JP2006094860A - 抗ウイルス蛋白質、そのdnaコード配列およびその使用 - Google Patents
抗ウイルス蛋白質、そのdnaコード配列およびその使用 Download PDFInfo
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- JP2006094860A JP2006094860A JP2005293007A JP2005293007A JP2006094860A JP 2006094860 A JP2006094860 A JP 2006094860A JP 2005293007 A JP2005293007 A JP 2005293007A JP 2005293007 A JP2005293007 A JP 2005293007A JP 2006094860 A JP2006094860 A JP 2006094860A
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Abstract
【解決手段】ノストック・エリプソスポラム由来の単離された抗ウィルスタンパク質、特にシアノピリン−Nとして知られる抗ウィルスタンパク質及びシュードモナス外毒素、ウィルスエンベロープタンパク質との複合物からなるウィルス感染阻害剤の提供。
【選択図】なし
Description
またはリシンA鎖成分(Tillら,Science 242,1166-1167,1988)に連結したsCD4−毒素複合物が調製されている。同様に、機能的sCD4活性のインビボでのクリアランス速度を減少させ、胎盤による移送を増大させ、病原体除去(例えば、食作用的吸引および抗体依存的細胞媒介細胞毒性による殺傷)の免疫学的機構に的を絞った補強をもたらしてHIV感染細胞およびウイルスを殺傷および/または除去するために、sCD4−免疫グロブリン複合物が調製されている(Capon ら,Nature 337,525-531,1989; Traunecker ら,Nature 339,68-70,1989; Langnerら,1993,上述)。このようなCD4−免疫グロブリン複合物(時々「免疫接合体」と呼ばれる)は、実際インビボで有利な薬物動態学的および分布的特性を、またインビトロで抗HIV効果を示したが、臨床試験は失望させるものであった(Schooleyら,1990,上述; Hussonら,1992,上述; Langner ら,1993,上述)。HIVの臨床上の分離株は研究室株とは反対にsCD4による結合および中和に対して非常に抵抗力があるので(Orloffら,1995,上述; Moore ら,1992,上述)、これは驚くべきことではない。それ故、機能的シアノビリンの異常に広範な抗ウイルス活性、並びにウイルス、例えば、一般に霊長類レトロウイルスおよび、特に臨床および研究室株へターゲッティングする特性(例えば、実施例7を参照)は、毒素、免疫グロブリンおよび他の選ばれたエフェクター蛋白質と組み合わせるのにとりわけ有利である。
さらに、McGroarty が教示する推奨および特徴、特に、女性の泌尿生殖器の感染に対する慣用のプロバイオティック使用のために最適な乳酸菌の選択に関する推奨および特徴は、本発明に関連がある。すなわち、「・・・プロバイオティック製剤に組み入れるために選ばれる乳酸菌は、容易に且つ、可能ならば安価で培養できるべきである・・・菌株は安定で、凍結乾燥後も生存力を保持し、そしてもちろん宿主に対して非病原性であるべきである・・・プロバイオティック製剤中での使用のために選ばれる乳酸菌は、膣上皮によく接着することが不可欠である・・・人工的に移植された乳酸菌は、膣上皮に接着し、元来存在する微生物と統合して増殖することが理想的である」(McGroarty,1993 上述)。McGroarty の教示は、特に、女性の泌尿生殖管の病原性細菌または酵母感染に対するプロバイオティック使用のための、「通常の」乳酸菌株の選択を述べているが、遺伝子操作および本発明に特に包含されるようなウイルス感染に対する「プロバイオティック」または「生物治療的な」適用のために最適な細菌株の選択にも、同様の考慮が当てはまるであろう。
この実施例において、抗HIVバイオアッセイによって導き出される、培養シアノバクテリア、ノストック・エリプソスポラムの水性抽出物由来の純粋なシアノビリンの単離と解明について詳細に述べる。単離および精製工程を測定し管理するために、Weislow ら(1989,上述)に記載の方法を用いた。シアノバクテリアの培養条件、培地、および分類は以前に述べた(Patterson,J.Phycol. 27,530-536,1991)ものと同様である。簡単にいえば、ノストック・エリプソスポラム(カルチャー Q68D170)の単藻株由来の細胞のかたまりを濾過により集菌し、凍結乾燥し、MeOH−CH2Cl2(1:1)で、続いてH2Oで抽出した。バイオアッセイはH2O抽出物のみがHIV阻害活性を有していることを示した。該水性抽出物の溶液(30mg/ml)を等量のエタノール(EtOH)の添加によって処理した。得られた1:1のH2O−EtOH溶液を−20℃で15時間保存した。そして、該溶液を遠心分離して、沈澱した物質(恐らく、高分子量のバイオポリマー類)を除去した。得られたHIV阻害性の上清を溶媒留去し、ワイドポアC4パッキング(300Å,BakerBond WP−C4)での逆相真空液体クロマトグラフィー(Collら,J.Nat.Prod. 49,934-936,1986; Pelletierら,J.Nat.Prod. 49,802-900,1986)によって分画し、H2O中のメタノール(MeOH)濃度を上昇させて溶出した。抗HIV活性はMeOH−H2O(2:1)で溶出した物質中で濃縮された。この画分のSDS−PAGE解析は、およそ10kDaの相対分子量(Mr)を有する、一つの主要な蛋白質のバンドを示した。1.9×15cm μBondapak C18(Waters Associates)カラムを用いた、H2O中で徐々に高くなるアセトニトリル濃度の勾配で溶出させる逆相HPLCを繰り返して最終的に精製した。移動相は0.05%(V/V)TFA、pH=2を含有した。溶出された蛋白質は、急速(rapid)スペクトル検出器(Pharmacia LKB モデル2140)を用いて、206、280、および294nmでのUV吸収によって検出した。UVクロマトグラムに基づいて個々の画分を集めてプールし、凍結乾燥した。プールしたHPLC画分を還元状態下でのSDS−PAGE(Laemmli,Nature 227,680-685,1970)、通常のアミノ酸解析、および抗HIV活性試験に付した。
この実施例において、シアノビリン遺伝子の合成について述べる。
シアノビリン−Nの化学的に類推されるアミノ酸配列をバックトランスレートし、DNAコード配列を得た。組換えシアノビリン−Nの最初の生産および精製を容易にするために、アフィニティー精製や検出のための試薬が入手可能な市販の発現ベクター(pFLAG−1、International Biotechnologies,Inc.,New Haven,CT より)を選択した。pFLAG−1に連結するための好適な制限サイト、および停止コドンをDNA配列に含めた。図2は合成シアノビリン遺伝子をコードするDNA配列の一例である。このDNA配列設計は、シアノビリンのN−末端でシアノビリン−Nをコードする領域を“FLAG”オクタペプチドのコドンに連結し、FLAG−シアノビリン融合蛋白質を与える。このDNA配列の合成の為のフローチャートを以下に示す。
この実施例において、合成シアノビリン遺伝子の発現について述べる。
以下のフローチャートに示すようにして行った。
実施例2に記載されたネイティブシアノビリン−Nの構築物を用いて、FLAG−シアノビリン−N融合蛋白質について記載した方法と同様の方法で細菌を形質転換した。クローニング、拡大、IPTGでの誘導、および採取は同様にして行った。粗ペリプラズム抽出物はバイオアッセイにおいて強い抗HIV活性を示した。
この実施例において、組換えシアノビリン蛋白質の精製について述べる。
抗FLAGモノクローナル抗体(International Biotechnologies,Inc.,New Haven,CT)に基づいたアフィニティーカラムを用いて、FLAG−シアノビリン−N融合蛋白質を以下のようにして精製することができた。
この実施例において、天然、および組換えシアノビリン−NおよびFLAG−シアノビリン−Nの抗HIV活性について述べる。はじめに純粋な蛋白質の抗ウイルス活性を、以前に述べられたXTT−テトラゾリウム 抗HIVアッセイ(Boyd,in AIDS,Etiology,Diagnosis,Treatment and Prevention,1988,上述;Gustafson ら,J.Med.Chem.35,1978-1986,1992;Weislow,1989,上述;Gulakowski,1991,上述)を用いて評価した。全てのアッセイで使用されるCEM−SSヒトリンパ球性標的細胞株は、フェノールレッドを含有せず、5%ウシ胎児血清、2mML−グルタミン、および50μg/mlゲンタマイシンを補ったRPMI1650培地(Gibco,Grand Island,NY)(完全培地)中で維持した。指数的に増殖している細胞を沈澱とし、完全培地で2.0×105細胞/mlの濃度に再懸濁した。HIVのHaitian変異株であるHTLV−IIIRF(3.54×106SFU/ml)を一貫して使用した。凍結したウイルスのストック溶液を使用直前に解凍し、1.2×125SFU/mlとなるように完全培地で再懸濁した。抗HIV評価の為に、適当な量の純粋な蛋白質をH2O−DMSO(3:1)に溶解し、ついで完全培地で所望の初期濃度に希釈した。全ての薬剤の逐次的な希釈、試薬の添加、およびプレートからプレートへの移動はオートメーション化されたBiomek1000 Workstation(Beckman Instruments,Palo Alto,CA)を用いて行った。
この実施例において、HIVウイルスのエンベロープgp120がシアノビリン−Nの主要な分子標的であることを述べる。XTT−テトラゾリウムアッセイ(Weislow ら,1989,上述)を用いた最初の実験では、シアノビリンでプレインキュベート(10nM、1時間)し次いでシアノビリン−Nのない状態に遠心分離した宿主細胞は、HIV感染に対する通常の感受性を維持したが、対照的に、濃縮ウイルスを同様に前処理し次いで阻害性のない濃度にまでシアノビリン−Nを希釈すると、感染性が本質的になくなった。このことはシアノビリン−Nが直接ウイルスそのものに作用している、すなわちウイルスが宿主細胞に侵入しうる前でもウイルス感染を防ぐために直接的な“殺ウイルス剤”として働いていることを示した。このことはXTT−テトラゾリウムアッセイ(Weislow ら,1989,上述)の試行と同様、添加時期実験においても確認された。該実験は、最大の抗ウイルス活性を得るためには、図7〔添加の時期(時間)に対する%非感染コントロールのグラフであり、該図は、HIV−1RFで感染されているCEM−SS細胞において抗HIV活性を示すシアノビリンの、添加時期実験の結果を示している〕に示されるようにシアノビリン−Nをウイルスの添加前、あるいは添加後可能な限り速やかに添加しなくてはならないことを示した。はじめのインキュベーションのあと、種々の時期で遅れてシアノビリン(●)あるいはddc(■)(各々10nMおよび5μM濃度)を導入し、ついで6日間インキュベートし、細胞の生存度(線グラフ)およびRT(棒グラフ(オープンバー)、挿入図)のアッセイを行った。ポイントは少なくとも3つの測定の平均(±S.D)を表している。逆転写酵素阻害剤であるddcとは極めて対照的に、たった3時間のシアノビリン−Nの添加の遅れは、結果として抗ウイルス活性を無くすかほとんど無くすかした(図7)。前述の結果は、シアノビリン−Nがウイルスの細胞との最初の相互作用の妨害によってHIV感染性を阻害したことを示唆した;したがって、これはおそらくシアノビリン−Nのウイルスgp120との直接的な相互作用を意味している。このことは限外濾過の実験やドット−ブロットアッセイによって確認された。
この実施例において、ヒトのあるいはヒト以外の霊長類の免疫不全性レトロウイルスの、研究室向けの、および臨床上の様々な株に対する極めて広範囲にわたる抗レトロウイルス活性について述べる。下の表1は種々の宿主細胞において広範囲のウイルス株に対して調べた、シアノビリン−N及びsCD4の抗免疫不全性ウイルス活性の比較範囲を示している。特に注目すべきことは、シアノビリン−Nがラボ向けのHIV株およびHIVの臨床分離株の両方に対して同等の能力を有することである。このことはsCD4が臨床的分離株に対してその活性を欠いていることとは明らかに対照的であった。
この実施例において、選択的にHIV−感染細胞を標的とし、死滅させるシアノビリン−毒素蛋白質コンジュゲートを得るための、コンジュゲートDNAコード配列の構築およびその発現についてさらに述べる。より具体的には、この実施例に、ウイルスのgp−120を発現している宿主細胞を選択的に殺すシアノビリン/シュードモナス−外毒素のコンジュゲートDNAコード配列の構築および発現について述べる。
FLAG−シアノビリン−NをコードしているDNA配列(配列表配列番号3)およびシュードモナスの外毒素のPE38断片をコードするDNA配列(Kreitmanら,Blood 83,426-434,1994)をpFLAG−1発現ベクター内で結合させた。PE38コード配列をプラスミドから切り出し、適合させ、FLAG−シアノビリン−Nコード配列のC末端の位置に、標準的な組換えDNAの手法を用いて連結した。この構築物を図9に模式的に示した。この構築物での大腸菌の形質転換、クローンの選択、およびIPTGでの遺伝子発現の誘導により、予測される分子量ならびに抗FLAG抗体を用いるウエスタンブロット解析における免疫反応性を有するコンジュケート蛋白質を産生した。キメラ分子をFLAGアフィニティークロマトグラフィーによって精製し(例えば実施例4のように)、HIVで感染されたヒトリンパ芽球様細胞(H9/IIIB細胞)およびそれらの非感染の対照物(H9およびCEM−SS細胞)に対する毒性で評価した。細胞を96ウエルのマイクロタイタープレートに撒きこみ、種々の濃度のコンジュゲート蛋白質(PPEと名付けた)に暴露した。3日後、XTTアッセイ(Gulakowskiら.,1991,上述)を用いて生存度を測定した。図10はこの実験の結果を示している。予期したように、細胞表面gp120を発現している、感染されているH9/IIIB細胞は、非感染のH9あるいはCEM−SS細胞よりも劇的にPPEの該毒性効果により感受性であった。濃度−効果曲線から決定されたIC50は、H9およびCEM−SSに対してそれぞれ0.48および0.42nMであったのに対して、H9/IIIBに対しては0.014nMであった。
この実施例において、その中でシアノビリンを発現するための、哺乳動物細胞の形質転換について述べる。哺乳動物細胞中でのシアノビリンの発現の証明に適した遺伝子構築物をFLAG−シアノビリン−NをコードするDNA配列をpFLAGCMV−1発現ベクター(IBI-Kodak,Rochester,NY)に連結させることによって調製した。FLAG−シアノビリン−Nコード配列(配列表配列番号3)をあらかじめ構築したプラスミドから切り出し、pFLAG CMV−1ベクターに標準的な組換えDNAの手法を用いて連結した。アフリカミドリザル細胞(COS−7細胞、American Type Culture Collection,Rockville,MD から入手)をDEAEデキストラン溶液中で該構築物に暴露することによって形質転換した。FLAG−シアノビリン−Nの発現を測定するために、細胞を72時間後に溶解し、PAGEおよびウエスタンブロット解析に付した。図11に示されるように、大腸菌中で産生されるネイティブ組換え FLAG−シアノビリン−Nに比べて実質的により大きなみかけ分子量ではあるが、形質転換されたCOS−7細胞において抗FLAG免疫反応性の物質が容易に検出された。以下の実施例10と同じ方法で行った消化産物の診断的解析は、この分子量の増加がFLAG−シアノビリン−Nの翻訳後の修飾(N結合型オリゴサッカライド)によるものであることを示した。
この実施例において、哺乳動物のものではない細胞、より具体的には酵母細胞内での形質転換およびシアノビリン発現について述べる。ピキア・パストリス中でのシアノビリンの発現を証明するために適した遺伝子の構築物を、シアノビリン−NをコードするDNA配列をpPIC9発現ベクター(Invitrogen Corporation,San Diego,CA)に連結することによって調製した。シアノビリン−Nコード配列(配列表配列番号1)をあらかじめ構築したプラスミドから切り出し、標準的な組換えDNAの手法を用いてベクターに連結した。酵母細胞をエレクトロポレーションによって形質転換し、特徴づけのためにクローンを選択した。いくつかのクローンが、抗シアノビリン−Nポリクローナル抗体(例えば実施例11参照)に反応する物質を発現し、培養培地中に分泌していることがわかった。実施例9に記載されている哺乳動物フォームでの観察と同様に、酵母由来の産物のPAGEおよびウエスタンブロット解析におけるみかけ分子量の上昇はこの発現システムにおいて、シアノビリン−Nの翻訳後の修飾が起こっていることを示唆した。
この実施例において、シアノビリンに特異的に結合する抗体についてさらに述べる。3羽の2月齢のニュージーランド白ウサギ(1.8−2.2kg)を以下の免疫手順に付した:全量100μgのシアノビリン−Nをリン酸緩衝塩類溶液(PBS)とフロインドの不完全アジュバントとの1:1の懸濁液100μlに溶解し、各々の後肢の2か所で筋肉内注射によって投与し;最初の注射から8−16カ月で、ウサギ1羽あたり最終ブースト50μgのシアノビリン−NをPBSとフロインドの不完全アジュバントとの1:1の懸濁液1000μlに溶解し、腹腔内注射によって投与し;42、70、98および122日目に、10mlの血液を各ウサギの耳静脈から取り;最後の腹腔内ブーストの14日後に該ウサギを屠殺して放血させた。上述のウサギから得られた免疫血清のIgG画分を、Goudswaardら(Scand.J.Immunol. 8,21-28,1978)の方法によってプロテイン−Aセファロースアフィニティークロマトグラフィーによって単離した。このポリクローナル抗体調製品のシアノビリン−Nに対する反応性を、ウサギIgG画分の1:1000から1:5000希釈物を用いてウエスタンブロット解析によって証明した。
Claims (35)
- 配列番号2のアミノ酸配列の少なくとも9個の隣接するアミノ酸を含む、単離および精製された抗ウイルス蛋白質または単離および精製された抗ウイルスペプチド。
- 配列番号2のアミノ酸配列と少なくとも約90%の相同性を有するアミノ酸配列を含む、単離および精製された抗ウイルス蛋白質または単離された抗ウイルスペプチド。
- エフェクター分子、ウイルス、ウイルス糖蛋白質、ポリエチレングリコール、アルブミン、デキストランまたは固形支持マトリックスに連結された請求の範囲1または2の蛋白質またはペプチドを含む蛋白質複合物またはペプチド複合物。
- 該エフェクター分子が毒素および免疫学的試薬からなる群より選ばれる請求の範囲3の複合物。
- 該エフェクター分子がシュードモナス外毒素である請求の範囲4の複合物。
- 請求の範囲1または2の蛋白質またはペプチドの取得方法であって、(a) 抗ウイルス活性を含むノストック・エリプソスポラムの抽出物を同定し、(b) 抗ウイルスバイオアッセイをガイドに該抽出物を分画して該蛋白質または該ペプチドの部分精製された抽出物を得、(c) 該部分精製抽出物を逆相HPLCによりさらに精製して該蛋白質または該ペプチドを得ることを含む方法。
- ウイルスまたはウイルスエンベロープ糖蛋白質をシアノビリンと複合物形成させる方法であって、単離および精製されたウイルスまたは単離および精製されたウイルスエンベロープ糖蛋白質に請求の範囲1または2の蛋白質またはペプチドを接触させ、該単離および精製されたウイルスまたは該単離および精製されたウイルスエンベロープ糖蛋白質と該蛋白質または該ペプチドとの接触によって、該蛋白質または該ペプチドが該単離および精製されたウイルスまたは該単離および精製されたウイルスエンベロープ糖蛋白質に結合し、それによって複合物を形成することを含む方法。
- 請求の範囲1〜5のいずれかの蛋白質、ペプチド、蛋白質複合物またはペプチド複合物をコードする、単離および精製された核酸分子。
- 請求の範囲1〜5のいずれかの蛋白質、ペプチド、蛋白質複合物またはペプチド複合物、あるいは請求の範囲7の方法により得られる複合物の抗ウイルス有効量およびそれ用の医薬上許容され得る担体を含む医薬組成物。
- 動物のウイルス感染阻害剤である請求の範囲9の医薬組成物。
- 請求の範囲8の核酸分子を含むベクター。
- 請求の範囲8の核酸分子または請求の範囲11のベクターを有効成分とする動物のウイルス感染阻害剤であって、ウイルス感染を阻害する必要のある動物の細胞をインビボで形質転換して、該核酸分子にコードされる抗ウイルス蛋白質、抗ウイルスペプチド、抗ウイルス蛋白質複合物または抗ウイルスペプチド複合物をインビボで発現させるべく投与されることを特徴とする該ウイルス感染阻害剤。
- 請求の範囲8の核酸分子または請求の範囲11のベクターで形質転換された宿主細胞。
- 該宿主細胞が哺乳動物細胞、細菌または酵母である請求の範囲13の宿主細胞。
- 該細菌が乳酸菌である請求の範囲14の宿主細胞。
- 請求の範囲13〜15のいずれかの宿主細胞中で蛋白質、ペプチド、蛋白質複合物またはペプチド複合物を発現させることを含む蛋白質、ペプチド、蛋白質複合物またはペプチド複合物の製造方法。
- 請求の範囲13〜15のいずれかの宿主細胞を有効成分とする動物のウイルス感染阻害剤であって、該核酸分子にコードされる抗ウイルス蛋白質、抗ウイルスペプチド、抗ウイルス蛋白質複合物または抗ウイルスペプチド複合物を発現するように動物中または動物上に置かれるべく投与されることを特徴とする該ウイルス感染阻害剤。
- 該宿主細胞が自己または同種の哺乳動物細胞である請求の範囲17のウイルス感染阻害剤。
- 請求の範囲1〜5の蛋白質、ペプチド、蛋白質複合物またはペプチド複合物の抗ウイルス有効量で無生物の対象物、溶液、懸濁液、乳液または他の材料を処理することを含む、ウイルス感染の拡大を阻害する方法。
- 請求の範囲1〜5の蛋白質、ペプチド、蛋白質複合物またはペプチド複合物の抗ウイルス有効量で血液、血液製剤、精液、細胞、組織または器官を生体外で処理することを含む、ウイルス感染の拡大を阻害する方法。
- 請求の範囲1〜5の蛋白質、ペプチドまたは複合物中の蛋白質もしくはペプチドに対する抗体。
- 抗ウイルス剤をウイルスに接触させる方法であって、請求の範囲1〜5の蛋白質、ペプチド、蛋白質複合物またはペプチド複合物の抗ウイルス有効量をウイルスに接触させることを含む方法。
- 試料からのウイルスの除去方法であって、
(a) 請求の範囲1〜5のいずれかの単離および精製された抗ウイルス蛋白質、抗ウイルスペプチドまたは複合物を含む組成物を該試料に接触させ(但し、(i) 該抗ウイルス蛋白質または抗ウイルスペプチドは配列番号2のアミノ酸配列の少なくとも9個の隣接するアミノ酸を含み、(ii) 該抗ウイルス蛋白質、抗ウイルスペプチドまたはその複合物は固形支持マトリックスに接着し、(iii) 該少なくとも9個の隣接するアミノ酸が該ウイルスに結合する)、
(b) 該試料と該組成物とを分離することにより、ウイルスを該試料から除去することを含む方法。 - 該試料が血液、血液成分、精液、細胞、組織または器官である請求の範囲23の方法。
- 該試料がワクチン製剤であり、除去されるウイルスが感染力のあったものである請求の範囲23の方法。
- 動物の膣、陰茎、直腸または口に局所投与されることを特徴とする請求の範囲10の医薬組成物。
- 乳剤、懸濁液剤、液剤、ゲル、クリーム、ペースト、泡、滑剤、スプレー、坐剤、ペッサリーまたはタンポンの剤形である請求の範囲10または26の医薬組成物。
- 避妊具中または避妊具上にある請求の範囲10、26または27の医薬組成物。
- 該避妊具がコンドームである請求の範囲28の医薬組成物。
- 避妊薬をさらに含有する請求の範囲10および26〜29のいずれかの医薬組成物。
- 該避妊薬がノノキシノール−9である請求の範囲30の医薬組成物。
- 別の抗ウイルス剤および/または抗生剤をさらに含有する請求の範囲10および26〜31のいずれかの医薬組成物。
- 該抗生剤が抗真菌剤または抗細菌剤である請求の範囲32の医薬組成物。
- 工程(b)の前に、該抽出物中に含まれる、該蛋白質または該ペプチドよりも高分子量の生体高分子を該抽出物から除去することを含む、請求の範囲6の方法。
- 免疫刺激剤をさらに含む請求の範囲9の医薬組成物。
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JPH06141885A (ja) | 1992-11-05 | 1994-05-24 | Chemo Sero Therapeut Res Inst | モノクローナル抗体 |
US5817767A (en) | 1993-02-24 | 1998-10-06 | Progenics Pharmaceuticals, Inc. | Synergistic composition of CD4-based protein and anti-HIV-1 antibody, and methods of using same |
AU7203194A (en) | 1993-06-04 | 1995-01-03 | New York University | Bispecific human monoclonal antibodies specific for human immunodeficiency virus |
DE69332911T2 (de) | 1993-08-24 | 2003-12-18 | Nissin Food Products Ltd | Rekombinanter humanisierter Antikörper gegen menschlichen Immunschwächevirus |
IT1272682B (it) * | 1993-09-24 | 1997-06-26 | Pietro Antonino Di | Struttura di profilattico a doppia membrana |
US5618922A (en) | 1994-07-25 | 1997-04-08 | Nissin Shokuhin Kabushiki Kaisha | NM03 antibody materials and methods |
US5843882A (en) * | 1995-04-27 | 1998-12-01 | The United States Of America As Represented By The Department Of Health And Human Services | Antiviral proteins and peptides |
US5962668A (en) * | 1995-04-27 | 1999-10-05 | The United States Of America As Represented By The Department Of Health And Human Services | Nucleic acids encoding antiviral proteins and peptides fused to effector proteins |
-
1995
- 1995-04-27 US US08/429,965 patent/US5843882A/en not_active Expired - Lifetime
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002538217A (ja) * | 1999-03-12 | 2002-11-12 | アメリカ合衆国 | シアノビリン複合体、マトリックス固定化シアノビリン及び抗シアノビリン抗体、及び関連組成物並びに使用方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2219105A1 (en) | 1996-10-31 |
ATE264914T1 (de) | 2004-05-15 |
DE69632256D1 (de) | 2004-05-27 |
WO1996034107A3 (en) | 1997-04-24 |
US6245737B1 (en) | 2001-06-12 |
EP0836647A2 (en) | 1998-04-22 |
JPH11504804A (ja) | 1999-05-11 |
US6586392B2 (en) | 2003-07-01 |
JP4081484B2 (ja) | 2008-04-23 |
AU5669196A (en) | 1996-11-18 |
AU707781B2 (en) | 1999-07-22 |
US5843882A (en) | 1998-12-01 |
US20030103997A1 (en) | 2003-06-05 |
EP0836647B1 (en) | 2004-04-21 |
US6743577B2 (en) | 2004-06-01 |
DE69632256T2 (de) | 2005-04-14 |
JP3803115B2 (ja) | 2006-08-02 |
US6015876A (en) | 2000-01-18 |
US5998587A (en) | 1999-12-07 |
US5962653A (en) | 1999-10-05 |
US5821081A (en) | 1998-10-13 |
US6420336B1 (en) | 2002-07-16 |
US20020151476A1 (en) | 2002-10-17 |
WO1996034107A2 (en) | 1996-10-31 |
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