JP2021501221A - 免疫チェックポイント経路阻害剤と併用したインターロイキン−10の組成物および使用方法 - Google Patents
免疫チェックポイント経路阻害剤と併用したインターロイキン−10の組成物および使用方法 Download PDFInfo
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Abstract
Description
AM0001成熟重鎖タンパク質配列(ヒトIgG4 S228Pフレームワーク):
EVQLLESGGGLVQPGGSLRLSCPASGFTFSSYAMSWVRQAPGKGLGWVSDISGGGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRGEDTAVYYCAKSGTVVTDFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号11)
AM0001成熟軽鎖タンパク質配列(ヒトラムダ−2フレームワーク):
SYVLTQPPSVSVAPGQTARVTCGGNSIGSYSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTAALTISRVEAGDEADYYCQVWDTSSYWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(配列番号12)
AM0001成熟重鎖DNA配列(ヒトIgG4 S228Pフレームワーク):
GAGGTCCAGCTCCTGGAATCCGGGGGCGGTCTGGTCCAGCCGGGCGGCTCGCTCCGCCTGTCCTGCCCGGCGAGCGGCTTCACCTTCTCCTCCTACGCCATGTCCTGGGTGAGGCAGGCCCCCGGCAAGGGCCTCGGCTGGGTCAGCGACATCTCCGGCGGCGGCGGCACCACGTACTACGCGGACTCGGTGAAGGGCCGGTTCACGATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCACTGCGGGGCGAGGACACGGCGGTGTATTACTGCGCCAAGTCCGGAACGGTTGTGACTGATTTCGACTACTGGGGCCAGGGCACCCTGGTGACCGTGTCCAGCGCCTCCACCAAGGGCCCCAGCGTGTTCCCCCTGGCGCCGTGCTCGCGGAGCACCAGCGAGTCCACCGCCGCGCTCGGTTGCCTCGTCAAGGACTACTTCCCCGAGCCGGTCACAGTGTCATGGAACTCCGGCGCGCTGACGAGCGGCGTGCACACCTTCCCGGCCGTGCTCCAGTCCAGCGGCCTGTACAGCCTCAGTAGCGTCGTGACGGTGCCCTCGTCGTCGCTGGGCACGAAGACCTACACCTGCAACGTGGACCACAAGCCGTCCAACACCAAGGTCGATAAGCGAGTGGAGAGCAAGTACGGCCCCCCGTGCCCCCCCTGCCCGGCCCCGGAGTTCCTGGGTGGCCCCTCCGTGTTCCTCTTCCCCCCGAAGCCCAAAGACACCCTCATGATCAGCCGGACGCCGGAGGTCACGTGCGTCGTCGTGGACGTGAGCCAGGAAGACCCGGAGGTCCAGTTCAACTGGTACGTGGACGGCGTCGAGGTGCATAACGCCAAGACCAAGCCTCGCGAGGAACAGTTCAACTCCACTTACCGCGTCGTGTCCGTCCTCACCGTCCTGCACCAGGACTGGCTCAACGGGAAGGAATACAAGTGCAAGGTCTCGAACAAGGGCCTGCCGTCGTCCATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCGCGGGAGCCCCAGGTCTACACCCTCCCCCCCTCCCAGGAAGAGATGACGAAGAACCAGGTGAGCCTGACGTGCCTCGTGAAGGGGTTCTACCCCTCCGACATCGCAGTCGAGTGGGAGAGCAACGGCCAGCCGGAGAACAACTACAAGACGACCCCCCCGGTGCTGGACAGCGACGGGTCCTTCTTCCTCTACTCGCGTCTCACAGTCGACAAGTCGCGCTGGCAGGAGGGCAACGTCTTCTCGTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCGCTGTCCCTGTCCCTGGGCAAG(配列番号13)
AM0001成熟軽鎖タンパク質配列(ヒトラムダ−2フレームワーク):
AGCTACGTGCTGACCCAGCCGCCCTCGGTGTCGGTCGCCCCGGGCCAGACGGCACGTGTGACCTGCGGCGGTAACAGCATCGGCTCCTACTCGGTCCACTGGTATCAGCAGAAGCCGGGGCAGGCCCCGGTCCTGGTGGTCTACGACGACAGCGACCGCCCGTCCGGCATCCCCGAACGCTTCAGCGGCTCAAACAGCGGGAACACCGCGGCCCTGACGATCTCGCGCGTCGAGGCGGGGGACGAAGCCGATTACTACTGCCAGGTCTGGGACACCTCGAGTTACTGGGTGTTCGGCGGGGGCACGAAGCTGACCGTCCTCGGCCAGCCGAAGGCCGCCCCCTCAGTAACCCTGTTCCCCCCGTCCTCGGAGGAGTTGCAGGCGAACAAGGCGACGCTGGTGTGCTTGATCTCGGACTTCTACCCCGGAGCGGTGACGGTCGCCTGGAAGGCCGACTCCTCCCCGGTCAAGGCGGGCGTGGAGACGACCACCCCCTCCAAGCAGAGCAACAACAAGTACGCCGCCTCGAGCTACCTCTCGCTGACACCCGAGCAGTGGAAGTCCCACCGGTCCTACTCGTGCCAGGTAACCCACGAGGGCTCCACCGTCGAGAAGACCGTGGCCCCCACCGAGTGCAGC(配列番号14)
本明細書で使用される場合、「IL−10剤」という用語は、IL−10受容体に結合し、IL−10と同じシグナル伝達経路を調節し、IL−10に特徴的な生物学的応答を誘発することができる2つのIL−10ポリペプチドを含むIL−10活性を有する、二量体分子を指す。IL−10剤という用語は、IL−10類似体およびIL−10変異体および修飾IL−10剤を含む。
SPGQGTQSEN SCTHFPGNLP NMLRDLRDAF SRVKTFFQMK DQLDNLLLKE SLLEDFKGYL GCQALSEMIQ FYLEEVMPQA ENQDPDIKAH VNSLGENLKT LRLRLRRCHR FLPCENKSKA VEQVKNAFNK LQEKGIYKAM SEFDIFINYI EAYMTMKIRN(配列番号25)
MSPGQGTQSE NSCTHFPGNL PNMLRDLRDA FSRVKTFFQM KDQLDNLLLK ESLLEDFKGY LGCQALSEMI QFYLEEVMPQ AENQDPDIKA HVNSLGENLK TLRLRLRRCH RFLPCENKSK AVEQVKNAFN KLQEKGIYKA MSEFDIFINY IEAYMTMKIR N(配列番号26)
N−ホルミル−MSPGQGTQSE NSCTHFPGNL PNMLRDLRDA FSRVKTFFQM KDQLDNLLLK ESLLEDFKGY LGCQALSEMI QFYLEEVMPQ AENQDPDIKA HVNSLGENLK TLRLRLRRCH RFLPCENKSK AVEQVKNAFN KLQEKGIYKA MSEFDIFINY IEAYMTMKIR N(配列番号27)
本開示は、対象における腫瘍性疾患、および腫瘍性疾患に関連する疾患、障害、または病態の治療および/または予防のための、1つ以上の免疫チェックポイント経路調節剤(複数可)と併用したIL−10剤(例えば、PEG−IL−10)の併用の投与を企図する。
上述のNSCLC研究の過程で評価した別のパラメータは、腫瘍変異負荷であった。Carboneらによって報告されているように、低または中等度の腫瘍変異負荷を有するNSCLC患者の111人中23人(21%)は、ニボルマブ単独に対する応答率が低減した(n=111人中23人、21%)。対照的に、低または中等度のTMBを有する8人中5人の患者(60%)は、以下の表10および添付の図面の図1にまとめられるように、AM0010と抗PD1との併用に対してPRを呈した。
転移は、がんによる死亡の約90%を占める、がんの罹患率および死亡率の主因である。Chaffer&Weinberg(2011).A perspective on cancer cell metastasis,Science.331:1559−64。肝転移を有する患者は、免疫チェックポイント阻害に対するより低い応答率を有する。Tumehら(2017)、Pillaiら(2017)(上記)。前述のNSCLC研究では、肝転移の評価を行い、結果を添付の図面の図5および6に提示する。例示されるように、AM0010とペンブロリズマブとの併用は、治療の過程にわたって測定可能な肝転移病変の有意な低減をもたらした。
文献に報告されているように、IFNγ関連の遺伝子発現プロファイル(例えば、STAT1、HLA−DRA、CXCL9、IDO、IFNγ、およびCXCL10の発現)が低い患者は、ペンブロリズマブに対する応答率が低減している(Pratら(2017)(上記)、Ayersら(2017)(上記))。上記のNSCLC研究の一部として、IFNg関連遺伝子発現プロファイルの関数としての、抗PD1mAb療法と併用したAM0010の併用に対する治療応答を評価した。結果を、添付の図面の図2に提示する。例示されるように、IFNγ関連遺伝子発現プロファイルが低い(5人中)2人の患者は、AM0010と抗PD−1mAb療法との併用に応答した部分応答を有し、追加の2人の対象が、6ヶ月超の安定疾患を呈した。
本開示は、様々な疾患、障害、および病態(例えば、がん)、ならびに/またはそれらの症状を治療および/または予防するための、1つ以上の免疫チェックポイント経路阻害剤と併用した、本明細書に記載のIL−10剤(例えば、PEG−IL−10)およびそれらの組成物の使用を企図する。いくつかの実施形態では、IL10剤は、特定の実施形態では皮下注射を含む、非経口注射によって投与される。1つ以上の免疫チェックポイント経路調節剤はまた、調節剤の性質および調節される免疫チェックポイント経路を考慮して、有効な任意の経路によって投与されてもよい。いくつかの実施形態では、IL−10剤および免疫チェックポイント経路調節剤(複数可)は、同じ経路によって(例えば、静脈内)投与することができる一方で、他の実施形態では、それらは、異なる経路によって投与することができる(例えば、IL−10剤は、皮下投与されてもよく、免疫チェックポイント経路調節剤(複数可)は、静脈内投与されてもよい)。
薬学的組成物を製剤化した後、それは、溶液、懸濁液、ゲル、乳濁液、固体、または脱水粉末もしくは凍結乾燥粉末として、無菌バイアル内で保管することができる。そのような製剤は、使用準備済みの形態、使用前に再構成が必要な凍結乾燥形態、使用前に希釈が必要な液体形態、または他の許容される形態のいずれかで保管することができる。いくつかの実施形態では、薬学的組成物は、使い捨て容器(例えば、使い捨てバイアル、アンプル、シリンジ、または自動注射器(例えば、EpiPen(登録商標)に類似したもの))内に提供される一方で、他の実施形態では、多用途容器(例えば、多用途バイアル)が提供される。留置剤(例えば、留置可能ポンプ)およびカテーテル系、緩徐注射ポンプおよびデバイスを含む、IL−10を送達するための任意の薬物送達装置を使用することができ、これらは全て、当業者に周知のものである。一般に皮下または筋肉内投与されるデポ注射もまた、本明細書に開示されるポリペプチドを定義された期間にわたって放出するために利用することができる。デポ注射は、通常、固体ベースまたは油ベースのいずれかであり、一般に本明細書に明記される製剤構成成分の少なくとも1つを含む。当業者は、可能な製剤およびデポ注射の使用に精通している。
Claims (46)
- 哺乳動物対象における腫瘍性疾患を治療または予防する方法であって、前記対象に、
a)治療有効量の免疫チェックポイント経路調節剤と、
b)治療有効量のIL−10剤と、を投与することを含む、方法。 - 前記腫瘍性疾患が、中等度の腫瘍変異負荷または低度の腫瘍変異負荷を有する腫瘍性疾患である、請求項1に記載の方法。
- 前記腫瘍性疾患が、原発性腫瘍である、請求項2に記載の方法。
- 前記IL−10剤が、治療の過程を通して少なくとも1.0ng/mLの平均IL−10剤血清トラフ濃度を維持するのに十分に投与される、請求項1に記載の方法。
- 前記IL−10剤が、各々が配列番号25のアミノ酸配列を有する2つのIL−10ポリペプチドを含む、請求項1〜4のいずれか一項に記載の方法。
- 前記IL−10剤が、各々が配列番号26のアミノ酸配列を有する2つのIL−10ポリペプチドを含む、請求項1〜4のいずれか一項に記載の方法。
- 前記IL−10剤が、各々が配列番号27のアミノ酸配列を有する2つのIL−10ポリペプチドを含む、請求項1〜4のいずれか一項に記載の方法。
- 前記IL−10剤が、ペグ化されている、請求項1〜7のいずれか一項に記載の方法。
- 前記免疫チェックポイント経路調節剤が、CTLA4、PD1、PDL1、BTLA、TIM3、LAG3、A2aR、およびキラー阻害性受容体に対するアンタゴニスト抗体からなる群から選択される、請求項1〜8のいずれか一項に記載の方法。
- 前記免疫チェックポイント経路調節剤が、CTLA4、PD1、PDL1、およびBTLAに対するアンタゴニスト抗体からなる群から選択される、請求項1〜8のいずれか一項に記載の方法。
- 前記免疫チェックポイント経路調節剤が、PD1免疫チェックポイント経路阻害剤である、請求項1〜8のいずれか一項に記載の方法。
- 前記腫瘍性疾患において、PD−L1の細胞表面発現が、中等度または低度である、請求項1〜11のいずれか一項に記載の方法。
- 前記PD1免疫チェックポイント経路阻害剤が、ペンブロリズマブ、ニボルマブ、およびAM0001からなる群から選択される、請求項12に記載の方法。
- 前記PD1免疫チェックポイント経路阻害剤が、小分子である、請求項13に記載の方法。
- 前記免疫チェックポイント経路調節剤が、CTLA4免疫チェックポイント経路阻害剤である、請求項1〜8のいずれか一項に記載の方法。
- 前記CTLA4免疫チェックポイント経路阻害剤が、イピルムマブである、請求項15に記載の方法。
- 前記腫瘍性疾患、障害、または病態が、がんである、請求項1〜16のいずれか一項に記載の方法。
- 前記がんが、固形腫瘍または血液学的障害である、請求項17に記載の方法。
- 前記がんが、黒色腫、肺がん、腎臓がん、および乳がんからなる群から選択される、請求項18に記載の方法。
- 前記方法が、第2の免疫チェックポイント経路調節剤の添加を含む、請求項1〜16のいずれか一項に記載の方法。
- 前記IL−10剤が、修飾IL−10剤を形成するための少なくとも1つの修飾を含み、前記修飾が、前記IL−10剤のアミノ酸配列を改変しない、請求項1〜20のいずれか一項に記載の方法。
- 前記修飾IL−10剤が、PEG−IL−10剤である、請求項21に記載の方法。
- 前記PEG−IL−10剤が、IL−10の少なくとも1つのサブユニットの少なくとも1つのアミノ酸残基に共有結合した少なくとも1つのPEG分子を含む、請求項22に記載の方法。
- 前記PEG−IL−10剤が、モノペグ化IL−10とジペグ化IL−10との混合物を含む、請求項21に記載の方法。
- 前記PEG−IL−10剤の前記PEG構成成分が、約5kDa〜約50kDaの分子量を有する、請求項21〜24のいずれか一項に記載の方法。
- 前記PEG−IL−10剤の前記PEG構成成分が、約20kDa〜約40kDaの分子量を有する、請求項21〜24のいずれか一項に記載の方法。
- 前記修飾が、リンカーを含む、請求項21〜26のいずれか一項に記載の方法。
- 前記修飾IL−10剤が、Fc融合分子である、請求項1〜20に記載の方法。
- 前記修飾IL−10剤が、血清アルブミンまたはアルブミン結合ドメイン(ABD)を含む、請求項1〜20に記載の方法。
- 前記修飾IL−10剤が、グリコシル化またはヘシル化されている、請求項1〜20に記載の方法。
- 前記免疫チェックポイント経路調節剤および前記IL−10剤の前記投与が、非経口注射による、請求項1〜30のいずれか一項に記載の方法。
- 前記IL−10剤の前記投与が、皮下注射による、請求項31に記載の方法。
- 前記免疫チェックポイント経路調節剤および前記IL−10剤が、同時に投与される、請求項1〜32のいずれか一項に記載の方法。
- 前記免疫チェックポイント経路調節剤および前記IL−10剤が、連続的に投与される、請求項1〜32のいずれか一項に記載の方法。
- 少なくとも1つの追加の予防剤または治療剤を投与することをさらに含む、請求項1〜32のいずれか一項に記載の方法。
- 前記予防剤または治療剤が、化学療法剤である、請求項35に記載の方法。
- 前記対象が、ヒトである、請求項1〜36のいずれか一項に記載の方法。
- 薬学的組成物であって、
a)治療有効量の免疫チェックポイント経路調節剤と、
b)治療有効量のIL−10剤、および薬学的に許容される希釈剤、担体、または賦形剤と、を含む、薬学的組成物。 - 前記免疫チェックポイント経路調節剤が、PD1免疫チェックポイント経路阻害剤であり、前記IL−10剤が、20kDa〜40kDaの分子量を有するPEGを含むPEG IL−10剤である、請求項38に記載の組成物。
- 前記組成物が、ヒトへの投与に好適である、請求項38または請求項39に記載の薬学的組成物。
- 少なくとも1つの追加の予防剤または治療剤をさらに含む、請求項38〜41のいずれか一項に記載の薬学的組成物。
- 前記予防剤または治療剤が、化学療法剤である、請求項38〜41のいずれか一項に記載の薬学的組成物。
- 請求項38〜42のいずれか一項に記載の薬学的組成物を含む、無菌容器。
- 前記無菌容器が、シリンジである、請求項43に記載の無菌容器。
- 請求項43または44に記載の無菌容器を含む、キット。
- 少なくとも1つの追加の予防剤または治療剤を含む第2の無菌容器をさらに含む、請求項45に記載のキット。
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EP3706779A1 (en) | 2020-09-16 |
US20200353050A1 (en) | 2020-11-12 |
WO2019094268A1 (en) | 2019-05-16 |
EP3706779B1 (en) | 2022-12-14 |
US20240108690A1 (en) | 2024-04-04 |
JP2022081545A (ja) | 2022-05-31 |
ES2939112T3 (es) | 2023-04-19 |
CN111315398A (zh) | 2020-06-19 |
CA3079844A1 (en) | 2019-05-16 |
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