JP2019530673A - 治療剤送達のための血小板組成物及び方法 - Google Patents
治療剤送達のための血小板組成物及び方法 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
Description
本出願は、参照により本明細書に明示的に組み込まれる、2016年9月13日に出願された米国特許仮出願第62/393,839号の利益を主張するものである。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含み、
治療剤が前記化学的リンカー部分を介して前記血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
治療剤が前記化学的リンカー部分を介して前記血小板細胞に共有結合している、がんの転移または再発を予防する方法が、本明細書にて開示される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む組成物を対象に投与することを含み、
治療剤が前記化学的リンカー部分を介して前記血小板細胞に共有結合しており、
前記組成物が、前記血小板細胞の活性化を介して創傷または外科的切除部位を標的とする、治療剤の標的化送達のための方法が、本明細書にて開示される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
治療剤が前記化学的リンカー部分を介して前記血小板細胞に共有結合している、治療剤の標的化送達のための方法が、本明細書で提供される。
本明細書及び本特許請求の範囲で使用される場合、単数形「a」、「an」及び「the」は、文脈上、別段の明確な指示がない限り、複数形の言及を含む。例えば、「細胞(a cell)」という用語は、その混合物を含む複数の細胞を含む。
一態様では、
血小板細胞と、
化学的リンカー部分と、
治療剤と、を含み、
治療剤が前記化学的リンカー部分を介して前記血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
化学的リンカー部分と、
免疫療法剤と、を含み、
免疫療法剤が、化学的リンカー部分を介して血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
化学的リンカー部分と、
抗PDL1抗体と、を含み、
抗PDL1抗体が、化学的リンカー部分を介して血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
マレイミドリンカーと、
免疫療法剤と、を含み、
免疫療法剤が、該化学的リンカー部分を介して血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
マレイミドリンカーと、
抗PDL1抗体と、を含み、
抗PDL1抗体が、該化学的リンカー部分を介して血小板細胞に共有結合している、組成物が、本明細書で提供される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、を含み、
治療剤が、ナノ粒子内にカプセル化される組成物が、本明細書で提供される。
噴霧乾燥技術を使用して、マイクロスフェア/ナノスフェアを形成するための方法は、Mathiowitzらの米国特許第6,620,617号に記載されている。この方法では、ポリマーを塩化メチレンのような有機溶媒または水中に溶解する。粒子に組み込まれる既知量の1以上の活性剤を、ポリマー溶液中に懸濁する(不溶性活性剤の場合)か、または共溶解する(可溶性活性剤の場合)。圧縮ガスの流れにより駆動するマイクロ化ノズルを通じて溶液または分散液を注入し、得られたエアロゾルを加熱された空気のサイクロンに懸濁し、溶媒をマイクロ液滴から蒸発させて、粒子を形成する。この方法を使用して、0.1〜10ミクロンの範囲のマイクロスフェア/ナノスフェアを得ることができる。
界面重合もまた、1以上の活性剤をカプセル化するために使用することができる。この方法を使用して、モノマー及び活性剤(複数可)を溶媒に溶解する。第2のモノマーを、第1の溶媒と不混和性の第2の溶媒(典型的には水性)に溶解する。エマルションは、第2の溶液中での撹拌により第1の溶液を懸濁することによって形成される。エマルションが安定化したら、開始剤を水相に添加し、エマルションの各液滴の界面で界面重合を引き起こす。
マイクロスフェアは、Mathiowitz et al.,Reactive Polymers,6:275(1987)に記載されているホットメルトマイクロカプセル化法を使用して、ポリエステル及びポリ無水物などのポリマーから形成することができる。この方法では、3〜75,000ダルトンの間の分子量を有するポリマーの使用が好ましい。この方法では、ポリマーは最初に溶融され、次に、50ミクロン未満に篩分けされた組み込まれる1以上の活性剤の固体粒子と混合される。混合物を(シリコンオイルのような)非混和性溶媒に懸濁し、そして連続的に撹拌しながら、ポリマーの融点より5℃高く加熱する。エマルションが安定化したら、ポリマー粒子が固化するまで冷却する。得られたマイクロスフェアを石油エーテルでデカントすることにより洗浄して、流動性のある粉末を得る。
相分離マイクロカプセル化技術では、ポリマー溶液を、任意に、カプセル化する1以上の活性剤の存在下で撹拌する。撹拌により材料を均一に懸濁し続けながら、ポリマーに対する非溶媒を前記溶液へとゆっくり添加し、ポリマーの溶解度を低下させる。溶媒及び非溶媒中のポリマーの溶解度に応じて、ポリマーは沈殿するか、またはポリマー濃厚相とポリマー希薄相とに分離する。適切な条件下で、ポリマー濃厚相中のポリマーは、連続相との界面に移動し、活性剤(複数可)を、外側ポリマーシェルを有する液滴中にカプセル化する。
自発的乳化は、温度の変化、溶媒の蒸発、または化学架橋剤を添加することによって、上で形成された乳化液体ポリマー液滴を固化させることを含む。カプセル化材料(encapsulant)の物理的及び化学的性質、ならびに発生しようとする粒子に任意に組み込まれる1以上の活性剤の性質が、カプセル化の適切な方法を決定づける。疎水性、分子量、化学的安定性、及び熱安定性などの要素がカプセル化に影響する。
溶媒蒸発技術を使用してマイクロスフェアを形成する方法は、E.Mathiowitz et al.,J.Scanning Microscopy,4:329(1990);L.R.Beck et al.,Fertil.Steril.,31:545(1979)、L.R.Beck et al Am J Obstet Gynecol 135(3)(1979)、S.Benita et al.,J.Pharm.Sci.,73:1721(1984)、及びMorishita et al.の米国特許第3,960,757号に記載されている。ポリマーを塩化メチレンのような揮発性有機溶媒に溶解する。組み込まれる1以上の活性剤を、任意に溶液に添加し、該混合物をポリ(ビニルアルコール)のような界面活性剤を含有する水溶液中に懸濁する。得られたエマルションを大部分の有機溶媒が蒸発するまで撹拌し、固体のマイクロスフェア/ナノスフェアを残す。この方法は、ポリエステル及びポリスチレンのような比較的安定なポリマーに有用である。しかしながら、ポリ無水物のような不安定なポリマーは、水が存在するために製造プロセス中に劣化するおそれがある。これらのポリマーについては、完全に無水の有機溶媒中で実施される以下の方法のいくつかがより有用である。
溶媒除去マイクロカプセル化技術は、主にポリ無水物のために設計されており、例えば、Brown University Research FoundationのWO93/21906に記載されている。この方法では、塩化メチレンのような揮発性有機溶媒中の選択したポリマーの溶液に、組み込まれる物質を分散または溶解する。この混合物を、シリコンオイルのような有機油中に撹拌することによって懸濁し、エマルションを形成する。この手順によって、1〜300ミクロンの間の範囲のマイクロスフェアを得ることができる。マイクロスフェアに組み込むことができる物質には、医薬品、殺虫剤、栄養素、造影剤、及び金属化合物が含まれる。
コアセルベーション技術を使用する種々の物質のカプセル化手順は、当技術分野、例えば、GB−B−929 406、GB−B−929 40 1、ならびに米国特許第3,266,987号、第4,794,000号,及び第4,460,563号において公知である。コアセルベーションは、高分子溶液を2つの不混和性液相に分離することを含む。1つの相は、濃厚なコアセルベート相であり、これは高濃度のポリマーカプセル化材料(及び任意には1以上の活性剤)を含有し、一方、第2の相は低濃度のポリマーを含有する。濃厚なコアセルベート相内では、ポリマーカプセル化材料は、ナノスケールまたはマイクロスケールの液滴を形成する。コアセルベーションは、温度変化、非溶媒の添加もしくはマイクロ塩の添加(単純コアセルベーション)、または別のポリマーの添加によりインターポリマー複合体が形成され得ること(複合コアセルベーション)により誘発することができる。
制御放出マイクロスフェアの極低温キャスティングの方法が、Gombotzらの米国特許第5,019,400号に記載されている。この方法では、ポリマーを、任意には1以上の溶解または分散した活性剤と共に溶媒に溶解する。次いで、混合物を、ポリマー液滴を凍結させるポリマー−物質溶液の凝固点未満の温度で、液体非溶媒を含有する容器に噴霧する。該液滴、及び該ポリマーに対する非溶媒が温められると、液滴中の溶媒が解凍され、非溶媒中に抽出され、その結果、マイクロスフェアが固化する。
ナノ粒子はまた、転相ナノカプセル化(PIN)法を使用して形成することができる。この方法では、ポリマーを「良」溶媒に溶解し、薬物のような組み込まれる物質の微粒子をポリマー溶液に混合または溶解し、そして該混合物をポリマーに対する強力な非溶媒へと注ぎ入れると、ポリマーマイクロスフェアを好ましい条件下で自発的に生成し、該ポリマーは、粒子で被覆されるか、または粒子がポリマー中に分散される。例えば、Mathiowitzらの米国特許第6,143,211号を参照のこと。この方法は、例えば、約100ナノメートル〜約10ミクロンを含む広範囲のサイズのナノ粒子及びマイクロ粒子の単分散集団を製造するために使用することができる。
多層ナノ粒子はまた、本明細書で「連続転相ナノカプセル化」(sPIN)と呼ばれるプロセスによって形成することもできる。sPINは、単分散のナノ粒子集団を形成するのに特に適しており、単分散のナノ粒子集団を実現するための追加の分離ステップを必要としない。
一態様では、
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
治療剤が、化学的リンカー部分を介して血小板細胞に共有結合している、がんの転移または再発を予防する方法が、本明細書にて開示される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
治療剤が、化学的リンカー部分を介して血小板細胞に共有結合している、がんを治療または予防する方法が、本明細書にて開示される。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む組成物を対象に投与することを含み、治療剤が、化学的リンカー部分を介して血小板細胞に共有結合しており、
組成物が、血小板細胞の活性化を介して創傷または外科的切除部位を標的とする、治療剤の標的化送達のための方法方法が、本明細書にて開示される。
いくつかの実施形態では、本明細書に記載の血小板組成物及び方法は、がんの転移または再発を治療または予防するのに有用である。いくつかの実施形態では、本明細書に記載の血小板組成物及び方法は、切除された固形腫瘍の再発の予防に有用である。いくつかの実施形態では、本明細書に記載の組成物及び方法は、切除された固形腫瘍の転移の予防に有用である。別の実施形態では、予防されるがんの再発は、黒色腫である。別の実施形態では、予防されるがんの再発は、乳癌である。さらなる実施形態では、予防されるがんの再発は、前立腺癌である。
血小板は、巨核球から放出される無核細胞断片であり、止血におけるそれらの機能について最もよく知られている。循環血小板の平均寿命は8〜9日であり、これは静脈内注射された治療薬の薬物動態を大きく改善し得る。さらに、輸血された血小板は、残存腫瘍が手術後に残る可能性がある外科的創傷部位へと遊走し得る。他方では、血小板が、原発腫瘍から血管系に流れ込み、そして転移をもたらした循環腫瘍細胞(CTC)を認識及び相互作用する能力を有するという証拠が示されている。これらの固有の創傷及びCTC向性特性に加えて、血小板はまた、多くの炎症状態を惹起及び改善する免疫「細胞」と考えることができる。
一実施形態では、リンカーを介して血小板にコンジュゲートする治療剤は、ペプチド、ポリペプチド、タンパク質、抗体、抗体断片、核酸または治療薬物(例えば、小分子)からなる群から選択することができる。
一実施形態では、免疫療法剤は、抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体、またはこれらの組み合わせから選択される。
いくつかの実施形態では、治療剤は、抗腫瘍剤である。例えば、抗腫瘍剤は、アビラテロンアセテート、Abitrexate(メトトレキサート)、Abraxane(パクリタキセル・アルブミン安定化ナノ粒子製剤)、ABVD、ABVE、ABVE−PC、AC、AC−T、Adcetris(ブレンツキシマブベドチン)、ADE、アドトラスツズマブエムタンシン、Adriamycin(ドキソルビシン塩酸塩)、Adrucil(フルオロウラシル)、アファチニブジマレエート、Afinitor(エベロリムス)、Akynzeo(ネツピタント・パロノセトロン塩酸塩)、Aldara(イミキモド)、アルデスロイキン、アレムツズマブ、Alimta(ペメトレキセド二ナトリウム)、Aloxi(パロノセトロン塩酸塩)、Ambochlorin(クロラムブシル)、Amboclorin(クロラムブシル)、アミノレブリン酸、アナストロゾール、アプレピタント、Aredia(パミドロン酸二ナトリウム)、Arimidex(アナストロゾール)、Aromasin(エキセメスタン)、Arranon(ネララビン)、三酸化ヒ素、Arzerra(オファツムマブ)、アスパラギナーゼエルウィニアクリサンチミー、Avastin(ベバシズマブ)、アキシチニブ、アザシチジン、BEACOPP、Becenum(カルムスチン)、Beleodaq(ベリノスタット)、ベリノスタット、ベンダムスチン塩酸塩、BEP、ベバシズマブ、ベキサロテン、Bexxar(トシツモマブ・ヨウ素 I 131 トシツモマブ)、ビカルタミド、BiCNU(カルムスチン),ブレオマイシン、ブリナツモマブ、Blincyto(ブリナツモマブ)、ボルテゾミブ、Bosulif(ボスチニブ)、ボスチニブ、ブレンツキシマブベドチン、ブスルファン、Busulfex(ブスルファン)、カバジタキセル、カボザンチニブ―S―マレート、CAF、Campath(アレムツズマブ)、Camptosar(イリノテカン塩酸塩)、カペシタビン、CAPOX、カルボプラチン、カルボプラチン−TAXOL、カルフィルゾミブ、Carmubris(カルムスチン)、カルムスチン、カルムスチン・インプラント、Casodex(ビカルタミド)、CeeNU(ロムスチン)、セリチニブ、Cerubidine(ダウノルビシン塩酸塩)、Cervarix(組換えHPV2価ワクチン)、セツキシマブ、クロラムブシル、クロラムブシル−プレドニゾン、CHOP、シスプラチン、Clafen(シクロホスファミド)、クロファラビン、Clofarex(クロファラビン)、Clolar(クロファラビン)、CMF、Cometriq(カボザンチニブ−S―マレート)、COPP、COPP−ABV、Cosmegen(ダクチノマイシン)、クリゾチニブ、CVP、シクロホスファミド、Cyfos(イホスファミド)、Cyramza(ラムシルマブ)、シタラビン、シタラビン、リポソーマル、Cytosar−U(シタラビン)、Cytoxan(シクロホスファミド)、ダブラフェニブ、ダカルバジン、Dacogen(デシタビン)、ダクチノマイシン、ダサチニブ、ダウノルビシン塩酸塩、デシタビン、デガレリクス、デニロイキンディフティトックス、デノスマブ、DepoCyt(リポソーマルシタラビン)、DepoFoam(リポソーマルシタラビン)、デキスラゾキサン塩酸塩、ジヌツキシマブ、ドセタキセル、Doxil(ドキソルビシン塩酸塩リポソーム)、ドキソルビシン塩酸塩、ドキソルビシン塩酸塩リポソーム、Dox−SL(ドキソルビシン塩酸塩リポソーム)、DTIC−Dome(ダカルバジン)、Efudex(フルオロウラシル)、Elitek(ラスブリカーゼ)、Ellence(エピルビシン塩酸塩)、Eloxatin(オキサリプラチン)、エルトロンボパグオラミン、Emend(アプレピタント)、エンザルタミド、エピルビシン塩酸塩、EPOCH、Erbitux(セツキシマブ)、エリブリンメシレート、Erivedge(ビスモデギブ)、エルロチニブ塩酸塩、Erwinaze(アスパラギナーゼエルウィニアクリサンチミー)、Etopophos(エトポシドホスフェート)、エトポシド、エトポシドホスフェート、Evacet(ドキソルビシン塩酸塩リポソーム)、エベロリムス、Evista(ラロキシフェン塩酸塩)、エキセメスタン、Fareston(トレミフェン)、Farydak(パノビノスタット)、Faslodex(フルベストラント)、FEC、Femara(レトロゾール)、フィルグラスチム、Fludara(フルダラビンホスフェート)、フルダラビンホスフェート、Fluoroplex(フルオロウラシル)、フルオロウラシル、Folex(メトトレキサート)、Folex PFS(メトトレキサート)、FOLFIRI、FOLFIRI−ベバシズマブ、FOLFIRI−セツキシマブ、FOLFIRINOX、FOLFOX、Folotyn(プララトレキセート)、FU−LV、フルベストラント、Gardasil(組換えHPV4価ワクチン)、Gardasil 9(組換えHPV9価ワクチン)、Gazyva(オビヌツズマブ)、ゲフィチニブ、ゲムシタビン塩酸塩、ゲムシタビン−シスプラチン、ゲムシタビン−オキサリプラチン、ゲムツズマブオゾガマイシン、Gemzar(ゲムシタビン塩酸塩)、Gilotrif(アファチニブジマレエート)、Gleevec(イマチニブメシレート)、Gliadel(カルムスチン・インプラント)、Gliadel wafer(カルムスチン・インプラント)、グルカルピダーゼ、ゴセレリンアセテート、Halaven(エリブリンメシレート)、Herceptin(トラスツズマブ)、HPV2価ワクチン、組換え,HPV9価ワクチン、組換え,HPV4価ワクチン、組換え,Hycamtin(トポテカン塩酸塩)、Hyper−CVAD、Ibrance(パルボシクリブ)、イブリツモマブチウキセタン、イブルチニブ、ICE、Iclusig(ポナチニブ塩酸塩)、Idamycin(イダルビシン塩酸塩)、イダルビシン塩酸塩、イデラリシブ、Ifex(イホスファミド)、イホスファミド、Ifosfamidum(イホスファミド)、イマチニブメシレート、Imbruvica(イブルチニブ)、イミキモド、Inlyta(アキシチニブ)、インターフェロンアルファ−2b、組換え,Intron A(組換えインターフェロンアルファ−2b)、ヨウ素 I 131 トシツモマブ・トシツモマブ、イピリムマブ、Iressa(ゲフィチニブ)、イリノテカン塩酸塩、Istodax(ロミデプシン)、イクサベピロン、Ixempra(イクサベピロン)、Jakafi(ルキソリチニブホスフェート)、Jevtana(カバジタキセル)、Kadcyla(アドトラスツズマブエムタンシン)、Keoxifene(ラロキシフェン塩酸塩)、Kepivance(パリフェルミン)、Keytruda(ペンブロリズマブ)、Kyprolis(カルフィルゾミブ)、ランレオチドアセテート、ラパチニブジトシレート、レナリドミド、レンバチニブメシレート、Lenvima(レンバチニブメシレート)、レトロゾール、ロイコボリンカルシウム、Leukeran(クロラムブシル)、ロイプロリドアセテート、Levulan(アミノレブリン酸)、Linfolizin(クロラムブシル)、LipoDox(ドキソルビシン塩酸塩リポソーム)、リポソーマルシタラビン、ロムスチン、Lupron(ロイプロリドアセテート)、Lupron Depot(ロイプロリドアセテート)、Lupron Depot−Ped(ロイプロリドアセテート)、Lupron Depot−3 Month(ロイプロリドアセテート)、Lupron Depot−4 Month(ロイプロリドアセテート)、Lynparza(オラパリブ)、Marqibo(ビンクリスチンスルフェートリポソーム)、Matulane(プロカルバジン塩酸塩)、メクロレタミン塩酸塩、Megace(メゲストロールアセテート)、メゲストロールアセテート、Mekinist(トラメチニブ)、メルカプトプリン、メスナ、Mesnex(メスナ)、Methazolastone(テモゾロミド)、メトトレキサート、Methotrexate LPF(メトトレキサート)、Mexate(メトトレキサート)、Mexate−AQ(メトトレキサート)、マイトマイシンC、ミトキサントロン塩酸塩、Mitozytrex(マイトマイシンC)、MOPP、Mozobil(プレリキサホル)、Mustargen(メクロレタミン塩酸塩)、Mutamycin(マイトマイシンC)、Myleran(ブスルファン)、Mylosar(アザシチジン)、Mylotarg(ゲムツズマブオゾガマイシン)、Nanoparticle Paclitaxel(パクリタキセル・アルブミン安定化ナノ粒子製剤)、Navelbine(ビノレルビンタルタレート)、ネララビン、Neosar(シクロホスファミド)、ネツピタント・パロノセトロン塩酸塩、Neupogen(フィルグラスチム)、Nexavar(ソラフェニブトシレート)、ニロチニブ、ニボルマブ、Nolvadex(タモキシフェンシトレート)、Nplate(ロミプロスチム)、オビヌツズマブ、Odomzo(ソニデジブ)、OEPA、オファツムマブ、OFF、オラパリブ、オマセタキシンメペスクシナート、Oncaspar(ペグアスパラガーゼ)、オンダンセトロン塩酸塩、Ontak(デニロイキン・ディフティトックス)、Opdivo(ニボルマブ)、OPPA、オキサリプラチン、パクリタキセル、パクリタキセル・アルブミン安定化ナノ粒子製剤、PAD、パルボシクリブ、パリフェルミン、パロノセトロン塩酸塩、パロノセトロン塩酸塩・ネツピタント、パミドロン酸二ナトリウム、パニツムマブ、パノビノスタット、Paraplat(カルボプラチン)、Paraplatin(カルボプラチン)、パゾパニブ塩酸塩、ペグアスパラガーゼ、ペグインターフェロンアルファ−2b、PEG−Intron(ペグインターフェロンアルファ−2b)、ペンブロリズマブ、ペメトレキセド二ナトリウム、Perjeta(ペルツズマブ)、ペルツズマブ、Platinol(シスプラチン)、Platinol−AQ(シスプラチン)、プレリキサホル、ポマリドミド、Pomalyst(ポマリドミド)、ポナチニブ塩酸塩、プララトレキセート、プレドニゾン、プロカルバジン塩酸塩、Proleukin(アルデスロイキン)、Prolia(デノスマブ)、Promacta(エルトロンボパグオラミン)、Provenge(シプロイセル−T)、Purinethol(メルカプトプリン)、Purixan(メルカプトプリン)、塩化ラジウム223、ラロキシフェン塩酸塩、ラムシルマブ、ラスブリカーゼ、R−CHOP、R−CVP、組換えヒトパピローマウイルス(HPV)2価ワクチン、組換えヒトパピローマウイルス(HPV)9価ワクチン、組換えヒトパピローマウイルス(HPV)4価ワクチン、組換えインターフェロンアルファ−2b、レゴラフェニブ、R−EPOCH、Revlimid(レナリドミド)、Rheumatrex(メトトレキサート)、Rituxan(リツキシマブ)、リツキシマブ、ロミデプシン、ロミプロスチム、Rubidomycin(ダウノルビジン塩酸塩)、ルキソリチニブホスフェート、Sclerosol Intrapleural Aerosol(タルク)、シルツキシマブ、シプロイセル−T、Somatuline Depot(ランレオチドアセテート)、ソニデジブ、ソラフェニブトシレート、Sprycel(ダサチニブ)、STANFORD V、Sterile Talc Powder(タルク)、Steritalc(タルク)、Stivarga(レゴラフェニブ)、スニチニブマレート、Sutent(スニチニブマレート)、Sylatron(ペグインターフェロンアルファ−2b)、Sylvant(シルツキシマブ)、Synovir(サリドマイド)、Synribo(オマセタキシンメペスクシナート)
、TAC、Tafinlar(ダブラフェニブ)、タルク、タモキシフェンシトレート、Tarabine PFS(シタラビン)、Tarceva(エルロチニブ塩酸塩)、Targretin(ベキサロテン)、Tasigna(ニロチニブ)、Taxol(パクリタキセル)、Taxotere(ドセタキセル)、Temodar(テモゾロミド)、テモゾロミド、テムシロリムス、サリドマイド、Thalomid(サリドマイド)、チオテパ、Toposar(エトポシド)、トポテカン塩酸塩、トレミフェン、Torisel(テムシロリムス)、トシツモマブ・ヨウ素 I 131 トシツモマブ、Totect(デクスラゾキサン塩酸塩)、TPF、トラメチニブ、トラスツズマブ、Treanda(ベンダムスチン塩酸塩)、Trisenox(三酸化二ヒ素)、Tykerb(ラパチニブジトシレート)、Unituxin(ジヌツキシマブ)、バンデタニブ、VAMP、Vectibix(パニツムマブ)、VeIP、Velban(ビンブラスチンスルフェート)、Velcade(ボルテゾミブ)、Velsar(ビンブラスチンスルフェート)、ベムラフェニブ、VePesid(エトポシド)、Viadur(ロイプロリドアセテート)、Vidaza(アザシチジン)、ビンブラスチンスルフェート、Vincasar PFS(ビンクリスチンスルフェート)、ビンクリスチンスルフェート、ビンクリスチンスルフェートリポソーム、ビノレルビンタルタレート、VIP、ビスモデギブ、Voraxaze(グルカルピダーゼ)、ボリノスタット、Votrient(パゾパニブ塩酸塩)、Wellcovorin(ロイコボリンカルシウム)、Xalkori(クリゾチニブ)、Xeloda(カペシタビン)、XELIRI、XELOX、Xgeva(デノスマブ)、Xofigo(塩化ラジウム223)、Xtandi(エンザルタミド)、Yervoy(イピリムマブ)、Zaltrap(Ziv−アフリベルセプト)、Zelboraf(ベムラフェニブ)、Zevalin(イブリツモマブチウキセタン)、Zinecard(デクスラゾキサン塩酸塩)、Ziv−アフリベルセプト、Zofran(オンダンセトロン塩酸塩)、Zoladex(ゴセレリンアセテート)、ゾレドロン酸、Zolinza(ボリノスタット)、Zometa(ゾレドロン酸)、Zydelig(イデラリシブ)、Zykadia(セリチニブ)、及びZytiga(アビラテロンアセテート)からなる群から選択することができる。
血小板はまた、損傷した血管を封止し、出血を止める栓を形成することによって、止血及び血栓症などのいくつかの生理学的及び病理学的プロセスにおいて重要な役割を果たすため、このプラットフォームは、関連する血管疾患の処置のために使用することもできる。
血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
治療剤が、化学的リンカー部分を介して血小板細胞に共有結合している、、血管疾患を治療または予防する方法が、本明細書に提供される。
共有結合アプローチを、化学的リンカーを介して血小板を修飾するために用いることができる。化学的リンカーを使用する利点の1つは、遺伝的変化の必要性が回避されることである。このような二官能性化学的リンカーは、治療剤を血小板細胞に連結することができる。二官能性リンカー基の例には、これらに限定されないが、糖、アミノ酸、アミノアルコール、カルボキシアルコール、アミノチオールなどのような部分が含まれる。
手術は、ほとんどの固形腫瘍に対する処置の主な選択肢である。外科的技術の継続的な改善にもかかわらず、腫瘍切除後の残存微小腫瘍及び/またはCTCは、依然として課題である1−3。加えて、手術が、がん転移の促進を誘発し得ることもまた示唆されている4,5。多くの患者は、術後に再発性疾患を発症し、これは重大な罹病率と死亡率につながるおそれがある。したがって、術後のがんの再発を防ぐための効果的な戦略構築に多大な関心が寄せられている。それらの中で、がん免疫療法は、近年非常に注目を集めている6。免疫療法剤は腫瘍を直接攻撃するのではなく、身体の免疫系を高めてがん細胞を殺す7。免疫チェックポイント遮断は、患者のサブセットにおいて長続きする抗腫瘍反応及び長期間の寛解を誘発した8−10。特に、チェックポイント阻害剤は、リンパ球上のプログラム細胞死タンパク質1(PD1)ならびに抗原提示細胞(APC)及び腫瘍細胞上のプログラム細胞死1リガンド1(PDL1)の相互作用を遮断し、様々な種類のがんの処置において刺激的な結果を示した11−14。さらに、最初のPD−L1阻害剤であるアテゾリズマブが、最近、米国食品医薬品局(FDA)から迅速承認を受けた15。著しい進歩にもかかわらず、チェックポイント遮断療法の現在の方法は、多くの患者において治療効果が制限される。臨床試験で観察された最大の制限は、自己免疫疾患などの副作用の重篤度であり得る16−18。免疫チェックポイント遮断療法で治療した場合、グレード3/4の有害事象が時々発生している15,19。その一方で、大多数の患者は、これらの薬剤に反応しなかった8,10,15。抗PD療法の客観的奏効率には、依然として改善が必要である。抗PD療法をどのように強化するかは、がん免疫学及び免疫療法の分野における中心的テーマの1つとなっている6,11。
共有結合アプローチを用いて、二官能性マレイミドリンカーを介してaPDL1により血小板を扱いやすいように修飾し、遺伝子改変の必要性を回避する44。血小板へのaPDL1の結合を、免疫蛍光法によって調べた(図6)。加えて、マレイミド不含aPDL1は、血小板に対してわずかな非特異的結合を示した(図7)。酵素結合免疫吸着法(ELISA)は、血小板が、血小板あたり最大約0.3pgまでaPDL1と容易に結合できることを示した(図8a)。血小板あたり0.1pg及び0.2pgのaPDL1を結合しても、これらの生存力に有意な影響を及ぼさないこともまた見出された(図8b)。このような共有結合は非常に安定であり、2日以内に有意な放出を示さなかった(図8c)。さらに、細胞接着及び遊走を調節する血小板のいくつかの表面タンパク質を調べた(図9)。まとめると、aPDL1とのコンジュゲーションは、これらの血小板細胞に著しい損傷を生じなかった。
血小板の活性化は、接着が起こった後に生じる45。血小板は、免疫機能を持つ多くの分子を含む約60の顆粒を含有する38。活性化すると、これらの顆粒は、それらの内包物質を細胞外環境に放出する。これらの内容物の多くは免疫分子としての役割を果たす。例えば、これらは他の免疫細胞を動員して活性化し、T細胞の遊走を誘導し、単球のDCへの分化を増加させることができる。加えて、PMPは、血小板活性化時に原形質膜から誘導され43、活性化血小板は、接着分子及びケモカインを運ぶPMPを放出し、PMP沈着部位での単球捕捉を促進する46。aPDL1修飾血小板(P−aPDL1)が刺激時に活性化され得るかどうかを調査するために、トロンビンを使用してin vitroでP−aPDL1を活性化した。活性化前後のP−aPDL1の透過型電子顕微鏡(TEM)画像の観察から、大量の生成されたPMPが電子顕微鏡下で検出された(図1b、図10)。血小板の樹状かつ広がった形態変化もまた観察された。さらに興味深いことに、活性化血小板からのaPDL1の顕著な放出が、ELISAアッセイによってモニターされた(図1c)。顕著なaPDL1放出は、血小板活性化時の原形質膜からの解離したPMPに起因するとした。この仮説を試験するために、活性化P−aPDL1の免疫蛍光イメージングを実施した。血小板をカルセインで染色し、aPDL1を蛍光二次抗体で染色した(図11)。血小板の活性化後、aPDL1がPMP上に存在することが検出された。
血小板表面へのaPDL1の結合は、それらのin vivo挙動を変える可能性を有する。したがって、全身投与後のP−aPDL1のin vivo薬物動態を健康なマウスで評価した。aPDL1、P−aPDL1、及び同時注射の非コンジュゲート血小板+a−PDL1を、同等のaPDL1用量でマウスに静脈内注射した。血液からのaPDL1のELISA分析は、遊離aPDL1(5.2時間)及び混合物(5.5時間)と比較して、血小板に結合したaPDL1については非常に長期間の血液循環半減期(34.8時間)が達成されたことを示した(図2a)。臨床における治療用抗体と比較して比較的短い血液循環時間は、ラット抗マウスIgGのより高い免疫原性及び非特異的結合に起因する。手術により原発腫瘍を不完全に切除した後、それらの創傷向性能を試験した。aPDL1をCy5.5によって標識し、次いで血小板にコンジュゲートした。ex vivo蛍光イメージングのために主要な臓器を収集して、P−aPDL1または遊離aPDL1の注射の2時間後にin vivo蛍光イメージングを実施した(図13)。血小板にコンジュゲートした場合、aPDL1は、残存腫瘍を有する外科的創傷付近に豊富に存在していたが、遊離aPDL1の創傷部位では顕著な蛍光シグナルが検出されなかった(図2b)。主要な臓器、及び残存微小腫瘍を有する創傷のex vivoイメージングにより、P−aPDL1の創傷向性能がさらに確認された(図2c、図13)。圧倒的なaPDL1蛍光シグナルが、遊離aPDL1を注射したマウスの肝臓で検出されたのに対し、P−aPDL1は、同じaPDL1用量で、遊離aPDL1を注射したマウスからのシグナルよりも著しく低いaPDL1シグナルを肝臓で示した。このことは、P−aPDL1の血液循環時間がより長いことを示す。その一方で、顕著な強いaPDL1シグナルが、残存微小腫瘍を有する外科的創傷付近で検出されたのに対し、遊離aPDL1に関連する試料では顕著な蛍光シグナルが検出されなかった。蛍光シグナルの定量化により、静脈内注射の2時間後、P−aPDL1の創傷での蓄積が、遊離aPDL1のものと比較して、9.4倍超効果的であることが示された(図2d)。微小腫瘍切片の共焦点画像により、血小板上にコンジュゲートされた場合に、aPDL1の腫瘍取り込みが顕著に増加することがさらに確認された(図2e、図14a)。さらに、血小板から放出されたaPDL1は、蛍光イメージングによってin vivoで明らかに観察された(図14b)。修飾血小板の止血効果もまた調べた。輸血後のマウス尾部出血時間により、P−aPDL1処置マウスは、未処置の血小板の輸血で処置したマウスと比較して、出血時間に統計学的に有意な差がないことが示された(図15)。
加えて、再発腫瘍からの腫瘍浸潤リンパ球(TIL)を採取し、16日目に免疫蛍光法及びフローサイトメトリーによって分析した。免疫蛍光染色は、対照群の残存腫瘍が、T細胞浸潤を制限していることを明らかにした。対照的に、P−aPDL1処置マウスの残存腫瘍は、CD8+及びCD4+T細胞の両方によって著しく浸潤されていた(図3a、図17)。腫瘍重量は、10日目のP−aPDL1処置マウスにおいて有意に低く(図3b)、これはまた、残存腫瘍におけるCD3+細胞の絶対数の増加に対応した(図3c)。より顕著なことには、CD8+T細胞の絶対数/腫瘍グラムは、PBS対照と比較してP−aPDL1処置マウスにおいてほぼ10倍増加し、遊離aPDL1処置マウスに対して3倍増加した(図3d〜f)。加えて、腫瘍浸潤CD4+FoxP3+T細胞を調べた(図3e)。Tエフェクター細胞対制御性T(Treg)細胞の腫瘍内比率は、P−aPDL1療法後のマウスにおいて有意に高まった(図3f−h)。加えて、細胞周期関連タンパク質Ki67の発現によって測定されるように、P−aPDL1マウスの腫瘍内でのCD8+及びCD4+エフェクターT細胞の高増殖が観察された。エフェクターT細胞とは対照的に、P−aPDL1療法を用いた腫瘍浸潤Treg細胞による増殖の有意な増加はなかった(図18)。総合すれば、これらの観察結果は、P−aPDL1が、aPDL1を腫瘍微小環境に効果的に送達し、強固かつT細胞媒介性の抗腫瘍免疫応答を引き起こすことができることを示している。
CTCの処置に対するP−aPDL1の効力をさらに示すために、P−aPDL1が、まず、術後にマウスにB16F10細胞を静脈内注射することによって、実験的転移腫瘍モデルで試験され、これはCTCが原発腫瘍から血液循環へ逃げるのを模倣した(図4a、図19)48。手術直後に、マウスに、単回用量のPBS、血小板、aPDL1(aPDL1=1mg/kgまたは2mg/kg)またはP−aPDL1(aPDL1=1mg/kg)を静脈内注射した。マウスにおけるB16F10細胞の生物発光シグナル(図4b、図19)によれば、遊離aPDL1処置により転移癌を予防することができたが、手術部位での局所的な腫瘍の再発は、2mg/kgの高用量であっても予防できなかったことが示された。これは、おそらく、aPDL1の蓄積が術後のそれらの残存微小腫瘍に対して不十分なためである(図13)。対照的に、肺全体の写真とそれらのヘマトキシリン及びエオシン(H&E)染色イメージング(図4c〜d)ならびに肺組織の蛍光イメージング(図20)によって確認されるように、手術床での腫瘍の再発及び肺転移が、P−aPDL1治療後に著しく減少した。肺における転移部位の平均数は、P−aPDL1で処置した場合に劇的に減少した(図4e)。さらに、処置マウスの生存期間は、対照群と比較して有意に増加した(図4f)。遊離aPDL1と比較したP−aPDL1のより良好な抗癌効果は、がん細胞周辺の抗体の局所濃度の増加に部分的に起因していた(図13)。その一方で、血小板活性化はまた、抗癌効果の機能的要素でもあった。活性化により、コンジュゲートされたaPDL1を放出することができただけでなく、他の多くの免疫細胞を動員してTMEに浸潤させるのにも役立つことができたためである。PDL1遮断により、これらの免疫細胞が強力な抗癌免疫反応を誘導し得る。
別の種類の癌の術後の再発防止におけるP−aPDL1の効力を評価するために、トリプルネガティブ乳癌(TNBC)4T1癌腫瘍モデルで試験を実施した。この実験では、BABL/cマウスに4T1腫瘍細胞を皮下(s.c.)注射した。皮下に腫瘍を接種した14日後、原発腫瘍を手術で切除し、残存微小腫瘍を約1%残した。aPDL1と結合した治療用血小板を手術直後にマウスに静脈内注射した。このモデルでは、1コースのP−aPDL1療法が、術後の残存腫瘍の増殖に影響を与えるのに十分意味があった(図5a−b)。加えて、遊離aPDL1処置マウスに中央値16個の小結節ならびに血小板処置マウス及び未処置のマウスにおいて約30個の小結節が見られたのとは対照的に、P−aPDL1処置マウスの肺では、ほんのわずかな小結節しか見られなかったため、肺転移に対する治療の効果もまた印象的であった(図5c〜d)。術後にP−aPDL1療法を受けたマウスは、対照群とは対照的に実質的な延命効果が得られた。マウスの75%が、腫瘍接種後60日生存した(図5e)。
細胞株
マウス黒色腫細胞株B16F10及びマウス乳癌細胞株4T1を、American Type Culture Collectionから購入した。B16F10−luc−GFP及び4T1−luc−GFP細胞は、Chapel HillのThe University of North CarolinaのDr.Leaf Huangから贈与された。B16F10細胞は、10%ウシ胎児血清(Invitrogen,Carlsbad,CA)、100U/mLのペニシリン(Invitrogen)、及び100U/mLのストレプトマイシン(Invitrogen)を添加したダルベッコ改変イーグル培地(Gibco,Invitrogen)中で維持した。4T1細胞は、10%ウシ胎児血清(Invitrogen,Carlsbad,CA)、100U/mLのペニシリン(Invitrogen)、及び100U/mLのストレプトマイシン(Invitrogen)を添加したRPMI−1640培地(Gibco,Invitrogen)中で維持した。マスターセルバンク及びワーキングセルバンクを、受領後すぐに作製した。第3継代及び第4継代が、腫瘍実験に使用された。細胞は、マイコプラズマの可能性について3ヶ月毎に試験された。受領後、細胞の再認証は実施しなかった。
C57BL/6マウス及びBALB/cマウスを、Jackson Lab(USA)から購入した。全ての実験を通じて、同齢の(6〜10週)雌動物を使用した。全てのマウス研究は、Chapel Hillのthe University of North Carolina及びNorth Carolina State Universityの所内動物実験委員会(Institutional Animal Care and Use Committee)によって承認された動物プロトコルの範疇で実施した。実験群のサイズは、統計的検出力、実現可能性、及び倫理的側面のバランスをとるように定義された後、動物福祉に関する規制当局によって承認された。全てのマウスは、Chapel Hillのthe University of North Carolina及びNorth Carolina State Universityの動物実験に関する連邦及び州の方針にしたがって飼育された。
in vivoで使用する抗PDL1抗体(aPDL1)を、Biolegend Incから購入した(Cat.#124329,Clone: 10F.9G2)。染色抗体には、製造元の指示にしたがって、蛍光活性化細胞選別(FACS)分析のために、CD3(Thermo Fisher Scientific,Cat.#A18644)、CD4(Thermo Fisher Scientific,Cat.#A18667)、CD8(Thermo Fisher Scientific,Cat.#A18609)、PD1(Biolegend,Cat.#135227)、CD11c(Biolegend,Cat.#117309)、PDL1(Biolegend,Cat.#124311)、CD20(Biolegend,Cat.#150411)、CD11b(Biolegend,Cat.#101211)、CD9(Biolegend,Cat.#124805),CD41(Biolegend,Cat.#133905)、CD61(Biolegend,Cat.#104307)、CD62P(Biolegend,Cat.#148305)、CD40L(Biolegend,Cat.#106505)、細胞内Ki67(Biolegend,Cat.#652405)、及び細胞内Foxp3(eBioscience,Cat.#.71−5775−40)が含まれた。染色細胞をCalibur FACS装置(BD)で分析し、FlowJoソフトウェア(バージョン10)を使用して分析した。ヤギ抗ラットIgG(H+L)二次抗体(Thermo Fisher Scientific,Cat.#A18866)、ウサギ抗ラットIgG(H+L)二次抗体(Thermo Fisher Scientific,Cat.#A18920)、ヤギ抗ラットIgG(minimal x−reactivity)抗体(Biolegend,Cat.#405408)を免疫染色に使用した。
記載のように、マウス血小板を単離した。52手短に言えば、全血をC57BL/6(またはBALB/c)マウスから採取(眼窩静脈叢または伏在静脈からの非ターミナル採血、20匹のマウスを採血に使用)し、1.0mLのクエン酸−リン酸−デキストロース(16mM クエン酸、90mM ナトリウムシトレート、16mM NaH2PO4、142mM デキストロース、pH7.4)を含有するプラスチックシリンジに入れ、中断することなく、室温において20分間100gで回転させた。多血小板血漿(PRP)をトランスファーピペット(ワイドオリフィス)を使用して別のチューブに移し、PGE1を各チューブに1μMの最終濃度まで添加した。(注意:PRPの色が赤みがかっている場合は、これらの試料を廃棄すること)。10分間800gで回転(中断なし)させることにより、血小板をPRPから単離した。血漿を廃棄し、血小板をタイロード緩衝液(134mM NaCl、12mM NaHCO3、2.9mM KCl、0.34mM Na2HPO4、1mM MgCl2、10mM HEPES、pH7.4)、またはPGE1を含むPBS(1μMの最終濃度)に慎重にゆっくりと再懸濁させた(注意:チューブの壁に沿ってゆっくりと緩衝液を流し、撹拌量を最小限に抑えること)。各in vivo注射には500〜600μlの全血が必要であった。
その後の調製ステップによる血小板の形状変化を回避するために、血小板を10%の緩衝ホルムアルデヒド溶液と混合することにより血小板の前固定を実施した。前固定の直後に、試料を室温において10分間800gで遠心分離した。上清の廃棄後、血小板を4℃で90分間、カコジル酸緩衝液、pH7.2中の2.5%グルタルアルデヒドで固定した(活性化血小板については、上清もTEMイメージングのために収集した)。固定後、血小板を4℃において10分間800gで遠心分離することにより2回洗浄した。次いで、血小板を2%の酢酸ウラニル及びクエン酸鉛で5分間、順次染色し、次いで銅グリッドに移した。54血小板のTEM画像を、80kVでJEOL 2000FX TEM装置によって得た。
P−aPDL1を活性化するために、0.5Uのトロンビン/mLをP−aPDL1(500μLのタイロード緩衝液中に約1×108の血小板、n=3)懸濁液に37℃で30分間添加した。50μlのP−aPDL1を異なる時点で抽出した。上清中の血小板から放出されたaPDL1及びサイトカインを、10分間800gで遠心分離することにより収集した。非活性化P−aPDL1を対照とした。上清溶液中の放出されたaPDL1及びサイトカインの量をELISAアッセイによって測定した。(eBioscience,Cat.No.88−50490−22(rat IgG)、88−7013−22(IL1β)、88−7064−22(IL6)、88−7324−22(TNF−α)、BMS6010(sCD40L))。吸光度は、Infinite(登録商標)200 PROプレートリーダーで読み取った。
3匹のマウスに、遊離aPDL1、P−aPDL1または非コンジュゲート血小板+a−PDL1混合物(各マウスにつき、200μLのPBS中のaPDL1、2mg/kg、血小板、2×108)を静脈内注射した。抗凝固チューブを使用して、異なる時点で尾から10μLの血液を抽出した。各試料を100μlの水(Sigma,Cat.No.W4502)に溶解し、細胞溶解のために超音波で処置してコンジュゲートaPDL1を放出させた。aPDL1をRat IgG total ELISA kit(eBioscience,Cat.No.88−50490−22)によって測定した。in vivo体内分布調査のために、約1%の残存組織を残して原発腫瘍を除去した後、マウスにCy5.5標識した遊離aPDL1またはP−aPDL1を静脈内注射した。in vivo蛍光画像をIVISシステム(付属のCy5.5用の励起/発光フィルターを用いて、露光時間、1秒)により記録した。ex vivoイメージングのために、処置マウスを注射の2時間後に屠殺した。主要臓器及び組織を収集し、IVISイメージングシステム(付属のCy5.5用の励起/発光フィルターを用いて、露光時間、1秒)(Perkin Elmer Ltd)で撮像した。
癌の再発に対する効果を測定するために、7日後、1×106の、B16F10(または4T1)またはルシフェラーゼタグ付きB16F10(または4T1)腫瘍細胞のいずれかを、マウスの右側腹部に移植した(腫瘍は約300mm3に達する)。手術床内の残存微小腫瘍を模倣するために、約1%の残存組織を残して腫瘍を切除した3。簡単に記せば、動物を、チャンバー導入によるイソフルラン(維持1〜3%、導入最大5%)麻酔で麻酔し、ノーズコーンを介して維持した。腫瘍領域を留め、無菌的に準備した。滅菌器具を使用して、腫瘍の約99%を切除した。創傷をAutoclip Wound Clip Systemによって閉じた。実験的転移モデルのために、200μLのPBS中の1×105のルシフェラーゼタグ付きB16F10(または4T1)腫瘍細胞を、原発腫瘍の切除後、尾静脈を介してマウスに静脈内注入した。マウスの体重を量り、異なる群にランダムに分けた(n=8)。手術後、マウスに異なる薬物製剤をその直後に静脈内注射した(マウスあたり200μLのPBS中にaPDL1=1mg/kg、1〜2×108の血小板)(ここで使用した新たに調製した血小板は、健康なマウスの同じ系統から収集した)。腫瘍負荷をがん細胞の生物発光シグナルによってモニターした。イメージングの前に、マウスを留め、除毛クリームを使用して剃毛した。IVIS Lumina imaging system(Caliper,USA)を使用して画像を撮影した。腫瘍はまた、デジタルノギスでも測定された。腫瘍体積(mm3)は、(長径×短径2)/2として計算された。転移負荷を生物発光により評価した。肺の重さを量り、微小転移を数えた。動物は、健康障害の徴候を示した場合、または腫瘍の体積が2cm3を超えた場合、安楽死させた。
IL−1β、IL−6、TNF−α、及びsCD40Lの局所レベル及び血漿レベルをELISA(eBioscience)によって測定した。創傷における異なるサイトカインの濃度を測定するため、血小板注射の6時間後、創傷組織を収集し、37℃で12時間培養した。分析のために、100μLの培地を除去し、−80℃で凍結した。血漿中のサイトカインレベルを測定するため、血小板注射の6時間後、分析のために、種々の処置後にマウスから血漿試料を単離し、希釈した。IL−1β、IL−6、TNF−α、及びsCD40Lの濃度をELISA(Thermo Scientific)によって測定した。全ての測定を3回実施した。
腫瘍をマウスから切り出し、O.C.Tで急速凍結した。クリオトームを使用して、いくつかのマイクロメートル切片を切断し、スライド上に載せた。切片を氷冷アセトン中で10分間固定した後、PBSで再水和した。BSA(3%)でブロッキング後、切片を一次抗体によって4℃で一晩染色した。蛍光標識二次抗体の添加後、スライドを、共焦点顕微鏡(Zeiss LSM 710)を使用して分析した。
生物発光画像を、IVIS Spectrum Imaging System(Perkin Elmer Ltd)によって収集した。DPBS(15mg/mL)中のd−ルシフェリン(Thermo Scientific(商標)Pierce(商標),Cat#PI88291)を、動物に腹腔内注射(10μL/g体重)した10分後に、Living Imageソフトウェア(Perkin Elmer Ltd)を使用してデータを取得した。生物発光撮像のための露光時間は5分であった。(読み取り時間を最適化するため、IVIS Imaging Systemを使用して1分間の露光時間で生物発光強度を30分間得た。)関心領域(ROI)は、平均放射輝度(カラーバーで表される光子 秒−1cm−2sr−1)として定量化された(IVIS Living Image 4.2)。
尾部出血時間を、末端マウス尾部の先端から3mmを取り除き、直ちに尾部を37℃のPBSに浸すことによって測定した。出血の完全な停止を出血時間のエンドポイントとして定義した。
全ての結果は、明記されるように平均値±s.d.、平均値±s.e.m.として表す。特に明記しない限り、生物学的反復実験を全ての実験で使用した。一元配置分散分析(ANOVA)を3つ以上の群を比較した場合に実施し、有意(P≦0.05)と判定された場合、Tukeyの事後検定を使用して多重比較を実施した。延命効果はログランク検定により測定した。全ての統計分析は、GraphPad Prism(5.0)によって実施した。*P≦0.05、**P≦0.01、***P≦0.001。動物実験または他の実験のための試料サイズを予め決定するための統計学的手法は使用しなかった。
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Claims (40)
- 血小板細胞と、
化学的リンカー部分と、
治療剤と、を含み、
前記治療剤が、前記化学的リンカー部分を介して前記血小板細胞に共有結合している、組成物。 - 前記治療剤が免疫療法剤である、請求項1に記載の組成物。
- 前記免疫療法剤が、抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体、またはこれらの組み合わせから選択される、請求項2に記載の組成物。
- 前記免疫療法剤が抗PDL1抗体である、請求項3に記載の組成物。
- 前記化学的リンカー部分が、マレイミドリンカー、PEGリンカー、PAS化、及びHES化から選択される、請求項1〜4のいずれか一項に記載の組成物。
- 前記化学的リンカー部分がマレイミドリンカーである、請求項5に記載の組成物。
- 前記血小板細胞がヒト血小板細胞である、請求項1〜6のいずれか一項に記載の組成物。
- 前記血小板細胞が自己由来の血小板細胞である、請求項1〜6のいずれか一項に記載の組成物。
- 血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
前記治療剤が、前記化学的リンカー部分を介して前記血小板細胞に共有結合している、がんの転移または再発を予防する方法。 - 前記治療剤が免疫療法剤である、請求項9に記載の方法。
- 前記免疫療法剤が、抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体、またはこれらの組み合わせから選択される、請求項10に記載の方法。
- 前記免疫療法剤が抗PDL1抗体である、請求項11に記載の方法。
- 前記化学的リンカー部分が、マレイミドリンカー、PEGリンカー、PAS化、及びHES化から選択される、請求項9〜12のいずれか一項に記載の方法。
- 前記化学的リンカー部分がマレイミドリンカーである、請求項13に記載の方法。
- 前記血小板細胞がヒト血小板細胞である、請求項9〜14のいずれか一項に記載の方法。
- 前記血小板細胞が自己由来のヒト血小板細胞である、請求項9〜14のいずれか一項に記載の方法。
- 前記がんが固形腫瘍である、請求項9〜16のいずれか一項に記載の方法。
- 前記がんが黒色腫である、請求項9〜16のいずれか一項に記載の方法。
- 前記がんが乳癌である、請求項9〜16のいずれか一項に記載の方法。
- 前記組成物が、追加の治療剤と組み合わせて投与される、請求項9〜19のいずれか一項に記載の方法。
- 前記追加の治療剤が抗腫瘍剤である、請求項20に記載の方法。
- 血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む組成物を対象に投与することを含み、
前記治療剤が、前記化学的リンカー部分を介して前記血小板細胞に共有結合しており、
前記組成物が、前記血小板細胞の活性化を介して創傷または外科的切除部位を標的とする、治療剤の標的化送達のための方法。 - 前記組成物が、前記血小板細胞の活性化時に、創傷または切除部位で血小板由来マイクロ粒子中でさらに放出される、請求項22に記載の方法。
- 前記治療剤が免疫療法剤である、請求項22に記載の方法。
- 前記免疫療法剤が、抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体、またはこれらの組み合わせから選択される、請求項24に記載の方法。
- 前記免疫療法剤が抗PDL1抗体である、請求項25に記載の方法。
- 前記化学的リンカー部分が、マレイミドリンカー、PEGリンカー、PAS化、及びHES化から選択される、請求項22〜26のいずれか一項に記載の方法。
- 前記化学的リンカー部分がマレイミドリンカーである、請求項27に記載の方法。
- 前記血小板細胞がヒト血小板細胞である、請求項22〜28のいずれか一項に記載の方法。
- 前記血小板細胞が自己由来の血小板細胞である、請求項22〜28のいずれか一項に記載の方法。
- 血小板細胞と、
化学的リンカー部分と、
治療剤と、
を含む治療上有効量の組成物を、それを必要とする対象に投与することを含み、
前記治療剤が、前記化学的リンカー部分を介して前記血小板細胞に共有結合している、血管疾患を治療または予防する方法。 - 前記治療剤が免疫療法剤である、請求項31に記載の方法。
- 前記免疫療法剤が、抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体、またはこれらの組み合わせから選択される、請求項32に記載の方法。
- 前記免疫療法剤が抗PDL1抗体である、請求項33に記載の方法。
- 前記化学的リンカー部分が、マレイミドリンカー、PEGリンカー、PAS化、及びHES化から選択される、請求項31〜34のいずれか一項に記載の方法。
- 前記化学的リンカー部分がマレイミドリンカーである、請求項35に記載の方法。
- 前記血小板細胞がヒト血小板細胞である、請求項31〜36のいずれか一項に記載の方法。
- 前記血小板細胞が自己由来の血小板細胞である、請求項31〜36のいずれか一項に記載の方法。
- 前記血管疾患が、組織損傷、炎症、または心血管疾患である、請求項31〜38のいずれか一項に記載の方法。
- 前記組成物が、追加の治療剤と組み合わせて投与される、請求項31〜39のいずれか一項に記載の方法。
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US11073462B2 (en) | 2017-12-06 | 2021-07-27 | Lightintegra Technology Inc. | Non-activated platelet transfusion methods for enhancement of patient treatment outcomes |
CN112135639B (zh) * | 2018-04-06 | 2023-10-20 | 北卡罗莱纳州立大学 | 细胞组装介导的癌症免疫治疗检查点抑制剂的递送 |
WO2020006539A1 (en) * | 2018-06-29 | 2020-01-02 | Platelet Biogenesis, Inc. | Compositions for drug delivery and methods of use thereof |
AU2019321429B2 (en) * | 2018-08-15 | 2022-12-08 | Aiviva Biopharma, Inc. | Multi-kinase inhibitors of VEGF and TGF beta and uses thereof |
JP2022512658A (ja) * | 2018-10-10 | 2022-02-07 | ノース カロライナ ステート ユニバーシティ | Pd-l1提示血小板は、新たに発症する1型糖尿病を逆転させる |
US20230310504A1 (en) * | 2020-07-01 | 2023-10-05 | Cello Therapeutics, Inc. | Platelet membrane coated nanoparticles and uses thereof |
CN112826941A (zh) * | 2020-08-14 | 2021-05-25 | 南京邮电大学 | 一种用于递送蛋白药物的磁性血小板复合物的制备方法 |
CN112891317A (zh) * | 2021-02-05 | 2021-06-04 | 东南大学 | 一种血小板载药系统的制备方法 |
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US11730765B2 (en) | 2023-08-22 |
EP3512554A4 (en) | 2020-06-17 |
CA3036693A1 (en) | 2018-03-22 |
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WO2018053010A1 (en) | 2018-03-22 |
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KR20230109771A (ko) | 2023-07-20 |
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