクリル(例えば、C1〜6アルク-C1〜12ヘテロアリール);(26)オキソ;(27)(C1〜12ヘテロシクリル)イミノ;(28)C2〜20アルケニル;並びに(29)C2〜20アルキニルからなる群から独立に選択される1、2、3、4又は5個の置換基で置換してもよい。一部の実施形態では、これらの基はそれぞれ、本明細書に記載のように更に置換することができる。例えば、C1-アルカリール又はC1-アルクヘテロシクリルのアルキレン基を、オキソ基で更に置換して、対応するアリールオイル及び(ヘテロシクリル)オイル置換基を得ることができる。
本明細書で使用される用語「組み合わせて投与される」又は「組合せ投与」は、2つ以上の多い薬剤が、同時に、又は患者に対するそれぞれの薬剤の効果の重複があってもよいような間隔内で対象に投与されることを意味する。一部の実施形態では、それらは、互いに90日以内(例えば、80、70、60、50、40、30、20、10、5、4、3、2、若しくは1日以内)、28日以内(例えば、14、7、6、5、4、3、2、若しくは1日以内)、24時間以内(例えば、12、6、5、4、3、2、若しくは1時間以内)、又は約60、30、15、10、5、若しくは1分以内に投与される。一部の実施形態では、薬剤の投与は、組合せ(例えば、相乗)効果が達成されるように十分に近い間隔で行われる。
治療的部分は、治療利益を提供する任意の分子又は分子の任意の部分を含む。一部の実施形態では、治療的部分は、タンパク質又はポリペプチド、例えば、抗体、その抗原結合断片である。一部の実施形態では、治療的部分は、低分子である。標的化部分は、所与の標的に結合する任意の分子又は分子の任意の部分を含む。一部の実施形態では、標的化部分は、抗体又はその抗原結合断片、ナノボディ、アフィボディ、及びIII型フィブロネクチンドメインに由来するコンセンサス配列(例えば、Centyrin又はAdnectin)等のタンパク質又はポリペプチドである。
ポリペプチドは、例えば、様々な血液作用剤(例えば、エリスロポエチン、血液凝固因子等を含む)、インターフェロン、コロニー刺激因子、抗体、酵素、及びホルモンのいずれかを含む。特定のポリペプチドの同一性は、本開示を限定することを意図されず、目的の任意のポリペプチドは、本発明の方法におけるポリペプチドであってもよい。
IgG抗体は、ジスルフィド結合によって一緒に連結された、2つの同一の軽鎖ポリペプチドと、2つの同一の重鎖ポリペプチドとからなる。それぞれの鎖のアミノ末端に位置する第1のドメインは、アミノ酸配列において可変性であり、それぞれ個々の抗体に見出される抗体結合特異性を提供する。これらのものは、可変重鎖(VH)及び可変軽鎖(VL)領域として公知である。それぞれの鎖の他のドメインは、アミノ酸配列において比較的不変であり、定常重鎖(CH)及び定常軽鎖(CL)領域として公知である。IgG抗体については、軽鎖は、1個の可変領域(VL)と、1個の定常領域(CL)とを含む。IgG重鎖は、可変領域(VH)、第1の定常領域(CH1)、ヒンジ領域、第2の定常領域(CH2)、及び第3の定常領域(CH3)を含む。IgE及びIgM抗体では、重鎖は、追加の定常領域(CH4)を含む。
インスリン様増殖因子1受容体は、インスリン様増殖因子1(IGF-1)及び2(IGF-2)によって活性化されるヒト細胞表面上に見出される膜貫通タンパク質である。IGF-1Rは、乳がん、非小細胞肺がん、前立腺がん、結腸がん、肉腫、及び副腎皮質癌を含むいくつかのがんに関与し、高レベルのIGF-1Rが、これらのがんの腫瘍細胞の表面上に発現される。
ナノボディは、単一のモノマー可変抗体ドメインからなる抗体断片である。ナノボディはまた、単一ドメイン抗体とも呼んでもよい。抗体と同様、ナノボディは特定の抗原に選択的に結合する。ナノボディは、重鎖可変ドメイン又は軽鎖ドメインであってもよい。ナノボディは、天然に存在してもよく、又は生物学的操作の産物であってもよい。ナノボディを、部位特異的突然変異誘発又は変異原性スクリーニング(例えば、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作することができる。
アフィボディは、特定の抗原に結合するように操作されたポリペプチド又はタンパク質である。そのため、アフィボディは、抗体のある特定の機能を模倣すると考えてよい。アフィボディは、ブドウ球菌プロテインAの免疫グロブリン結合領域中のBドメインの操作されたバリアントであってもよい。アフィボディは、Fab領域に対する親和性がより低いBドメインである、Zドメインの操作されたバリアントであってもよい。アフィボディを、部位特異的突然変異誘発又は変異原性スクリーニング(例えば、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作することができる。
III型フィブロネクチンドメインは、様々な細胞外タンパク質に見出される進化的に保存されたタンパク質ドメインである。III型フィブロネクチンドメインは、特定の抗原に選択的に結合することができる分子を産生するための分子足場として使用されている。選択的結合のために操作されたIII型フィブロネクチンドメイン(FN3)のバリアントを、モノボディと呼ぶこともできる。FN3ドメインを、部位特異的突然変異誘発又は変異原性スクリーニング(例えば、CISディスプレイ、ファージディスプレイ、酵母ディスプレイ、細菌ディスプレイ、mRNAディスプレイ、リボソームディスプレイ)によって生物学的に操作することができる。
本発明のポリペプチドは、改変アミノ酸配列を有してもよい。改変ポリペプチドは、対応する参照ポリペプチドと実質的に同一であってもよい(例えば、改変ポリペプチドのアミノ酸配列は、参照ポリペプチドのアミノ酸配列に対する少なくとも50%、60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、又は100%の同一性を有してもよい)。ある特定の実施形態では、改変は、所望の生物活性を有意に破壊しない。改変は、元のポリペプチドの生物活性を低下させてもよく(例えば、少なくとも5%、10%、20%、25%、35%、50%、60%、70%、75%、80%、90%、若しくは95%)、それに対する効果がなくてもよく、又はそれを増加させてもよい(例えば、少なくとも5%、10%、25%、50%、100%、200%、500%、若しくは1000%)。改変ポリペプチドは、in vivoでの安定性、バイオアベイラビリティ、毒性、免疫学的活性、免疫学的同一性、及びコンジュゲーション特性等の、ポリペプチドの特徴を有するか、又はそれを最適化してもよい。
架橋基は、共有結合によって2つ以上の分子を連結することができる反応基である。架橋基を使用して、リンカー及びキレート化部分を、治療的部分又は標的化部分に結合することができる。また、架橋基を使用して、リンカー及びキレート化部分を、in vivoで標的に結合することもできる。一部の実施形態では、架橋基は、アミノ反応性若しくはチオール反応性架橋基、又はソルターゼ媒介性カップリングである。一部の実施形態では、アミノ反応性、メチオニン反応性又はチオール反応性架橋基は、ヒドロキシスクシンイミドエステル、2,3,5,6-テトラフルオロフェノールエステル、4-ニトロフェノールエステル等の活性化エステル又はイミデート、無水物、チオール、ジスルフィド、マレイミド、アジド、アルキン、歪みアルキン、歪みアルケン、ハロゲン、スルホネート、ハロアセチル、アミン、ヒドラジド、ジアジリン、ホスフィン、テトラジン、イソチオシアネート、若しくはオキサジリジンを含む。一部の実施形態では、ソルターゼ認識配列は、末端グリシン-グリシン-グリシン(GGG)及び/又はLPTXGアミノ酸配列(式中、Xは任意のアミノ酸である)を含んでもよい。当業者であれば、本発明の実施における架橋基の使用が、本明細書に開示される特定の構築物に限定されず、むしろ他の公知の架橋基を含んでもよいことを理解できる。
検出剤は、ポリペプチド、例えば、抗体又はその抗原結合断片にコンジュゲートされて投与され、抗原を含有する細胞を探すことによる疾患の診断、放射線処置計画、又は疾患の処置において有用である分子又は原子である。有用な検出剤としては、限定されるものではないが、放射性同位体、染料(ビオチン-ストレプトアビジン複合体を含むもの等)、造影剤、蛍光化合物又は分子、発光剤、及び磁気共鳴イメージング(MRI)のための増強剤(例えば、常磁性イオン)が挙げられる。ポリペプチド成分に検出剤を搭載するために、それを、検出剤又は複数の検出剤に結合するリンカーを有する試薬と反応させる必要があり得る。
検出剤としてのその使用のための当業界で公知の放射性同位体及び放射性核種としては、限定されるものではないが、3H、14C、15N、18F、35S、47Sc、55Co、60Cu、61Cu、62Cu、64Cu、67Cu、75Br、76Br、77Br、89Zr、86Y、87Y、90Y、97Ru、99Tc、99mTc、105Rh、109Pd、111In、123I、124I、125I、131I、149Pm、149Tb、153Sm、166Ho、177Lu、186Re、188Re、198Au、199Au、203Pb、211At、212Pb、212Bi、213Bi、223Ra、225Ac、227Th、229Th、66Ga、67Ga、68Ga、82Rb、117mSn、201Tlが挙げられる。
検出剤としてのその使用のための当業界で公知のキレート化部分としては、限定されるものではないが、DOTA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸)、DOTMA((1R,4R,7R,10R)-α,α',α'',α'''-テトラメチル-1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸)、DOTAM(1,4,7,10-テトラキス(カルバモイルメチル)-1,4,7,10-テトラアザシクロドデカン)、DOTPA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラプロピオン酸)、DO3AM-酢酸(2-(4,7,10-トリス(2-アミノ-2-オキソエチル)-1,4,7,10-テトラアザシクロドデカン-1-イル)酢酸)、DOTA-GAアンヒドリド(2,2',2''-(10-(2,6-ジオキソテトラヒドロ-2H-ピラン-3-イル)-1,4,7,10-テトラアザシクロドデカン-1,4,7-トリイル)三酢酸、DOTP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラ(メチレンホスホン酸))、DOTMP(1,4,6,10-テトラアザシクロデカン-1,4,7,10-テトラメチレンホスホン酸)、DOTA-4AMP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラキス(アセタミド-メチレンホスホン酸)、CB-TE2A(1,4,8,11-テトラアザビシクロ[6.6.2]ヘキサデカン-4,11-二酢酸)、NOTA(1,4,7-トリアザシクロノナン-1,4,7-三酢酸)、NOTP(1,4,7-トリアザシクロノナン-1,4,7-トリ(メチレンホスホン酸)、TETPA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-テトラプロピオン酸)、TETA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-四酢酸)、HEHA(1,4,7,10,13,16-ヘキサアザシクロヘキサデカン-1,4,7,10,13,16-六酢酸)、PEPA(1,4,7,10,13-ペンタアザシクロペンタデカン-N,N',N'',N''',N''''-五酢酸)、H4Octapa(N,N'-ビス(6-カルボキシ-2-ピリジルメチル)-エチレンジアミン-N,N'-二酢酸)、H2Dedpa(1,2-[[6-(カルボキシ)-ピリジン-2-イル]-メチルアミノ]エタン)、H6phospa(N,N'-(メチレンホスホネート)-N,N'-[6-(メトキシカルボニル)ピリジン-2-イル]-メチル-1,2-ジアミノエタン)、TTHA(トリエチレンテトラミン-N,N,N',N'',N''',N'''-六酢酸)、DO2P(テトラアザシクロドデカンジメタンホスホン酸)、HP-DO3A(ヒドロキシプロピルテトラアザシクロドデカン三酢酸)、EDTA(エチレンジアミン四酢酸)、デフェロキサミン、DTPA(ジエチレントリアミン五酢酸)、DTPA-BMA(ジエチレントリアミン五酢酸-ビスメチルアミド)、HOPO(オクタデンテートヒドロキシピリジノン)、又はポルフィリンが挙げられる。キレート化基を、マンガン、鉄、及びガドリニウム等の金属並びに47Sc、55Co、60Cu、61Cu、62Cu、64Cu、67Cu、66Ga、67Ga、68Ga、82Rb、86Y、87Y、90Y、97Ru、99mTc、105Rh、109Pd、111In、117mSn、149Tb、149Pm、153Sm、177Lu、186Re、188Re、199Au、201Tl、203Pb、212Pb、212Bi、213Bi、225Ac、及び227Th等の同位体(例えば、60〜4,000keVの一般エネルギー範囲の同位体)との金属キレート組合せにおいて使用することができる。
本発明のリンカーは、式I:
A-L1-(L2)n-B
式I
[式中、Aはキレート化部分又はその金属錯体であり;
L1は、置換されていてもよいC1〜C6アルキル、置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール又はヘテロアリールであり;
Bは、治療的部分、標的化部分、若しくは架橋基、又はその薬学的に許容される塩であり;
nは1〜5であり;
L2はそれぞれ独立に、構造:
(-X1-L3-Z1-)
式II
(式中、X1は、C=O(NR1)、C=S(NR1)、OC=O(NR1)、NR1C=O(O)、NR1C=O(NR1)、-CH2PhC=O(NR1)、-CH2Ph(NH)C=S(NR1)、O、NR1であり、R1は、H又は置換されていてもよいC1〜C6アルキル若しくは置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール若しくはヘテロアリールであり;
L3は、置換されていてもよいC1〜C50アルキル又は置換されていてもよいC1〜C50ヘテロアルキル又はC5〜C20ポリエチレングリコールであり;
Z1は、CH2、C=O、C=S、OC=O、NR1C=O、NR1であり、R1は水素又は置換されていてもよいC1〜C6アルキル、ピロリジン-2,5-ジオンである)
を有する]
の構造を有してもよい。
モジュールAは、検出剤(例えば、キレート化部分又はその金属錯体)の組込みのために含まれる。金属錯体は、イメージング放射性核種を含んでもよい。
本発明のリンカーは、式I:
A-L1-(L2)n-B
式I
[式中、Aはキレート化部分又はその金属錯体であり;
L1は、置換されていてもよいC1〜C6アルキル、置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール又はヘテロアリールであり;
Bは、治療的部分、標的化部分、若しくは架橋基、又はその薬学的に許容される塩であり;
nは1〜5であり;
L2はそれぞれ独立に、構造:
(-X1-L3-Z1-)
式II
(式中、X1は、C=O(NR1)、C=S(NR1)、OC=O(NR1)、NR1C=O(O)、NR1C=O(NR1)、-CH2PhC=O(NR1)、-CH2Ph(NH)C=S(NR1)、O、NR1であり、R1は、H又は置換されていてもよいC1〜C6アルキル若しくは置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール若しくはヘテロアリールであり;
L3は、置換されていてもよいC1〜C50アルキル又は置換されていてもよいC1〜C50ヘテロアルキル又はC5〜C20ポリエチレングリコールであり;
Z1は、CH2、C=O、C=S、OC=O、NR1C=O、NR1であり、R1は水素又は置換されていてもよいC1〜C6アルキル、ピロリジン-2,5-ジオンである)
を有する]
の構造を有してもよい。
モジュールBは、治療的部分(例えば、抗体、抗原結合断片)、標的化部分(例えば、ナノボディ、アフィボディ、III型フィブロネクチンドメインに由来するコンセンサス配列)、又は架橋基(例えば、アミノ反応性、チオール反応性架橋基、又はソルターゼ媒介性カップリング)である。
本発明はまた、治療有効量の本発明の化合物を含有する医薬組成物を特徴とする。組成物を、様々な薬物送達系における使用のために製剤化することができる。1又は複数の生理学的に許容される賦形剤又は担体を、適切な製剤のために組成物中に含有させることもできる。本発明における使用のための好適な製剤は、Remington's Pharmaceutical Sciences、Mack Publishing Company、Philadelphia、PA、第17版、1985に見出される。薬物送達のための方法の簡単な概説については、例えば、Langer(Science 249:1527〜1533頁、1990)を参照されたい。
一般的な材料及び方法
使用した抗体は、HuMIgG(Aldrich社、I4506)であった。ルテチウム-177は、0.05N塩酸溶液中の塩化ルテチウムとしてPerkin Elmer社から受領した。
4-{[11-オキソ-11-(2,3,5,6-テトラフルオロフェノキシ)ウンデシル]カルバモイル}-2-[4,7,10-トリス(カルボキシメチル)-1,4,7,10-テトラアザシクロドデカン-1-イル]ブタン酸(化合物B)の合成
二官能性キレート、4-{[11-オキソ-11-(2,3,5,6-テトラフルオロフェノキシ)ウンデシル]カルバモイル}-2-[4,7,10-トリス(カルボキシメチル)-1,4,7,10-テトラアザシクロドデカン-1-イル]ブタン酸(化合物B)を、図2に提供されるスキームに従って合成した。ACN(2.0mL)中の5-(tert-ブトキシ)-5-オキソ-4-(4,7,10-トリス(2-(tert-ブトキシ)-2-オキソエチル)-1,4,7,10-テトラアザシクロドデカン-1-イル)ペンタン酸(DOTA-GA-(tBu)4、50mg、0.07mmol)の溶液に、DSC(50mg、0.21mmol)、次いで、ピリジン(0.20mL、2.48mmol)を添加した。反応物を室温で1時間撹拌した。反応混合物に、11-アミノウンデカン酸(70mg、0.36mmol)、次いで、PBS溶液(1.0mL)を室温で添加した。反応物を室温で72時間撹拌した。反応混合物を、シリンジフィルターを用いて濾過し、方法6を使用する分取HPLCによって直接精製したところ、中間体2-A(71mg、74.8%)が得られた。
4-{[2-(2-{2-[3-オキソ-3-(2,3,5,6-テトラフルオロフェノキシ)プロポキシ]エトキシ}エトキシ)エチル]カルバモイル}-2-[4,7,10-トリス(カルボキシメチル)-1,4,7,10-テトラアザシクロドデカン-1-イル]ブタン酸(化合物C)の合成
二官能性キレート、4-{[2-(2-{2-[3-オキソ-3-(2,3,5,6-テトラフルオロフェノキシ)プロポキシ]エトキシ}エトキシ)エチル]カルバモイル}-2-[4,7,10-トリス(カルボキシメチル)-1,4,7,10-テトラアザシクロドデカン-1-イル]ブタン酸(化合物C)を、図3に提供されるスキームに従って合成した。ACN(8.0mL)中の5-(tert-ブトキシ)-5-オキソ-4-(4,7,10-トリス(2-(tert-ブトキシ)-2-オキソエチル)-1,4,7,10-テトラアザシクロドデカン-1-イル)ペンタン酸(DOTA-GA(tBu)4、100mg、0.143mmol)の溶液に、DSC(73mg、0.285mmol)及びピリジン(0.80mL、9.89mmol)を添加した。反応混合物を、周囲温度で90分撹拌した。この溶液を、100mLの丸底フラスコ中のアミノ-PEG3-酸(63mg、1.2mLのDMF中の0.285mmol)の半溶液に添加した。周囲温度で4時間後、反応物を、気流下で乾燥するまで濃縮することによって仕上げた。HPLC溶出法2によって粗材料を精製した(粗材料を6mLの20%ACN/H2O中に溶解した)。生成物を含有する画分をプールし、減圧下で濃縮した後、ACN(3×2mL)を用いて共蒸発させた。中間体1-Aが、82%の収率で得られた。
[177Lu]-化合物A-ヒトIgGの合成
化合物A(1.34μmol)を、酢酸ナトリウム緩衝液(20μL、pH6.5)に溶解し、重炭酸緩衝液(pH8.5)中の抗体ヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で45分後、抗体コンジュゲート産物を、HPLC SECカラムにより精製した(1mL/分、酢酸緩衝液(pH6.5、1mMアスコルビン酸)で溶出)。MALDI-TOF-MS(陽イオン):化合物A-ヒトIgG:実測値m/z 150360[M+H]+;ヒトIgG:実測値m/z 148339[M+H]+。
[177Lu]-化合物B-ヒトIgGの合成
化合物B(1.17μmol)を、酢酸ナトリウム緩衝液(0.117mL、pH6.5)に溶解した。化合物B溶液のアリコート(2μL、10nmol)を、重炭酸緩衝液(pH8.5)中のヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で1時間後、抗体コンジュゲート生成物を、Sephadex G-50樹脂充填カラムにより精製した。抗体コンジュゲート化合物A-ヒトIgGを、酢酸緩衝液(pH6.5)を用いてカラムから溶出させた。MALDI-TOF-MS(陽イオン):化合物B-ヒトIgG実測値m/z 149949[M+H]+; ヒトIgG実測値m/z 148540[M+H]+。
[177Lu]-化合物C-ヒトIgGの合成
化合物C(0.96μmol)を、酢酸ナトリウム緩衝液(95μL、pH6.5)に溶解した。化合物C溶液のアリコート(2μL、20nmol)を、重炭酸緩衝液(pH8.5)中のヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で1時間後、抗体コンジュゲート生成物を、Sephadex G-50樹脂充填カラムにより精製した。抗体コンジュゲート化合物C-ヒトIgGを、酢酸緩衝液(pH6.5)を用いてカラムから溶出させた。MALDI-TOF-MS(陽イオン):化合物C-ヒトIgG実測値m/z 150095[M+H]+; ヒトIgG実測値m/z 148540[M+H]+。
ヒトIgGに基づく化合物の薬物動態試験及び代謝試験
4匹又は5匹のマウスの群(正常CD-1マウス又は無胸腺CD-1ヌードマウス)に、約15マイクロキュリーの放射標識された試験化合物を静脈内注射した。様々なリンカーを有する試験化合物を合成し、ルテチウム-177で放射標識した。薬物動態試験のために、動物を特定の時点で犠牲にし、血液及び腫瘍(適用可能な場合)を、総放射活性について分析した。代謝試験のために、動物を、24時間から最大で7日間毎の尿及び糞便の収集のために、代謝ケージ(ケージあたり4〜5匹)に入れた。尿及び糞便試料の放射活性含量を定量し、体重に基づいて総尿又は糞便出力に変換した。尿、糞便、又は総排出(尿+糞便)に関する排出プロファイルを、時間に対する累積注射用量%(%ID)をプロットすることによって生成した。
[225Ac]-化合物A-ヒトIgGの合成
化合物A(1.34μmol)を、酢酸ナトリウム緩衝液(20μL、pH6.5)に溶解し、重炭酸緩衝液(pH8.5)中のヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で45分後、抗体コンジュゲート生成物を、HPLC SECカラムにより精製した(1mL/分、酢酸緩衝液(pH6.5、1mMアスコルビン酸)で溶出)。MALDI-TOF-MS(陽イオン):化合物A-ヒトIgG実測値m/z 150360[M+H]+; ヒトIgG実測値m/z 148339[M+H]+。
[225Ac]-化合物B-ヒトIgGの合成
化合物B(1.17μmol)を、酢酸ナトリウム緩衝液(0.117mL、pH6.5)に溶解した。化合物B溶液のアリコート(2μL、10nmol)を、重炭酸緩衝液(pH8.5)中のヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で1時間後、抗体コンジュゲート生成物を、Sephadex G-50樹脂充填カラムにより精製した。抗体コンジュゲート、化合物A-ヒトIgGを、酢酸緩衝液(pH6.5)を用いてカラムから溶出させた。MALDI-TOF-MS(陽イオン):化合物B-ヒトIgG実測値m/z 149949[M+H]+; ヒトIgG実測値m/z 148540[M+H]+。
[225Ac]-化合物C-ヒトIgGの合成
化合物C(0.96μmol)を、酢酸ナトリウム緩衝液(95μL、pH6.5)に溶解した。化合物C溶液のアリコート(2μL、20nmol)を、重炭酸緩衝液(pH8.5)中のヒトIgG抗体(6.7nmol)を含有する溶液に添加した。周囲温度で1時間後、抗体コンジュゲート生成物を、Sephadex G-50樹脂充填カラムにより精製した。抗体コンジュゲート、化合物C-ヒトIgGを、酢酸緩衝液(pH6.5)を用いてカラムから溶出させた。MALDI-TOF-MS(陽イオン):化合物C-ヒトIgG実測値m/z 150095[M+H]+; ヒトIgG実測値m/z 148540[M+H]+。
本発明を、その特定の実施形態と関連して説明してきたが、それを更に改変することができ、本出願が、一般的に、本発明の原理に従う本発明の任意の変更、使用、又は適合化を包含することを意図し、本発明が属する当業界内の公知又は慣用的な実務の範囲内にあり、前記の本質的な特徴に適用することができる本開示からのそのような逸脱を含むことが理解される。
Claims (31)
- 構造:
A-L1-(L2)n-B
式I
[式中、Aはキレート化部分又はその金属錯体であり;
L1は、置換されていてもよいC1〜C6アルキル、置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール又はヘテロアリールであり;
Bは、治療的部分、標的化部分、又は架橋基、
又はその薬学的に許容される塩であり;
nは1〜5であり;
L2はそれぞれ独立に、構造:
(-X1-L3-Z1-)
式II
(式中、X1は、C=O(NR1)、C=S(NR1)、OC=O(NR1)、NR1C=O(O)、NR1C=O(NR1)、-CH2PhC=O(NR1)、-CH2Ph(NH)C=S(NR1)、O、NR1であり、R1は、H又は置換されていてもよいC1〜C6アルキル若しくは置換されていてもよいC1〜C6ヘテロアルキル、置換されていてもよいアリール若しくはヘテロアリールであり;
L3は、置換されていてもよいC1〜C50アルキル又は置換されていてもよいC1〜C50ヘテロアルキル又はC5〜C20ポリエチレングリコールであり;
Z1は、CH2、C=O、C=S、OC=O、NR1C=O、NR1であり;
R1は水素又は置換されていてもよいC1〜C6アルキル、ピロリジン-2,5-ジオンである)
を有する]
を有する化合物。 - 前記キレート化部分が、DOTA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸)、DOTMA((1R,4R,7R,10R)-α,α',α'',α'''-テトラメチル-1,4,7,10-テトラアザシクロドデカン-1,4,7,10-四酢酸)、DOTAM(1,4,7,10-テトラキス(カルバモイルメチル)-1,4,7,10-テトラアザシクロドデカン)、DOTPA(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラプロピオン酸)、DO3AM-酢酸(2-(4,7,10-トリス(2-アミノ-2-オキソエチル)-1,4,7,10-テトラアザシクロドデカン-1-イル)酢酸)、DOTA-GAアンヒドリド(2,2',2''-(10-(2,6-ジオキソテトラヒドロ-2H-ピラン-3-イル)-1,4,7,10-テトラアザシクロドデカン-1,4,7-トリイル)三酢酸)、DOTP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラ(メチレンホスホン酸))、DOTMP(1,4,6,10-テトラアザシクロデカン-1,4,7,10-テトラメチレンホスホン酸)、DOTA-4AMP(1,4,7,10-テトラアザシクロドデカン-1,4,7,10-テトラキス(アセタミド-メチレンホスホン酸))、CB-TE2A(1,4,8,11-テトラアザビシクロ[6.6.2]ヘキサデカン-4,11-二酢酸)、NOTA(1,4,7-トリアザシクロノナン-1,4,7-三酢酸)、NOTP(1,4,7-トリアザシクロノナン-1,4,7-トリ(メチレンホスホン酸))、TETPA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-テトラプロピオン酸)、TETA(1,4,8,11-テトラアザシクロテトラデカン-1,4,8,11-四酢酸)、HEHA(1,4,7,10,13,16-ヘキサアザシクロヘキサデカン-1,4,7,10,13,16-六酢酸)、PEPA(1,4,7,10,13-ペンタアザシクロペンタデカン-N,N',N'',N''',N''''-五酢酸)、H4Octapa(N,N'-ビス(6-カルボキシ-2-ピリジルメチル)-エチレンジアミン-N,N'-二酢酸)、H2Dedpa(1,2-[[6-(カルボキシ)-ピリジン-2-イル]-メチルアミノ]エタン)、H6phospa(N,N'-(メチレンホスホネート)-N,N'-[6-(メトキシカルボニル)ピリジン-2-イル]-メチル-1,2-ジアミノエタン)、TTHA(トリエチレンテトラミン-N,N,N',N'',N''',N'''-六酢酸)、DO2P(テトラアザシクロドデカンジメタンホスホン酸)、HP-DO3A(ヒドロキシプロピルテトラアザシクロドデカン三酢酸)、EDTA(エチレンジアミン四酢酸)、デフェロキサミン、DTPA(ジエチレントリアミン五酢酸)、DTPA-BMA(ジエチレントリアミン五酢酸-ビスメチルアミド)、又はポルフィリンである、請求項1に記載の化合物。
- 前記金属が、イメージング剤又は治療剤としての使用のために、Bi、Pb、Y、Mn、Cr、Fe、Co、Zn、Ni、Tc、In、Ga、Cu、Re、Sm、ランタニド、又はアクチニドから選択することができる、請求項1から4のいずれか一項に記載の化合物。式(I)の化合物との錯体化にとって好適な放射性核種の特定例としては、47Sc、55Co、60Cu、61Cu、62Cu、64Cu、67Cu、66Ga、67Ga、68Ga、82Rb、86Y、87Y、90Y、97Ru、99mTc、105Rh、109Pd、111In、117mSn、149Pm、149Tb、153Sm、177Lu、186Re、188Re、199Au、201Tl、203Pb、212Pb、212Bi、213Bi、225Ac、及び227Thが挙げられる。
- Bが治療的部分又は標的化部分である、請求項1から5のいずれか一項に記載の化合物。
- 治療的部分又は標的化部分が、抗体、その抗原結合断片又はナノボディ、アフィボディ、及びIII型フィブロネクチンドメインに由来するコンセンサス配列等の他の標的化タンパク質である、請求項6に記載の化合物。
- 抗体、又はその抗原結合断片が、インスリン様増殖因子-1受容体(IGF-1R)に特異的に結合する、請求項7に記載の化合物。
- 架橋基が、アミノ反応性、メチオニン反応性、又はチオール反応性架橋基である、請求項1から5のいずれか一項に記載の化合物。
- アミノ反応性、メチオニン反応性、又はチオール反応性架橋基が、ヒドロキシスクシンイミドエステル、2,3,5,6-テトラフルオロフェノールエステル、4-ニトロフェノールエステル又はイミデート、無水物、チオール、ジスルフィド、マレイミド、アジド、アルキン、歪みアルキン、歪みアルケン、ハロゲン、スルホネート、ハロアセチル、アミン、ヒドラジド、ジアジリン、ホスフィン、テトラジン、イソチオシアネート、又はオキサジリジン等の活性化エステルを含む、請求項9に記載の化合物。
- Y1がHである、請求項3から11のいずれか一項に記載の化合物。
- X1がC=O(NR1)であり、R1がHである、請求項1から12のいずれか一項に記載の化合物。
- Z1が-CH2である、請求項1から13のいずれか一項に記載の化合物。
- L2が1のn値を有する、請求項1から14のいずれか一項に記載の化合物。
- 前記金属が放射性核種である、請求項1から16のいずれか一項に記載の化合物。
- 前記放射性核種がIn111である、請求項17に記載の化合物。
- 前記放射性核種がGa68である、請求項17に記載の化合物。
- 前記金属がアルファ線放射性核種である、請求項1から16のいずれか一項に記載の化合物。
- 前記放射性核種が、Ac225又はその子孫核種(娘同位体)である、請求項20に記載の化合物。
- 請求項1から21に記載の化合物と、薬学的に許容される賦形剤とを含む医薬組成物。
- 放射線処置計画及び/又は放射線処置の方法であって、それを必要とする対象に、請求項1から21のいずれか一項に記載の化合物又は請求項22に記載の組成物を投与する工程を含む、方法。
- がんを処置する方法であって、それを必要とする対象に、請求項1から22のいずれか一項に記載の化合物又は請求項23に記載の組成物の第1の用量を、放射線処置計画にとって有効な量で投与した後、請求項1から22のいずれか一項に記載の化合物又は請求項23に記載の組成物のその後の用量を、治療有効量で投与する工程を含む、方法。
- 第1の用量で投与される化合物又は組成物と、第2の用量で投与される化合物又は組成物が同じである、請求項24に記載の方法。
- 第1の用量で投与される化合物又は組成物と、第2の用量で投与される化合物又は組成物が異なる、請求項24に記載の方法。
- 前記がんが、固形腫瘍又は血液(液性)がんである、請求項24から26のいずれか一項に記載の方法。
- 前記固形腫瘍がんが、乳がん、非小細胞肺がん、小細胞肺がん、膵がん、頭頸部がん、前立腺がん、結腸直腸がん、肉腫、副腎皮質癌、ユーイング肉腫、多発性骨髄腫、又は急性骨髄性白血病である、請求項27に記載の方法。
- 抗増殖剤、放射線増感剤、又は免疫調節性剤若しくは免疫調節剤を投与する工程を更に含む、請求項24から28のいずれか一項に記載の方法。
- 請求項1から21のいずれか一項に記載の化合物又は請求項22に記載の組成物と、抗増殖剤又は放射線増感剤とが、互いに28日以内に投与される、請求項29に記載の方法。
- 請求項1から22のいずれか一項に記載の化合物又は請求項22に記載の組成物と、免疫調節性剤又は免疫調節剤とが、互いに90日以内に投与される、請求項29に記載の方法。
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EA201992595A1 (ru) | 2020-04-21 |
CL2019003168A1 (es) | 2020-08-28 |
US20190030194A1 (en) | 2019-01-31 |
EP3619191A4 (en) | 2020-12-16 |
US20220054664A1 (en) | 2022-02-24 |
AU2018261888A1 (en) | 2019-11-28 |
BR112019023246B1 (pt) | 2023-11-14 |
MA48861A (fr) | 2020-04-01 |
CN111263747B (zh) | 2023-10-27 |
AU2018261888B2 (en) | 2022-06-30 |
RU2019139432A3 (ja) | 2021-06-16 |
CA3062553A1 (en) | 2018-11-08 |
WO2018204869A1 (en) | 2018-11-08 |
RU2019139432A (ru) | 2021-06-07 |
CN117603148A (zh) | 2024-02-27 |
KR102612882B1 (ko) | 2023-12-11 |
ZA201908071B (en) | 2023-04-26 |
AU2022221451A1 (en) | 2022-09-22 |
BR112019023246A2 (pt) | 2020-05-19 |
KR20200006087A (ko) | 2020-01-17 |
CA3062553C (en) | 2024-02-06 |
EP3619191A1 (en) | 2020-03-11 |
CN111263747A (zh) | 2020-06-09 |
BR112019023246A8 (pt) | 2021-02-23 |
JP2023090748A (ja) | 2023-06-29 |
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