JP2019504849A - 疾患治療のための抗体−薬剤相乗作用技術 - Google Patents
疾患治療のための抗体−薬剤相乗作用技術 Download PDFInfo
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Abstract
Description
本発明の一つの利点は、対象体の疾患の治療において相乗的で増強された効果を作り出す方法であって、抗体を提供する工程、ここで前記抗体は前記対象体中の第1標的をブロックする古典的抗体又は修飾生体分子である;
薬剤を提供する工程、ここで前記薬剤は、前記対象体中の前記第1標的又は第2標的をブロックする小分子物質である:
前記抗体と前記薬剤とをリンカで接続して抗体−薬剤相乗作用(ADS)化合物を形成する工程;そして、
前記疾患を前記ADS化合物によって治療する工程、を有する。
前記リンカは、前記対象体中において、ある時間をかけて加水分解され、それによって、前記抗体と前記薬剤との両方がそれらの機能を同時に提供し、前記ADS化合物は、当該ADS化合物の相乗作用により、前記抗体又は前記薬剤単独よりも良好な効果を提供する。
抗体、当該抗体は前記対象体における第1標的を遮断する古典的な抗体または修飾された生物学的分子である;
薬剤、当該薬剤は、前記対象体における第1標的または第2標的を遮断する小分子物質である;そして、
前記抗体および前記薬剤の両方がそれらの機能を同時に発揮するようにある時間にわたって前記対象体において加水分解されるリンカ。
前記ADS化合物は、前記抗体と前記薬剤との相乗作用により、前記抗体または前記薬剤単独よりも優れた有効性を提供する。
以下、その具体例が添付の図面に図示された本発明の実施例について詳細に言及する。
1)ADS技術の抗体は疾患修飾薬として使用されるのに対して、ADC技術の抗体は単に小分子物質を癌細胞に標的化するためのキャリアとして使用される。従って、ADSでは、抗体と小分子とは標的疾患に対して相乗効果を有するが、ADCでは抗体と小分子は相乗効果を有さない。
2)ここに開示される方法におけるリンカは、小分子物質を放出するために細胞外(例えば、眼の硝子体液中)で切断されるのに対して、ADC技術のリンカは癌細胞内で切断されるか、全く切断されない。
3)ADS技術は、小分子物質の効果を長引かせるために注入部位で小分子物質を放出するためにリンカをゆっくりと破壊するキャリアとしても機能するが、ADCでは抗体はこの機能を果たさない。
本出願は、その概念を示すために眼疾患に焦点を当てるが、ここに開示の方法は、局所薬物投与が適切な治療である任意の疾患に使用することができる。
1)局所送達経路を用いることにより、経口小分子マルチキナーゼ阻害剤の副作用を回避することができる。
2)バイオ薬剤は、新血管疾患に対してそれ自身の有効性を有するばかりでなく、その元の効果を増強し、追加の標的を調節するための小分子物質のキャリアとしても作用する。
3)切断可能なリンカは、硝子体液、房水、テノン嚢下、角膜、結膜または脈絡膜、網膜などの標的組織の近くで数時間から数ヶ月以内に加水分解され、治療期間を延長するように設計することができる。この新規概念は、硝子体内送達のような後眼部送達のための小分子の処方の困難性も解決するだろう。
4)本発明は、それ自体で相乗効果を達成し、したがって成功の可能性を高めるために、臨床において効力が証明されたバイオ薬剤および小分子物質の任意の組み合わせの選択を可能にする。そのようなADS分子は、眼新生血管疾患の複数の病原性経路を標的とすることによって有効性を増強する。
湿性AMDの一次標的疾患に加えて、本発明は、下記の他の脈管形成および線維症の徴候用にも有用である。例えば、加齢性黄斑変性症(AMD)、脈絡膜新生血管(CNV)、脈絡膜新生血管膜(CNVM)、嚢胞様黄斑浮腫(CME)、網膜前膜(ERM)と黄斑円孔、近視関連脈絡膜血管新生、脈管ストリーク、網膜剥離、糖尿病性網膜症、糖尿病性黄斑浮腫(DME)、網膜色素上皮(RPE)の萎縮性変化、網膜色素上皮(RPE)の肥大性変化、網膜静脈閉塞、脈絡膜網膜静脈閉塞、黄斑浮腫、網膜静脈閉塞による黄斑浮腫、色素性網膜炎、シュタルガルト病、緑内障、炎症状態、白内障、難治性異常(regractory anomalies)、円錐角膜、未熟児網膜症、網膜下浮腫と網膜内浮腫、眼前部の血管新生、角膜炎後の角膜血管新生、角膜移植又は角膜形成術、低酸素症および翼状片による角膜血管新生を含む。
一例として、ベバシズマブが、3−4日の半減期を有する硝子体液中で加水分解するリンカによって、ニンテダニブに結合される。このADSでは、ベバシズマブはそのVEGF遮断活性を保持している。硝子体液に硝子体内注射すると、ニンテダニブはADS化合物から徐々に放出され、元のADS化合物がクリアされる前の有効濃度を維持する。 ADSは、血管新生の退縮を誘発し、ベバシズマブおよびニンテダニブの両方による複数の病原性経路の遮断に起因する相乗作用によって治療有効性を改善する。ベバシズマブはVEGF−Aをブロックする。 ニンテダニブは3つ全てのVEGFRをブロックし、VEGFシグナル伝達経路のより効果的な阻害を達成する。ニンテダニブはまた、PDGFRおよびFGFRを阻害して、湿性AMDに対するさらなる治療上の利益を提供する。
Claims (19)
- 対象体の疾患を治療するに当たって相乗的かつ増強された有効性を作り出す方法であって、
抗体を提供する工程と、
薬剤を提供する工程と、
前記抗体と前記薬剤とをリンカで接続して抗体−薬剤相乗作用(ADS)化合物を形成する工程と、
前記疾患を前記ADS化合物によって治療する工程と、を有し、
前記抗体は前記対象体中の第1標的をブロックする古典的抗体又は修飾生体分子であり、
前記薬剤は、前記対象体中の前記第1標的又は第2標的をブロックする小分子物質であり、
前記リンカは、前記対象体中において、ある時間をかけて加水分解され、それによって、前記抗体と前記薬剤との両方がそれらの機能を同時に提供し、そして、
前記ADS化合物は、当該ADS化合物の相乗作用により、前記抗体又は前記薬剤単独よりも良好な効果を提供する方法。 - 前記疾患は、眼疾患、皮膚疾患または関節疾患である請求項1に記載の方法。
- 前記眼疾患は、異常な血管形成および血管漏出を伴う新生血管疾患である請求項2に記載の方法。
- 前記ADS化合物は、硝子体内、眼内、脈絡膜上、結膜下、テノン嚢下または局所的な眼を通して前記対象体の眼に送達または注入される請求項3に記載の方法。
- 前記抗体は、VEGF、PDGFおよびPIGFのファミリーメンバーおよびその受容体からなるグループから選択される1つまたは複数の血管新生促進因子の活性を遮断する請求項1に記載の方法。
- 前記抗体は、ベバシツマブ、ラニビズマブ、ラムシルマブ、アフリバーセプト又はコンバーセプトである請求項5に記載の方法。
- 小分子薬剤は、VEGFR、PDGFRおよびFGFRのファミリーメンバー、または抗血管新生阻害剤からなるグループから選択される1つまたは複数を阻害するマルチキナーゼ阻害剤である請求項1に記載の方法。
- 前記マルチキナーゼ阻害剤は、アキシチニブ、セディラニブ、リニファニブ、モテサニブ、ニンテダニブ、パゾパニブ、ポナチニブ、レゴラフェニブ、ソラフェニブ、スニチニブ、チボザニブ、バタラニブ、LY2874455またはSU5402である請求項7に記載の方法。
- 前記抗血管新生阻害剤はスクアラミンである請求項7に記載の方法。
- 前記リンカは、1〜24時間、1〜28日、または1〜4ヶ月の半減期で加水分解される請求項1に記載の方法。
- 対象体の疾患を治療する抗体−薬剤相乗作用(ADS)化合物であって、
抗体と、薬剤と、前記抗体および前記薬剤の両方がそれらの機能を同時に発揮するようにある時間にわたって前記対象体において加水分解されるリンカと、を有し、
前記抗体は前記対象体における第1標的を遮断する古典的な抗体又は修飾された生体分子であり、
前記薬剤は、前記対象体における前記第1標的又は第2標的を遮断する小分子物質であり、そして、
前記ADS化合物は、前記抗体と前記薬剤との相乗作用により、前記抗体又は前記薬剤単独よりも良好な効果を提供するADS化合物。 - 前記疾患は、眼疾患、皮膚疾患又は関節疾患である請求項11に記載のADS化合物。
- 前記眼疾患は、異常な血管形成および血管漏出を伴う新生血管疾患である請求項12に記載のADS化合物。
- 前記抗体はPEG化されている請求項11に記載のADS化合物。
- 前記抗体は、ベバシツマブ、ラニビズマブ、ラムシルマブ、アフリバーセプト又はコンバーセプトである請求項14に記載のADS化合物。
- 小分子薬剤は、アキシチニブ、セディラニブ、リニファニブ、モテサニブ、ニンテダニブ、パゾパニブ、ポナチニブ、レゴラフェニブ、ソラフェニブ、スニチニブ、チボザニブ、バタラニブ、LY2874455、SU5402又はスクアラミンである請求項11に記載のADS化合物。
- 前記リンカは、1〜24時間、1〜28日、または1〜4ヶ月の半減期で加水分解される請求項11に記載のADS化合物。
- 前記リンカは、エステル、カーボネート、カーバメート、エーテル、アミド、イミン、リン酸塩、ヒドロゾーン結合、またはポリマー小分子コンジュゲートである請求項17に記載のADS化合物。
- 前記ADS化合物は、使用前の再水和用の乾燥粉末、ゲル、またはインプラントである請求項11に記載のADS化合物。
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