JP2021046455A - 皮膚t細胞リンパ腫を処置するための組成物および方法 - Google Patents
皮膚t細胞リンパ腫を処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2013年1月7日に出願された米国特許仮出願第61/749,739号に対して米国特許法119条(e)の下で優先権を主張し、該出願はその全体が参照により本明細書に組み入れられる。
本発明は、National Institutes of Healthにより授与された助成金番号5R01 CA122569-4およびR01 FD004092の下、政府の援助で行われた。政府は本発明においてある一定の権利を有する。
皮膚T細胞リンパ腫(CTCL)は、米国において100,000人当たり約0.29の症例の年間発生率を有する、比較的まれな疾患である。CTCLは、東欧での一般性の約半分であると報告されているが、この不一致は、出現における真の差よりはむしろ、医師の疾患の認識が異なることに帰する可能性がある。米国においては、毎年約1,500の新たな症例が特定され、年に約100〜200人が死亡する。CTCLは通常、高齢者において見られ(診断時の中央年齢は55〜60歳である)、女性の2倍の男性を襲う。診断時の平均余命は、処置無しであっても7〜10年である。
[本発明1001]
必要とする対象において皮膚T細胞リンパ腫(CTCL)を処置または改善する方法であって、治療的有効量の、免疫応答修飾因子(IRM)化合物を含む薬学的組成物を、局所的に、経皮的に、皮内に、または病変内に、該対象に投与する工程を含み、それにより該対象におけるCTCLが処置または改善される、方法。
[本発明1002]
対象への組成物の投与が局所的である、本発明1001の方法。
[本発明1003]
IRM化合物が、4-アミノ-α,α-ジメチル-2-エトキシメチル-1H-イミダゾ[4,5-c]キノリン-1-エタノールまたはその薬学的に許容される塩を含む、本発明1001の方法。
[本発明1004]
組成物がゲルを含む、本発明1001の方法。
[本発明1005]
組成物が約0.01%(w/w)IRM〜約0.5%(w/w)IRMを含む、本発明1001の方法。
[本発明1006]
組成物が約0.03%(w/w)IRM〜約0.06%(w/w)IRMを含む、本発明1005の方法。
[本発明1007]
組成物が対象の少なくとも1つのCTCL病変に適用される、本発明1001の方法。
[本発明1008]
投与が、組成物が適用された少なくとも1つのCTCL病変の少なくとも部分的な除去を結果としてもたらす、本発明1007の方法。
[本発明1009]
投与が、組成物が適用されなかった少なくとも1つのCTCL病変の少なくとも部分的な除去を結果としてもたらす、本発明1007の方法。
[本発明1010]
投与が、対象における全CTCL病変の50%またはそれより多くの除去を結果としてもたらす、本発明1001の方法。
[本発明1011]
対象に投与されるIRMの量が、約1μg/kg〜約10 mg/kgである、本発明1001の方法。
[本発明1012]
対象に投与されるIRMの量が、約100 ng/病変〜約1 mg/病変である、本発明1011の方法。
[本発明1013]
組成物が、少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、本発明1001の方法。
[本発明1014]
組成物が、少なくとも1日、少なくとも1週間、少なくとも1か月間、または少なくとも1年間の持続期間にわたって繰り返し対象に投与される、本発明1001の方法。
[本発明1015]
投与が、対象において全身の細胞媒介性抗腫瘍免疫応答を活性化する、本発明1001の方法。
[本発明1016]
投与が、対象における少なくとも1つの病変において活性化NK細胞または活性化T細胞の浸潤を誘導する、本発明1015の方法。
[本発明1017]
投与が、対象における少なくとも1つの病変においてグランザイムまたはIFN-αのレベルの増大を結果としてもたらす、本発明1016の方法。
[本発明1018]
投与が、対象の血液において循環骨髄樹状細胞または循環NK細胞を活性化する、本発明1015の方法。
[本発明1019]
活性化循環骨髄樹状細胞が、増大したCD80発現を有する、本発明1018の方法。
[本発明1020]
組成物が、第1の処置期間中および第2の処置期間中に対象に投与され、かつ該第1の処置期間と該第2の処置期間とが、非処置期間によって隔てられている、本発明1001の方法。
[本発明1021]
組成物が、第1の処置期間中に少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、本発明1020の方法。
[本発明1022]
ゲルが、第2の処置期間中に少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、本発明1020の方法。
[本発明1023]
第1の処置期間が、少なくとも約2週間、少なくとも約3週間、少なくとも約4週間、少なくとも約5週間、少なくとも約6週間、少なくとも約7週間、または少なくとも約8週間である、本発明1020の方法。
[本発明1024]
第2の処置期間が、少なくとも約2週間、少なくとも約3週間、少なくとも約4週間、少なくとも約5週間、少なくとも約6週間、少なくとも約7週間、または少なくとも約8週間である、本発明1020の方法。
[本発明1025]
第1の処置期間と第2の処置期間とを隔てる非処置期間が、少なくとも約1週間、少なくとも約2週間、少なくとも約3週間、または少なくとも約4週間である、本発明1020の方法。
[本発明1026]
対象が哺乳動物である、本発明1001の方法。
[本発明1027]
哺乳動物がヒトである、本発明1026の方法。
[本発明1028]
CTCLを患っている対象において細胞媒介性免疫応答を増大させる方法であって、治療的有効量の、免疫応答修飾因子(IRM)化合物を含む薬学的組成物を、局所的に、経皮的に、皮内に、または病変内に、該対象に投与する工程を含み、それにより該対象における該細胞媒介性免疫応答が増大される、方法。
[本発明1029]
IRM化合物が、4-アミノ-α,α-ジメチル-2-エトキシメチル-1H-イミダゾ[4,5-c]キノリン-1-エタノールまたはその薬学的に許容される塩を含む、本発明1028の方法。
[本発明1030]
組成物が約0.01%(w/w)IRM〜約0.5%(w/w)IRMを含む、本発明1028の方法。
[本発明1031]
組成物が対象の少なくとも1つのCTCL病変に適用される、本発明1028の方法。
[本発明1032]
投与が、組成物が適用されたCTCL病変または組成物が適用されなかったCTCL病変からなる群より選択される少なくとも1つの、少なくとも部分的な除去を結果としてもたらす、本発明1031の方法。
[本発明1033]
組成物が、少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、本発明1028の方法。
[本発明1034]
組成物が、第1の処置期間中および第2の処置期間中に対象に投与され、かつ該第1の処置期間および該第2の処置期間が、非処置期間によって隔てられている、本発明1028の方法。
[本発明1035]
対象が哺乳動物である、本発明1028の方法。
[本発明1036]
哺乳動物がヒトである、本発明1035の方法。
本発明は、対象において皮膚T細胞リンパ腫(CTCL)を処置する方法を含む。進行したCTCLを有する患者は、細胞媒介性免疫応答を生じる能力が有意に損なわれており、この損傷のために、患者の免疫系がCTCLを制御しかつ抑えることが困難になる。非限定的な態様において、本発明は、他による免疫応答を刺激する免疫応答修飾因子(IRM)化合物、さらにCTCLを制御しかつ抑えることを助ける応答性免疫細胞集団を使用する。
別の方法で定義されない限り、本明細書において使用されるすべての技術用語および科学用語は、本発明が属する技術分野における当業者により一般的に理解されるものと同じ意味を有する。本明細書に記載されているものと同様または同等の任意の方法および材料を、本発明の実施または試験において使用することができるが、好ましい方法および材料を記載する。
CTCLは、第一位的に皮膚に影響を及ぼし、第二位的にのみ対象の他の部位に影響を及ぼす、白血球の無痛性(低悪性度)癌である。この疾患は、ヘルパーT(TH)細胞として公知であるTリンパ球の制御不可能な増殖を伴う。ヘルパーT細胞の増殖は、これらの異常細胞の皮膚の真皮層および表皮層中への浸透または浸潤を、結果としてもたらす。
1つの局面において、本発明は、必要とする対象において皮膚T細胞リンパ腫(CTCL)を処置または改善する方法を含む。ある特定の非限定的な態様において、方法は、治療的有効量の、免疫応答修飾因子(IRM)化合物を含む薬学的組成物を、局所的に、経皮的に、皮内に、または病変内に、対象に投与する工程を含み、それにより該対象におけるCTCLが処置または改善される。
IRM化合物は、細胞をインビトロで接触させることまたは対象への投与に適した製剤において提供されてもよい。1つの態様において、製剤は、吸入経路、局所経路、経口経路、鼻経路、口腔経路、直腸経路、胸膜経路、腹膜経路、膣経路、筋肉内経路、皮下経路、経皮経路、硬膜外経路、クモ膜下経路、または静脈内経路により対象に投与される。別の態様において、製剤は、局所的に、皮内に、経皮的に、または病変内に投与される。さらに別の態様において、IRM化合物を含有する製剤はゲルである。
本発明の薬学的組成物の制御放出性または持続放出性の製剤は、従来の技術を用いて作製され得る。いくつかの場合に、使用される剤形は、変動する割合において望ましい放出プロファイルを提供するように、例えば、ヒドロプロピルメチルセルロース、他のポリマーマトリクス、ゲル、透過性膜、浸透圧システム、多層コーティング、微粒子、リポソーム、もしくはマイクロスフェア、またはこれらの組み合わせを用いて、その中の1つまたは複数の活性成分の緩徐放出または制御放出として提供され得る。本明細書において記載されているものを含む、当業者に公知である適した制御放出性製剤が、本発明の薬学的組成物での使用のために容易に選択され得る。
本明細書において初めて記載されるように、第IA期〜第IIA期のCTCL患者に対する、変動する用量のレシキモドゲルの第I相非盲検試験が開始された。
実施例1において報告された第I相試験を、合計で10人の患者(そのすべては、少なくとも2回の先行の治療に失敗し、その大部分は5回またはそれより多い先行の治療に失敗している)に拡大させた。それらの患者のうちの8人は、0.06%レシキモドゲルでの処置を受け、他方、2人の残りの患者は、0.03%レシキモドケルでの処置を受けた。
Claims (36)
- 必要とする対象において皮膚T細胞リンパ腫(CTCL)を処置または改善する方法であって、治療的有効量の、免疫応答修飾因子(IRM)化合物を含む薬学的組成物を、局所的に、経皮的に、皮内に、または病変内に、該対象に投与する工程を含み、それにより該対象におけるCTCLが処置または改善される、方法。
- 対象への組成物の投与が局所的である、請求項1に記載の方法。
- IRM化合物が、4-アミノ-α,α-ジメチル-2-エトキシメチル-1H-イミダゾ[4,5-c]キノリン-1-エタノールまたはその薬学的に許容される塩を含む、請求項1に記載の方法。
- 組成物がゲルを含む、請求項1に記載の方法。
- 組成物が約0.01%(w/w)IRM〜約0.5%(w/w)IRMを含む、請求項1に記載の方法。
- 組成物が約0.03%(w/w)IRM〜約0.06%(w/w)IRMを含む、請求項5に記載の方法。
- 組成物が対象の少なくとも1つのCTCL病変に適用される、請求項1に記載の方法。
- 投与が、組成物が適用された少なくとも1つのCTCL病変の少なくとも部分的な除去を結果としてもたらす、請求項7に記載の方法。
- 投与が、組成物が適用されなかった少なくとも1つのCTCL病変の少なくとも部分的な除去を結果としてもたらす、請求項7に記載の方法。
- 投与が、対象における全CTCL病変の50%またはそれより多くの除去を結果としてもたらす、請求項1に記載の方法。
- 対象に投与されるIRMの量が、約1μg/kg〜約10 mg/kgである、請求項1に記載の方法。
- 対象に投与されるIRMの量が、約100 ng/病変〜約1 mg/病変である、請求項11に記載の方法。
- 組成物が、少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、請求項1に記載の方法。
- 組成物が、少なくとも1日、少なくとも1週間、少なくとも1か月間、または少なくとも1年間の持続期間にわたって繰り返し対象に投与される、請求項1に記載の方法。
- 投与が、対象において全身の細胞媒介性抗腫瘍免疫応答を活性化する、請求項1に記載の方法。
- 投与が、対象における少なくとも1つの病変において活性化NK細胞または活性化T細胞の浸潤を誘導する、請求項15に記載の方法。
- 投与が、対象における少なくとも1つの病変においてグランザイムまたはIFN-αのレベルの増大を結果としてもたらす、請求項16に記載の方法。
- 投与が、対象の血液において循環骨髄樹状細胞または循環NK細胞を活性化する、請求項15に記載の方法。
- 活性化循環骨髄樹状細胞が、増大したCD80発現を有する、請求項18に記載の方法。
- 組成物が、第1の処置期間中および第2の処置期間中に対象に投与され、かつ該第1の処置期間と該第2の処置期間とが、非処置期間によって隔てられている、請求項1に記載の方法。
- 組成物が、第1の処置期間中に少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、請求項20に記載の方法。
- ゲルが、第2の処置期間中に少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、請求項20に記載の方法。
- 第1の処置期間が、少なくとも約2週間、少なくとも約3週間、少なくとも約4週間、少なくとも約5週間、少なくとも約6週間、少なくとも約7週間、または少なくとも約8週間である、請求項20に記載の方法。
- 第2の処置期間が、少なくとも約2週間、少なくとも約3週間、少なくとも約4週間、少なくとも約5週間、少なくとも約6週間、少なくとも約7週間、または少なくとも約8週間である、請求項20に記載の方法。
- 第1の処置期間と第2の処置期間とを隔てる非処置期間が、少なくとも約1週間、少なくとも約2週間、少なくとも約3週間、または少なくとも約4週間である、請求項20に記載の方法。
- 対象が哺乳動物である、請求項1に記載の方法。
- 哺乳動物がヒトである、請求項26に記載の方法。
- CTCLを患っている対象において細胞媒介性免疫応答を増大させる方法であって、治療的有効量の、免疫応答修飾因子(IRM)化合物を含む薬学的組成物を、局所的に、経皮的に、皮内に、または病変内に、該対象に投与する工程を含み、それにより該対象における該細胞媒介性免疫応答が増大される、方法。
- IRM化合物が、4-アミノ-α,α-ジメチル-2-エトキシメチル-1H-イミダゾ[4,5-c]キノリン-1-エタノールまたはその薬学的に許容される塩を含む、請求項28に記載の方法。
- 組成物が約0.01%(w/w)IRM〜約0.5%(w/w)IRMを含む、請求項28に記載の方法。
- 組成物が対象の少なくとも1つのCTCL病変に適用される、請求項28に記載の方法。
- 投与が、組成物が適用されたCTCL病変または組成物が適用されなかったCTCL病変からなる群より選択される少なくとも1つの、少なくとも部分的な除去を結果としてもたらす、請求項31に記載の方法。
- 組成物が、少なくとも1日に1回、少なくとも1週に1回、または少なくとも1か月に1回の頻度で対象に投与される、請求項28に記載の方法。
- 組成物が、第1の処置期間中および第2の処置期間中に対象に投与され、かつ該第1の処置期間および該第2の処置期間が、非処置期間によって隔てられている、請求項28に記載の方法。
- 対象が哺乳動物である、請求項28に記載の方法。
- 哺乳動物がヒトである、請求項35に記載の方法。
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HUE051988T2 (hu) | 2021-04-28 |
EP2941233B1 (en) | 2020-10-07 |
EP2941233A2 (en) | 2015-11-11 |
RS61101B1 (sr) | 2020-12-31 |
LT2941233T (lt) | 2020-10-26 |
MX2015008773A (es) | 2015-11-06 |
RU2669941C2 (ru) | 2018-10-17 |
HRP20201630T1 (hr) | 2020-12-25 |
SI2941233T1 (sl) | 2021-01-29 |
EP3756669A1 (en) | 2020-12-30 |
ES2828735T3 (es) | 2021-05-27 |
PT2941233T (pt) | 2020-11-13 |
CN105025854A (zh) | 2015-11-04 |
CY1123674T1 (el) | 2022-03-24 |
AU2014203896A1 (en) | 2015-07-16 |
JP6457401B2 (ja) | 2019-01-23 |
RU2015132959A (ru) | 2017-02-09 |
US20150335637A1 (en) | 2015-11-26 |
JP2019065026A (ja) | 2019-04-25 |
CA2896966A1 (en) | 2014-07-10 |
KR20150103718A (ko) | 2015-09-11 |
PL2941233T3 (pl) | 2021-03-08 |
CA2896966C (en) | 2021-03-30 |
WO2014107663A3 (en) | 2014-10-16 |
DK2941233T3 (da) | 2020-10-19 |
HK1217165A1 (zh) | 2016-12-30 |
JP2016504386A (ja) | 2016-02-12 |
WO2014107663A2 (en) | 2014-07-10 |
AU2014203896B2 (en) | 2018-05-31 |
EP2941233A4 (en) | 2016-06-22 |
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