JP7420841B2 - 核酸送達のためのイオン化可能な脂質 - Google Patents
核酸送達のためのイオン化可能な脂質 Download PDFInfo
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- JP7420841B2 JP7420841B2 JP2021577003A JP2021577003A JP7420841B2 JP 7420841 B2 JP7420841 B2 JP 7420841B2 JP 2021577003 A JP2021577003 A JP 2021577003A JP 2021577003 A JP2021577003 A JP 2021577003A JP 7420841 B2 JP7420841 B2 JP 7420841B2
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Description
[0002]本出願は2019年6月29日に出願された米国特許仮出願第62/868,900号、及び2020年4月13日に出願された同第63/009,042号の優先権を主張する。
[0004]開示される主題は一般にイオン化可能な脂質、特に、生の細胞に遺伝物質をトランスフェクトすることができるイオン化可能な脂質に関する。
[0007]疾患の核酸処置戦略の数は、初期の遺伝的原因をもたない疾患でさえ、増え続けている。各々の核酸治療は異なる形態、化学、及び電荷を有しており、典型的には異なる送達モダリティーを必要とする。
[0013]式中、pは0又は1であり;
[0014]E1は-O-δ1、-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、-OC(O)S-δ1、-C(O)N(Q)-δ1、-C(O)O-δ1、-N(Q)C(O)-δ1、-N(Q)C(O)O-δ1、-N(Q)C(O)S-δ1、及び-N(Q)C(O)N(Q)-δ1から選択され;QはH、又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し;
[0015]R1は
から選択され;ここで
[0016]R3及びR4は各々独立してC1~C6アルキル、C2~C6アルケニル、及びC2~C6アルキニルからなる群から選択されるか;又はR3及びR4は一緒になって、酸素(O)若しくは2個以下の窒素(N)を含有し、各々独立してC1~C6アルキル、シクロプロピル、OH、及びC1~C3アルコキシ基からに選択される1~2個の置換基で任意選択で置換されている4~6員の環を形成していてもよく;
[0017]R5はC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C6シクロアルキル、及び2-ヒドロキシエチル基から選択され;
[0018]R6はH、及びC1~C6アルキル基から選択され;
[0019]aは1、2、3、4又は5であり;
[0020]b及びcは独立して0、1、又は2であり;
[0021]c’は1、2、3、4、又は5であり;
[0022]dは1、又は2であり;
[0023]eは0、1、又は2であり;
[0024]E2は-OC(O)-δ2、-OC(O)O-δ2、-OC(O)N(Q)-δ2、-O-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され;QはH又はC1~C5アルキルであり;δ2はR2基に連結される結合を示し;
[0025]R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで、
[0026]L1及びL2は各々独立して、直接結合、-O-δ3、-CH2OC(O)-δ3、及び-CH2O-δ3であり;δ3はR7及びR8基に連結される結合を示し;
[0027]R7及びR8は各々独立してC4~C10アルキル、C4~C10アルケニル又はC4~C10アルキニルであり;
[0028]fは0、1、2、3、4、又は5であり;
[0029]L3は
から選択され;
[0030]R9はH及びC4~C8アルキル基から選択され;
[0031]gは1~18の範囲の整数であり;
[0032]hは0、1、2又は3であり;
[0034]
[0035]式中、E1は-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、及び-OC(O)S-δ1から選択され;QはH又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し;
[0036]R1は、
から選択され;
[0037]ここで、
[0038]R3及びR4は各々独立してC1~C6アルキル基から選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
[0039]R5はC1~C6アルキル、及びC3~C6シクロアルキル基から選択され;
[0040]R6はH、及びC1~C6アルキル基から選択され;
[0041]aは1、2、3、又は4であり;
[0042]b及びcは独立して0、1、又は2であり;
[0043]c’は2、3、又は4であり;
[0044]dは2であり;
[0045]eは0、又は1であり;
[0046]E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、ここでδ2はR2基に連結される結合を示し;
[0047]R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで
[0048]L1及びL2は各々独立して、直接結合、-O-δ3、-CH2OC(O)-δ3、及び-CH2O-δ3であり;δ3はR7及びR8基に連結される結合を示し;
[0049]R7及びR8は各々独立してC4~C10アルキル、C4~C10アルケニル又はC4~C10アルキニルであり、
[0050]fは0、1、2、3、4、又は5であり;
[0051]L3は
から選択され;
[0052]R9はH及びC4~C8アルキル基から選択され;
[0053]gは1~18の範囲の整数であり;
[0054]hは0、1、又は2であり;
[0056]式中E1は-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、及び-OC(O)S-δ1から選択され;QはH又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し、
[0057]R1は
から選択され、
[0058]ここで
[0059]R3及びR4は各々独立してC1~C6アルキル基から選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
[0060]R5はC1~C6アルキル、及びシクロプロピル基から選択され;
[0061]R6はH、及びC1~C6アルキル基から選択され;、
[0062]aは1、2、3、又は4であり;
[0063]bは0、又は1であり;
[0064]cは0、1、又は2であり;
[0065]c’は2、3、又は4であり;
[0066]dは2であり;
[0067]eは1であり;
[0068]E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、ここでδ2はR2基に連結される結合を示し、
[0069]R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで
[0070]L1及びL2は各々直接結合であり;
[0071]R7及びR8は各々独立してC4~C10アルキル基から選択され;
[0072]fは0、又は1であり;
[0073]L3は
から選択され;
[0074]R9はH及びC4~C8アルキル基から選択され;
[0075]gは1~18の範囲の整数であり;
[0076]hは0、1、又は2である。
[0078]
[0079]R1は、
から選択され、
[0080]式中、
[0081]R3及びR4は各々独立してC1~C6アルキル基から選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
[0082]R5はC1~C6アルキル、及びシクロプロピル基から選択され;
[0083]R6はH、及びC1~C6アルキル基から選択され;
[0084]aは1、2、3、又は4であり;
[0085]bは0、又は1であり;
[0086]cは0、1、又は2であり;
[0087]c’は2、3、又は4であり;
[0088]dは2であり;
[0089]eは1であり;
[0090]E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、ここでδ2はR2基に連結される結合を示し;
[0091]R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで
[0092]L1及びL2は各々直接結合であり;
[0093]R7及びR8は各々独立してC4~C10アルキル基から選択され;
[0094]fは0、又は1であり;
[0095]L3は
から選択され;
[0096]R9はH及びC4~C8アルキル基から選択され;
[0097]gは1~18の範囲の整数であり;
[0098]hは0、1、又は2である。
[00100]
の1つである。
[00102]
である。
から選択され、ここでδ1はR1基に連結される結合を示す。
から選択され、ここでδ2はR2基又はその薬学的に許容できる塩に連結される結合を示す。
[00177]マイクロ流体二相液滴技術が適用されて、薬物送達のための単分散のポリマー微小粒子を生産しているか、又は細胞、タンパク質、又はその他の生体分子のカプセル化のための大きい小胞を生産している。制御された大きさの単分散リポソームを作り出すための、試薬の迅速な混合を提供する一般的なマイクロ流体技術である流体力学的流動絞り込みの使用が立証されている。
[00198]1つの実施形態において、本発明の化合物、組成物、方法及び使用は生物学的に活性な薬剤を肝臓細胞(例えば肝細胞)に送達するためのものである。1つの実施形態において、本発明の化合物、組成物、方法及び使用は生物学的に活性な薬剤を腫瘍又は腫瘍細胞(例えば原発性腫瘍又は転移性がん細胞)に送達するためのものである。別の実施形態において、化合物、組成物、方法及び使用は生物学的に活性な薬剤を皮膚脂肪、筋肉及びリンパ節に送達する(皮下投与)ものである。
[00230]遺伝子編集はゲノムの特定の位置で遺伝子配列を付加するか、除去するか、又は修飾することにより生物のDNAを変えるために使用することができる1群の科学技術である。CRISPR(「clustered regularly interspaced short palindromic repeats」)及びCRISPR関連タンパク質9(「Cas9」)を含むゲノム編集の幾つかのアプローチが開発されている。CRISPR-Cas9は侵入するウイルスからDNAの小片を捕獲し、CRISPRアレイとして公知のDNAセグメントを作り出す細菌におけるゲノム編集系から適合された。CRISPRアレイは細菌がウイルスを「覚えている」ことを可能にし、したがって、ウイルスが再び攻撃すれば、細菌はCRISPRアレイからRNAセグメントを産生してウイルスのDNAを標的とさせる。次いで細菌はCas9又は類似の酵素を使用してDNAを切断分離し、ウイルスを無能にする。
[00271]全ての溶媒及び試薬は商業製品であり、他に断らない限りそのまま使用した。温度はセ氏温度で示す。最終の出発材料、中間体及び最終産物の構造は標準的分析法、例えば、MS又はNMRにより確認する。他に断らない限り、1H NMRスペクトルはAVANCE NEO NanoBay Bruker 400MHz NMR分光計を用いてCDCl3溶液中298Kで記録した。化学シフトはTMS(0.00)に対する百万部の部(ppm)で示し、結合定数Jは1Hに対するヘルツ(Hz)で示す。以下の略語を用いてシグナルパターンを示す:s=一重項、d=二重項、t=三重項、q=四重項、p=五重項(pentet)、m=多重項、dd=二重項の二重項、br s=広い一重項、dt=三重項の二重項。他に断らない限り、カラム精製はアイソレラ(Isolera)(商標)プライムを用い、アイソクラチック又は勾配組成の適当な溶離剤を用いて行った。
[00273]ACD-A=抗凝固剤クエン酸デキストロース溶液
[00274]AcOH=酢酸
[00275]aq.=水性
[00276]cat.=触媒
[00277]DCM=ジクロロメタン
[00278]DIPEA=N,N-ジイソプロピルエチルアミン
[00279]DMAP=4-ジメチルアミノジメチルアミノピリジン
[00280]DMF=N,N-ジメチルホルムアミド
[00281]EDCI=1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド
[00282]EPO=エリスロポエチン
[00283]ESI=エレクトロスプレーイオン化
[00284]EtOAc=酢酸エチル
[00285]Et2O=ジエチルエーテル
[00286]g=グラム
[00287]h=時間
[00288]Hz=ヘルツ
[00289]K=ケルビン
[00290]MC3=DLin-MC3-DMA
[00291]MeOH=メタノール
[00292]mg=ミリグラム
[00293]MHz=メガヘルツ
[00294]min=分
[00295]mL=ミリリットル
[00296]mmol=ミリモル
[00297]MS=質量分析
[00298]NMR=核磁気共鳴
[00299]Pet.=石油
[00300]ppm=百万部の部
[00301]Satd.=飽和
[00302]TFA=トリフルオロ酢酸
[00303]THF=テトラヒドロフラン
[00304]TLC=薄層クロマトグラフィー
[00305]TMS=テトラメチルシラン
[00306]TNS=6-(p-トルイジノ)-2-ナフタレンスルホン酸ナトリウム塩
[00307]UHPLC=超高速液体クロマトグラフィー
[00308]℃=セ氏温度
1,4-無水キシリトール(1)の合成
[00310]PNI 121、122、127、321、325、328、329、336、538、539及び540の合成
[00312](±)-1(1.25g、9.3mmol)の乾燥DMF(15mL)中溶液に、DMAP(cat.)を加え、続いて4-(ジメチルアミノ)ブタン酸塩酸塩(1.56g、9.3mmol)の乾燥DMF(10mL)中溶液をN2雰囲気下で加えた。DCM(25mL)を反応混合物に加えた。最後に、固体のEDCI塩酸塩(3.56g、18.6mmol)を反応混合物に加え、室温で4h撹拌した。反応混合物のTLC分析は(±)-1の完全な消費を示す。更に、DMAP(cat.)を反応混合物に加え、続いてリノール酸(7.2mL、23.3mmol)及びEDCI塩酸塩(7.13g、37.2mmol)を加えた。次に、乾燥DMF(20mL)及び乾燥CH2Cl2(10mL)を加え、反応混合物を一晩室温で撹拌した。反応混合物をロータリーエバポレーター上で濃縮し、EtOAc(50mL)で希釈し、水(3×20mL)で洗浄した。有機層をブラインで洗浄し、anhyd.Na2SO4上で乾燥し、ロータリーエバポレーター上で蒸発乾固させて粗製混合物を得、5%MeOH/CH2Cl2を溶離剤として用いてシリカゲルカラムクロマトグラフィーにより精製した。PNI 121を無色の油状物(590mg、0.76mmol)として8%収率で得た。1H (500MHz, CDCl3) δ 5.42-5.31 (m, 9H), 5.13-5.11 (m, 1H), 4.33-4.23 (m, 3H), 4.20-4.16(m, 1H), 3.76 (dd, 1H, J = 15.0 Hz, 5.0 Hz), 2.78 (見かけ上t,4H, J = 5.0 Hz), 2.40-2.32 (m, 8H), 2.26 (s, 6H), 2.06 (q, 8H, J = 15.0 Hz, 5.0Hz), 1.85-1.79 (m, 2H), 1.65-1.60 (m, 4H), 1.39-1.26 (m, 28H), 0.90 (見かけ上t, 6H, J = 7.5 Hz). C47H82NO7の分子量[M+H]+ 計算値772.6091. 実測値772.6126.
実施例3
PNI 342及び541の合成
[00332]乾燥EtOH(580mL)中オレイン酸(58g、205mmol)の撹拌した溶液に、conc.H2SO4(1.094mL、20.53mmol)をゆっくり加え、反応混合物を16h還流した。TLCにより示される反応の完了後、溶媒を減圧下で蒸発させた。残渣を0℃に冷却し、satd.aq.NaHCO3溶液で中和し、DCM(3×250mL)で抽出した。合わせた有機層を無水のNa2SO4上で乾燥し、ろ過し、濃縮してオレイン酸エチル(2、61.6g、198mmol、97%収率)を無色の油状物として得た。このエステルは更なる精製なしにそのまま次のステップに使用した。1H (400MHz, CDCl3) δ 5.39-5.31 (m, 2H), 4.13 (q, 2H, J = 8.0), 2.29 (t, 2H, J = 8.0),2.02 (見かけ上q, 4H, J = 8.0), 1.62 (p, 2H, J = 8.0),1.35-1.24 (m, 23H), 0.89 (t, 3H, J = 6.0). RT = 3.73分. 純度99.5%. C20H39O2のESI-MS: m/z = 311 [M+H]+.
[00334]ジヨードメタン(31.2mL、386mmol)のトルエン(120mL)中溶液を窒素雰囲気下-15℃で撹拌した。ジエチル亜鉛(129mL、193mmol、トルエン中1.5M溶液)を反応混合物に-15℃で30min滴下して加えた。注:反応混合物の内部温度は0℃未満に維持するべきである。次いで、2(30g、97mmol)のトルエン(30mL)中溶液を上の反応混合物に、内部温度が0℃未満に維持されるように滴下して加えた。反応混合物を同じ温度で15min撹拌し、30minかけて徐々に室温に温まらせた。7h室温で撹拌した後、TLC分析は反応の完了を示した。反応混合物を0℃に冷却し、satd.aq.NH4Cl溶液(100mL)でクエンチした。有機層を分離し、aq.層をトルエン(2×75mL)で抽出した。合わせた有機層を無水のNa2SO4上で乾燥し、ろ過し、濃縮した。粗生成物をPet.エーテル中の6%EtOAcを用いたシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して3(28.05g、86mmol、89%収率)を淡黄色の油状物として得た。1H (400MHz, CDCl3) δ 4.13 (q, 2H, J = 8.0), 2.29 (t, 2H, J = 8.0), 1.63 (p, 2H, J =8.0), 1.38-1.24 (m, 25H), 1.19-1.08 (m, 2H), 0.89 (t, 3H, J = 6.0), 0.68-0.62(m, 2H), 0.59-0.54 (m, 1H), -0.34 (見かけ上q, 1H, J = 4.0).RT = 4.01分. 純度98.7%. C21H41O2のESI-MS: m/z = 325 [M+H]+.
[00336]LiOH(1.660g、69.3mmol)をEtOH(105mL)及び水(45mL)中の3(15g、46.2mmol)の撹拌した溶液に加え、反応混合物を周囲温度で16h撹拌した。TLCにより示される反応の完了時、反応混合物を真空中で濃縮して残渣を得た。残渣を水(100mL)で希釈し、MTBE(2×100mL)で洗浄した。aq.層を0℃に冷却し、6N HClで酸性化し、EtOAc(3×300mL)で抽出した。合わせた有機層をanhyd.Na2SO4上で乾燥し、ろ過し、濃縮して4(13.05g、43.0mmol、93%収率)を白色の固体として得た。1H (400MHz, CDCl3) δ 2.36 (t, 2H, J = 6.0), 1.64 (p, 2H, J = 8.0), 1.39-1.28 (m, 22H),1.19-1.10 (m, 2H), 0.89 (t, 3H, J = 6.0), 0.68-0.62 (m, 2H), 0.59-0.54 (m, 1H),-0.33 (見かけ上q, 1H, J = 4.0). RT = 2.91分. 純度97.7%. C19H35O2のESI-MS: m/z = 295 [M-H]-.
PNI 535の合成
PNI 119、120及び344の合成
PNI 534の合成
PNI 532の合成
[00350]乾燥DCM(100mL)中の8-(tert-ブトキシ)-8-オキソオクタン酸(6、11.36g、49.3mmolの撹拌した溶液にDMAP(0.524g、4.29mmol)を窒素雰囲気下、室温で加えた。(Z)-ノン-2-エン-1-オール(7、6.1g、42.9mmol)を上の混合物に加え、撹拌を15min続けた。反応を0℃に冷却し、DCC(9.73g、47.2mmol)を加えた。反応混合物を放置して室温に到達させ、16h撹拌した。TLC分析は出発物質の完全な消費を示した。沈殿した尿素をセライトパッドに通してろ過し、DCM(2×50mL)で洗浄した。合わせたろ液を濃縮し、残渣をsatd.aq.NaHCO3溶液(2×50mL)で洗浄した。有機層を分離し、無水のNa2SO4上で乾燥した。溶媒を減圧下で除去し、残渣をPet.エーテル中3%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して(Z)-1-(tert-ブチル)8-(ノン-2-エン-1-イル)オクタンジオエート(8、11.35g、29.8mmol、69.4%収率)を得た。1H (400MHz, CDCl3) δ 5.68-5.61 (m, 1H), 5.56-5.49 (m, 1H), 4.63 (d, 2H, J = 4.0), 2.31(t, 2H, J = 8.0), 2.20 (t, 2H, J = 8.0), 2.10 (見かけ上q,2H, J = 8.0), 1.67-1.57 (m, 4H), 1.44 (s, 9H), 1.40-1.25 (m, 12H), 0.89 (t, 3H,J = 6.0). RT = 1.40分. 純度89.2%.C21H38O4NaのESI-MS: m/z= 377 [M+Na]+.
[00352]TFA(10.00mL、130mmol)を乾燥DCM(50mL)中の8(5g、14.10mmol)の撹拌した溶液に窒素雰囲気下、室温で滴下して加え、撹拌を16h続けた。TLC分析は8の存在を示した。再度、TFA(10.00mL、130mmol)を加え、反応混合物を16h還流した。反応は完了に至らず、TLC分析は8の存在を示した。反応を停止し、混合物を減圧下で蒸発させた。粗製物質をPet.エーテル中30%EtOAcを用いてカラムシリカゲル(100~200メッシュ)クロマトグラフィー(アイソレラ(商標))により精製して(Z)-8-(ノン-2-エン-1-イルオキシ)-8-オキソオクタン酸(9、3.41g、11.43mmol、81%収率)を褐色の油状物として得、また600mgの8も回収した。1H (400MHz, CDCl3) δ 5.68-5.61 (m, 1H), 5.56-5.49 (m, 1H), 4.63 (d, 2H, J = 4.0),2.37-2.30 (m, 4H), 2.10 (見かけ上q, 2H, J = 8.0), 1.68-1.60(m, 4H), 1.40-1.24 (m, 12H), 0.89 (t, 3H, J = 6.0).
PNI 127、573、574及び575の合成
[00356]100mLの1ツ口丸底フラスコに、乾燥ピリジン(25mL)中の(±)-1,4-無水キシリトール(1、5.1g、38.0mmol)のよく撹拌した溶液、塩化トリチル(10.07g、36.1mmol)を窒素雰囲気下、室温で加え、撹拌を16h続けた。TLCにより示される反応の完了後、過剰の溶媒を減圧下で濃縮した。残渣をDCM(100mL)及び水(200mL)に溶かした。有機層を分離し、aq.層をDCM(3×50mL)で抽出した。合わせた有機層をブライン(3×100mL)で洗浄し、anhyd.Na2SO4上で乾燥し、ろ過し、濃縮した。粗製生成物をPet.エーテル中50%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィーにより精製して(±)-10(8.65g、22.93mmol、60.3%収率)を白色粘着性の固体として得た。1H (400MHz, CDCl3) δ 7.47-7.43 (m, 6H), 7.34-7.30 (m, 6H), 7.28-7.23 (m, 3H), 4.32 (brs, 1H), 4.28-4.23 (m, 3H), 3.77 (dd, 1H, J = 12.0, 4.0), 3.50 (dd, 1H, J =12.0, 4.0), 3.43 (dd, 1H, J = 8.0, 4.0), 3.14 (br s, 1H). RT = 2.66分. 純度99.9%. C24H23O4のESI-MS: m/z = 375 [M-H]-.
[00358]250mLの3ツ口丸底フラスコに、乾燥DCM(50mL)中のリノール酸(6.55g、23.36mmol)の撹拌した溶液、DMAP(2.85g、23.36mmol)、EDCI塩酸塩(17.91g、93mmol)及びDIPEA(9.38ml、53.7mmol)を窒素雰囲気下、室温で加えた。反応混合物を15min撹拌し、(±)-10(3.52g、9.34mmol)の乾燥DCM(20mL)中溶液を加えた。16h撹拌した後、反応混合物を水(150mL)でクエンチし、DCM(3×50mL)で抽出した。合わせた有機層をブライン(3×75mL)で洗浄し、anhyd.Na2SO4上で乾燥し、ろ過し、濃縮した。粗製生成物をPet.エーテル中5%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して(±)-11(7.21g、7.84mmol、33.6%収率)を淡黄色の油状物として得た。1H (400MHz, CDCl3) δ 7.44-7.42 (m, 6H), 7.32-7.28 (m, 6H), 7.26-7.22 (m, 3H), 5.43-5.31(m, 9H), 5.12-5.10 (m, 1H), 4.35-4.31 (m, 1H), 4.26 (dd, 1H, J = 8.0, 4.0),3.74 (dd, 1H, J = 12.0, 4.0), 3.35 (見かけ上t, 1H, J =8.0), 3.16 (dd, 1H, J = 8.0, 6.0), 2.79 (t, 4H, J = 6.0), 2.36 (t, 2H, J =8.0), 2.16-1.99 (m, 10H), 1.65 (p, 2H, J = 8.0), 1.40-1.22 (m, 30H), 0.90 (t,6H, J = 6.0). RT = 3.95分. 純度98.1%.C60H84O6NaのESI-MS: m/z= 923 [M+Na]+.
[00360]TFA(0.427ml、5.55mmol)を(±)-11(2.0g、2.219mmol)及びトリエチルシラン(1.772ml、11.09mmol)の乾燥DCM(50ml)中溶液に窒素雰囲気下、0℃で加えた。反応混合物を0℃で1h撹拌したところ、TLC分析は11の完全な消費を示した。混合物をsatd.aq.NaHCO3溶液(50mL)でクエンチし、DCM(2×50mL)で抽出した。有機層をanhyd.Na2SO4上で乾燥し、ろ過し、濃縮した。粗製生成物をPet.エーテル中10%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して(±)-12(1.15g、1.745mmol、79%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 5.43-5.29 (m, 9H), 5.11-5.09 (m, 1H), 4.51 (dd, 1H, J = 12.0, 8.0),4.30 (dd, 1H, J = 8.0, 4.0), 4.20-4.16 (m, 2H), 4.11-4.07 (m, 1H), 3.76 (dd,1H, J = 12.0, 4.0), 2.78 (t, 4H, J = 6.0), 2.37-2.30 (m, 4H), 2.06 (q, 8H, J =8.0), 1.69-1.62 (m, 4H), 1.40-1.25 (m, 28H), 0.90 (t, 6H, J = 6.0). RT = 2.29分. 純度92.5%. C41H71O6のESI-MS: m/z = 659 [M+H]+.
[00362]乾燥DCM(30ml)中の1,4-ジメチルピペリジン-4-カルボン酸塩酸塩(0.970g、5.01mmol)のよく撹拌した溶液を含有する100mLの2ツ口丸底フラスコに、DMAP(0.556g、4.55mmol)及びEDCI塩酸塩(1.745g、9.10mmol)を窒素雰囲気下で加えた。反応混合物を25℃で10分撹拌し、(±)-12(3g、4.55mmol)の乾燥DCM(15mL)中溶液を加え、反応混合物を25℃で16時間撹拌した。TLCにより示される反応の完了後、溶媒を減圧下で蒸発させた。残渣をEtOAc(150mL)に溶かし、水(2×100mL)、ブライン(2×100mL)で洗浄し、anhyd.Na2SO4上で乾燥し、ろ過し、濃縮した。粗製生成物をDCM中3%MeOHを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製してPNI 127(2.96g、3.71mmol、81%収率)を淡黄色の油状物として得た。
PNI 576、577及び578の合成
[00370]化合物13は11の合成に使用した方法と同様な方法を用いて合成した。13の合成は乾燥DCM(70mL)中4(9.06g、30.5mmol)、DMAP(4.05g、33.2mmol)、EDCI塩酸塩(10.15g、53.1mmol)、DIPEA(14.28mL、80mmol)、及び乾燥DCM(30mL)中(±)-10(5.0g、13.28mmol)を用いて行った。粗製生成物をPet.エーテル中5%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して13(11.1g、11.89mmol、90%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 7.46-7.44 (m, 6H), 7.34-7.24 (m, 9H), 5.44 (d, 1H, J = 4.0),5.14-5.12 (m, 1H), 4.37-4.33 (m, 1H), 4.28 (dd, 1H, J = 12.0, 4.0), 3.76 (dd,1H, J = 12.0, 4.0), 3.38 (dd, 1H, J = 12.0, 8.0), 3.19 (dd, 1H, J = 12.0, 8.0),2.39 (見かけ上t, 2H, J = 6.0), 2.18-2.02 (m, 2H), 1.67 (p,2H, J = 8.0), 1.50-1.24 (m, 46H), 1.19-1.13 (m, 4H), 0.92 (t, 6H, J = 6.0),0.71-0.65 (m, 4H), 0.62-0.57 (m, 2H), -0.30 (q, 2H, J = 6.0).
[00372]化合物14は12の合成に使用した方法と同様な方法を用いて合成した。14の合成は乾燥DCM(100ml)中の(±)-13(11.0g、11.78mmol)及びEt3SiH(9.41ml、58.9mmol)、並びにTFA(1.489mL、11.78mmol)を用いて行った。粗製生成物をPet.エーテル中10%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して14(5.5g、7.96mmol、67.5%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 5.28-5.10 (m, 2H), 4.53-4.07 (m, 3H), 3.78-3.56 (m, 2H), 2.40-2.31(m, 4H), 1.68-1.59 (m, 4H), 1.38-1.10 (m, 44H), 1.17-1.10 (m, 4H), 0.89 (t, 6H,J = 6.0), 0.68-0.62 (m, 4H), 0.59-0.54 (m, 2H), -0.33 (q, 2H, J = 6.0). C43H79O6のESI-MS: m/z = 691 [M+H]+.
PNI 579及び580の合成
[00380]化合物15は11の合成に使用した方法と同様な方法を用いて合成した。15の合成は乾燥DCM(40mL)中2-ヘキシルデカン酸(3.92g、15.27mmol)、DMAP(1.866g、15.27mmol)、続いてEDCI塩酸塩(6.37g、33.2mmol)、DIPEA(5.80ml、33.2mmol)、及び乾燥DCM(10mL)中(±)-10(2.5g、6.64mmol)を用いて行った。粗製生成物をPet.エーテル中2%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して15(5.12g、6.00mmol、90%収率)を淡黄色の油状物として得た。1H (400MHz, CDCl3) δ 7.47-7.45 (m, 6H), 7.33-7.22 (m, 9H), 5.29 (d, 1H, J = 4.0),5.09-5.07 (m, 1H), 4.29-4.24 (m, 2H), 3.75 (dd, 1H, J = 8.0, 4.0), 3.42 (dd,1H, J = 12.0, 8.0), 3.22 (dd, 1H, J = 12.0, 4.0), 2.43-2.34 (m, 1H), 2.22-2.15(m, 1H), 1.66-1.38 (m, 8H), 1.36-1.12 (m, 40H), 0.92-0.86 (m, 12H).
[00382]化合物16は12の合成に使用した方法と同様な方法を用いて合成した。16の合成は乾燥DCM(70mL)中(±)-15(5.1g、5.98mmol)、トリエチルシラン(4.77mL、29.9mmol)、及びTFA(1.151mL、14.94mmol)を用いて行った。粗製生成物をPet.エーテル中2%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して(±)-16(3.23g、5.29mmol、88%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 5.26 (d, 1H, J = 4.0), 5.16 (s, 1H), 4.29 (dd, 1H, J = 12.0, 4.0),4.21-4.17 (m, 1H), 3.80-3.74 (m, 2H), 3.58 (dd, 1H, J = 12.0. 4.0), 2.43-2.32(m, 2H), 2.15 (br s, 1H), 1.67-1.41 (m, 8H), 1.34-1.19 (m, 40H), 0.89 (t, 12H,J = 6.0). RT = 2.18分. 純度99.9%.C37H71O6のESI-MS: m/z =611 [M+H]+.
[00387]PNI 580はPNI 574の合成に使用した方法と同様な方法を用いて合成した。PNI 580の合成は乾燥DCM(20mL)中4-(ジメチルアミノ)ブタン酸塩酸塩(0.165g、0.982mmol)、DMAP(0.120g、0.982mmol)、EDCI塩酸塩(0.377g、1.964mmol)、及び乾燥DCM(5mL)中16(0.4g、0.655mmol)を用いて行った。粗製生成物をDCM中4%MeOHを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製してPNI 580(0.39g、0.539mmol、82%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 5.33 (d, 1H, J = 4.0), 5.10 (d, 1H, J = 4.0), 4.33-4.21 (m, 4H),3.75 (dd, 1H, J = 8.0, 4.0), 2.42-2.29 (m, 12H), 1.91-1.79 (m, 2H), 1.64-1.41(m, 8H), 1.34-1.20 (m, 40H), 0.88 (t, 12H, J = 6.0). RT = 2.49分. 純度98.7%. C43H82NO7のESI-MS: m/z = 724 [M+H]+.
PNI 581、582及び583の合成
[00389]窒素雰囲気下0℃の500mLの3ツ口RBF内において乾燥DMF(100mL)及び乾燥THF(100mL)中の10(2.0g、5.31mmol)の撹拌した溶液に、NaH(1.062g、26.6mmol)をゆっくり加え、反応混合物を同じ温度で15分撹拌した、次いで、臭化リノレイル(5.25g、15.94mmol)を加え、反応混合物をゆっくり25℃に温め、7hr撹拌した。TLCにより示される反応の完了後、反応混合物を氷冷水(250mL)でクエンチし、EtOAc(3×120mL)で抽出した。合わせた有機層をブライン(3×150mL)で洗浄し、Na2SO4上で乾燥し、ろ過し、濃縮して粗製物を得た。粗製生成物をPet.エーテル中3%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して17(2.4g、2.75mmol、51.7%収率)を淡黄色の油状物として得た。1H (400MHz, CDCl3) δ 7.49-7.45 (m, 6H), 7.30-7.20 (m, 9H), 5.42-5.31 (m, 8H), 4.22-4.18(m, 1H), 4.04 (dd, 1H, J = 8.0, 4.0), 3.91-3.86 (m, 1H), 3.84 (d, 1H, J = 4.0),3.73 (dd, 1H, J = 12.0, 4.0), 3.50-3.43 (m, 2H), 3.39-3.28 (m, 3H), 3.22 (dd,1H, J = 12.0, 8.0), 2.78 (t, 4H, J = 6.0), 2.06 (q, 8H, J = 8.0), 1.59 (p, 4H,J = 4.0), 1.43-1.23 (m, 32H), 0.91-0.88 (m, 6H). RT = 3.86分. 純度98.1%. C60H88O4NaのESI-MS: m/z = 896 [M+Na]+.
[00391]250mLの2ツ口RBF中窒素雰囲気下DCM(40mL)中の17(2.35g、2.69mmol)及びEt3SiH(2.149ml、13.45mmol)の撹拌した溶液にTFA(0.427mL、5.55mmol)を0℃で加え、反応混合物を0℃で1h撹拌した。TLCにより示される反応の完了後、反応混合物をsatd.NaHCO3溶液(60mL)でクエンチし、DCM(2×50mL)で抽出した。有機層をNa2SO4上で乾燥し、ろ過し、濃縮して粗製物を得た。粗製生成物をPet.エーテル中8%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して18(1.46g、2.314mmol、86%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 5.42-5.30 (m, 8H), 4.13 (dd, 1H, J = 8.0, 4.0), 4.09-4.05 (m, 1H),3.96-3.92 (m 2H), 3.90-3.81 (m, 2H), 3.75 (dd, 1H, J = 12.0, 4.0), 3.64-3.59(m, 1H), 3.47-3.42 (m, 3H), 2.78 (t, 4H, J = 6.0), 2.06 (q, 8H, J = 8.0),1.62-1.48 (m, 4H), 1.40-1.26 (m, 32H), 0.90 (t, 6H, J = 6.0). RT = 2.63分. 純度99.9%. C41H75O4のESI-MS: m/z = 631 [M+H]+.
PNI 76の合成
[00399](±)-19(600mg、3.65mmol)の乾燥DMF(10mL)中溶液に、DMAP(cat.)を加え、続いて4-(ジメチルアミノ)ブタン酸塩酸塩(1.56g、9.3mmol)の乾燥DMF(10mL)中溶液をN2雰囲気下で加えた。CH2Cl2(10mL)を反応混合物に加えた。次いで固体のEDCI塩酸塩(1.39g、7.30mmol)を反応混合物に加え、室温で4h撹拌した。反応混合物のTLC分析が(±)-19の完全な消費を示す。更に、DMAP(cat.)を反応混合物に加え、続いて乾燥DMF(10mL)に溶かしたミリスチン酸(2.73g、11.98mmol)及びEDCI塩酸塩(3.50g、18.25mmol)を固体として加えた。次に、乾燥DCM(10mL)を加え、反応混合物を一晩室温で撹拌した。反応混合物をロータリーエバポレーター上で濃縮し、EtOAc(20mL)で希釈し、水(3×10mL)で洗浄した。有機層をブラインで洗浄し、無水のNa2SO4上で乾燥し、ロータリーエバポレーター上で蒸発乾固させて粗製混合物を得、5%MeOH/DCMを溶離剤として用いてシリカゲルカラムクロマトグラフィーにより精製した。PNI 76を無色の油状物(294mg、0.32mmol)として9%の全収率で得た。
[00401]PNI 76を最少量のanhyd.ジエチルエーテルに溶かした。エーテル中HClをpHが3~5になるまで加えた(pH試験紙によりチェックした)。溶媒を蒸発させ、微量のHClを除くためにCH2Cl2を加え2~3倍蒸発させた。次に、化合物を少量の脱イオン水に溶かし、凍結乾燥してPNI 76のHCl塩を得た。1H (500MHz, CDCl3) δ 5.38 (d, 1H, , J = 3.0 Hz), 5.22-5.19 (m, 1H), 5.07 (d, 1H, J = 5.0Hz), 4.61 (d, 1H, J = 10.0 Hz), 4.26 (dd, 1H, J = 10.0 Hz, 5.0 Hz), 4.21 (dd,1H, J = 10.0 Hz, 5.0 Hz), 4.13 (dd, 1H, J = 15.0 Hz, 5.0 Hz), 3.79 (d, 1H, J =10.0 Hz), 2.42-2.29 (m, 14H), 2.23 (見かけ上t, 2H, J = 7.5Hz), 1.84 (p, 2H, J = 6.3 Hz), 1.65-1.54 (m, 6H), 1.30-1.27 (m, 60H), 0.89 (見かけ上t, 9H, J = 7.5 Hz). C54H102NO9の分子量[M+H]+ 計算値908.7555. 実測値908.7511.
PNI 369の合成
[00403]乾燥トルエン(70mL)中の2-(ドデシルオキシ)エタノール(20、3.7g、16.06mmol)及びトリフェニルホスフィン(10.53g、40.1mmol)の撹拌した溶液に、四臭化炭素(13.31g、40.1mmol)をゆっくり加え、反応混合物を60℃で16h撹拌した。TLC分析により示される反応の完了後、反応混合物を減圧下で濃縮し、粗製生成物をPet.エーテル中5%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して1-(2-ブロモエトキシ)ドデカン(21、4.55g、15.20mmol、95%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 3.74 (d, 2H, J = 6.0), 3.50-3.45 (m, 4H), 1.59 (p, 2H, J = 8.0),1.38-1.21 (m, 18H), 0.89 (t, 3H, J = 6.0). RT = 3.40分. 純度96.6%.
[00405]化合物22は17の合成に使用した方法と同様な方法を用いて合成した。22の合成は乾燥DMF(10mL)及び乾燥THF(10mL)中10(1.0g、2.66mmol)、水素化ナトリウム(0.531g、13.28mmol、鉱油中60%分散液)、並びに1-(2-ブロモエトキシ)ドデカン(21、2.337g、7.97mmol)を用いて行った。粗製生成物をPet.エーテル中5%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して22(1.1g、1.373mmol、51.7%収率)を無色の油として得た。1H (400MHz, CDCl3) δ 7.46 (d, 6H, J = 8.0), 7.30-7.20 (m, 9H), 4.25-4.21 (m, 1H), 4.06-4.02(m, 2H), 4.00 (d, 1H, J = 4.0), 3.79-3.75 (m, 1H), 3.72-3.58 (m, 5H), 3.52-3.46(m, 3H), 3.41-3.28 (m, 5H), 3.22 (d, 1H, J = 8.0, 4.0), 1.60 (t, 2H, J = 6.0),1.48 (p, 2H, J = 8.0), 1.35-1.21 (m, 36H), 0.89 (t, 6H, J = 6.0). RT = 2.63分. 純度97.8%. C52H80O6NaのESI-MS: m/z = 823.5 [M+Na]+.
[00407]化合物23は18の合成に使用した方法と同様な方法を用いて合成した。23の合成は乾燥DCM(30mL)中22(1.1g、1.373mmol)及びEt3SiH(1.096mL、6.86mmol)、並びにTFA(0.264mL、3.43mmol)を用いて行った。粗製生成物をPet.エーテル中20%EtOAcを用いてシリカゲル(100~200メッシュ)カラムクロマトグラフィー(アイソレラ(商標))により精製して23(0.58g、1.038mmol、76%収率)を無色の油状物として得た。1H (400MHz, CDCl3) δ 4.15-4.03 (m, 4H), 3.87-3.76 (m, 4H), 3.66-3.54 (m, 7H), 3.47-3.43(m, 4H), 1.61-1.54 (m, 4H), 1.36-1.20 (m, 36H), 0.90-0.87 (m, 6H). RT = 1.97分. 純度99.1%. C33H67O6のESI-MS: m/z = 559.5 [M+H]+.
代表的な化合物の合成スキーム
ヒト全血由来初代T細胞の単離及び増殖
[00411]他に断らない限り、全ての試薬はSTEMCELL Technologies、Vancouver、Canadaから購入した。
T細胞の活性化/増殖
[00418]T細胞の活性化の科学的背景はTrickett A.らによる2003年の論文6に見られる。実施例8の細胞懸濁液をComplete T Cell培地(ThermoFisher)で1E6細胞/mlに希釈し、T Cell培地1mL当たり25μlのImmunoCult(商標)Human CD3/CD28/CD2三重T Cell Activator(商標)又はImmunoCult(商標)Human CD3/CD28二元T Cell Activator(商標)のいずれかを加えることによりT細胞を活性化した。細胞の成長は拡大下毎日の細胞計数によりモニターした。細胞をComplete T Cell培地で希釈して約1E6細胞/mLの濃度を維持した。5、6又は7日頃、T細胞は成長の対数期に入り、迅速な増殖が起こった。
処置したT細胞の下流の処理及び分析:フローサイトメトリー及びELISA
[00420]試薬は他に断らない限りStemcell Technologiesから入手した。T細胞は単一のドナーから単離された。脂質粒子mRNA曝露の48H後、細胞懸濁液を予めラベルを付けた1.5mLのチューブに移し、300×G、4℃で10分遠心分離することにより、処置したT細胞を収集した。上清を除去し、ペレットをPBSに再懸濁した。0.5ulの量のBD Horizon(商標)Fixable Viability Stain 575V(商標)(BD Biosciences)を加え、混合物を暗い中で10分RTでインキュベートした。この染料はアミンに結合する。
脂質粒子(LNP)中への核酸治療物質(NAT)のマイクロ流体的混合
[00425]他に特記する場合を除き、これらの実験全てに対してN/P=10を使用した。脂質ミックス組成物溶液は、エタノール中の個々の脂質ストックから規定量の脂質(表3参照)を混合することによってエタノール中で調製した。NanoAssembl(登録商標)スパーク(SPARK)(商標)については37.5mMの脂質ミックス溶液濃度を使用し、NanoAssembl(登録商標)ベンチトップ又はイグナイト(商標)については12.5mMの脂質ミックス溶液を通例使用した。
[00433]Trilink Cleancap(登録商標)eGFP mRNA:Cat.L-7601(Trilink Biotechnologies、San Diego、CA);Trilink Cleancap(登録商標)EPO mRNA:Cat.L-7209(Trilink Biotechnologies);Millipore Sigma TagRFP Simplicon RNA Kit:Cat.SCR712(両方のTagRFP RNA & B18R RNAを含有する)(Millipore Sigma Canada、Oakville Ontario);EGFPレポーターを有するCD19 CARプラスミドはCreative Biolabs(Shirley、NY)から購入し、pcDNA内にT7プロモーター(Mut)-シグナルペプチド-scFv-CD8ヒンジ膜貫通-4-1BB-CD3zeta-T2A-eGFPレポーター遺伝子CARカセット(2353bp)を含有する。このカスタムCD19 CARプラスミドDNA鋳型の全体の大きさはおよそ7649~7661bpであった。
[00437]初代ヒトT細胞においてeGFP mRNA LNPと共に活性を示す脂質の比較データ
[00438]試薬は他に断らない限りAbcam、Cambridge、UKから入手した。mRNA送達及び活性をインビトロで示すためにeGFP SimpleStep(商標)ELISA(登録商標)Kitを使用した。アッセイはeGFP SimpleStep ELISA(登録商標)Kitプロトコルにより指示されている通りに行った。簡単に言うと、前もって負の選択プロトコルを用いて新鮮なヒト全血から単離した凍結されたヒトT細胞を解凍し、三重活性化剤を用いて活性化した。活性化の10日後、T細胞に500,000細胞当たり2μgのmRNAでeGFPをコードするN/P10のmRNA LNPを投与した。mRNA LNPでの処理の48時間後T細胞を収集し、総eGFP含有量のために溶解させた。
エリスロポエチンmRNA送達及び発現
[00450]Quantikine(登録商標)IVD Human Epo ELISA2抗体サンドイッチ測定法を使用してインビトロでのmRNA送達及び活性を立証した。試薬はQuantikine、Minneapolis、MNから入手した。アッセイはQuantikine(登録商標)IVD(登録商標)ELISA Human Erythropoietin ImmunoassayプロトコルREF DEP00 Package Insertに指示されている通りに行った。簡単に言うと、負の選択プロトコルを用いて初代ヒトT細胞を新鮮な全血から単離し、三重活性化剤を用いて活性化した。活性化の7日後、T細胞に500,000細胞当たり2μgのmRNA及びN/P10でEPOをコードするmRNA LNPを投与した。Quantikine(登録商標)Human Serum Controlを使用した。mRNA LNPで処理して48時間後T細胞を収集し、溶解させて細胞質EPOを得、培地上清から分泌EPOサンプルを採取した。結果をmIU/mLで図6に示す。表5は図6のデータ並びにPNI 76及び121についてEPOのMC3に対する増分(倍数)を示す。PNI 121を含有するLNPにより媒介されたEPO発現がMC3を含有するものより高かったことが判明した。
実施例21 脂質核酸粒子又は「LNP」の特性決定及びカプセル化
[00453]脂質粒子を上記に記載したようにして作成した後、ゼータサイザー(商標)Nano ZS(商標)(Malvern Instruments、UK)を用いた動的光散乱(DLS)により粒径(粒子の流体力学直径)を決定した。波長633nmに調整したHe/Neレーザーを光源として使用した。データは後方散乱検出モード(測定角度=173)で行った散乱強度データから測定した。測定値はサンプル当たり各々2サイクルの10回の平均であった。Z-平均の大きさが粒径として報告され、調和強度平均粒子直径と定義される。
[00456]
Simplex(商標)自動ELISAによるhEPO/サイトカイン測定
[00457]hEPO mRNA LNPで処置したマウス由来の血液を、自動化されたELISAプラットフォーム「ELLA」を用い、Simplex(商標)抗体パネルカートリッジを用いて分析した。ヒトに特異的なEPO並びにマウスに特異的なIL-5、IL-6、TNF-α、及びIFN-γを測定した(試薬はBio-techne)。簡単に言うと、50μLのサンプル試薬(希釈した生物サンプル、品質管理、又は較正点サンプル)を各々のサンプル注入口に入れ、1mLの洗浄緩衝液をカートリッジの対応する注入口に入れた。全ての免疫検定操作(例えば、システムを起動する、サンプルを流しチャンネルに分割する、サンプルをインキュベートする、洗浄する、再水和し二次抗体を流す、洗浄する、再水和しストレプトアビジン染料コンジュゲートを流す、インキュベートする、洗浄する、スキャンする)は自動的に行われた。生のシグナルレベル(相対蛍光単位、RFU)、平均シグナル値、標準偏差、及び各々のガラスナノ反応器(GNR)値に対する変動係数(CV)が提供される。RFU値は、製造業者の所定の較正方法を用いて検体/サンプルに応じた検体濃度を生み出すためにELLAにより自動的にバックフィットされる。結果を図10に示す。
単離された初代ヒトT細胞におけるmRNA-LNPにより媒介されたCD19 CAR発現
[00459]ILをN/P8のCT10組成物と共に含有するmRNAをインビトロ曝露後アッセイした。CARベクターpcDNA3.1抗CD19-h(BBラムダ)-EGFP-2nd-CAR(T7 Mut)7661bpはCreative BioLabs、NY、USAから購入した。
OvaをコードするmRNA LNPの筋肉内投与によるインビボ送達
[00461]組成LM02bのLNPを使用してOVA抗原をコードするCleanCap(登録商標)OVA WT mRNA[TriLink L7610]又はCleanCap(登録商標)OVA 5-moU mRNA[TriLink L7210]をカプセル化した。全てエタノール中のイオン化可能な脂質、DOPE、コレステロール、及びPEG-DMG2000の脂質混合物を、NanoAssemblr(登録商標)イグナイト(商標)マイクロ流体ミキサーを用いてN/P比8のOVA mRNAの低PH緩衝溶液と混合した。アミコン(商標)ウルトラろ過技術を用いてLNPをろ過し、大きさ、PDI及びカプセル化効率を特徴付けた。大きさ及びPDIは動的光散乱技術を用いて測定し、核酸カプセル化効率はQuantiT RiboGreen RNAアッセイから計算した。これらのOVA mRNA-LNPの流体力学直径は約83nmで、多分散性指数は約0.1、カプセル化効率は約97%であった。
pKa研究
[00468]いろいろなイオン化可能な脂質から得られるLNPにおいて表面pKaにより発揮されるLNPトランスフェクション後導入遺伝子発現に対する効果を検討した。
プラスミドカプセル化
[00472]GenScript USA Inc、Piscataway、NJにより特注された大きさ5514ntのpCX-EGFPプラスミドを用いた。脂質粒子の調製は上に記載した通りである。PNIイオン化可能な脂質PNI 121、PNI 127、PNI 328、PNI 329、及びPNI 541を、N/P6のLM02組成物を用いNanoAssemblr(登録商標)イグナイト(商標)システムを用いて哺乳類発現(上記)に適したプラスミドをカプセル化する能力について試験した。試験した全ての脂質が平均流体力学直径110nm及びPDI0.2の容認できるLNPを80%より大きいカプセル化効率で生じた。
1. Garg, S.; Heuck, G.; Ip, S.; Ramsay, E.,Microfluidics: a transformational tool for nanomedicine development andproduction. J Drug Target 2016, 24 (9), 821-835.
2. Zhang, S.-h.; Shen, S.-c.; Chen, Z.;Yun, J.-x.; Yao, K.-j.; Chen, B.-b.; Chen, J.-z., Preparation of solid lipidnanoparticles in co-flowing microchannels. Chemical Engineering Journal 2008,144 (2), 324-328.
3. JEFFS, L. B., et al., A Scalable,Extrusion-Free Method for Efficient Liposomal
Encapsulation of Plasmid DNA.Pharmaceutical Research 2005, 22 (3), 362-372.
4. Gaj, T.; Gersbach, C. A.; Barbas, C. F.,3rd, ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends inbiotechnology 2013, 31 (7), 397-405.
5. McClure, W. O.; Edelman, G. M.,Fluorescent Probes for Conformational States of Proteins. I. Mechanism ofFluorescence of 2-p-Toluidinylnaphthalene-6-sulfonate, a Hydrophobic Probe*.Biochemistry 1966, 5 (6), 1908-1919.
6. Trickett, A.; Kwan, Y. L., T cellstimulation and expansion using anti-CD3/CD28 beads. J Immunol Methods 2003,275 (1-2), 251-5.
7. Lundstrom, K. Nanoparticle-baseddelivery of self-amplifying RNA. Gene Ther 27, 183-185 (2020).
8. Peng, M., Mo, Y., Wang, Y. et al.Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer 18, 128 (2019).
9. Roujian Lu 1, Xiang Zhao 1, Juan Li 2,et al. “Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus:Implications for Virus Origins and Receptor Binding” Lancet 2020 Feb22;395(10224):565-574.
10. Morokata T, et.al, Immunology (1999)345-351.
Giuliani et al. (2006) Proc Natl Head Sci USA103(29):10834-9
Claims (17)
- 式(I)の化合物、又はその薬学的に許容できる塩
[式中、
pは0又は1であり;
E1は-O-δ1、-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、-OC(O)S-δ1、-C(O)N(Q)-δ1、-C(O)O-δ1、-N(Q)C(O)-δ1、-N(Q)C(O)O-δ1、-N(Q)C(O)S-δ1、及び-N(Q)C(O)N(Q)-δ1から選択され;QはH又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し;
R1は
から選択され、ここで、
R3及びR4は各々独立してC1~C6アルキル、C2~C6アルケニル、及びC2~C6アルキニルからなる群から選択されるか;又はR3及びR4は一緒になって、酸素(O)若しくは2個以下の窒素(N)を含有し、各々独立してC1~C6アルキル、シクロプロピル、OH、及びC1~C3アルコキシ基から選択される1~2個の置換基で任意選択で置換されている4~6員の環を形成していてもよく;
R5はC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C6シクロアルキル、及び2-ヒドロキシエチル基から選択され;
R6はH、及びC1~C6アルキル基から選択され;
aは1、2、3、4又は5であり;
b及びcは独立して0、1、又は2であり;
c’は1、2、3、4、又は5であり;
dは1、又は2であり;
eは0、1、又は2であり;
E2は-OC(O)-δ2、-OC(O)O-δ2、-OC(O)N(Q)-δ2、-O-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、QはH又はC1~C5アルキルであり;δ2はR2基に連結される結合を示し;
R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで、
L1及びL2は各々独立して直接結合、-O-δ3、~CH2OC(O)-δ3、及び~CH2O-δ3であり、δ3はR7及びR8基に連結される結合を示し;
R7及びR8は各々独立してC4~C10アルキル、C4~C10アルケニル又はC4~C10アルキニルであり;
fは0、1、2、3、4、又は5であり;
L3は
から選択され、
R9はH及びC4~C8アルキル基から選択され、
gは1~18の範囲の整数であり、
hは0、1、2、又は3である]。 - 式(II)の化合物、又はその薬学的に許容できる塩
[式中、E1は-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、及び-OC(O)S-δ1から選択され;QはH又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し;
R1は
から選択され;ここで、
R3及びR4は各々独立してC1~C6アルキル基から選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
R5はC1~C6アルキル、及びC3~C6シクロアルキル基から選択され;
R6はH、及びC1~C6アルキル基から選択され;
aは1、2、3、又は4であり;
b及びcは独立して0、1、又は2であり;
c’は2、3、又は4であり;
dは2であり;
eは0、又は1であり;
E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、ここでδ2はR2基に連結される結合を示し;
R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで、
L1及びL2は各々独立して直接結合、-O-δ3、-CH2OC(O)-δ3、及び-CH2O-δ3であり;δ3はR7及びR8基に連結される結合を示し;
R7及びR8は各々独立してC4~C10アルキル、C4~C10アルケニル又はC4~C10アルキニルであり;
fは0、1、2、3、4、又は5であり;
L3は
から選択され;
R9はH及びC4~C8アルキル基から選択され;
gは1~18の範囲の整数であり;
hは0、1、又は2である]。 - 式(II)の化合物、又はその薬学的に許容できる塩
[式中、E1は-OC(O)O-δ1、-OC(O)-δ1、-OC(O)N(Q)-δ1、及び-OC(O)S-δ1から選択され;QはH又はC1~C5アルキルであり;δ1はR1基に連結される結合を示し;
R1は
から選択され;ここで、
R3及びR4は各々C1~C6アルキル基から独立的に選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
R5はC1~C6アルキル、及びシクロプロピル基から選択され;
R6はH、及びC1~C6アルキル基から選択され;
aは1、2、3、又は4であり;、
bは0、又は1であり;
cは0、1、又は2であり;
c’は2、3、又は4であり;
dは2であり;
eは1であり;
E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され、ここでδ2はR2基に連結される結合を示し;
R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで
L1及びL2は各々直接結合であり;
R7及びR8は各々C4~C10アルキル基から独立的に選択され;
fは0、又は1であり;
L3は
から選択され;
R9はH及びC4~C8アルキル基から選択され;
gは1~18の範囲の整数であり;
hは0、1、又は2である]。 - 式(III)の化合物、又はその薬学的に許容できる塩
[R1は
から選択され;ここで、
R3及びR4は各々独立してC1~C6アルキル基から選択されるか;又はR3及びR4は一緒になって、2個以下の窒素(N)を含有し、C1~C6アルキル基から選択される1~2個の置換基で任意選択で置換されている5~6員の環を形成していてもよく;
R5はC1~C6アルキル、及びシクロプロピル基から選択され;
R6はH、及びC1~C6アルキル基から選択され;
aは1、2、3、又は4であり;
bは0、又は1であり;
cは0、1、又は2であり;
c’は2、3、又は4であり;
dは2であり;
eは1であり;
E2は-O-δ2、-OC(O)-δ2、-OCH2CH2O-δ2、及び-OC(O)(CH2)6C(O)O-δ2から選択され;ここでδ2はR2基に連結される結合を示し;
R2は
から選択されるか、又は式-(CH2)g-[L3-(CH2)]h-R9を有し、ここで、
L1及びL2は各々直接結合であり;
R7及びR8は各々独立してC4~C10アルキル基から選択され;
fは0、又は1であり;
L3は
から選択され;
R9はH及びC4~C8アルキル基から選択され;
gは1~18の範囲の整数であり;
hは0、1、又は2である]。 - 以下の構造のいずれか1つの化合物
又はその薬学的に許容できる塩。 - 以下の構造のいずれか1つの化合物
又はその薬学的に許容できる塩。 - 構造脂質、ステロール、及び安定剤並びに少なくとも1種の治療剤と組み合わせた請求項1~6のいずれか一項に記載の化合物のいずれかを含む脂質ミックス組成物。
- 構造脂質がDSPC(ジステアロイルホスファチジルコリン)、DSPE(ジステアロイル-ホスファチジルエタノールアミン)、DPPC(ジパルミトイルホスファチジルコリン)、DOPC(ジオレオイルホスファチジルコリン)、POPC(パルミトイルオレオイルホスファチジルコリン)、及びDOPE(ジオレオイル-ホスファチジルエタノールアミン)からなる群から選択される1種又は複数の構造脂質を含む、請求項7に記載の脂質ミックス組成物。
- 化合物が10Mol%~90Mol%で存在し、構造脂質が0~50Mol%で存在し、ステロールが0~45Mol%で存在し、安定剤が0~10Mol%で存在し、全成分の総mol%が100mol%である、請求項7又は8に記載の脂質ミックス組成物。
- 化合物が40Mol%~60Mol%で存在し、構造脂質が11~40Mol%で存在し、全成分の総mol%が100mol%である、請求項9に記載の脂質ミックス組成物。
- 化合物の、残りの成分に対するモル比が30Mol%~70Mol%である、請求項9に記載の脂質ミックス組成物。
- 組成物が脂質粒子の形態である、請求項7~11のいずれか一項に記載の脂質ミックス組成物。
- ナノ粒子の実験値pKaが5.6~7.1の範囲である、請求項1~6のいずれか一項に記載の化合物又はその薬学的に許容できる塩。
- 請求項1~6のいずれか一項に記載の化合物及び少なくとも1種の薬学的に許容できる担体又は賦形剤を含む医薬組成物。
- 化合物が40Mol%で存在し、DSPC(ジステアロイルホスファチジルコリン)が20Mol%で存在し、コレステロールが37.5Mol%で存在し、ポリオキシエチレン(10)ステアリルエーテルが2.5Mol%で存在する、請求項7~12のいずれか一項に記載の脂質ミックス組成物。
- 化合物が40~47.5Mol%で存在し、DSPC(ジステアロイルホスファチジルコリン)が12.5Mol%で存在し、コレステロールが38.5~46Mol%で存在し、PEG-DMG 2000が1.5Mol%で存在する、請求項7~12のいずれか一項に記載の脂質ミックス組成物。
- 化合物が40~47.5Mol%で存在し、DOPE(ジオレオイル-ホスファチジルエタノールアミン)が12.5Mol%で存在し、コレステロールが38.5~46Mol%で存在し、PEG-DMG 2000が1.5Mol%で存在する、請求項7~12のいずれか一項に記載の脂質ミックス組成物。
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AU2019359299B2 (en) | 2018-10-09 | 2022-04-21 | The University Of British Columbia | Compositions and systems comprising transfection-competent vesicles free of organic-solvents and detergents and methods related thereto |
WO2022115645A1 (en) | 2020-11-25 | 2022-06-02 | Akagera Medicines, Inc. | Lipid nanoparticles for delivery of nucleic acids, and related methods of use |
EP4282855A1 (en) * | 2021-02-05 | 2023-11-29 | Immorna (Hangzhou) Biotechnology Co., Ltd. | Ionizable lipid molecule, preparation method therefor, and application thereof in preparation of lipid nanoparticle |
CN112961065B (zh) * | 2021-02-05 | 2023-03-14 | 嘉晨西海(杭州)生物技术有限公司 | 一种可电离脂质分子及其制备方法及其在制备脂质纳米颗粒的应用 |
CN114149337B (zh) * | 2021-07-07 | 2022-04-29 | 天津键凯科技有限公司 | 一种用于核酸递送的新型可电离脂质及其lnp组合物 |
KR20230017730A (ko) | 2021-07-27 | 2023-02-06 | 에스케이바이오사이언스(주) | 단백질 발현을 위한 mRNA와 이를 위한 주형 |
JP2024533865A (ja) | 2021-09-14 | 2024-09-12 | レナゲード セラピューティクス マネージメント インコーポレイテッド | 環状脂質及びその使用方法 |
US11510975B1 (en) | 2021-11-29 | 2022-11-29 | Replicate Bioscience, Inc. | Compositions and methods for inducing ESR1, PI3K, HER2, and HER3 immune responses |
WO2023230587A2 (en) | 2022-05-25 | 2023-11-30 | Akagera Medicines, Inc. | Lipid nanoparticles for delivery of nucleic acids and methods of use thereof |
WO2024006863A1 (en) | 2022-06-30 | 2024-01-04 | Precision NanoSystems ULC | Lipid nanoparticle formulations for vaccines |
WO2024126423A1 (en) | 2022-12-12 | 2024-06-20 | Precision NanoSystems ULC | Lipid nanoparticles lyophilization methods and compositions |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009052102A (ja) | 2007-08-28 | 2009-03-12 | Jfe Steel Kk | 表面処理鋼板、樹脂被覆鋼板、缶および缶蓋 |
JP2011509258A (ja) | 2008-01-02 | 2011-03-24 | テクミラ ファーマシューティカルズ コーポレイション | 核酸の送達のための改善された組成物および方法 |
WO2012108397A1 (ja) | 2011-02-08 | 2012-08-16 | 第一三共株式会社 | 新規脂質 |
JP2014505145A (ja) | 2011-01-11 | 2014-02-27 | アルニラム・ファーマシューティカルズ・インコーポレーテッド | Peg化脂質および薬剤送達のためのそれらの使用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0854716A (ja) * | 1994-08-12 | 1996-02-27 | Konica Corp | ハロゲン化銀写真感光材料およびその処理方法 |
WO2010054401A1 (en) * | 2008-11-10 | 2010-05-14 | Alnylam Pharmaceuticals, Inc. | Novel lipids and compositions for the delivery of therapeutics |
EP2817287B1 (en) * | 2012-02-24 | 2018-10-03 | Arbutus Biopharma Corporation | Trialkyl cationic lipids and methods of use thereof |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009052102A (ja) | 2007-08-28 | 2009-03-12 | Jfe Steel Kk | 表面処理鋼板、樹脂被覆鋼板、缶および缶蓋 |
JP2011509258A (ja) | 2008-01-02 | 2011-03-24 | テクミラ ファーマシューティカルズ コーポレイション | 核酸の送達のための改善された組成物および方法 |
JP2014505145A (ja) | 2011-01-11 | 2014-02-27 | アルニラム・ファーマシューティカルズ・インコーポレーテッド | Peg化脂質および薬剤送達のためのそれらの使用 |
WO2012108397A1 (ja) | 2011-02-08 | 2012-08-16 | 第一三共株式会社 | 新規脂質 |
Non-Patent Citations (1)
Title |
---|
Bioorg. Med. Chem. Lett.,2015年,25,496-503 |
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CA3143578A1 (en) | 2021-01-07 |
CN115279743A (zh) | 2022-11-01 |
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EP3990441A1 (en) | 2022-05-04 |
US20220378917A1 (en) | 2022-12-01 |
JP2024054110A (ja) | 2024-04-16 |
WO2021000041A1 (en) | 2021-01-07 |
EP3990441A4 (en) | 2022-08-24 |
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