JPWO2019183578A5 - - Google Patents
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- JPWO2019183578A5 JPWO2019183578A5 JP2020550606A JP2020550606A JPWO2019183578A5 JP WO2019183578 A5 JPWO2019183578 A5 JP WO2019183578A5 JP 2020550606 A JP2020550606 A JP 2020550606A JP 2020550606 A JP2020550606 A JP 2020550606A JP WO2019183578 A5 JPWO2019183578 A5 JP WO2019183578A5
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Description
実施形態９０．該追加の治療剤が、ＣＴＬＡ－４、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＴＩＭ－３、またはＬＡＧ３の阻害剤である治療用抗体またはその抗原結合断片である、実施形態８９に記載の方法。
本発明の実施形態において、例えば以下の項目が提供される。
（項目１）
細胞外小胞と、インターフェロン遺伝子刺激因子タンパク質（ＳＴＩＮＧ）アゴニストとを含む、組成物。
（項目２）
前記細胞外小胞が、エキソソーム、ナノ小胞、アポトーシス小体、微小胞、リソソーム、エンドソーム、リポソーム、脂質ナノ粒子、ミセル、多層膜構造体、再小胞化された小胞、または押し出された細胞である、項目１に記載の組成物。
（項目３）
前記細胞外小胞が、エキソソームである、項目２に記載の組成物。
（項目４）
前記ＳＴＩＮＧアゴニストが、前記細胞外小胞に会合している、項目１～３のいずれか１項に記載の組成物。
（項目５）
前記ＳＴＩＮＧアゴニストが、前記細胞外小胞内に封入される、項目４に記載の組成物。
（項目６）
前記ＳＴＩＮＧアゴニストが、任意選択でリンカーによって、前記細胞外小胞の脂質二重層に連結されている、項目４に記載の組成物。
（項目７）
前記細胞外小胞が、ＰＴＧＦＲＮタンパク質を過剰発現する、項目１～６のいずれか１項に記載の組成物。
（項目８）
前記ＳＴＩＮＧアゴニストが、任意選択でリンカーによって、前記ＰＴＧＦＲＮタンパク質に連結されている、項目７に記載の組成物。
（項目９）
前記細胞外小胞が、ＰＴＧＦＲＮタンパク質を過剰発現する細胞によって産生される、項目１～８のいずれか１項に記載の組成物。
（項目１０）
前記細胞外小胞が、グリカン修飾されている、項目１～９のいずれか１項に記載の組成物。
（項目１１）
前記細胞外小胞が、脱シアリル化されている、項目１～１０のいずれか１項に記載の組成物。
（項目１２）
前記細胞外小胞が、脱グリコシル化されている、項目１～１１のいずれか１項に記載の組成物。
（項目１３）
前記細胞外小胞が、前記ＳＴＩＮＧアゴニストに結合するか、またはそれと酵素的に反応するタンパク質を更に含む、項目１～１２のいずれか１項に記載の組成物。
（項目１４）
前記細胞外小胞が、リガンド、サイトカイン、または抗体を更に含む、項目１～１３のいずれか１項に記載の組成物。
（項目１５）
前記リガンドが、ＣＤ４０Ｌ、ＯＸ４０Ｌ、及び／またはＣＤ２７Ｌを含む、項目１４に記載の組成物。
（項目１６）
前記サイトカインが、ＩＬ－７、ＩＬ－１２、及び／またはＩＬ－１５を含む、項目１４に記載の組成物。
（項目１７）
前記抗体が、アンタゴニスト抗体及び／またはアゴニスト抗体を含む、項目１４に記載の組成物。
（項目１８）
前記ＳＴＩＮＧアゴニストが、環状ジヌクレオチドである、項目１～１７のいずれか１項に記載の組成物。
（項目１９）
前記ＳＴＩＮＧアゴニストが、非環状ジヌクレオチドである、項目１～１７のいずれか１項に記載の組成物。
（項目２０）
前記ＳＴＩＮＧアゴニストが、脂質結合タグを含む、項目１～１９のいずれか１項に記載の組成物。
（項目２１）
前記ＳＴＩＮＧアゴニストが、物理的及び／または化学的に修飾されている、項目１～２０のいずれか１項に記載の組成物。
（項目２２）
前記修飾型ＳＴＩＮＧアゴニストが、対応する未修飾型ＳＴＩＮＧアゴニストとは異なる極性及び／または電荷を有する、項目２１に記載の組成物。
（項目２３）
前記細胞外小胞に会合した前記ＳＴＩＮＧアゴニストの濃度が、約０．０１μＭ～１００μＭである、項目１～２２のいずれか１項に記載の組成物。
（項目２４）
前記細胞外小胞に会合した前記ＳＴＩＮＧアゴニストの濃度が、約０．０１μＭ～０．１μＭ、０．１μＭ～１μＭ、１μＭ～１０μＭ、１０μＭ～５０μＭ、または５０μＭ～１００μＭである、項目２３に記載の組成物。
（項目２５）
前記細胞外小胞に会合した前記ＳＴＩＮＧアゴニストの濃度が、約１μＭ～１０μＭである、項目２４に記載の組成物。
（項目２６）
前記ＳＴＩＮＧアゴニストが、
［式中、
Ｘ
１
は、Ｈ、ＯＨ、またはＦであり、
Ｘ
２
は、Ｈ、ＯＨ、またはＦであり、
Ｚは、ＯＨ、ＯＲ
１
、ＳＨ、またはＳＲ
１
であり、ここで、
ｉ）Ｒ
１
は、ＮａもしくはＮＨ
４
であるか、または
ｉｉ）Ｒ
１
は、ピバロイルオキシメチル等の、インビボでＯＨまたはＳＨをもたらす酵素不安定基であり、
Ｂｉ及びＢ２は、下記から選定される塩基であるが、
但し、
－式（Ｉ）において、Ｘ
１
及びＸ
２
がＯＨではなく、
－式（ＩＩ）において、Ｘ
１
及びＸ
２
がＯＨであるとき、Ｂ
１
がアデニンではなく、かつＢ
２
がグアニンではなく、かつ
－式（ＩＩＩ）において、Ｘ
１
及びＸ
２
がＯＨであるとき、Ｂ
１
がアデニンではなく、Ｂ
２
がグアニンではなく、かつＺがＯＨではないことを条件とする］、またはその薬学的に許容される塩を含む、項目１～２５のいずれか１項に記載の組成物。
（項目２７）
前記ＳＴＩＮＧアゴニストが、
及びその薬学的に許容される塩からなる群から選択される、項目２６に記載の組成物。
（項目２８）
前記ＳＴＩＮＧアゴニストが、前記細胞外小胞の内腔中にあり、足場部分に連結されていない、項目２７に記載の組成物。
（項目２９）
前記ＳＴＩＮＧアゴニストに会合した前記細胞外小胞が、以下の特性、すなわち、
（ｉ）樹状細胞、例えば骨髄樹状細胞を活性化する、
（ｉｉ）前記ＳＴＩＮＧアゴニスト単独（「遊離ＳＴＩＮＧアゴニスト」）よりも低い程度に単球細胞を活性化する、
（ｉｉｉ）単球細胞を活性化しない、
（ｉｖ）前記遊離ＳＴＩＮＧアゴニストと比較してより広い治療指数を有する、
（ｖ）前記遊離ＳＴＩＮＧアゴニストよりも低い全身毒性を有する、
（ｖｉ）前記遊離ＳＴＩＮＧアゴニストよりも低い免疫細胞殺傷性を有する、
（ｖｉｉ）前記遊離ＳＴＩＮＧアゴニストよりも高い細胞選択性を有する、
（ｖｉｉｉ）前記遊離ＳＴＩＮＧアゴニストよりも低い用量で腫瘍防御免疫を提供する、（ｉｘ）抗原提示細胞、例えば樹状細胞において、インビボで特異的細胞応答を誘導する、
（ｘ）局所投与後に遠位領域で免疫応答を誘導することができる、及び
（ｘｉ）前記遊離ＳＴＩＮＧアゴニストよりも低いレベルで投薬することができる、
のうちの１つまたは複数を示す、項目１～２８のいずれか１項に記載の組成物。
（項目３０）
前記ＳＴＩＮＧアゴニストに会合した前記細胞外小胞が、哺乳動物に投与されたとき、前記哺乳動物においてＴ細胞及び／またはマクロファージを枯渇させない、項目１～２９のいずれか１項に記載の組成物。
（項目３１）
前記ＳＴＩＮＧアゴニストに会合した前記細胞外小胞が、哺乳動物に投与されたとき、前記哺乳動物において、前記遊離ＳＴＩＮＧアゴニストよりも低い程度にＴ細胞及び／またはマクロファージを枯渇させる、項目１～２９のいずれか１項に記載の組成物。
（項目３２）
項目１～３１のいずれか１項に記載の組成物と、薬学的に許容される担体とを含む、薬学的組成物。
（項目３３）
項目１～３２のいずれか１項に記載の組成物と、使用説明書とを含む、キット。
（項目３４）
ＳＴＩＮＧアゴニストを含むＥＶ、例えばエキソソームの生産方法であって、
ａ．ＥＶ、例えばエキソソームを得ることと、
ｂ．前記ＥＶ、例えばエキソソームを溶液中でＳＴＩＮＧアゴニストと混合することと、
ｃ．前記ＥＶ、例えばエキソソームと、前記ＳＴＩＮＧアゴニストとの前記混合物を、緩衝液を含む溶液中、好適な条件下でインキュベートすることと、
ｄ．前記ＳＴＩＮＧアゴニストを含む前記ＥＶ、例えばエキソソームを精製することと、
を含む、前記方法。
（項目３５）
前記好適な条件が、前記ＥＶ、例えばエキソソームと、前記ＳＴＩＮＧアゴニストとを約２～２４時間インキュベートすることを含む、項目３４に記載の方法。
（項目３６）
前記好適な条件が、前記ＥＶ、例えばエキソソームと、前記ＳＴＩＮＧアゴニストとを約１５～９０℃でインキュベートすることを含む、項目３４または３５に記載の方法。
（項目３７）
前記好適な条件が、前記ＥＶ、例えばエキソソームと、前記ＳＴＩＮＧアゴニストとを約３７℃でインキュベートすることを含む、項目３６に記載の方法。
（項目３８）
前記混合ステップにおける前記ＳＴＩＮＧアゴニストの量が、少なくとも０．０１ｍＭ～１００ｍＭを含む、項目３４～３７のいずれか１項に記載の方法。
（項目３９）
前記混合ステップにおける前記ＳＴＩＮＧアゴニストの量が、少なくとも１ｍＭ～１０ｍＭを含む、項目３４～３８のいずれか１項に記載の方法。
（項目４０）
前記混合ステップにおける前記エキソソームの量が、少なくとも約１０
８
個～少なくとも約１０
１６
個の総粒子を含む、項目３４～３９のいずれか１項に記載の方法。
（項目４１）
前記混合ステップにおける前記ＥＶ、例えばエキソソームの量が、少なくとも約１０
１２
個の総粒子を含む、項目３４～４０のいずれか１項に記載の方法。
（項目４２）
前記緩衝液が、リン酸緩衝食塩水（ＰＢＳ）を含む、項目３４～４１のいずれか１項に記載の方法。
（項目４３）
前記精製ステップが、１つまたは複数の遠心分離ステップを含む、項目３４～４２のいずれか１項に記載の方法。
（項目４４）
前記１つまたは複数の遠心分離ステップが、約１００，０００×ｇでのものである、項目４３に記載の方法。
（項目４５）
免疫応答及び／または炎症性応答の誘導または調節を必要とする対象における前記免疫応答及び／または炎症性応答の誘導方法または調節方法であって、前記対象に薬学的有効量の項目１～３１のいずれか１項に記載の組成物または項目３２に記載の薬学的組成物を投与することを含む、前記方法。
（項目４６）
腫瘍の処置を必要とする対象における前記腫瘍の処置方法であって、前記対象に項目１～３１のいずれか１項に記載の組成物または項目３２に記載の薬学的組成物を投与することを含む、前記方法。
（項目４７）
前記投与が、前記対象において前記免疫応答及び／または前記炎症性応答を誘導するか、または調節する、項目４５または４６に記載の方法。
（項目４８）
前記投与が樹状細胞を活性化する、項目４５～４７のいずれか１項に記載の方法。
（項目４９）
前記投与が骨髄樹状細胞を活性化する、項目４５～４８のいずれか１項に記載の方法。
（項目５０）
前記投与が、前記遊離ＳＴＩＮＧアゴニストと比較して低減された単球細胞活性化をもたらす、項目４５～４９のいずれか１項に記載の方法。
（項目５１）
前記投与が単球細胞活性化を誘導しない、項目４５～５０のいずれか１項に記載の方法。
（項目５２）
前記投与がインターフェロン－β（ＩＦＮ－β）産生を誘導する、項目４５～５１のいずれか１項に記載の方法。
（項目５３）
前記投与が、前記遊離ＳＴＩＮＧアゴニストと比較して低減された全身性炎症をもたらす、項目４５～５２のいずれか１項に記載の方法。
（項目５４）
前記投与が、非実質的な量の全身性炎症をもたらす、項目４５～５３のいずれか１項に記載の方法。
（項目５５）
前記投与が、非経口的、経口的、静脈内、筋肉内、腫瘍内、腹腔内、または任意の他の適切な投与経路を介するものである、項目４５～５４のいずれか１項に記載の方法。
（項目５６）
前記投与が静脈内である、項目４５～５５のいずれか１項に記載の方法。
（項目５７）
前記免疫応答が抗腫瘍応答である、項目４５～５６のいずれか１項に記載の方法。
（項目５８）
前記組成物が、ＩＦＮ－βを誘導する及び／または樹状細胞を活性化するのに十分な量である、項目４５～５７のいずれか１項に記載の方法。
（項目５９）
前記組成物が、１つの場所の第１の腫瘍において腫瘍内投与され、前記第１の腫瘍において投与された前記組成物が、第２の場所での１つまたは複数の腫瘍の転移を予防する、項目４５～５８のいずれか１項に記載の方法。
（項目６０）
追加の治療剤を投与することを更に含む、項目４５～５９のいずれか１項に記載の方法。
（項目６１）
前記追加の治療剤が免疫調節剤である、項目６０に記載の方法。
（項目６２）
前記追加の治療剤が、抗体またはその抗原結合断片である、項目６０または６１に記載の方法。
（項目６３）
前記抗体またはその抗原結合断片が、ＣＴＬＡ－４、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＴＩＭ－３、またはＬＡＧ３の阻害剤である、項目６２のいずれか１項に記載の方法。
（項目６４）
前記投与が、前記対象において前記腫瘍の転移を予防する、項目４５～６３のいずれか１項に記載の方法。
Embodiment 90. 28. Embodiment 89, wherein the additional therapeutic agent is a therapeutic antibody or antigen-binding fragment thereof that is an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, or LAG3. the method of.
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
A composition comprising extracellular vesicles and an interferon gene stimulating factor protein (STING) agonist.
(Item 2)
The extracellular vesicles are exosomes, nanovesicles, extracellular vesicles, microvesicles, lysosomes, endosomes, liposomes, lipid nanoparticles, micelles, multilayer structures, re-vesicularized vesicles, or extruded cells. The composition according to item 1.
(Item 3)
The composition according to item 2, wherein the extracellular vesicle is an exosome.
(Item 4)
The composition according to any one of items 1 to 3, wherein the STING agonist is associated with the extracellular vesicle.
(Item 5)
The composition according to item 4, wherein the STING agonist is encapsulated in the extracellular vesicle.
(Item 6)
The composition according to item 4, wherein the STING agonist is optionally linked to the lipid bilayer of the extracellular vesicle by a linker.
(Item 7)
Item 6. The composition according to any one of Items 1 to 6, wherein the extracellular vesicles overexpress the PTGFRN protein.
(Item 8)
7. The composition of item 7, wherein the STING agonist is optionally linked to the PTGFRN protein by a linker.
(Item 9)
The composition according to any one of items 1 to 8, wherein the extracellular vesicle is produced by a cell that overexpresses the PTGFRN protein.
(Item 10)
Item 6. The composition according to any one of items 1 to 9, wherein the extracellular vesicles are glycan-modified.
(Item 11)
Item 6. The composition according to any one of Items 1 to 10, wherein the extracellular vesicles are desialylated.
(Item 12)
Item 6. The composition according to any one of items 1 to 11, wherein the extracellular vesicles are deglycosylated.
(Item 13)
The composition according to any one of items 1 to 12, wherein the extracellular vesicle further comprises a protein that binds to or enzymatically reacts with the STING agonist.
(Item 14)
Item 6. The composition according to any one of items 1 to 13, wherein the extracellular vesicle further comprises a ligand, a cytokine, or an antibody.
(Item 15)
14. The composition of item 14, wherein the ligand comprises CD40L, OX40L, and / or CD27L.
(Item 16)
14. The composition of item 14, wherein the cytokine comprises IL-7, IL-12, and / or IL-15.
(Item 17)
14. The composition of item 14, wherein the antibody comprises an antagonist antibody and / or an agonist antibody.
(Item 18)
The composition according to any one of items 1 to 17, wherein the STING agonist is a cyclic dinucleotide.
(Item 19)
Item 6. The composition according to any one of items 1 to 17, wherein the STING agonist is an acyclic dinucleotide.
(Item 20)
Item 6. The composition according to any one of items 1 to 19, wherein the STING agonist comprises a lipid binding tag.
(Item 21)
The composition according to any one of items 1 to 20, wherein the STING agonist is physically and / or chemically modified.
(Item 22)
21. The composition of item 21, wherein the modified STING agonist has a different polarity and / or charge than the corresponding unmodified STING agonist.
(Item 23)
The composition according to any one of items 1 to 22, wherein the concentration of the STING agonist associated with the extracellular vesicle is about 0.01 μM to 100 μM.
(Item 24)
23. Item 23, wherein the concentration of the STING agonist associated with the extracellular vesicle is about 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 10 μM, 10 μM to 50 μM, or 50 μM to 100 μM. Composition.
(Item 25)
24. The composition of item 24, wherein the concentration of the STING agonist associated with the extracellular vesicles is from about 1 μM to 10 μM.
(Item 26)
The STING agonist
[During the ceremony,
X 1 is H, OH, or F,
X 2 is H, OH, or F,
Z is OH, OR 1 , SH, or SR 1 where,
i) R 1 is Na or NH 4 or
ii) R 1 is an enzyme-labile group that results in OH or SH in vivo, such as pivaloyloxymethyl.
Bi and B2 are bases selected from the following,
however,
-In formula (I), X 1 and X 2 are not OH,
-In formula (II), when X 1 and X 2 are OH, B 1 is not adenine and B 2 is not guanine.
-In formula (III), provided that when X 1 and X 2 are OH, B 1 is not adenine, B 2 is not guanine, and Z is not OH], or pharmaceutically thereof. The composition according to any one of items 1 to 25, which comprises an acceptable salt.
(Item 27)
The STING agonist
26. The composition of item 26, selected from the group consisting of and pharmaceutically acceptable salts thereof.
(Item 28)
27. The composition of item 27, wherein the STING agonist is in the lumen of the extracellular vesicle and is not linked to a scaffold portion.
(Item 29)
The extracellular vesicles associated with the STING agonist have the following characteristics:
(I) Activate dendritic cells, such as bone marrow dendritic cells,
(Ii) Activates monocyte cells to a lower degree than the STING agonist alone (“free STING agonist”).
(Iii) Does not activate monocyte cells,
(Iv) has a broader therapeutic index as compared to the free STING agonist.
(V) Has lower systemic toxicity than the free STING agonist.
(Vi) has a lower immune cell killing property than the free STING agonist.
(Vii) has higher cell selectivity than the free STING agonist.
(Viii) Induces a specific cellular response in vivo in antigen-presenting cells, such as dendritic cells, which provide tumor protective immunity at lower doses than said free STING agonists.
(X) Can induce an immune response in the distal region after topical administration, and
(Xi) Can be administered at lower levels than the free STING agonist,
The composition according to any one of items 1 to 28, which indicates one or more of them.
(Item 30)
The composition according to any one of items 1 to 29, wherein the extracellular vesicles associated with the STING agonist do not deplete T cells and / or macrophages in the mammal when administered to the mammal.
(Item 31)
Items 1-29, wherein the extracellular vesicles associated with the STING agonist deplete T cells and / or macrophages in the mammal to a lower extent than the free STING agonist when administered to the mammal. The composition according to any one item.
(Item 32)
A pharmaceutical composition comprising the composition according to any one of items 1 to 31 and a pharmaceutically acceptable carrier.
(Item 33)
A kit comprising the composition according to any one of items 1 to 32 and an instruction manual.
(Item 34)
A method for producing an EV containing a STING agonist, for example, an exosome.
a. Obtaining EVs, such as exosomes,
b. Mixing the EV, eg exosomes, in solution with a STING agonist,
c. Incubating the mixture of the EV, eg, an exosome, and the STING agonist in a solution containing a buffer under suitable conditions.
d. Purifying the EV containing the STING agonist, such as an exosome,
The method described above.
(Item 35)
34. The method of item 34, wherein the preferred conditions include incubating the EV, eg, an exosome, with the STING agonist for about 2-24 hours.
(Item 36)
34. The method of item 34 or 35, wherein the preferred conditions include incubating the EV, eg, an exosome, with the STING agonist at about 15-90 ° C.
(Item 37)
36. The method of item 36, wherein the preferred conditions include incubating the EV, eg, an exosome, with the STING agonist at about 37 ° C.
(Item 38)
The method according to any one of items 34 to 37, wherein the amount of the STING agonist in the mixing step comprises at least 0.01 mM to 100 mM.
(Item 39)
The method according to any one of items 34 to 38, wherein the amount of the STING agonist in the mixing step comprises at least 1 mM to 10 mM.
(Item 40)
The method according to any one of items 34 to 39, wherein the amount of the exosomes in the mixing step comprises at least about 108 to at least about 1016 total particles.
(Item 41)
The method of any one of items 34-40, wherein the amount of the EV, eg, exosomes, in the mixing step comprises at least about 1012 total particles.
(Item 42)
The method according to any one of items 34 to 41, wherein the buffer solution comprises phosphate buffered saline (PBS).
(Item 43)
The method of any one of items 34-42, wherein the purification step comprises one or more centrifugation steps.
(Item 44)
43. The method of item 43, wherein the one or more centrifugation steps are at about 100,000 xg.
(Item 45)
The method for inducing or regulating an immune response and / or an inflammatory response in a subject in need of induction or regulation of the immune response and / or the inflammatory response, wherein the subject has a pharmaceutically effective amount of items 1-31. The method according to any one of the above, comprising administering the composition according to any one item or the pharmaceutical composition according to item 32.
(Item 46)
A method for treating a tumor in a subject requiring treatment of the tumor, wherein the subject is administered with the composition according to any one of items 1 to 31 or the pharmaceutical composition according to item 32. Included, said method.
(Item 47)
45. The method of item 45 or 46, wherein said administration induces or regulates said immune and / or said inflammatory response in said subject.
(Item 48)
The method according to any one of items 45 to 47, wherein the administration activates dendritic cells.
(Item 49)
The method according to any one of items 45 to 48, wherein the administration activates bone marrow dendritic cells.
(Item 50)
The method of any one of items 45-49, wherein the administration results in reduced monocyte cell activation as compared to the free STING agonist.
(Item 51)
The method according to any one of items 45 to 50, wherein the administration does not induce monocyte cell activation.
(Item 52)
The method according to any one of items 45 to 51, wherein the administration induces interferon-β (IFN-β) production.
(Item 53)
The method of any one of items 45-52, wherein the administration results in reduced systemic inflammation as compared to the free STING agonist.
(Item 54)
The method of any one of items 45-53, wherein the administration results in a non-substantial amount of systemic inflammation.
(Item 55)
35. Item 2. Method.
(Item 56)
The method according to any one of items 45 to 55, wherein the administration is intravenous.
(Item 57)
The method according to any one of items 45 to 56, wherein the immune response is an antitumor response.
(Item 58)
The method according to any one of items 45 to 57, wherein the composition is in an amount sufficient to induce IFN-β and / or activate dendritic cells.
(Item 59)
The composition is administered intratumorally in a first tumor at one location and the composition administered in the first tumor prevents metastasis of one or more tumors at a second location. , The method according to any one of items 45 to 58.
(Item 60)
The method of any one of items 45-59, further comprising administering an additional therapeutic agent.
(Item 61)
60. The method of item 60, wherein the additional therapeutic agent is an immunomodulator.
(Item 62)
60 or 61. The method of item 60 or 61, wherein the additional therapeutic agent is an antibody or antigen-binding fragment thereof.
(Item 63)
Item 6. The method according to any one of item 62, wherein the antibody or antigen-binding fragment thereof is an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, or LAG3.
(Item 64)
The method according to any one of items 45 to 63, wherein the administration prevents metastasis of the tumor in the subject.
Claims (27)
［式中、
Ｘ１は、Ｈ、ＯＨ、またはＦであり、
Ｘ２は、Ｈ、ＯＨ、またはＦであり、
Ｚは、ＯＨ、ＯＲ１、ＳＨ、またはＳＲ１であり、ここで、
ｉ）Ｒ１は、ＮａもしくはＮＨ４であるか、または
ｉｉ）Ｒ１は、ピバロイルオキシメチル等の、インビボでＯＨまたはＳＨをもたらす酵素不安定基であり、
Ｂｉ及びＢ２は、下記から選定される塩基であるが、
但し、
－式（Ｉ）において、Ｘ１及びＸ２がＯＨではなく、
－式（ＩＩ）において、Ｘ１及びＸ２がＯＨであるとき、Ｂ１がアデニンではなく、かつＢ２がグアニンではなく、かつ
－式（ＩＩＩ）において、Ｘ１及びＸ２がＯＨであるとき、Ｂ１がアデニンではなく、Ｂ２がグアニンではなく、かつＺがＯＨではないことを条件とする］、またはその薬学的に許容される塩を含む、請求項１～７のいずれか１項に記載の組成物。 The STING agonist
[During the ceremony,
X 1 is H, OH, or F,
X 2 is H, OH, or F,
Z is OH, OR 1 , SH, or SR 1 where,
i) R 1 is Na or NH 4 , or ii) R 1 is an enzyme unstable group that results in OH or SH in vivo, such as pivaloyloxymethyl.
Bi and B2 are bases selected from the following,
however,
-In formula (I), X 1 and X 2 are not OH,
-In formula (II), when X 1 and X 2 are OH, B 1 is not adenine and B 2 is not guanine, and-in formula (III), X 1 and X 2 are OH. When B 1 is not adenine, B 2 is not guanine, and Z is not OH], or any 1 of claims 1-7 comprising a pharmaceutically acceptable salt thereof. The composition according to the section.
及びその薬学的に許容される塩からなる群から選択される、請求項８に記載の組成物。 The STING agonist
8. The composition of claim 8 , selected from the group consisting of pharmaceutically acceptable salts thereof.
またはその薬学的に許容される塩である、請求項４に記載の組成物。The composition according to claim 4, which is a pharmaceutically acceptable salt thereof.
（ｉ）樹状細胞、例えば骨髄樹状細胞を活性化する、
（ｉｉ）前記ＳＴＩＮＧアゴニスト単独（「遊離ＳＴＩＮＧアゴニスト」）よりも低い程度に単球細胞を活性化する、
（ｉｉｉ）単球細胞を活性化しない、
（ｉｖ）前記遊離ＳＴＩＮＧアゴニストと比較してより広い治療指数を有する、
（ｖ）前記遊離ＳＴＩＮＧアゴニストよりも低い全身毒性を有する、
（ｖｉ）前記遊離ＳＴＩＮＧアゴニストよりも低い免疫細胞殺傷性を有する、
（ｖｉｉ）前記遊離ＳＴＩＮＧアゴニストよりも高い細胞選択性を有する、
（ｖｉｉｉ）前記遊離ＳＴＩＮＧアゴニストよりも低い用量で腫瘍防御免疫を提供する、（ｉｘ）抗原提示細胞、例えば樹状細胞において、インビボで特異的細胞応答を誘導する、
（ｘ）局所投与後に遠位領域で免疫応答を誘導することができる、及び
（ｘｉ）前記遊離ＳＴＩＮＧアゴニストよりも低いレベルで投薬することができる、
のうちの１つまたは複数を示す、請求項１～１１のいずれか１項に記載の組成物。 The extracellular vesicles associated with the STING agonist have the following characteristics:
(I) Activate dendritic cells, such as bone marrow dendritic cells,
(Ii) Activates monocyte cells to a lower degree than the STING agonist alone (“free STING agonist”).
(Iii) Does not activate monocyte cells,
(Iv) has a broader therapeutic index as compared to the free STING agonist.
(V) Has lower systemic toxicity than the free STING agonist.
(Vi) has a lower immune cell killing property than the free STING agonist.
(Vii) has higher cell selectivity than the free STING agonist.
(Viii) Induces a specific cellular response in vivo in antigen-presenting cells, such as dendritic cells, which provide tumor protective immunity at lower doses than said free STING agonists.
(X) can induce an immune response in the distal region after topical administration, and (xi) can be administered at lower levels than said free STING agonists.
The composition according to any one of claims 1 to 11 , indicating one or more of the above.
ａ．ＥＶ、例えばエキソソームを得ることと、
ｂ．前記ＥＶ、例えばエキソソームを溶液中でＳＴＩＮＧアゴニストと混合することと、
ｃ．前記ＥＶ、例えばエキソソームと、前記ＳＴＩＮＧアゴニストとの前記混合物を、緩衝液を含む溶液中、好適な条件下でインキュベートすることと、
ｄ．前記ＳＴＩＮＧアゴニストを含む前記ＥＶ、例えばエキソソームを精製することと、
を含む、前記方法。 A method for producing an EV containing a STING agonist, for example, an exosome.
a. Obtaining EVs, such as exosomes,
b. Mixing the EV, eg exosomes, in solution with a STING agonist,
c. Incubating the mixture of the EV, eg, an exosome, and the STING agonist in a solution containing a buffer under suitable conditions.
d. Purifying the EV containing the STING agonist, such as an exosome,
The method described above.
26. The composition of claim 26 , wherein the antibody or antigen-binding fragment thereof is an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, or LAG3.
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