JP4762132B2 - サポシンc−dops:新規抗腫瘍剤 - Google Patents
サポシンc−dops:新規抗腫瘍剤 Download PDFInfo
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- JP4762132B2 JP4762132B2 JP2006507237A JP2006507237A JP4762132B2 JP 4762132 B2 JP4762132 B2 JP 4762132B2 JP 2006507237 A JP2006507237 A JP 2006507237A JP 2006507237 A JP2006507237 A JP 2006507237A JP 4762132 B2 JP4762132 B2 JP 4762132B2
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Description
本出願は、2003年4月28日に出願された米国仮特許出願第60/466,166号、及び2004年3月16日に出願された米国非仮特許出願第10/ ,
号(代理人整理番号CHM08−GN003)(これらは、それらの全体が参照されて本明細書中の一部とする)に対する優先権及びの有益性を主張する。
本発明は、助成番号R01DK57690の下、政府支援を受けて行われた。米国政府は、本発明においてある特定の権利を有する。
小さな(およそ80個のアミノ酸)熱安定性糖タンパク質のファミリーであるサポシンは、スフィンゴ糖脂質の代謝経路における幾つかのリソソーム酵素のin vivoでの加水分解活性に必須である(グラボウスキー他(Grabowski et al.)(1990年) Crit.Rev.Biochem.Mol.Biol.第25巻:385〜414ページ、フルスト他(Furst et al.)(1992年)Biochim.Biophys.Acta.第1126巻:1〜16ページ、キシモト他(Kishimoto et al.)(1992年)J.Lipid Res.第33巻:1255〜1267ページを参照)。サポシンファミリーの4つの成員(A、B、C及びD)は、単一の前駆体タンパク質であるプロサポシンからタンパク質分解的に加水分解される(フジバヤシ他(Fujibayashi et al.)(1985年)Am.J.Hum.Genet.第37巻:741〜748ページ、オー’ブリエン他(O’Brien et al.)(1988年)Science 第241巻:1098〜1101ページ、ローマン他(Rorman et al.)(1989年)Genomics 第5巻:486〜492ページ、ナカノ他(Nakano et al.)(1989年)J.Biochem.(東京)第105巻:152〜154ページ、レイナー他(Reiner et al.)(1989年)J.Mol.Neurosci.第1巻:225〜233ページ(参照されて本明細書の一部とする)を参照)。サポシンA、B、C及びDに関する完全アミノ酸配列、並びにプロサポシンのゲノム機構及びcDNA配列が報告されている(フジバヤシ他(Fujibayashi et al.)(1985年)Am.J.Hum.Genet.第37巻:741〜748ページ、オー’ブリエン他(O’Brien et al.)(1988年)Science 第241巻:1098〜1101ページ、ローマン他(Rorman et al.)(1989年)Genomics 第5巻:486〜492ページを参照)。
原形質膜の内葉及び外葉の構成成分の分布を調節するための組成物及び方法が提供される。本発明の作用物質が、内葉構成成分及びプロサポシン関連ポリペプチドを含む。「内葉構成成分」とは、細胞、特に動物細胞、より詳細には哺乳類細胞の原形質膜の内葉において天然に存在する任意の分子又はその構造的類似体を意図する。ある実施形態では、内葉構成成分は、ホスファチジルセリン又はその構造的類似体、例えばジオレオイルホスファチジルセリン(DOPS)である。プロサポシンのアミノ酸配列は、配列表において配列番号1に記載される。プロサポシン関連ポリペプチドは、配列番号1に記載のアミノ酸配列又はそのフラグメントに対して少なくても80%同一性を共有し、原形質膜親和性を保持する。ある実施形態では、プロサポシン関連ポリペプチドは、サポシンC(配列表の配列番号2)又はサポシンC関連ポリペプチドである。サポシンC関連ポリペプチドは、配列番号2に記載のアミノ酸配列に対して少なくとも80%同一性を共有し、原形質膜親和性を保持する。本発明の作用物質におけるポリペプチド対内葉構成成分のモル比は、約1:1〜約1:50、好ましくは約1:1〜約1:25、より好ましくは約1:1〜約1:10の範囲であり、さらに好ましくは約1:7又は約1:3である。ある実施形態では、本発明の作用物質は、医薬的に許容可能なキャリアをさらに含む。本発明の作用物質は、細胞死、例えばアポトーシスによる細胞死を促進する。ある実施形態では、作用物質は、腫瘍細胞及び癌細胞のような(しかし、これらに限定されない)過剰増殖性細胞において、アポトーシスを優先的に誘導する。したがって、本発明のある実施形態では、作用物質は、抗腫瘍剤である。本発明のある態様では、作用物質は、肉腫細胞、神経芽腫細胞及び扁平上皮癌細胞のような(しかし、これらに限定されない)癌細胞において、アポトーシスを優先的に誘導する。
本発明は、原形質膜における内葉構成成分の分布を調節するための組成物及び方法に関する。さらに、本発明は、過剰増殖細胞、特に過剰増殖細胞を包含する障害(disorder)、より詳細には腫瘍及び癌(例えば、扁平上皮癌及びリンパ腫)を調節するための組成物及び方法に関する。上記組成物は、プロサポシン関連ポリペプチド、特にサポシンC、及び内葉構成成分、特にホスファチジルセリン又はその構造的類似体、より詳細にはジオレオイルホスファチジルセリン(DOPS)を有する作用物質を含む。これらの2つの化合物の組み合わせは、抗腫瘍活性を示し、したがって抗腫瘍剤と称される。「抗腫瘍活性」とは、細胞増殖の速度の減少、したがって既存の腫瘍の成長速度又は療法中に出現する腫瘍の減退、及び/又は既存の新生(腫瘍)細胞又は新たに形成される新生細胞の崩壊、したがって療法中の腫瘍の全体的な大きさの減少を意図する。サポシンC(又はプロサポシン関連ポリペプチド)及びDOPS(又は内葉構成成分)の組み合わせによる処置は、原形質膜における内葉構成成分の分布を調節する生理学的応答を引き起こす。
実施例1.組換えサポシンCの精製
pET系を含むイソプロピル−1−チオ−β−D−ガラクトピラノシドを使用することにより、組換えサポシンCをE.コリ(E.coli)において過剰発現させた(キ他(Qi et al.)(1994年) J.Biol.Chem.第269巻:16746〜16753ページ、その全体が参照されて本明細書の一部とする)。Hisタグを有する発現されたポリペプチドをニッケルカラムから溶出させた。透析後、以下のようにHPLCクロマトグラフィにより、ポリペプチドをさらに精製した。C4逆相カラムを、0.1%トリフルオロ酢酸(TFA)で10分間平衡化させた。アセトニトリル中0.1%TFAの直線的(0〜100%)濃度勾配で60分かけて、タンパク質を溶出させた。主要なタンパク質ピークを収集して、凍結乾燥させた。これまでに記載されるように、タンパク質濃度を決定した(キ他(Qi et al.)(1994年) J.Biol.Chem.第269巻:16746〜16753ページ)。
ジオレオイルホスファチジルセリン(DOPS)は、アバンティポーラーリピズ(Avanti Polar Lipids)(アラバマ州アラバスター)から入手した。クロロホルム中のDOPS 20〜30モルをN2及び真空下で脂質フィルムへと乾燥させた。サポシンCポリペプチド5〜10μモルを乾燥させたフィルムへ添加して、McIlvanine緩衝液(pH4.7)50μl中に懸濁させた。次に、細胞培地又はリン酸緩衝生理食塩水(PBS)のいずれかを用いて、懸濁液を1ml容量とした(アウシュベル他(Ausubel et al.)(2002年) Current Protocols in Molecular Biology.ジョンウィリー&サンズ(John Wiley&Sons)、ニューヨーク州ニューヨーク、参照されて本明細書の一部とする)。混合物をおよそ20分間、浴槽ソニケーター中で超音波処理した。サンプルが過熱するのを防ぐのに必要である場合、氷を添加した。
扁平上皮癌(SCC)細胞及びL5178Y細胞を、10%FBAを補充したDEME培地(ギブコ(Gibco))中で培養した。正常な不死化ケラチノサイト(NIK)細胞を50%カスケード培地154(カスケードバイオロジクス(Cascade Biologics)及び50%ケラチノサイト−SFM培地(ギブコ(Gibco))中で成長させた。
扁平上皮癌(SCC)細胞及び対照(NIK細胞)を本明細書中で別の箇所に記載する培地中で成長させた。SCCは、ヒト皮膚ケラチノサイト中で多段階プロセスにより発生すると示唆されているため、NIKを対照として使用した(クボ他(Kubo et al.)(2002年) J.Med.Invest.第49巻:111〜117ページ)。NIK及びSCC細胞の確立されたプレートから、培地を除去した。処理、サポシンC、DOPSを含有しない培地、又は8μMサポシンC+26μM DOPSを含有する培地を、NIK及びSCC細胞の確立されたプレートへ添加した。処理の48〜72時間後に細胞を検査した。1つのかかる実験からの結果を図1に示す。
組織培養プレートにマウスL5178Y−Rリンパ腫細胞を播種した。培養物の確立後、培地を除去して、細胞を洗浄した。薬物を補充しないか、60μM DOPS、20μMサポシンC、又は10μMサポシンC及び30μM DOPSを補充したDEME+10%FBAで細胞を覆った。培養物を24〜48時間インキュベートした。インキュベーション期間後に、培養物を検査した。1つのかかる実験からの結果を図2に示す。
研究室マウスの配慮を統治するシンシナシティチルドレンズリサーチファウンデーション(Cincinnati Children’s Research Foundation)ガイドラインに従って、ヌードマウスを維持した。5匹のヌードマウスの2つの群に、2×106個のSCCを背部の上部に皮下注射して、腫瘍成長を開始させた。2つの腫瘍が各マウスに確立された。腫瘍を21日間確立させた。21日目に、動物に腫瘍部位でPBS希釈剤単独又はサポシンC(10mg/kg(体重))及びDOPS(2mg/kg(体重))を含む作用物質のいずれかの皮下注射を施した。27日目に、動物に腫瘍部位でPBS希釈剤単独又はサポシンC(10mg/kg(体重))及びDOPS(2mg/kg(体重))を含む作用物質のいずれかの第2の皮下注射を施した。カリパスで隔日に腫瘍サイズを測定し、式V=(π/4)LW2に従って、容積を推定した。1つのかかる実験から得られる結果を図3のパネルAに示す。
当該技術分野で既知の方法により、SCC腫瘍を用いて、マウス異種移植片を調製した。蛍光標識ニトロベンズオキサジアゾール(NBD)をホスファチジルセリンに連結させて、NBD−PS及びDOPSの混合物を調製した。NBD−DOPSを用いて、蛍光標識されたNBD−PS/DOPS/サポシンC複合体を調製した。NBD−PS/DOPSをNBD−PS 0.1mg/kg(体重)及びDOPS 2mg/kg(体重)で腫瘍に注射した。NBD−PS/DOPS/サポシンCをNBD−PS 0.1mg/kg(体重)、DOPS 2mg/kg(体重)及びサポシンC 10mg/kg(体重)で腫瘍に注射した。作用物質の投与の24時間後に、腫瘍を収集した。腫瘍の検鏡試片を蛍光に関して検査した。かかる実験からの結果を図4に示す。
ヒト癌組織及び健常組織由来の細胞を、細胞系に適した培地中で成長させた。以下の癌組織及び健常組織細胞系由来の細胞を分析した:乳癌:MCF−7、ドミナントネガティブなカスパーゼ9でトランスフェクトしたMCF−7、ベクター対照でトランスフェクトしたMCF−7、BT−549;頭部及び頸部:SCC−25、FaDu;黒色腫:MeWo、Sk−Mel−28;白血病:K−562、HL60;子宮頸癌:Hela;卵巣癌:PA1、ドミナントネガティブなカスパーゼ9でトランスフェクトしたPA1、PA1−E6;SK−OV3;前立腺癌:DU145、PC3;神経芽細胞腫:SK−N−SH、SK−SY−5Y、CHLA−79;ユーイング肉腫:5838;T細胞リンパ腫;Rodu T;GCT;肺癌:A549、H441;肝臓癌:HepG2;健常胸部:MCF−10A及び健常ケラチノサイト:NIK。96−ウェル平底組織培養プレート(ファルコン、ベクトン・ディクソンラブウェア(Falcon,Becton-Dickson Labware)、ニュージャージー州フランクリン)に、ウェル1つ当たり104個の細胞の密度で細胞を播種した。本発明の作用物質あり又はなしで、細胞を完全培地中で平板培養した。
モル比1:7、1:3及び1:10でのサポシンC及びDOPSの混合物を調製した。サポシンCタンパク質の様々なフラグメントから構成されるポリペプチドを、これまでに記載されるように調製した(ワング他(Wang et al.)(2003年) Arch.Biochem.&Biophys.第415巻:45〜53ページ、その全体が参照されて本明細書の一部とする)。突然変異サポシンCポリペプチドは、以下の通りである:HNSCは、アミノ酸残基1〜40から構成され、H1は、残基4〜20から構成され、H−2は、アミノ酸残基24〜40から構成される。
研究室マウスの配慮を統治するシンシナシティチルドレンズリサーチファウンデーション(Cincinnati Children’s Research Foundation)ガイドラインに従って、ヌードマウスを維持した。マウスに、2×106個のSCCを背部の上部に皮下注射して、腫瘍成長を開始させた。腫瘍を確立させた。動物を、DOPS(2mg/kg(体重))又はサポシンC(10mg/kg(体重))及びDOPS(2mg/kg(体重))を含む作用物質のいずれかで、動物を処理した。処理を施した48時間後に、腫瘍を収集した。
Claims (37)
- 内葉構成成分及びプロサポシン関連ポリペプチドを含む医薬組成物であって、前記内葉構成成分はジオレオイルホスファチジルセリンであり、前記ポリペプチドは配列番号2に記載するアミノ酸配列を有する、医薬組成物。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:50の範囲である、請求項1に記載の医薬組成物。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:10の範囲である、請求項1に記載の医薬組成物。
- 医薬的に許容可能なキャリアをさらに含む、請求項1に記載の医薬組成物。
- 前記医薬組成物は、過剰増殖性細胞において細胞死を促進する、請求項1に記載の医薬組成物。
- 前記過剰増殖性細胞は、腫瘍細胞及び癌細胞からなる群から選択される、請求項5に記載の医薬組成物。
- 動物の細胞の原形質膜における内葉構成成分の分布を調節するための組成物を調製するための、(i)内葉構成成分及び(ii)プロサポシン関連ポリペプチドの使用であって、前記内葉構成成分はジオレオイルホスファチジルセリンであり、前記ポリペプチドは配列番号2に記載するアミノ酸配列を有する、前記使用。
- 前記原形質膜の外葉における前記内葉構成成分の分布が変更される、請求項7に記載の使用。
- 前記外葉における前記内葉構成成分の濃度が増加される、請求項8に記載の使用。
- 前記内葉構成成分の分布は、過剰増殖性細胞において調節される、請求項7に記載の使用。
- 前記過剰増殖性細胞は、腫瘍細胞及び癌細胞からなる群から選択される、請求項10に記載の使用。
- 前記使用は細胞死を促進する、請求項7に記載の使用。
- 動物における腫瘍容積を調節するための組成物を調製するための(i)内葉構成成分及び(ii)プロサポシン関連ポリペプチドの使用であって、前記内葉構成成分はジオレオイルホスファチジルセリンであり、前記ポリペプチドは配列番号2に記載するアミノ酸配列を有する、前記使用。
- 前記組成物は、過剰増殖性細胞において細胞死を促進する、請求項13に記載の使用。
- 前記過剰増殖性細胞は、腫瘍細胞及び癌細胞からなる群から選択される、請求項14に記載の使用。
- 前記癌細胞は、肉腫、神経芽細胞腫、乳癌及び扁平上皮癌細胞からなる群から選択される、請求項15に記載の使用。
- 前記腫瘍容積は減少する、請求項13に記載の使用。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:50の範囲である、請求項13に記載の使用。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:10の範囲である、請求項18に記載の使用。
- 前記組成物は、医薬的に許容可能なキャリアをさらに含む、請求項13に記載の使用。
- 動物における癌を処置するための組成物を調製するための、i)内葉構成成分及び(ii)プロサポシン関連ポリペプチドの使用であって、前記内葉構成成分はジオレオイルホスファチジルセリンであり、前記ポリペプチドは配列番号2に記載するアミノ酸配列を有する、前記使用。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:50の範囲である、請求項21に記載の使用。
- 前記ポリペプチド対前記内葉構成成分のモル比は、1:1〜1:10の範囲である、請求項22に記載の使用。
- 前記組成物は、医薬的に許容可能なキャリアをさらに含む、請求項21に記載の使用。
- 前記組成物は、過剰増殖性細胞において細胞死を促進する、請求項21に記載の使用。
- 前記細胞死は、アポトーシスにより起きる、請求項25に記載の使用。
- 前記過剰増殖性細胞は、癌細胞および腫瘍細胞からなる群から選択される、請求項25に記載の使用。
- 前記癌細胞が、肉腫、神経芽細胞腫、乳癌及び扁平上皮癌細胞からなる群から選択される、請求項27に記載の使用。
- 前記組成物は、経腸的に、非経口的に、皮下的に、静脈内に、腹腔内に、あるいは局所的に投与される、請求項21に記載の使用。
- 複数回投与の前記組成物が前記動物に投与される、請求項21に記載の使用。
- 単回投与の前記組成物が前記動物に投与される、請求項21に記載の使用。
- 配列番号2に記載するアミノ酸配列を有するポリペプチド及びジオレオイルホスファチジルセリンを含む抗腫瘍剤。
- 前記ポリペプチド対ジオレオイルホスファチジルセリンの質量比は、5:1である、請求項32に記載の抗腫瘍剤。
- 前記ポリペプチド対ジオレオイルホスファチジルセリンの質量比は、15:7である、請求項32に記載の抗腫瘍剤。
- 前記ポリペプチド対ジオレオイルホスファチジルセリンの質量比は、15:1〜3:10の範囲である、請求項32に記載の抗腫瘍剤。
- 10μMポリペプチド及び30μMジオレオイルホスファチジルセリンを含む、請求項32に記載の抗腫瘍剤。
- 10μMポリペプチド及び70μMジオレオイルホスファチジルセリンを含む、請求項32に記載の抗腫瘍剤。
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US10/801,517 US7834147B2 (en) | 2003-04-28 | 2004-03-16 | Saposin C-DOPS: a novel anti-tumor agent |
PCT/US2004/008020 WO2004096159A2 (en) | 2003-04-28 | 2004-03-17 | Saposin c-dops: a novel anti-tumor agent |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7834147B2 (en) * | 2003-04-28 | 2010-11-16 | Childrens Hospital Medical Center | Saposin C-DOPS: a novel anti-tumor agent |
EP2020988B1 (en) * | 2006-04-28 | 2017-08-16 | Children's Hospital Medical Center | Compositions comprising fusogenic proteins or polypeptides derived from prosaposin for application in transmembrane drug delivery systems |
CA2666953A1 (en) * | 2006-10-20 | 2008-05-02 | Children's Hospital Medical Center | Spontaneous forming ellipsoidal phospholipid unilamellar vesicles |
AU2013203640B2 (en) * | 2007-06-22 | 2017-04-13 | Children's Medical Center Corporation | Methods and uses thereof of prosaposin |
EP2190448B1 (en) | 2007-06-22 | 2016-04-20 | Children's Medical Center Corporation | Methods and uses thereof of a fragment of saposin a |
EP3925670A1 (en) * | 2009-12-17 | 2021-12-22 | Children's Medical Center, Corp. | Saposin-a derived peptides and uses thereof |
US9585972B2 (en) | 2011-05-09 | 2017-03-07 | Sherry L. Thornton | Method for imaging a site of arthritis in an animal |
AU2012358269B2 (en) | 2011-12-22 | 2017-11-02 | Children's Medical Center Corporation | Saposin-A derived peptides and uses thereof |
EP2919759A4 (en) * | 2012-11-14 | 2016-07-20 | Ohio State Innovation Foundation | MATERIALS AND METHODS FOR THE TREATMENT OF GLIOBLASTOMES |
ES2608857T3 (es) | 2012-12-18 | 2017-04-17 | Salipro Biotech Ag | Partículas Salipro |
CN105358708A (zh) * | 2013-03-14 | 2016-02-24 | 儿童医学中心公司 | Cd36鉴定癌症对象以用于治疗的用途 |
HUE052677T2 (hu) | 2013-09-13 | 2021-05-28 | Salipro Biotech AB | Antigén és eljárás annak elõállítására |
CN106659764B (zh) | 2014-03-26 | 2021-11-02 | 儿童医学中心公司 | 环状鞘脂激活蛋白原肽及其用途 |
CN110248673A (zh) * | 2016-11-21 | 2019-09-17 | 百祥制药公司 | 用于治疗胰腺癌的包括SapC-DOPS的联合疗法 |
WO2019079164A1 (en) | 2017-10-16 | 2019-04-25 | University Of Cincinnati | COMBINATION OF AS1411 AND SAPC-DOPS FOR THE TREATMENT OF MULTIPLE GLIOBLASTOMA |
WO2019079245A1 (en) | 2017-10-16 | 2019-04-25 | University Of Cincinnati | COMBINATORY THERAPY OF FRACTIONAL RADIATION AND SAPC-DOPS FOR THE TREATMENT OF TUMORS |
JP7081865B2 (ja) * | 2018-03-23 | 2022-06-07 | ベキシオン ファーマシューティカルズ インコーポレイテッド | サポシンc薬学的組成物および癌を治療する方法 |
WO2021183596A1 (en) * | 2020-03-10 | 2021-09-16 | University Of Cincinnati | Materials and methods for the treatment of gaucher disease |
WO2023174210A1 (en) | 2022-03-14 | 2023-09-21 | Laekna Limited | Combination treatment for cancer |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63250323A (ja) * | 1987-04-03 | 1988-10-18 | Nichirei:Kk | 新規な制癌剤 |
JP2000500124A (ja) * | 1995-11-06 | 2000-01-11 | カルデン,ヨーアヒム・ローベルト | ウイルス、腫瘍、細菌および寄生体の抑制において免疫応答を特に調節するための医薬 |
JP2000506853A (ja) * | 1996-03-05 | 2000-06-06 | リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | プロサポジン由来のペプチドを使用する神経障害痛の軽減方法 |
JP2001524944A (ja) * | 1997-03-05 | 2001-12-04 | ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 神経障害性疼痛の緩和方法 |
JP2002530273A (ja) * | 1998-07-13 | 2002-09-17 | パーカシュ エス. ギル, | 脈管形成および腫瘍増殖の新規インヒビター |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2002A (en) * | 1841-03-12 | Tor and planter for plowing | ||
US2001A (en) * | 1841-03-12 | Sawmill | ||
US2003A (en) * | 1841-03-12 | Improvement in horizontal windivhlls | ||
NZ201918A (en) | 1981-09-18 | 1987-04-30 | Genentech Inc | N-terminal methionyl analogues of bovine growth hormone |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4552811A (en) | 1983-07-26 | 1985-11-12 | Appleton Papers Inc. | Capsule manufacture |
US4588580B2 (en) | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
US4904475A (en) | 1985-05-03 | 1990-02-27 | Alza Corporation | Transdermal delivery of drugs from an aqueous reservoir |
GB8514665D0 (en) | 1985-06-11 | 1985-07-10 | Eroceltique Sa | Oral pharmaceutical composition |
US4873192A (en) | 1987-02-17 | 1989-10-10 | The United States Of America As Represented By The Department Of Health And Human Services | Process for site specific mutagenesis without phenotypic selection |
US4788062A (en) | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
US4816258A (en) | 1987-02-26 | 1989-03-28 | Alza Corporation | Transdermal contraceptive formulations |
US4927408A (en) | 1988-10-03 | 1990-05-22 | Alza Corporation | Electrotransport transdermal system |
CA2025907A1 (en) * | 1989-09-21 | 1991-03-22 | Franklin D. Collins | Method of transporting compositions across the blood brain barrier |
MX9305070A (es) | 1992-08-21 | 1994-04-29 | Genentech Inc | Compocicion farmaceutica que contiene un antagonista de lfa-1 para el tratamiento de transtornos o desordenes mediados por el lfa-1 |
US5700909A (en) * | 1993-07-30 | 1997-12-23 | The Regents Of The University Of California | Prosaposin and cytokine-derived peptides |
US5707649A (en) * | 1993-08-13 | 1998-01-13 | Seikagaku Corporation | Agent for treating neuronal diseases |
ES2159630T3 (es) * | 1994-02-08 | 2001-10-16 | Amgen Inc | Sistema de administracion por via oral de proteinas g-csf quimicamente modificadas. |
US5605793A (en) | 1994-02-17 | 1997-02-25 | Affymax Technologies N.V. | Methods for in vitro recombination |
US5837458A (en) | 1994-02-17 | 1998-11-17 | Maxygen, Inc. | Methods and compositions for cellular and metabolic engineering |
CA2279259A1 (en) * | 1997-02-04 | 1998-08-06 | Abbott Laboratories | Pain reducing parenteral liposome formulation |
AU7795698A (en) * | 1997-03-24 | 1998-10-20 | Myelos Corporation | Synthetic saposin c-derived neurotrophic peptides |
US20020177551A1 (en) | 2000-05-31 | 2002-11-28 | Terman David S. | Compositions and methods for treatment of neoplastic disease |
US6465230B2 (en) | 2000-02-28 | 2002-10-15 | Millennium Pharmaceuticals, Inc. | 27411, a novel human PGP synthase |
US20020081698A1 (en) | 2000-02-29 | 2002-06-27 | Glucksmann Maria Alexandra | 32621, novel human phospholipid scramblase-like molecules and uses thereof |
US6872406B2 (en) | 2000-02-11 | 2005-03-29 | Children's Hospital Research Foundation | Fusogenic properties of saposin C and related proteins and polypeptides for application to transmembrane drug delivery systems |
US7166691B2 (en) | 2002-12-20 | 2007-01-23 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Saposin C and receptors as targets for treatment of benign and malignant disorders |
US7834147B2 (en) * | 2003-04-28 | 2010-11-16 | Childrens Hospital Medical Center | Saposin C-DOPS: a novel anti-tumor agent |
EP2020988B1 (en) * | 2006-04-28 | 2017-08-16 | Children's Hospital Medical Center | Compositions comprising fusogenic proteins or polypeptides derived from prosaposin for application in transmembrane drug delivery systems |
CA2666953A1 (en) | 2006-10-20 | 2008-05-02 | Children's Hospital Medical Center | Spontaneous forming ellipsoidal phospholipid unilamellar vesicles |
WO2012155147A2 (en) | 2011-05-12 | 2012-11-15 | Webtrends, Inc. | Graphical-user-interface-based method and system for designing and configuring web-site testing and analysis |
-
2004
- 2004-03-16 US US10/801,517 patent/US7834147B2/en not_active Expired - Fee Related
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- 2004-03-17 BR BRPI0409926 patent/BRPI0409926A/pt not_active Application Discontinuation
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-
2018
- 2018-12-19 US US16/226,468 patent/US20190192623A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63250323A (ja) * | 1987-04-03 | 1988-10-18 | Nichirei:Kk | 新規な制癌剤 |
JP2000500124A (ja) * | 1995-11-06 | 2000-01-11 | カルデン,ヨーアヒム・ローベルト | ウイルス、腫瘍、細菌および寄生体の抑制において免疫応答を特に調節するための医薬 |
JP2000506853A (ja) * | 1996-03-05 | 2000-06-06 | リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | プロサポジン由来のペプチドを使用する神経障害痛の軽減方法 |
JP2001524944A (ja) * | 1997-03-05 | 2001-12-04 | ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 神経障害性疼痛の緩和方法 |
JP2002530273A (ja) * | 1998-07-13 | 2002-09-17 | パーカシュ エス. ギル, | 脈管形成および腫瘍増殖の新規インヒビター |
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US20090269373A1 (en) | 2009-10-29 |
AU2004233775C1 (en) | 2010-03-18 |
US20190192623A1 (en) | 2019-06-27 |
CA2522833A1 (en) | 2004-11-11 |
AU2004233775B2 (en) | 2009-10-22 |
EP1635856A4 (en) | 2011-04-06 |
EP1635856B1 (en) | 2020-08-12 |
US10188698B2 (en) | 2019-01-29 |
CA2522833C (en) | 2016-01-19 |
US7834147B2 (en) | 2010-11-16 |
CA2911022C (en) | 2021-07-20 |
AU2010200264A1 (en) | 2010-02-25 |
US8937156B2 (en) | 2015-01-20 |
BRPI0409926A (pt) | 2006-04-25 |
US20150125497A1 (en) | 2015-05-07 |
CA2911022A1 (en) | 2004-11-11 |
US20040229799A1 (en) | 2004-11-18 |
WO2004096159A3 (en) | 2005-09-01 |
WO2004096159A2 (en) | 2004-11-11 |
EP1635856A2 (en) | 2006-03-22 |
AU2004233775A1 (en) | 2004-11-11 |
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