JP2019535810A - 体腔の免疫調節治療 - Google Patents
体腔の免疫調節治療 Download PDFInfo
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- JP2019535810A JP2019535810A JP2019542827A JP2019542827A JP2019535810A JP 2019535810 A JP2019535810 A JP 2019535810A JP 2019542827 A JP2019542827 A JP 2019542827A JP 2019542827 A JP2019542827 A JP 2019542827A JP 2019535810 A JP2019535810 A JP 2019535810A
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Abstract
Description
2016年10月25日に出願された米国暫定特許出願第62/412,482号に権利が主張されており、その内容はそれらの全体において参照することにより援用される。
本明細書に提供されるのは、1つ以上の治療薬が生体適合性ヒドロゲル組成物に埋め込まれ、かつ生体適合性ヒドロゲル組成物からゆっくり放出される、少なくとも2つの免疫調節剤の併用によって、体腔の癌、特に尿路癌を治療するための組成物及び方法である。
癌は異常細胞の制御されない増殖による疾患である。膀胱の尿路上皮癌はすべての膀胱癌の90%以上を占め、そのうち約80%は非筋肉浸潤性膀胱癌(NMIBC)であり、表在性癌の一種である。経尿道的切除術及び根治的膀胱摘除術は、それぞれNMIBC及びMIBC(筋肉浸潤性膀胱癌)の治療の主力であり続けている。マイトマイシンを用いた膀胱内療法は、疾患の再発及び進行を減少させることを目的とした外科手術に対する好ましい補助療法である。しかしながら、いくつかの癌は、現在の生物学的及び化学療法的治療に不応性である。
独特な熱可逆性ヒドロゲル組成物において、TLRアゴニストと、例えば限定されないがCTLA−4、PDL−1又はPD−1のアンタゴニストなどの免疫チェックポイントモジュレーターとの併用を含む組成物による体腔の癌の治療からの有意な利益の発見が本明細書にて提供される。したがって本明細書では、TLRアゴニストと免疫チェックポイントモジュレーターとの併用、及び熱可逆性ヒドロゲル組成物が記載される。
用語の説明
特に説明がない限り、本明細書で使用されるすべての技術用語及び科学用語は、本開示が属する技術分野の当業者によって一般に理解されるものと同じ意味を有する。単数形の用語「a」、「an」、及び「the」は、文脈が明らかにそうでないと示さない限り、複数の指示対象を含む。同様に、単語「又は」とは、文脈が明らかにそうでないと示さない限り、「及び」を含めることを意図する。さらに、核酸、ポリペプチド、及び小分子について与えられたすべての塩基サイズ又はアミノ酸サイズ、並びにすべての分子量又は分子質量値は近似値であり、説明のために提供されていることを理解されたい。本明細書に記載されるものと類似又は同等の方法及び材料を本開示の実施又は試験に使用することができるが、適切な方法及び材料を以下に記載する。用語の「comprise(含む)」は「include」を意味する。略語は、「e.g.」(例えば)とはラテン語の「exempli gratia」から派生し、非限定的例を示すために本明細書で使用される。したがって、略語「e.g.」(例えば)は、用語「for example」と同義である。
本明細書では、熱可逆性ヒドロゲル組成物を含む、ヒト被験体への投与に適した癌免疫療法組成物であり;有効量のTLRアゴニスト;及び熱可逆性ヒドロゲル組成物が、Aは親水性ブロックであり、かつBは疎水性ブロックである、一般式ABA若しくはBABのコポリマーを有する少なくとも1つのトリブロックコポリマー又はキトサンを含み有効量の免疫チェックポイントモジュレーターが記載される。
本明細書に記載されるのは、尿路の腔などの内部体腔の中又は表面上に見られる癌を治療するための組成物である。記載の組成物は、(a)トール様受容体(TLR)アゴニスト、(b)例えば限定されないがCTLA−4、PDL−1又はPD−1などの、チェックポイントモジュレーターのアンタゴニスト、及び(c)熱可逆性ヒドロゲル組成物又は熱可逆性ヒドロゲルの併用を含む。
当然のことながら、特定の実施形態において、TLRアゴニストと免疫チェックポイントモジュレーター(例えば、CTLA−4、PDL−1、又はPD−1)アンタゴニストとの記載の併用の有効量は、所望の熱可逆性ヒドロゲルと組み合わせた製剤で提供され得る。逆に、特定の実施形態では、アゴニスト成分及びアンタゴニスト成分は、提供された活性剤をある期間にわたって及び特定の条件下で放出させるために、異なる特性及び能力を有する別々の熱可逆性ヒドロゲル製剤で提供され得る。
さらに、本明細書に記載されるのは、有効量のTLRアゴニストと有効量の免疫チェックポイントモジュレーターとの併用の投与による内部体腔の癌の治療方法であり、少なくとも1つの活性化剤が、1つ以上の熱可逆性ヒドロゲル組成物による局所的、持続的な様式で提供される。
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この実施例で使用するための材料は市販されている。特記しない限り、方法は標準的な手順に従う。特定の関連材料及び方法は、Doninら、Urol Oncol.(https://www.ncbi.nlm.nih.gov/pubmed/28341495)2017 Feb;35(2):39.el−39に記載されるとおりである。
6〜8週齢の32匹の雌性C57Bl/6マウスを試験に使用した。膀胱を0.1%ポリ−L−リジンで20分間前処理した。前処理後、106個のMB49腫瘍細胞を50%マトリゲルにおいて膀胱に1時間点滴注入した。
マウスを4つの計画のうちの1つで治療した:腫瘍移植後3、6、及び9日目において、1)ビヒクル+アイソタイプ、2)TMX−101+アイソタイプ、3)ビヒクル+抗PD−L1、又は4)併用療法(TMX−101+抗PD−L1)。
膀胱内TMX−101を3日目、6日目、及び9日目に20分間投与した。4日目及び7日目に腹腔内(ip)注射によりaPD−L1を投与した。
膀胱重量を腫瘍量の尺度として使用し、クラスカル−ワリス検定を使用して比較した。膀胱の組織学的分析を行った。末梢血単核球(PBMC)、脾臓、及び局所リンパ節の蛍光活性化細胞選別(FACS)分析をT細胞集団について実施した。
以下の図1及び表1に示されるとおり、TMX−101と抗PD−L1の併用は、いずれかの処置単独で処置されたマウス及び対照処置マウスより有意に膀胱重量を減少させた(p<0.05)。
TMX−101とaPD−L1との併用は、尿路上皮癌(UC)のマウスモデルにおいていずれかの処置単独よりも有意に膀胱重量(腫瘍量のマーカー)を減少させた。
実施例1は、免疫チェックポイント阻害剤の全身投与及びTLR−7アゴニストの局所投与を含む治療が、尿路上皮癌(UC)の治療に大きな利益をもたらすことを実証している。本実施例は、免疫チェックポイント阻害剤及びTLR−7アゴニストとの局所的投与併用療法についての少なくとも同様の利益を記載する。
1.プラセボ(例えば、200〜400μg)で処置したMBT−2腫瘍マウス;
2.TLR−7アゴニストのみ(例えば、0.1〜0.4%)で処置したMBT−2腫瘍マウス;
3.aCTLA又はaPDL−1又はaPD−1のみ(例えば、200〜400ug)で処置したMBT−2腫瘍マウス;
4.TLR−7及びaCTLA−4又はaPDL−1又はaPD−1(例えば0.1〜0.4%のTLR−7及び例えば200〜400ugのaCTLA/aPDL−1/PD−1)の両方で処置したMBT−2腫瘍マウス。
Claims (23)
- ヒト被験体への投与に適した癌免疫療法組成物であって:
熱可逆性ヒドロゲル組成物;
有効量のTLRアゴニスト及び
有効量の免疫チェックポイントモジュレーターを含み、
熱可逆性ヒドロゲル組成物は、Aは親水性ブロックであり、かつBは疎水性ブロックである、一般式ABA若しくはBABコポリマーを有する少なくとも一つのトリブロックコポリマー又はキトサンを含む、前記免疫療法組成物。 - TLRアゴニストがTLR−2アゴニスト、TLR−4アゴニスト、TLR−7アゴニスト、TLR−8アゴニスト、又はTLR−9アゴニストである、請求項1に記載の癌免疫療法組成物。
- TLRアゴニストが、イミダゾキノリンアミン、テトラヒドロイミダゾキノリンアミン、イミダゾピリジンアミン、1,2−架橋イミダゾキノリンアミン、6,7−縮合シクロアルキルイミダゾピリジンアミン、イミダゾナフチリジンアミン、テトラヒドロイミダゾナフチリジンアミン、オキサゾロキノリンアミン、チアゾロキノリンアミン、オキサゾロピリジンアミン、チアゾロピリジンアミン、オキサゾロナフチリジンアミン、チアゾロナフチリジンアミン、TMX201、TMX202、TMX−30X、TMX302、モトリモド、DUK−CPG−001、IMO−2055(EMD1201081)、CpG−28、アガトリモド、SD−101、MGN1703、G100、BCG、QS−21又はAS15を含む、請求項2に記載の癌免疫療法組成物。
- 免疫チェックポイントモジュレーターが、PD1、PDL1、CTLA4、KIR、LAG3、VISTA、TIM3、B7−H3、B7−H4、及びBTLAから選択される抗原に結合するアンタゴニスト抗体である、請求項1に記載の癌免疫療法組成物。
- 抗体が、ペムブロリズマブ(Keytrude、MK−3475)、ニボルマブ(Opdivo、BMS−936558)、ピジリズマブ(CT−011)、MEDI0680(AMP514)、TSR−042、AMP−224、デュルバルマブ(MEDI4736)、アヴェルマブ(MSB0010718C)、アテゾリズマブ(MPDL3280A)、MDX1105(BMS−936559)、イピリムマブ(Yervoy)、トレメリムマブ(CP−675,206)、リリルマブ(BMS986015)、IPH2101、BMS986016、IMP321、TSR−033、JNJ−61610588、TSR022、エノブリツズマブ(MGA271)、MGD009、又はDS−5573aを含む、請求項4に記載の癌免疫療法組成物。
- 免疫チェックポイントモジュレーターが、41BB(CD137)、OX40(CD134)、CD28、ICOS(CD278)又はCD40からなる群から選択される抗原に結合するアゴニスト抗体である、請求項1に記載の癌免疫療法組成物。
- 抗体が、ウトミルマブ(PF05082566)、ウレルマブ(BMS663516)、MEDI6469、PF04518600(PF−8600)、MOXROS16、GSK3174998、TGN1412(TAB08)、MEDI−570、GSK3359609及びCP870890から選択される、請求項6に記載の癌免疫療法組成物。
- ABA式を有するトリブロックコポリマーが、EPO/PPO/EPOブロックコポリマーである、請求項1に記載の癌免疫療法組成物。
- ABA式を有するトリブロックコポリマーが、8500〜16000DA(両端値を含む)の平均分子量を有する、請求項8に記載の癌免疫療法組成物。
- ABA式を有するトリブロックコポリマーが、ポロキサマー407である、請求項8に記載の癌免疫療法組成物。
- 膀胱癌、尿路癌、上部尿路癌、腎臓癌、消化器癌、結腸癌、直腸癌及び女性生殖系癌からなる群から選択される癌の治療において使用するための、請求項1〜10のいずれか一項に記載の癌免疫療法組成物。
- 癌が、膀胱腔、尿管腔、口腔、食道腔、胃腔、腸管腔、及び結腸腔から選択される体腔の癌である、請求項11に記載の癌免疫療法組成物。
- 膀胱癌が、非筋肉浸潤性膀胱癌(NMIBC)、筋肉浸潤性膀胱癌(MIBC)、又は転移性膀胱癌である、請求項11に記載の癌免疫療法組成物。
- 熱可逆性ヒドロゲルが、0.1%(w/w)〜5%(w/w)の粘膜付着性ポリマーをさらに含む、請求項1に記載の癌免疫療法組成物。
- 熱可逆性ヒドロゲル組成物が、15%(w/w)〜40%(w/w)のポロキサマー407を含む、請求項8又は請求項10に記載の癌免疫療法組成物。
- TLR−7アゴニストが0.005%(w/v)〜10%(w/v)、特に0.01%(w/v)〜5%(w/v)、0.1%(w/v)〜4%(w/v)、0.1%(w/v)〜3%(w/v)及び0.1%(w/v)〜2%(w/v)の濃度で提供されるイミダゾキノリン(アミン)誘導体である、請求項2に記載の癌免疫療法組成物。
- CTLA4阻害剤が5(mg/Kg B.W)〜50(mg/Kg B.W)の濃度で提供されるイピリムマブ又はトレメリムマブであり、PDL−1阻害剤が5(mg/Kg B.W)〜70(mg/Kg B.W)の濃度で提供されるアテゾリズマブ、デュルバルマブ、又はアヴェルマブであり、かつPD−1阻害剤が0.5(mg/Kg B.W)〜30(mg/Kg B.W)の濃度で提供されるペムブロリズマブ又はニボルマブである、請求項4に記載の癌免疫療法組成物。
- 被験体の内部体腔の癌を治療するための方法であって、それを必要とする被験体に、
治療有効量のTLRアゴニスト;
治療有効量の免疫チェックポイントモジュレーター;及び
Aは親水性ブロックであり、かつBは疎水性ブロックである、一般式ABA又はBABを有するトリブロックコポリマー又はキトサンを含む少なくとも1つの熱可逆性ヒドロゲル組成物、
を投与することを含む、前記方法。 - TLRアゴニストが局所的に投与される、請求項18に記載の方法。
- 免疫チェックポイントモジュレーターが全身的又は局所的に投与される、請求項18に記載の方法。
- 被験体に癌免疫療法を提供するためのキットであって:
治療有効量のTLRアゴニスト;
治療有効量の免疫チェックポイントモジュレーター;
及びAは親水性ブロックであり、かつBは疎水性ブロックである、一般式ABA又はBABを有する少なくとも1つのトリブロックコポリマー又はキトサンを含む少なくとも1つの熱可逆性ヒドロゲル組成物、
並びにその投与及び使用のための説明書を含む、前記キット。 - ヒト被験体の内部体腔の癌の治療計画であって:
aPD1抗体(抗PD1抗体)、aPDL1抗体(抗PDL1抗体)又はaCTLA4抗体(抗CTLA4抗体)とTLR7アゴニストとの併用療法の少なくとも1サイクルを被験体へ投与することを含み、前記サイクルは、少なくとも12週間の1〜3回の週投薬計画に従うTLR7アゴニストの投与と組み合わせて、1〜3週間の投薬スケジュールに従う治療有効量のaPD1抗体又はaPDL1抗体又はaCTLA4抗体を投与することを含む、前記治療計画。 - ヒト被験体の内部体腔の癌の治療のための方法であって、該方法はそれを必要とする被験体に、治療有効量の:
(a)TLR7アゴニスト;及び
(b)抗PD1抗体、抗PDL1抗体、又は抗CTLA4抗体、
を投与することを含む方法であって、
(A)誘導期の間、TLR7アゴニストを12週間にわたって1〜3週毎に投与し、かつ抗PD1抗体、抗PDL1抗体又は抗CTLA4抗体を12週間にわたって合計4〜12回投薬するために週毎から3週毎に投与し、続いて、
(B)維持期の間、12〜36ヶ月の1〜6ヶ月毎にTLR7アゴニストを投与する、又は3〜12週毎に抗PD1抗体、抗PDL1抗体又は抗CTL4抗体のみを投与する、又は3〜12週毎に抗PD1抗体、抗PDL1抗体又は抗CTL4抗体を投与し、かつ1〜6ヶ月毎にTLR7アゴニストを投与する、前記方法。
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US20190201334A1 (en) | 2019-07-04 |
JP7265989B2 (ja) | 2023-04-27 |
WO2018078620A1 (en) | 2018-05-03 |
US20230218521A1 (en) | 2023-07-13 |
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