JP2019504895A - スギ花粉エピトープを封入するtimp(組織性メタロプロテアーゼ阻害因子) - Google Patents
スギ花粉エピトープを封入するtimp(組織性メタロプロテアーゼ阻害因子) Download PDFInfo
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- 238000013518 transcription Methods 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical group OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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Abstract
【解決手段】
本発明は、スギ花粉に関連する1つ以上のエピトープを封入する負のゼータ電位を有する粒子を含む組成物を提供する。該粒子を投与することにより、スギ花粉に対する免疫学的寛容を誘導する方法も提供される。
【選択図】図1
Description
本出願は、参照によりその内容全体が本明細書に組み込まれる、2016年2月9日に出願された米国仮出願第62/293,261号の優先権を主張する。
本明細書とともに電子的に提出されるテキストファイルの内容は、参照によりそれらの全体が本明細書に組み込まれる:配列表のコンピュータ可読形式のコピー(ファイル名:COUR_014_02WO_SeqList_ST25.txt、記録日:2017年2月9日、ファイルサイズ:12キロバイト)。
MDNPIDSSWRGDSNWAQNRMKLADSAVGFGSSTMGGKGGDLYTVTNSDDDPVNPAPGTLRYGATRDRPLWIIFSGNMNIKLKMPMYIAGYKTFDGRGAQVYIGNGGPSVFIKRVSNVIIHGLHLYGSSTSVLGNVLINESFGVEPVHPQDGDALTLRTATNIWIDHNSFSNSSDGLVDVTLSSTGVTISNLFFNHHKVMLLGHDDAYSDDKSMKVTVAFNQFGPNSGQRMPRARYGLVHVANNYDPWTIYAIGGSSNPTILSEGNSFTAPNESYKKQVTIRIGSKTSSSSSNWVWQSTQDVFYNGAYFVSSGKYEGGNIYTKKEAFN(配列番号1)
VENGNATPQLTKNAGVLTSSLSKRCRKVEHSRHDAINIFNVEKYGAVGDGKHDSTEAFSTAWQAASKXPSAMLLVPGNKKFVVNNLFFNGPSQPHFTFKVDGIIAAYQNPASWI^NRIWLQFAKITGFTLMGKGVIDGQGKQWWAGQSKXVVNGREISNDRDRPTAIKFDFSTGLIIQGLKMNSPEFHLVFGNSEGVKIIGISITAPRDSPNTDGIDIFASKNFHLQKNTIGTGDDSVAIGTGSSNIVIEDLISGPGHGISIGSLGRENSRAEVSYVHVNGAKFIDTQNGLRIKTWQGGSGMASHIIYENVEMINSENPILINQFYSTSASASQNQRSAVQIQDVTYKNTIRGTSATAAAIQLKSSDSMPSKDIKLSDISLKLTSGKIASSL(配列番号2)
上述されるように、低濃度においても溶液の粘着性が高いままであるJCPを封入するという課題のために、スギ花粉症の治療においてスギ花粉(JCP)エキスを封入する粒子の使用には限界がある。二重エマルション−溶媒蒸発法を使用してJCPを封入するTIMP粒子(TIMP−JCPP)を調製する実験を行った(図2C)。要約すると、試験されるJCPエキスのバッチに応じて、200μLの5mg/mLのJCP溶液を、DCM中の0.5mLの20%w/vのPLGAに付加するか、または400μLの5mg/mLのJCP溶液を、DCM中の1.0mLの20%w/vのPLGAに付加した。超音波処理により各溶液を乳化して、一次エマルションを生成した。次いで、PEMA溶液(10mLの1%w/vの水性PEMA)を、そのエマルションに付加し、超音波処理により再乳化して、二次エマルションを生成した。掻き混ぜながら、エマルションを200mLの0.5%w/vの水性PEMAに注ぎ入れた。粒子を精製し、凍結乾燥させ、後で使用するために−20度で保存した。DMSO中で粒子を溶解することにより、前述されるように粒子の抗原用量を判定した後にCBQCA分析を行った。Zetasizer Nano ZSP(Malvern Instruments,Westborough,MA)で、動的光散乱法を使用して、水中のナノ粒径及びゼータ電位を測定した。ロット放出基準は、700nm±250nmのTIMP−JCPPの直径を必要とし、少なくとも−30mVで荷電し、少なくとも5μgの抗原/1mgのPLGAを含有する。粒子製作のための条件及びJCP封入の結果を図4に示す。
吸入アレルゲンに対する急性アレルギー性応答を有するマウスモデルは、喘息における免疫学的及び炎症応答の根本的な原因となる機構を解明するため、かつアレルギー性炎症を制御するための新規の標的の同定及び調査のために広く使用されている。
アレルギー性気道炎症モデル
マウスを、ミョウバン(3mg)中の大量のスギ花粉アレルゲンである、2回分の用量の10μgのCRYJ1及びCRYJ2、またはミョウバン及びPBSのみを用いて腹腔内(i.p.)免疫付与する。次いで、マウスを3日間連続で20分間エアロゾル化CRYJ1及びCRYJ2(10mg/ml)で抗原投与した後に組織を収集した。
肺を1mLの気管支肺胞洗浄流体(BALF、1mMのEDTA及びPBS中10%のFBS)で流す。細胞の総数を判定し、試料をスライド上にサイトスパンし、分別細胞数に関して、DiffQuik(Siemens,Newark,DE)で染色する。
肺を収集し、ホルマリン固定し、パラフィンに加工する。パラフィン切片をヘマトキシリン及びエオシン(H&E)または過ヨウ素酸シッフ(PAS)で染色する。
屠殺後、血清をマウスから収集し、CRYJ1/2特異的IgEをサンドイッチELISAにより定量化する。捕捉抗体として抗マウスIgE(BD Biosciences)を使用し、二次試薬としてビオチン化CRYJ1/2(Pierce[Rockford,IL]のEZ−Link Sulfo−NHS−LC−Biotinキットを使用して調製する)を使用する。精製されたマウスCRYJ1/2−IgEを使用して生成される標準的な曲線によりCRYJ1/2−IgEの量を判定する。
IL−4、IL−5、IL−13、IL−10、IL−17、及びIFNγに関して、磁気Milliplex MAPマルチプレックスアッセイ(Millipore,Billerica,MA)により、BAL流体及び再応答培養物からの上清(48時間の時点で収集)をアッセイする。
精製されたスギ花粉エキスは、日本気象庁(Japanese Aerology Society)を供給源とする。さらに、前述されるように組み換えスギ花粉抗原を製造する(Fujimura T,Int.Arch.Allergy Immunol.2015;168(1):32−43)。JCP中の免疫優勢エピトープのアミノ酸配列は、CRYJ1(受託番号AB081309、配列番号1)及びCRYJ2(受託番号AB211810、配列番号2)である。
上述されるように、組み換えJCP抗原をTIMP中に封入する。JCPアレルギーのマウスモデルにおける効能試験のために、200mgのTIMP−CRYJ1及び/またはCRYJ2(TIMP−JCP(登録商標))、ならびに200mgのTIMP−OVA対照を使用する。5〜10匹のマウスの6つの群を、1回分の用量(群1〜3)または2回分の用量(群3〜6)のレジメンのいずれかを与えて、TIMP−OVAまたはTIMP−JCP(登録商標)で処置する。動物をJCP抗原に感作させる(TIMP処置の前または後のいずれか)。28及び29日目に、気道抗原投与を行い、以下に記載される一次読み出し及び成功測定尺度を使用して処置の効能を判定する。群7のマウスをJCPの代わりにOVAで抗原投与して、これらのマウスをOVAに感作させ、陽性アレルギー対照として使用することを留意されたい。
表5に示されるように、5〜10匹のマウスの6つの群を、1回分の用量(群1〜3)または2回分の用量(群4〜6)のレジメンのいずれかを与えて、TIMP−OVAまたはTIMP−JCP(登録商標)で処置する。次いで、動物をJCP抗原に感作させる。28及び29日目に、気道抗原投与を行い、以下に記載される一次読み出し及び成功測定尺度を使用して処置の効能を判定する。群7のマウスをJCPの代わりにOVAで抗原投与して、これらのマウスをOVAに感作させ、陽性アレルギー対照として使用することを留意されたい。
以下の表6に示されるように、JCPに感作させた後に6つの群のマウスをTIMP−JCP(登録商標)またはTIMP−OVAで処置する。2回分の用量レジメンを試験する。これは、1回分のTIMP用量レジメン(群1〜3)及び2回分の用量レジメン(群4〜6)を含み、7日間の間分ける。28及び29日目に、空気抗原投与を行い、以下に記載される一次読み出し及び成功測定尺度を使用して処置の効能を判定する。
感作前にTIMP−JCP(登録商標)処置を受けたマウスにおける一次読み出し及び成功測定尺度を測定する。TIMP−JCP(登録商標)で処置したマウスは、空気抗原投与後に、ベースライン温度と比較して温度変化を有さない。TIMP−JCP(登録商標)で処置したマウスにおいて、ベースライン測定尺度と比較して血液好酸球及びマスト細胞の数に変化がない。TIMP−JCP(登録商標)で処置したマウスは、JCPに感作させてTIMP−OVAで処置したマウスと比較してJCP特異的IgEを著しく低減した。TIMP−JCP(登録商標)で処置したマウスは、JCPに感作させたTIMP−OVAで処置したマウスと比較して全身性IL−4、IL−5、及びIL−13も著しく低減した。TIMP−JCP(登録商標)で処置したマウスをTIMP−OVAで処置したマウスと比較する。
定量的高密度スギ花粉に曝露された日本人季節アレルギー鼻炎(SAR)患者の単一施設の非盲検のプラセボ対照研究においてTIMP−JCPの効能及び安全性を評価するための臨床研究を行う。
環境性曝露ユニットを使用して、スギ花粉にアレルギーを持つ患者におけるTIMP−JCPの安全性及び効能を判定する。多くの環境性曝露ユニット(EEU)が存在するが、この研究は、和歌山県にある日本健康支援ネットワークユニットと協同で行われる。従来の手法の多くの制限にとらわれず、EEUにより、精密な対照研究が計画され、実行することができる(同様の研究計画は、Enomoto,et al.,2009により記載されている)。以下のダイヤグラムは、投薬及び事象スケジュールを概説する。
臨床研究において合計25人の対象が存在する。5人の対象をプラセボで治療する。20人の対象をTIMP−JCPで治療する。
組入れ基準:
・SARを有する日本人患者。
・少なくとも2年のスギ花粉症の症状の既往歴を有する患者。
・陽性IgE(スギ花粉抗原に対して):スクリーニング曝露試験当日より1.5年前以内に蛍光酵素免疫アッセイ(FEIA)または化学発光性酵素免疫アッセイ(CLEIA)により判定される。
・スクリーニング曝露の開始90〜150分後の少なくとも1つの評定ポイントで、8以上のTNSS及び2(中程度)以上の鼻詰まりスコアを有する患者。(TNSS)及び鼻詰まりスコアは、基準を満たす場合)、任意の他の評定ポイントの時点のものであってもよい。・年齢≧20かつ≦65歳(性別不問)。
・告知に基づく同意書にサインした患者。
・通年性アレルギー性鼻炎の症状を有する患者。
・重篤な喘息、気管支拡張症、重篤な肝機能不全、腎機能不全、または心機能不全、血液病、内分泌疾患、及び他の重症な合併症を有する患者。
・TIMP−JCPの効能の判断を妨害し得る鼻疾患(肥厚性鼻炎、副鼻腔炎、鼻ポリープ、鼻中隔湾曲症など)または眼疾患を有する患者。
・治療曝露の当日、上気道炎及び/または下気道炎(風邪などの存在下の急性鼻炎、慢性鼻炎、欝血性鼻炎、萎縮性鼻炎、化膿性鼻汁、副鼻腔炎)のエビデンスを有する患者。
・TIMP−JCPの評価に影響を与え得る以下の薬剤(抗競合物質剤(anti−contestant)及び免疫修飾剤を含む)のいずれかを摂取している患者。
・抗アレルギー性薬物、抗ヒスタミン剤(H1及びH2遮断薬:経口投与、点鼻薬、点眼薬、注射、及び局所使用)、抗コリン作用薬、血管収縮点鼻薬、抗ヒスタミン含有風邪薬、抗アレルギー性効果/抗ヒスタミン性効果を有することが期待され得る薬剤(漢方薬及びグリチルリチンを含む)、及びアレルギー性症状(くしゃみ、鼻漏、鼻詰まり、及び眼の痒みなど)に適応される他の薬剤。
・ステロイド(経口用、吸入用、点鼻薬、点眼薬、または局所使用)、免疫抑制剤(経口用、局所使用、または注射用)、アゾール殺菌剤、及びヒスタミン含有ガンマグロブリン調製物。
・アゾール殺菌剤、マクロライド系抗生物質、及び水酸化アルミニウム/水酸化マグネシウムを含有する調製物。
・デポーステロイド調製物。
・ステロイド注射
・特定の減感作に対する維持療法を受けた患者または非特定の代替的な療法を受けた患者。
・別の研究に参加している患者または告知に基づく同意より6ヶ月前以内に別の研究に以前参加したことがある患者。
・調査員/副調査員により、いずれの他の基準に関してもこの研究への参加が不適当であると見なされる患者。
・抗ヒスタミン剤または抗ヒスタミン薬剤(フェキソフェナジンHCIが含まれる)、及び塩酸プソイドエフェドリンに対する過敏症の既往歴を有する患者。
・別の研究に参加している患者またはスクリーニング曝露試験当日より6ヶ月前以内に別の研究に以前参加したことがある患者。
・妊娠しているか、妊娠の可能性があるか、または現在授乳中の女性。
a)1つ以上の予想外の薬物に関連する重症有害事象(SAE)がデータ安全性モニタリング委員会に報告された場合。
b)研究薬物に明白に関係していない過剰及び/または予想外の有害事象。
c)予想外の患者の死亡(複数可)。
薬物:TIMP−JCP、ポリ(乳酸−コ−グリコール酸)免疫寛容原性免疫修飾
安全性:
・AE及び特別な目的のAEの発症及び重篤性(過敏症及び免疫媒介性反応の標準的な報告基準を含む)。
・バイタルサイン(腋窩温、座った状態での血圧、及び座った状態での脈拍数)
・標準的な研究室評価
・12誘導ECG研究室試験(血液学、生化学作用、及び尿分析)
・スギ花粉に関するプリック試験
・抗体及びヒスタミン放出試験により生じたパラメータ。
・抗体:IgG抗体、特異的IgG抗体(抗JCP、抗CRYJ1、及び抗CRYJ2)、特異的IgG4抗体(抗JCP)、IgE抗体、特異的IgE抗体(抗JCP)
・サイトカイン(IFN−ガンマ、IL−4、IL−5、IL−10、IL−12、及びIL−13)
・免疫細胞表現型(Tレグ、エフェクターT細胞、及び単球)
・スギ花粉に対する末梢性B及びT細胞応答。
・TSSの変化、各症状スコアの変化、鼻汁の量、くしゃみの数、及び患者の印象。
・鼻汁の量:患者が鼻をかんだ後のティッシュペーパーの重量を1時間毎に測定する。鼻をかむ前の重量との差を鼻汁の量として計算する。
・くしゃみの数:患者自身で1時間毎のくしゃみの数を記録する。
・研究薬物投与の間、少数採取計画において毎日測定されるTIMP−JCPの血清濃度。
Claims (55)
- スギ花粉由来の1つ以上の封入抗原エピトープを含む生分解性粒子を含む組成物であって、前記生分解性粒子が負のゼータ電位を有する、組成物。
- 前記生分解性粒子が、ポリ(ラクチド−コ−グリコリド)(PLG)を含む、請求項1に記載の組成物。
- 前記生分解性粒子が、約50:50のポリ乳酸:ポリグリコール酸のコポリマー比を有するPLGを含む、請求項1または2に記載の組成物。
- 前記生分解性粒子の表面が、カルボキシル化されている、請求項1〜3のいずれかに記載の組成物。
- 前記カルボキシル化が、ポリ(エチレン−alt−無水マレイン酸)(PEMA)、ポリ(アクリル酸)、またはデオキシコール酸ナトリウムを使用することにより達成される、請求項4に記載の組成物。
- 前記生分解性粒子が、約−100mV〜約0mVのゼータ電位を有する、請求項1〜5のいずれかに記載の組成物。
- 前記生分解性粒子が、約−50mV〜約−40mVのゼータ電位を有する、請求項1〜6のいずれかに記載の組成物。
- 前記生分解性粒子が、約−75mV〜約−50mVのゼータ電位を有する、請求項1〜7のいずれかに記載の組成物。
- 前記生分解性粒子が、約−50mVのゼータ電位を有する、請求項1〜8のいずれかに記載の組成物。
- 前記生分解性粒子が、約−30mVのゼータ電位を有する、請求項1〜9のいずれかに記載の組成物。
- 前記生分解性粒子が、約−40mVのゼータ電位を有する、請求項1〜10のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.1μm〜約10μmの直径を有する、請求項1〜11のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.3μm〜約5μmの直径を有する、請求項1〜12のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.5μm〜約3μmの直径を有する、請求項1〜13のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.5μm〜約1μmの直径を有する、請求項1〜14のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.2μm〜約0.7μmの直径を有する、請求項1〜15のいずれかに記載の組成物。
- 前記生分解性粒子が、約0.7μmの直径を有する、請求項16に記載の組成物。
- 前記生分解性粒子が、約0.5μmの直径を有する、請求項16に記載の組成物。
- スギ花粉由来の前記1つ以上の封入抗原エピトープが、CRYJ1、またはその断片もしくは変異体を含む、請求項1〜18のいずれかに記載の組成物。
- CRYJ1が、配列番号1のアミノ酸配列を有する、請求項19に記載の組成物。
- 前記CRYJ1の断片が、配列番号1に対して少なくとも90%の配列同一性を有する少なくとも10、少なくとも20、少なくとも30、少なくとも40、または少なくとも50個の連続アミノ酸を含む、請求項20に記載の組成物。
- 前記CRYJ1の変異体が、配列番号1に対して少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、少なくとも98%、または少なくとも99%の配列同一性を有するアミノ酸配列を有する、請求項20に記載の組成物。
- 前記CRYJ1の断片が、p16−30、p81−95、p106−120、p111−125、p211−225、及びp301−315からなる群から選択される、請求項20に記載の組成物。
- スギ花粉由来の前記1つ以上の封入抗原エピトープが、CRYJ2、またはその断片もしくは変異体を含む、請求項1〜23のいずれかに記載の組成物。
- CRYJ2が、配列番号2のアミノ酸配列を有する、請求項24に記載の組成物。
- 前記CRYJ2の断片が、配列番号2に対して少なくとも90%の配列同一性を有する少なくとも10、少なくとも20、少なくとも30、少なくとも40、または少なくとも50個の連続アミノ酸を含む、請求項25に記載の組成物。
- 前記CRYJ2の変異体が、配列番号2に対して少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、少なくとも98%、または少なくとも99%の配列同一性を有するアミノ酸配列を有する、請求項25に記載の組成物。
- 前記CRYJ2の断片が、p66−80、p81−95、p141−155、p186−200、p236−250、p346−360、p351−365、及びp336−350からなる群から選択される、請求項25に記載の組成物。
- 前記生分解性粒子が、1μg/mg〜15μg/mgの抗原対ポリマー比を含む、請求項1〜28のいずれかに記載の組成物。
- 前記生分解性粒子が、5μg/mg〜15μg/mgの抗原対ポリマー比を含む、請求項29に記載の組成物。
- 前記生分解性粒子が、少なくとも約5μg/mgの抗原対ポリマー比を含む、請求項1〜30のいずれかに記載の組成物。
- 前記生分解性粒子が、スギ花粉タンパク質由来の2つ以上の封入抗原エピトープを含む、請求項1〜31のいずれかに記載の組成物。
- 前記2つ以上の封入エピトープが、融合タンパク質中に含有され、前記融合タンパク質中の前記2つ以上の封入エピトープが切断可能リンカーにより分離される、請求項32に記載の組成物。
- 前記切断可能リンカーのアミノ酸配列が、細胞のファゴリソソーム内に位置するプロテアーゼ及び/または前記細胞のサイトゾル内に位置するプロテアーゼにより切断可能である、請求項33に記載の組成物。
- 前記切断可能リンカーのアミノ酸配列が、細胞のファゴリソソーム内に位置するプロテアーゼ及び前記細胞のサイトゾル内に位置するプロテアーゼにより切断可能である、請求項34に記載の組成物。
- 前記切断可能リンカーが、フューリン感受性リンカーまたはカテプシン感受性リンカー、請求項34または35に記載の組成物。
- 前記切断可能リンカーが、フューリン感受性リンカーである、請求項34〜36のいずれかに記載の組成物。
- 前記切断可能リンカーが、カテプシン感受性リンカーである、請求項34〜36のいずれかに記載の組成物。
- 前記カテプシン感受性リンカーが、カテプシンA、カテプシンB、カテプシンC、カテプシンD、カテプシンE、カテプシンF、カテプシンG、カテプシンH、カテプシンK、カテプシンL、カテプシンO、カテプシンW、及び/またはカテプシンZのうちの1つ以上による切断に対して感受性がある、請求項38に記載の組成物。
- 前記リンカーのアミノ酸配列が、Gly−Ala−Val−Val−Arg−Gly−Ala(配列番号3)である、請求項34に記載の組成物。
- スギ花粉由来の前記1つ以上の封入抗原エピトープが、前記生分解性粒子に共有結合されている、請求項1〜40のいずれかに記載の組成物。
- スギ花粉由来の前記1つ以上の封入抗原エピトープが、コンジュゲート分子により前記生分解性粒子に共有結合されている、請求項41に記載の組成物。
- 前記コンジュゲート分子が、カルボジイミド化合物を含む、請求項42に記載の組成物。
- 前記カルボジイミド化合物が、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDC)を含む、請求項43に記載の組成物。
- スギ花粉由来の1つ以上の封入抗原エピトープを含む生分解性粒子を含む組成物であって、前記生分解性粒子が、少なくとも約−30mVの負のゼータ電位、約0.7μmの直径、及び少なくとも約5μg/mgの抗原対ポリマー比を有する、組成物。
- 請求項1〜45のいずれかに記載の生分解性粒子を含む、薬学的組成物。
- 薬学的に許容される担体をさらに含む、請求項46に記載の薬学的組成物。
- 薬学的に許容される賦形剤をさらに含む、請求項47に記載の薬学的組成物。
- 請求項1〜45のいずれかに記載の生分解性粒子を含む、凍結乾燥組成物。
- 対象においてスギ花粉に対する抗原特異的寛容を誘導する方法であって、請求項46〜49のいずれかに記載の薬学的組成物の有効量を前記対象に投与することを含む、方法。
- 治療を必要とする対象におけるスギ花粉アレルギーの治療のための方法であって、請求項46〜49のいずれかに記載の薬学的組成物を投与することを含む、方法。
- 予防を必要とする対象におけるスギ花粉アレルギーの予防のための方法であって、請求項46〜49のいずれかに記載の薬学的組成物を投与することを含む、方法。
- 対象においてスギ花粉に対する抗原特異的寛容を誘導する方法であって、請求項49に記載の凍結乾燥粒子を戻して、戻された薬学的組成物を得、前記戻された薬学的組成物を前記対象に投与することを含む、方法。
- 治療を必要とする対象におけるスギ花粉アレルギーの治療のための方法であって、請求項49に記載の凍結乾燥粒子を戻して、戻された薬学的組成物を得、前記戻された薬学的組成物を前記対象に投与することを含む、方法。
- 予防を必要とする対象におけるスギ花粉アレルギーの予防のための方法であって、請求項49に記載の凍結乾燥粒子を戻して、戻された薬学的組成物を得、前記戻された薬学的組成物を前記対象に投与することを含む、方法。
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US9517257B2 (en) | 2010-08-10 | 2016-12-13 | Ecole Polytechnique Federale De Lausanne (Epfl) | Erythrocyte-binding therapeutics |
US9850296B2 (en) | 2010-08-10 | 2017-12-26 | Ecole Polytechnique Federale De Lausanne (Epfl) | Erythrocyte-binding therapeutics |
AU2011289579B2 (en) | 2010-08-10 | 2016-11-17 | Ecole Polytechnique Federale De Lausanne | Erythrocyte-binding therapeutics |
EP2841098A4 (en) | 2012-04-23 | 2016-03-02 | Allertein Therapeutics Llc | NANOPARTICLES FOR THE TREATMENT OF ALLERGIES |
MX2015013894A (es) | 2013-04-03 | 2015-12-11 | Allertein Therapeutics Llc | Composiciones de nanoparticulas novedosas. |
US10953101B2 (en) | 2014-02-21 | 2021-03-23 | École Polytechnique Fédérale De Lausanne (Epfl) | Glycotargeting therapeutics |
SG10202010936RA (en) | 2014-02-21 | 2020-12-30 | Ecole Polytecnique Fed De Lausanne Epfl Epfl Tto | Glycotargeting therapeutics |
US10046056B2 (en) | 2014-02-21 | 2018-08-14 | École Polytechnique Fédérale De Lausanne (Epfl) | Glycotargeting therapeutics |
US10946079B2 (en) | 2014-02-21 | 2021-03-16 | Ecole Polytechnique Federale De Lausanne | Glycotargeting therapeutics |
EP3400069A4 (en) * | 2016-01-04 | 2019-09-25 | Cour Pharmaceuticals Development Company Inc. | Particles for the Encapsulation of Fusion Proteins with Bundled Epitopes |
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WO2015023796A2 (en) * | 2013-08-13 | 2015-02-19 | Shea Lonnie D | Peptide conjugated particles |
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WO2015023796A2 (en) * | 2013-08-13 | 2015-02-19 | Shea Lonnie D | Peptide conjugated particles |
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EUROPEAN JOURNAL OF IMMUNOLOGY, 19 AUG 2016, VOL.46, ISSUE S1, ABSTRACT NO. 2138, JPN6021003925, ISSN: 0004440080 * |
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