JP6219372B2 - 放射性医薬錯体 - Google Patents
放射性医薬錯体 Download PDFInfo
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- JP6219372B2 JP6219372B2 JP2015510840A JP2015510840A JP6219372B2 JP 6219372 B2 JP6219372 B2 JP 6219372B2 JP 2015510840 A JP2015510840 A JP 2015510840A JP 2015510840 A JP2015510840 A JP 2015510840A JP 6219372 B2 JP6219372 B2 JP 6219372B2
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
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- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Description
ist”,第5版,Lippincott Williams & Wilk
ins,Philadelphia PA,USA,2000を参照されたい)。このことにより、アルファ放射性核種のきわめて高い細胞毒性が説明されるとともに、このような同位体の生物学的標的化ならびに許容されない副作用を回避するのに必要なアルファ放射性核種の分布の管理および研究のレベルに対して厳しい要求が生じる。
これより以下の非限定的な実施例によって本発明を説明する。実施例に例示される化合物はいずれも本発明の好ましい実施形態を形成し(好ましい中間体および前駆物質を含む)、文脈上可能であれば任意の態様で個々にも任意に組み合わせても使用し得るものである。したがって、例えば、実施例2の化合物2〜4、実施例3の化合物10、実施例4の化合物7のそれぞれおよびすべてが、その様々なタイプの好ましい実施形態を形成する。
AG0003−比較用配位子(下の構造13)
AG0015−本発明の高溶解性配位子。
AG0700−実施例5で作製される抗CD33抗体
AG0715−高溶解性配位子(12)とコンジュゲートしたAG0700
AGC1100−実施例(13)で作製される抗DC22抗体
AGC1115−高溶解性配位子(12)とコンジュゲートしたAGC1100
アクチニウム−227カウからトリウム−227を単離する。ラジウム−226の熱中性子照射、次いでラジウム−227(t1/2=42.2m)からアクチニウム−227への崩壊によりアクチニウム−227が生成した。陰イオン交換クロマトグラフィーにより、アクチニウム−227崩壊混合物の8M HNO3溶液からトリウム−227を選択的に保持した。AG(登録商標)1−X8樹脂(200〜400メッシュ、硝酸形態)70mgを詰めた内径2mm、長さ30mmのカラムを使用した。アクチニウム−227、ラジウム−223および娘核種をカラムから溶出した後、12M HClでトリウム−227をカラムから抽出した。トリウム−227を含有する溶出液を蒸発乾固させ、残渣を0.01M HClに再懸濁させた。
段階1
1H−NMR(CDCl3,400MHz):2.92(m,2H),3.58−3.62(m,4H),4.51(s,2H),7.25−7.37(m,5H)
1H−NMR(CDCl3,400MHz):3.71−3.76(m,2H),4.06−4.12(m,2H),4.47(s,2H),7.217−7.22(m,2H),7.26−7.36(m,4H)
MS(ESI−pos,m/z,):321.0
1H−NMR(CDCl3,300MHz):3.69−3.75(m,2H),4.01−4.07(m,2H),4.46(s,2H),5.37(s,2H),6.97(s,1H),7.19−7.39(m,8H),7.44−7.51(m,2H)
MS(ESI−pos,m/z):371.1,763.2
1H−NMR(CDCl3,300MHz):2.90(t,J=7.3Hz,2H),3.77−3.84(m,2H),4.18−4.23(m,2H),4.35(t,J=7.3Hz,2H),4.51(s,2H),5.33(s,2H),6.11(d,7.0Hz,1H),7.21−7.48(m,11H)
MS(ESI−pos,m/z):503.1
1H−NMR(CDCl3,400MHz):2.20−2.32(m,10H),2.44−2.50(m,2H),3.05−3.20(m,10H),3.23−3.27(m,1H),3.69−3.77(m,8H),4.06−4.15(m,8H),4.43(s,8H),5.24(s,8H),6.62(d,J=7.2Hz,4H),7.13(d,J=7.2Hz,4H),7.16−7.38(m,42H),7.82−7.93(m,6H)
MS(ESI−pos,m/z):899.2
1H−NMR(D2O,400MHz):2.70−2.95(m,2H),3.00−3.10(m,2H),3.15−3.65(m,19H),3.75−4.23(m,16H),6.25(bs,4H),7.04(d,J=7.0Hz,4H),7.44(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H)
MS(ESI−pos,m/z):1076.4
MS(ESI−pos,m/z):1118.4
0.9%NaCl溶液1.0mLに溶かしてろ過したトラスツズマブ(9.5mg/mL)および金属不含水5〜35μLに溶かした新規なキレート剤(式IX)(10mg/mL)を無菌ろ過したホウ砂緩衝液(70mM、pH9)1.0mLに加えた。反応混合物を37℃で一晩、緩やかに攪拌し、得られたコンジュゲートを0.9%NaCl溶液中、Amicon Ultra−4(30k MWCO)遠心ろ過ユニットを用いて精製し濃縮した。LC/MS分析によりコンジュゲーションの成功を確認した。
0.9%NaCl50μLに溶かした実施例3のコンジュゲート(5μg/μL)に酢酸ナトリウム緩衝液(0.5M、pH5.5)100μL、次いで227Th溶液(0.05M HCl1〜4μL中、約0.5〜1MBq)を加えた。37℃で1時間または室温(約20℃)で15分間、緩やかにかき混ぜながら反応を実施し、得られた生成物を溶出緩衝液として酢酸ナトリウム緩衝液を用いたNAP−5カラムで精製した。保持された遊離の放射性金属を含む使用済みカラムおよび標識タンパク質を含有する溶出画分をHPGe検出器GEM(15)で測定して、反応収率および生成物の比活性を求めた(表1)。
(1)に記載され(2)に公開されているモノクローナル抗体(mAb)HuM195の配列をAGC0700作製の鋳型として用いた。IgG1重鎖遺伝子からC末端リジン(Lys)をコードするコドンを削除した。得られるタンパク質は、完全長遺伝子から生成したときに抗体中に存在する3つの変異体のうちの1つであり、他の2つの変異体ではそれぞれ、重鎖の一方または両方にリジンが結合している。このLys残基を除去することにより、実施例6に概説される通り、コンジュゲートと抗体の比(CAR)をより正確に決定することが可能になることが期待される。AGC0700の完全なアミノ酸配列の概要を表2に示す。
裸の抗体AGC0700を水溶性キレート剤AGC0015(12)とコンジュゲート(カップリング)させた。AGC0015を金属不含溶液で調製した。キレート剤(12)を下に示す:
アクチニウム−227発生器システムからトリウム−227を4+イオンとして単離した。簡潔に述べると、陰イオン交換クロマトグラフィーにより、8M HNO3中のAc−227崩壊混合物からTh−227を選択的に保持した(227Th4+と負荷電硝酸錯体を形成した)。Ac−227、Ra−223および娘核種をカラムから洗浄した後、12M HClを用いてTh−227を溶出した。Th−227溶出液を蒸発乾固させ、残基を0.5M HClに溶かした。
CD33陽性HL−60細胞との結合をフローサイトメトリーにより試験した。プロットした曲線に基づいてEC50を求めることにより、親和性の近似値がわかる。親和性の評価には市販のマウス抗ヒトCD33(BD Pharmingen;#555450、1mg/mL)を参照抗体とし、分析するmAbとの50:50混合物の設定を含めて用いた。このアッセイを用いてほかにも、標的結合親和性がキレート剤とのコンジュゲーションによる悪影響を受けないことを確認した。
放射性免疫錯体が外側細胞膜に結合した後の内部移行の程度は、殺細胞作用の効力を決定する1つの因子である。放射性免疫錯体AGC0715−Th−227および陰性対照トラスツズマブ−AC0015−Th−227のHL−60細胞への内部移行を試験した。
in vitroの細胞毒性をCD33陽性HL−60細胞で調査した。AGC0715および対照トラスツズマブとコンジュゲートしたAGC0015を用いて、比活性が44kBq/μgになるようTh−227をキレートした。HL−60細胞を37℃、5%CO2で増殖させ、週3回、1:5に分割した。アッセイ前日、培地(20%FBSおよび1%ペニシリン/ストレプトマイシンを含有するイスコフ改変ダルベッコ培地(IMDM))を新しい培地と交換し、1mL当たりの細胞数が400000個になるよう体積を調整した。
雌NMRIヌードマウスにヒトHL−60腫瘍細胞系の細胞を異種移植した。HL−60細胞は急性前骨髄球性白血病の患者に由来し、Sutherlandら(3)によればCD33を発現する。この細胞系をヌードマウスの皮下に接種すると腫瘍原性を示すことが明らかにされている(4)。この試験には雌NMRIヌードマウス(Taconic、Europe)54匹を用いた。
細胞調製および雌NMRIヌードマウスの異種移植を実施例9に記載される通りに実施する。マウスには試験に用いる前に少なくとも5日間の馴化期間を設け、腫瘍接種前の時点で4週齢である。試験開始時、マウスの体重は約20グラムである。マウスは空気をHEPAフィルターに通す換気されたケージ(IVC、Scanbur)で個体ごとに飼育し、「Rat and mouse nr.3 Breeding」餌料(Scanbur BK)およびモル濃度が1mM(pH3.0)になるまでHClを加えて酸性化した水を自由摂取させる。マウスの腫瘍の平均サイズが75〜150mm3の範囲内に収まるようにするため、投与の約10日前に腫瘍細胞をマウスに接種する。マウスを無作為化により4つの治療群および3つの対照群に割り付ける(n=10/グループ)。治療群のマウスにはAGC0715−Th−227を75kBq/mL、150kBq/mL、225kBq/mLまたは300kBq/mL含有する100μLを尾静脈内に注射して250、500、750または1000kBq/kg体重(b.w.)とする。対照群のマウスには溶媒のみ(緩衝液)、非放射性抗体(AGC0715)または比活性が500kBq/kgになるよう標識したトラスツズマブ−Th−227(アイソタイプ対照)のいずれかを投与する。
エプラツズマブとも呼ばれ、ここではAGC1100と称するモノクローナル抗体(mAb)hLL2の配列を(1)に記載されている通りに構築した。本実施例に使用されるmAbはImmunomedics社(New Jersey、USA)によって作製されたものである。このmAbの作製は、例えば、軽鎖および重鎖をコードする遺伝子をコードするプラスミドをトランスフェクトしたチャイニーズハムスター卵巣浮遊(CHO−S)細胞で実施することができる。標準的な方法を用いて最初の安定なクローンを選択する。使い捨てのバイオリアクターに入れて約14日後、上清をろ過した後にモノクローナル抗体が回収され得る。プロテインAアフィニティークロマトグラフィー(MabSelect SuRe、Atoll、Weingarten/Germany)、次いでイオン交換段階によってAGC1100をさらに精製する。静電性および疎水性に基づく3つ目の精製段階を用いて、生成物から凝集体および残存している可能性のある不純物をさらに除去し得る。等電点電気泳動、SDS−PAGE分析、N末端配列決定およびLC/MS分析によりAGC1100の同一性を確認する。サイズ排除クロマトグラフィー(SEC)により試料の純度をさらに分析する。
(1) Leung,Goldenberg,Dion,Pellegrini,Shevitz,ShihおよびHansen.Molecular Immunology 32:1413−27,1995。
抗体AGC1100を水溶性キレート剤AGC0015(12)とコンジュゲートさせた。コンジュゲーション反応は、pH8.5の70mMホウ酸緩衝液と混合したPBSの1:1(v/v)混合物中で実施した。キレート剤、AGC0015を下に示す:
アクチニウム−227(227Ac)発生器システムからトリウム−227(227Th)を4+イオンとして単離した。陰イオン交換クロマトグラフィーにより、8M HNO3中の227Ac崩壊混合物から227Thを選択的に保持し、227Th4+と負荷電硝酸錯体を形成した。227Acおよび娘核種をカラムから洗浄し、12M HClで227Thを溶出した。227Th溶出液を蒸発乾固させ、残渣を0.5M HClに溶かした。
AGC1115およびAGC1100(抗ヒトCD22、Immunomedics;hLL2、#1003164、10mg/ml)とCD22陽性Raji細胞(ATCC、#CCL−86)との結合をフローサイトメトリーにより分析した。近似曲線から求めたEC50値を抗体と抗体コンジュゲートの結合能の比較に用いた。この分析を用いて、抗体コンジュゲートのCD22との結合能がコンジュゲーション法による影響を受けないことを確認した。
in vitroの細胞毒性をCD22陽性Ramos細胞で調査した(実施例6を参照されたい)。AGC1115およびAGC0015とコンジュゲートした対照トラスツズマブを用いて、比活性が44kBq/μgになるようTh−227をキレートした。
別のカップリング化学反応を可能にする水溶性キレート剤の酸誘導体の作製。
この実施例では成功した酸誘導体の合成を示す。このキレート剤の誘導体により、例えば、腫瘍標的化タンパク質のイプシロンアミンとのアミド結合形成が可能になる。
リジンカップリングを用いることになっていたため、キレート剤とのコンジュゲーションの前にアフィボディ融合タンパク質の遊離のシステインを化学的にブロックした。基本的にTolmachevら(1)により記載されている通りに大腸菌(E.coli)で作製したアフィボディ融合タンパク質PEP9237(配列番号10)を、2mMトリス(2−クロロエチル)ホスフィン(TCEP)を含有するPBS(Biochrom L1825;0.9%NaCl、リン酸緩衝液、pH7.4)に1.32mg/mlになるよう溶かし、ジスルフィド形成を阻害した。アフィボディ融合タンパク質溶液1mlを0.14Mホウ酸緩衝液0.985mlと混合し、pHが約8.4であることを確認した。ヨードアセトアミド(Sigma 1149−5g)の1mg/ml溶液15μLを加え、反応混合物を室温で1時間インキュベートした。
AEAKYAKEMRNAYWEIALLPNLTNQQKRAFIRKLYDDPSQSSELLSEAKKLNDSQAPSGSGSLAEAKEAANAELDCYGVSDFYKRLIDKAKTVEGVEALKDAILAALPG
実施例19で作製した2種類のアフィボディ融合タンパク質キレート剤コンジュゲートの透明なPBS溶液を−20℃で凍結させた後、解凍した。AGC0003コンジュゲートを含有する溶液には明らかな乳白色の沈殿物が見られたが、AGC0015コンジュゲートの溶液には見られなかった。この沈殿は氷上で冷却すると一層明瞭に見えるようになった。
Tolmachev,Orlova,Pehrson,Galli,Baastrup,Andersson,Sandstrom,Rosik,Carlsson,Lundqvist,Wennborg,Nilsson.Radionuclide therapy of HER2−positive microxenografts using a 177Lu−Labeled HER2−specific Affibody molecule.Cancer Res.67:2773−82,2007。
配列番号2;HuM195モノクローナル抗体を逆翻訳し、最適化してチャイニーズハムスター卵巣浮遊細胞にサブクローニングした。
配列番号3;HuM195モノクローナル抗体を逆翻訳し、最適化してチャイニーズハムスター卵巣浮遊細胞にサブクローニングした。
配列番号4;HuM195モノクローナル抗体を逆翻訳し、最適化してチャイニーズハムスター卵巣浮遊細胞にサブクローニングした。
配列番号5;マウス由来モノクローナル抗体
配列番号6;ヒト化マウス由来モノクローナル抗体
配列番号7;マウス由来モノクローナル抗体
配列番号8;ヒト化マウス由来モノクローナル抗体
配列番号9;ヒト化マウス抗CD22モノクローナル抗体
配列番号10;大腸菌に発現させたアフィボディ融合タンパク質
Claims (14)
- ‐モノクローナル抗体またはポリクローナル抗体、Fab、F(ab’) 2 、Fab’またはscFvを含む抗体フラグメント、このような抗体およびフラグメントの構築物および抗体模倣物から選択される組織標的化部分と、
‐式I
基R 4 からR 6 が、Hであり、
R 3 がOHであり、および、
R 2 が、=Oである)
の4つのキレート3,2−HOPO部分を含む八座ヒドロキシピリジノン含有配位子と、
‐アルファ放射性トリウム放射性核種 227 Thの4 + イオン
とを含む組織標的化錯体。 - 前記4つのHOPO基のそれぞれの前記N置換基がそれぞれ独立してHOCH2−、HOCH2CH2−、HO−CH2CH2CH2−、HO−CH(CH3)CH2−、HO−CH2CH2CH2CH2−、HO−CH(CH3)CH2CH2−、HO−CH(CH2CH3)CH2−、HO−C(CH3)2CH2−、HO−CH(CH3)CH(CH3)−およびHOCH2CH(CH2CH3)−から選択される、請求項1に記載の錯体。
- 式VI:
の配位子部分を含み、式中、RL が、配位子部分が組織標的化部分に結合するためのリンカー部分である、請求項1に記載の錯体。 - ‐モノクローナル抗体またはポリクローナル抗体、Fab、F(ab’) 2 、Fab’またはscFvを含む抗体フラグメント、このような抗体およびフラグメントの構築物および抗体模倣物から選択される組織標的化部分と、
‐式I
基R 4 からR 6 が、Hであり、
R 3 がOHであり、および、
R 2 が、=Oである)
の4つのキレート3,2−HOPO部分を含む八座ヒドロキシピリジノン含有配位子と、
‐アルファ放射性トリウム放射性核種 227 Thの4 + イオン
とを含む、
治療を必要とするヒトまたは非ヒト動物を治療するための組成物。 - 過形成性疾患、または、腫瘍性疾患、癌腫、肉腫、骨髄腫、白血病、リンパ腫または混合型癌を治療するための、請求項4に記載の組成物。
- 少なくとも1つの医薬担体または添加剤とともに含む、請求項1に記載の組織標的化錯体を含む、医薬組成物。
- 請求項4に記載の組成物を含むキットであって、
4つの3,2−HOPO部分を含む八座ヒドロキシピリジノン含有配位子とコンジュゲートしているかコンジュゲート可能な組織標的化部分を含み、前記4つのHOPO部分のうちの全てがが、N位においてヒドロキシアルキル可溶化基で置換されており、
アルファ放射性トリウム放射性核種 227 Thを含む、
キット。 - 組織標的化錯体を形成する方法であって、
水溶液中で組織標的化部分と八座ヒドロキシピリジノン含有配位子とをカップリングさせることを含み、
前記錯体が、4つの3,2−HOPO部分とアルファ放射性トリウム放射性核種のイオンとを含み、
前記4つのHOPO部分のうちの全てが、N位においてヒドロキシアルキル可溶化基で置換されている、
方法。 - 第一の八座ヒドロキシピリジノン含有配位子の水溶液および第二の前記組織標的化部分の水溶液を調製することと、前記第一の水溶液と前記第二の水溶液とを接触させることとを含む、請求項8に記載の方法。
- 前記接触を40℃未満で実施する、請求項9に記載の方法。
- 前記接触を、いかなる有機溶媒も実質的に存在しない状態で実施する、請求項9に記載の方法。
- 前記カップリングにより、前記配位子部分と前記標的化部分との間にアミド結合、エステル結合、エーテル結合またはアミン結合が生じる、請求項8に記載の方法。
- 前記アミド結合またはエステル結合が、少なくとも1つの活性エステル基によって形成される、請求項12に記載の方法。
- 前記アミド結合またはエステル結合が、N−ヒドロキシマレイミドカップリング試薬、カルボジイミドカップリング試薬またはアゾジカルボキシラートカップリング試薬によって形成される、請求項12に記載の方法。
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CA2873142A1 (en) | 2013-11-14 |
CN104540530A (zh) | 2015-04-22 |
US20150147272A1 (en) | 2015-05-28 |
CN104602716A (zh) | 2015-05-06 |
JP2015523326A (ja) | 2015-08-13 |
HK1206981A1 (en) | 2016-01-22 |
EP2846844B1 (en) | 2020-04-01 |
KR20150092701A (ko) | 2015-08-13 |
WO2013167755A1 (en) | 2013-11-14 |
CA2873144A1 (en) | 2013-11-14 |
JP2015517482A (ja) | 2015-06-22 |
EP2846844A1 (en) | 2015-03-18 |
KR20150092700A (ko) | 2015-08-13 |
CA2873144C (en) | 2021-03-16 |
US20150110817A1 (en) | 2015-04-23 |
CA2873143A1 (en) | 2013-11-14 |
GB201208309D0 (en) | 2012-06-27 |
EP2846842A1 (en) | 2015-03-18 |
CN104619355A (zh) | 2015-05-13 |
HK1206982A1 (en) | 2016-01-22 |
US20150104385A1 (en) | 2015-04-16 |
WO2013167756A1 (en) | 2013-11-14 |
HK1207307A1 (en) | 2016-01-29 |
JP2015517483A (ja) | 2015-06-22 |
JP6211066B2 (ja) | 2017-10-11 |
WO2013167754A1 (en) | 2013-11-14 |
KR20150092702A (ko) | 2015-08-13 |
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