JP5128539B2 - 治療薬 - Google Patents
治療薬 Download PDFInfo
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- JP5128539B2 JP5128539B2 JP2009091136A JP2009091136A JP5128539B2 JP 5128539 B2 JP5128539 B2 JP 5128539B2 JP 2009091136 A JP2009091136 A JP 2009091136A JP 2009091136 A JP2009091136 A JP 2009091136A JP 5128539 B2 JP5128539 B2 JP 5128539B2
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Classifications
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Description
a.ほ乳類がウイルスに対する中和抗体を産生するように、前記ほ乳類を前記ウイルスに曝露する段階、および
b.前記ほ乳類から前記中和抗体を収集する段階が含まれる。実施例では、HIVウイルスとヤギから得られたHIV中和抗体を混合することによってAAV2と称されるHIVワクチンを得ている。
抗原に特異的な異種抗体、および
抗原を含む免疫調節組成物であって、
前記異種抗体が薬剤担体と組み合わさるために抗原と複合体を形成する組成物を提供している。実施例は国際公開第97/02839号の場合と同様で、また、HIVウイルスとヤギから得られたHIV中和抗体を混合することによってAAV2と称されるHIVワクチンを得ている。
(1)ヤギ免疫系をHIVに曝露する段階、
(2)HIVチャレンジ後、ヤギから抗体を精製する段階、および
(3)患者を前記の段階2で得られた抗体で治療する段階を含むHIV感染の予防方法またはHIVに感染した患者の治療方法を提供している。
ヤギに、市販の標準上清に懸濁させた溶解HIV-3bウイルスを1ml当たり109ウイルス粒子の濃度で筋肉内注射して接種した。ウイルスは60℃で30分間加熱して予め死滅させておいた。血液試料を適切な間隔を空けて、たとえば最初の評価のためには2週間後に採取した。最適な方法では、ヤギに4週間毎週注射して、その後6週目に採血して反応物(reagent)を得た。
1.ほとんどすぐに患者の生活の質が改善される。
2.CD4およびCD8細胞の増殖が起こり、それによってCD4およびCD8細胞数が増加する。
3.患者におけるウイルス負荷量が一般的に0.5logずつ増加して理論的にゼロに減少する。
4.P24値がゼロに減少する。
1.注射後60分未満で中程度から重症の鬱が回復する。
2.一般的に注射後2時間以内に患者の食欲が回復し、活発に食物を求めるようになる。
3.最初の治療から約2週間以内に、患者の体重が上昇し始める。
4.最初の治療から4から6週間後にウイルス負荷量およびP24値が実質的に下降し、CD4およびCD8細胞が劇的に増加することが独立した研究室報告によって確認された。
5.副作用は全く認められなかった。
ヤギに筋肉内注射によって溶解しフロインドアジュバントで処方したHIVウイルスカクテルを接種した。ウイルスは予め60℃で30分間熱殺菌した。血液試料を適切な間隔で、たとえば2週間して、最初の評価のために採取した。最適な方法では、ヤギに毎週4週間注射して、その後6週間後に反応物を得るために採血した。
材料
必要量の塩化ナトリウム、オルトリン酸二水素ナトリウムおよびオルトリン酸二水素二ナトリウムを1リットルの水に溶解して、1リットルのリン酸緩衝生理食塩水(PBS)を作製した。
換算係数1.0275を使用して(すなわち、1000mLは1027.5gである)、処理すべき血漿の必要量を計量する。
材料
材料
限外濾過(UF)装置に少なくとも1枚の0.1m2 30,000MWCO膜を装着する。
開始溶液が25g/Lで2リットルであれば50gである。ダイアフィルトレーションで除去する溶液の量は1リットルである。したがって、濃度は50/l=50g/Lである。
IgGの量=1300mL。蛋白質濃度=30mg/mL
IgGの全量=39000mg
必要濃度=最終濃度10mg/mL
序論
AIDS患者にHIVで免疫したヤギの血清を投与すると、場合によっては見かけ上劇的に改善されるらしいことが非公式の研究によって示されたので、可能性のある機構を探索している。ヤギにHIVを注射すると、免疫応答の特異は高いと考えられるが、これに基づいて多発硬化症、場合によっては癌の患者で認められた利益は説明できない。
Dalgleishおよびその共同研究者らは、数年前にHIV進入口としてのCD4受容体を発見したが、HIVは感染がAIDSに進行するにつれてCD4細胞を殺して、測定可能なほど減少させるという古典的な解釈はこの病気の発生の説明には適さない。この解釈にうまく合わない主な観察点には、
(1)感染からAIDSの発症までに長い期間があること(約10年)。
(2)ほとんど全てのチンパンジーおよびHIVに感染したヒトの約5%でこの疾患が認められないこと。チンパンジーはヒトと同様の受容体および共受容体を備えており、CD4数が減少していない感染チンパンジーでも容易にウイルスを検出することができることが含まれる。
(1)外来細胞(すなわち、異なるHLA型)によるチャレンジに対する応答に関わるキラーT細胞はまた、HIVに感染した自己細胞を殺すこと、
(2)(自己であることを決定するHLA分子に構造的に相同であると考えられる)GP120として知られているHIVウイルスのエンベロープは、HLAと非常によく似た様式でペプチドに結合することができることが示された。さらに、T細胞はペプチドを増加させ、GP120に似たHLAはまたペプチドを有するGP120に応答するが、ペプチドを有さないGP120には応答しないことによって、ペプチドに結合する能力、したがって感受性のある患者において慢性免疫活性化を引き起こす能力はその構造が非常に重要であることが示唆された。
(3)さらに近年、我々はペプチドがHLAに結合する領域がGP120上に存在し、Sodroski教授がボストンのDana Faberで実施して下さったように、分子のこの部分を除去すると、ペプチドはもはや結合しないことを示した。
ヤギ血清が炎症特性を有するかどうかを確認するために、遺伝子背景の異なる2人の異なる患者の細胞を混合することによって生じた反応に血清を添加した。驚いたことに、血清はこの反応を極めて効果的に阻害した。多くの分子抗体を使用して、ヤギ反応性に近い唯一の抗体は抗HLAクラスIIであることを確認することができた。抗クラスI抗体は、この反応を部分的に減少させるのみであった。HIV V3ループに対する抗体はワクチンの主要な標的であることは科学界の大方の判断であり、実際に全体的活性化を損なわせることは非常に興味深い。この発見は、ウイルスに対する免疫応答によって実際に増殖が起こり、ウイルスの「放出を助けるので、免疫活性化理論に合致しており、この発見によってどうしてこの領域を目標とするワクチンはそれほど効果がないのかを説明できるだろう。
(1) HIVエンベロープはHLAクラスIIと非常に類似しているので、完全に異なるHLAレパートリーを有するヤギ免疫系によってこのように認識される。
(2) 第2の可能性としては、免疫原、すなわちウイルス調製物では、ウイルスが発芽する細胞表面にあるHLAが見出され、免疫応答はウイルスにではなく、一緒に結合したHLAに起こる。
(3) 第3の説明には、前記の2つの説明の組合せが含まれる。発芽しているウイルスは準備が整うとHLAと融合することが可能で、この結合はヤギ血清によって非常に強く見出される。最近の報告では、ウイルスがHLAを備えた細胞から発芽して、HLAが膜に取り込まれなければ、ウイルスは感染しないままであることが示された。このことは、宿主から得られたHLAの中には細胞進入機構を活性化するものがあるに違いないことを意味している。
導入
HIV-3Bウイルス溶解物または6種類の異なるHIV-1単離物のNIHウイルスカクテルで免疫した動物からヤギ血清を入手した。この血清の中には既に良好な効果をもたらす実験的治療計画の一部として使用されたが、その作用機構がわかっていないものがある。作用機構を明らかにするために、HIV-1、gp120、HLA-DR1に対してELISAプレートで血清をスクリーニングして、ウイルス表面の糖蛋白質の異なる領域からペプチドを選択したところ、いくつかはHLAと配列相同性を有していた。
血清および抗体
患者治療に使用してきた元のHIV-3B免疫ヤギ血清試料およびHIV-3Bウイルス溶解物で免疫した数頭のヤギ(動物番号0125番、0126番、0127番、0128番、0129番は1999年9月14日、1999年9月21日に免疫し、9月29日および2000年11月07日に再度免疫した)の試料には、採血および免疫日程に関する情報が添えられていた。ELISAは、後期段階(2000年11月30日および2000年12月01日)で得られた血液の血清試料をスクリーニングするために単純に選択した。動物番号378番を以下のHIV単離物(92HT593、92US657、92US660、92US714、92US723、91US056)から成るNIHウイルスカクテルで免疫した。免疫は11月7日および28日に実施した。2001年1月25日に得た血液から得られた血清をELISAスクリーニングに使用した。対照ヤギ血清もまた提供した。血清と一緒に、ELISAと混合リンパ球反応研究の両方に抗ヒトHLA-DRおよび抗ヒトHLA-DR、DPおよびDQ(Pharmingen)を含め、MLR研究にはHarvey Holmes博士(MRC ADIS reagents programme, National Institute for Biological Standards and Control, Potter's Bar, UK)を通じてJ Laman博士から入手したHIV-i IIJb(IRIQRGPGR)のV3ドメインに特異的なマウス抗gp120IgG(EVA3047)を含めた。
組換えHIV-i IIIB gp120は、チャイニーズハムスターの卵巣細胞で産生させ、MRC AIDS reagents programでHarvey Holmes博士を介してJ Raina博士から頂いた。組換えHLA-DR1は、ペプチド結合実験で使用したDon C. Wiley教授から頂いた蛋白質と同じであった。この研究で使用したHIV-1ペプチドを表1に挙げる。ペプチドARP7022、ARP7 10、ARP740-23、-28、-42、-44、-45、-46および-47はMRC AIDS reagents programmeでHarvey Holmes博士から頂いた。対照ペプチドP12は、HIV-1 gp120のCS領域のスクランブル配列を表し、School of Biological and Chemical Sciences, Birkbeck College London, UKのE. F. Hounsell教授から頂いた。ペプチドは小分けして使用するまで-20℃で保存した。
ELISAは、Brown et al.(J Immunological methods 1997, 200:79-88)が記載した方法と同様の方法に従って実施した。ペプチドは0.05M 炭酸塩/重炭酸塩pH9.6結合緩衝液と16μg/mlで混合し、蛋白質は1μg/mlで混合して、Immulon 4 LIBX 高結合マイクロタイタープレート(Dynex Technologies, INC. 14340 Sullyfield Circle, Chantilly, VA 20151-1683, USA)に2連で一晩40℃でコーティングした。ウェルをPBSに5mg/mlで溶かしたカゼインでブロックして、一晩40℃で放置した。ヤギ血清をPBS/0.25%カゼインで1/500および1/1000倍に希釈し、一方精製抗体はそれぞれ1/1000および1/3000倍に希釈して、37℃で1時間インキュベートした。ウェルをWellwash 4 machine(Denley)を使用してPBS/0.05%Tween 20で3回洗浄した。
ARP7022:(DQQLLGIWGCSGKLICTTAVPWNC)
HIV gp41(593-616)の保存領域から得られた24残基ペプチドは、ほとんどのヨーロッパおよびアフリカのHIV陽性血清によって認識された。対照ペプチド。
ARP710:(VKIEPLGVAPTKAKRRVVQREKR)
HIV gp120(486-508)の保存されたC末端(CS)ドメインから得られた23残基ペプチドは、gp120/41切断部位を導いた。HLAとの構造的な相同性を有する。
ARP740/23:(RPVVSTQLLLNGSLAEEEVV)
gp120のC2領域(252-271)から得られた20残基ペプチド。HLA DR4 β鎖と相同な配列を含有する。
ARP740/28:(NTRKRIRIQRGPGRAFVTIG)(302-321)
V3 ループHIV-1 gp120から得られた20残基ペプチド。
ARP740/42:(GQIRCSSNITGLLLTRDGGNS)(438-458)
DR-β1鎖との相同性を有する。
ARP740/44:(NNESEIFRLGGGDMRDNWRS)(459-478)
HLA-A2と相同な配列を含有する。
ARP740/45:(GQDMRDMWRSELYKYKVVKI)(469-488)
HLA-CおよびC5領域と交差反応する抗体、M38によって認識される配列。
ARP740/46:(ELYKYKVVKIEPLGVAPTKA)(469-478)
gp120のC5末端から得られた20残基ペプチド。C末端に相同性のある最初の3残基を含有する。
ARP740/47:(EPLGVAPTKAKRRVVQREKR)(479-498)
gp120のC5領域から得られた20残基ペプチド。HLAと構造的な相同性を有する。
P12.(RAKTVERKVERRK)
E.Hounsellから頂いたHIV gp120のCSドメインのスクランブル配列。WV陽性血清によっては認識されない。対照配列。
血液提供者
HLAクラスII不一致血液試料は、South Thames Blood transfusion service, Tooting, LondonのLiz Bucklandを通じて提供者の同意を得て入手した。
新たに採取した静脈血をハンクス液(HBSS; SIGMA)で希釈して、注意深くHistopaque(SIGMA)に重層して、800gで20℃で25分間遠心した。PBMCを密度の界面からパスツールピペットで収集して、HBSSで3回洗浄して、ベックマンコールターカウンタを使用して計数した。
所定のMLRでは、2種類のHLAクラスII不一致患者のPBMCを10%熱不活性化ヒトAB血清(SIGMA)、L-グルタミン4nM、ペニシリン(100U/ml)およびストレプトマイシン(100μg/ml)(SIGMA)および指定された刺激細胞または応答細胞を含有するRPMI 1640媒体に再懸濁した。細胞は、1×細胞/ウェルの刺激細胞および1×10〜細胞/ウェルの応答細胞と共に応答細胞と刺激細胞の比が10:1になるように3連でプレートに入れた。ヤギ血清および様々な抗体によって引き出された細胞増殖に対する阻害効果を測定するために、希釈していないヤギ血清3μlまたは精製抗体1μlを、混合細胞培養物を含有するウェルに添加し、37℃で5%CO2において6日間インキュベートした。培養物はトリチウム標識メチルチミジン(3H-Thd、Amersham)1μCiで5日目の細胞収集18時間前にパルス標識した。Tomtec Harvester 96 Mach III細胞収集装置を使用してガラスファイバフィルターマット上に細胞を収集し、Wallac 1450 microbeta液体シンチレーションカウンターを使用して3H-Thdの取り込みを測定した。結果は1分当たりの平均計数として示す(cpm)。
ヤギ血清に存在する抗HLAクラスII抗体
多くがHLAと配列的および構造的に相同な配列を有するHIV-1 gp120の異なる領域から得られたHIV-1 gp120ペプチド(表1)を、異なるヤギ血清が認識できる範囲を調べた。これらのアッセイにおいて、溶解性HIV-1 gp120およびHLA-DR1もまた含めた。結果を図1から図9に示す。Bgはバックグラウンド値を示す。0.1を上回るOD値は、陽性結果として見なし、免疫前の血清ではいかなる抗原に対しても反応性は見られなかった。
図10および11のMLRでは、無作為なミスマッチ患者の細胞を使用した。これらは必ずしも増殖が最良ではなかったが(そのときは培地に問題があった)、ヤギ血清(それぞれの場合において元のHIV-3B免疫血清を使用した)によってMLRの増殖阻害が示される傾向が現れた。その後、増殖性のよいHLAクラスIIミスマッチ細胞(図12)を使用し始めた。抗HLA-DR抗体のように、ヤギ血清によって細胞増殖を完全に阻害することに成功し、抗炎症活性が示されることが可能である。
以下のデータは既に実施された同様の実験から得られたもので、通常の治療がもはや適していない多発硬化症およびAIDSに罹ったボランティアの治療形態として使用したヤギ血清中に抗HLA抗体を確認した。我々の研究では、治療後これらの患者の回復におけるヤギ血清について提案されている抗炎症作用機構を解明することが必要である。これは、以前抗HLA抗体が発見されたときに提案された。しかし、細胞がFAS受容体を発現して数時間以内にアポトーシスを誘導する能力があるとするならば、ここでこのヤギ血清には抗FAS抗体の役割が存在することを付け加える。
応答対象から得られたヤギ血清は混合リンパ球反応(MLR)に添加すると細胞に損傷を与えるという結果が得られる抗FAS抗体を探索し始めた。MLRは異なるHLA型の2人の別々のヒトから得られたリンパ球が非特異的方法で反応した結果で、リンパ球の増殖と代謝回転の増加が引き起こされる。自己免疫反応はいずれもHLAクラス2分子上に不適切に発現する自己ペプチドに対して生じるので、これは抗炎症抗体を試験するよい系であると思う。
他の変更として、抗体を得るための免疫原としてHIVウイルスを使用することは必要なく、ヒト白血球細胞を免疫原として使用して効果的な抗体調製物が得られる。図30は、HIVカクテル、およびSHULAと称するヒト白血球細胞で免疫したヤギ血清の特性を示す。
Claims (1)
- HIVの治療のためのヒトにおける使用のための医薬の調製における、ポリクローナルヤギ抗HLA抗体の使用。
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WO2001060156A1 (en) * | 2000-02-14 | 2001-08-23 | Gary R. Davis, M.D., L.L.C. | Neutralizing antibody and immunomodulatory enhancing compositions |
DE60035337T2 (de) * | 2000-05-12 | 2008-02-28 | Gpc Biotech Ag | Humane Peptide/Proteine, die das Töten von Zellen, einschliesslich lymphoider Tumorzellen, herbeiführen oder bewirken |
EP1156062A1 (en) * | 2000-05-12 | 2001-11-21 | GPC Biotech AG | Immunomodulatory human MHC class II antigen-binding peptides/proteins |
WO2002007760A2 (en) * | 2000-07-21 | 2002-01-31 | Ice Biologics Limited | Therapeutic agent against aids comprising anti hiv goat antibody |
US20100291102A1 (en) * | 2001-07-02 | 2010-11-18 | Ice Biologics Limited | Therapeutic Agent |
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