JP2015523970A - Gi症候群及び移植片対宿主病の治療方法 - Google Patents
Gi症候群及び移植片対宿主病の治療方法 Download PDFInfo
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- JP2015523970A JP2015523970A JP2015514243A JP2015514243A JP2015523970A JP 2015523970 A JP2015523970 A JP 2015523970A JP 2015514243 A JP2015514243 A JP 2015514243A JP 2015514243 A JP2015514243 A JP 2015514243A JP 2015523970 A JP2015523970 A JP 2015523970A
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Abstract
Description
本出願は、2012年5月25日に出願された仮出願番号61/651,729号の利益を主張し、35 U.S.C. § 119(e)の下、参照により、本明細書中に全体が明記されているかのように、その全内容が本明細書に組み込まれる。
本発明は、国立衛生研究所により授与された契約番号CA85704の下、政府の支援により行われた。政府は本発明について一定の権利を有する。
放射線は、依然として幅広い種類の悪性細胞に対する最も有効である治療の一つである。しかしながら、骨髄、毛包、表皮及び胃腸管の正常細胞は、放射線細胞死に極めて敏感であり、がんの治療のためのこの療法の効果的な使用が制限されている。放射線胃腸(GI)症候群は、放射線疾患がもたらす典型的な結果であり、それは放射線/核事故後に起こるかもしれない深刻な致死毒性である。核爆発又は核事故を介した放射性物質災害の可能性は長く存在し続けており、しかしながら、放射線散布機器を用いた攻撃の脅威により、安全かつ効果的な医学的放射線対策(MRC)の緊急性が増している。バイオシールド計画(The Project BioShield Act)及び保健社会福祉省は、有効なMRC緩和剤は、核災害24時間(これは、都市人口のかなりの部分に対して治療を動員するのに必要である最短時間を意味する)後に投与される場合でさえ、効果的であるべきだと推定する。放射線胃腸(GI)症候群(RGS)は、陰窩/絨毛ユニット内の腸幹細胞区画の破壊を伴う深刻な致死毒性であり、結果として粘膜露出、栄養素吸収の喪失及び常在細菌叢に対する脆弱性を生じる。臨床的には、RGSは、食欲不振、嘔吐、下痢、脱水症、全身性感染症、並びに極端な場合には敗血性ショック及び死を呈する。正常組織への放射線の効果の大規模な研究にもかかわらず、第一応答者、軍人又は汚染地区に入る修復労働者に対し使用可能な、放射線GI症候群に有効な予防用又は治療用緩和剤がない。
GI症候群、GvHD、放射線疾患、及びGI損傷と関連している特定の自己免疫疾患、並びに高レベルの内皮のアポトーシスを特徴とする状態、及びセラミドリッチプラットフォーム(CRP)の形成と関連している疾患などの動物の疾患(以下「列挙された疾患」)の予防及び治療に対する効率の良い手段が欠乏していることを含む、1以上の不足に先行技術が陥っていることを、我々は見出した。方法の多くは、列挙された疾患を治療する(「緩和する」を含む)ために使用されるであろうが、例えば対象への放射線照射前又は対象が移植を受ける前など十分に早く処置が行われる場合、対応する疾患(それぞれGI症候群又はGvHD)が予防されることがある。
一般に、本明細書中記載された、細胞及び組織培養、分子生物学、免疫学、微生物学、遺伝学、タンパク質及び核酸、化学、及びハイブリダイゼーションに関連して使用される命名並びにそれらの技術は、当技術分野において周知かつ通常使用されるものである。別段表示しない限り、本発明の方法及び技術は、おおむね、本明細書全体を通して引用し論じた、さまざまな一般的参考文献及びより具体的な参考文献に記載のとおり、当技術分野で周知の従来の方法に従って、行われる。例えば、Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989); Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992,及びSupplements to 2002); Harlow and Lan, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990); Principles of Neural Science, 第4版., 編者Eric R. Kandel, James H. Schwart, Thomas M. Jessell. McGraw-Hill/Appleton & Lange: New York, N. Y. (2000).を参照。別段明確にしない限り、本明細書使用する全ての技術及び科学用語は、当業者によって通常理解されるのと同一の意味を有する。
細胞外細胞表面セラミドは、放射線アポトーシスに必要である。
胃腸(GI)粘膜のクロノゲン区画は、放射線誘発性GI損傷の特異的及び直接の標的であると、長く受け入れられてきた。食欲不振、嘔吐、下痢、脱水症、全身性感染症、極端な場合は敗血性ショック及び死によって臨床的に特徴づけられる放射線胃腸(GI)症候群は、陰窩/絨毛ユニットの破壊、粘膜構造の喪失及び常在細菌叢による感染を伴う。(Hendry, J.H., Potten C.S., Roberts N.P. The gastrointestinal syndrome and mucosal clonogenic cells: relationships between target cell sensitivities, LD50 and cell survival, and their modification by antibiotics. Radiat Res. 1983; 96 (1): 100-112; Hendry, J.H., Roberts S.A., Potten C.S. The clonogen content of murine intestinal crypts: dependence on radiation dose used in its determination. Radiat Res. 1992; 132 (1): 115-119; Potten C.S., A comprehensive study of the radiobiological response of the murine (BDF1) small intestine. Int. J. Radiat Biol. 1990; 58 (6): 925-973.を参照)。従来の放射線生物学は、幹細胞クロノゲン(SCC)中の修復されない又は誤って修復されたDNA二本鎖切断を、不可逆的な組織損傷をもたらす自発性病変とみなしているが、我々の最近の研究はこのパラダイムに挑み、急性の内皮損傷もGI管損傷において重要な役割を果たすという遺伝的な証拠を示した(Paris F., et al., Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001; 293 (5528): 293-297; Rotolo J.A., Kolesnick R., Fuks Z. Timing of lethality from gastrointestinal syndrome in mice revisited. Int J Radiat Oncol Biol Phys. 2009; 73 (1): 6-8; Rotolo J.A., et al., Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys. 2008; 70 (3): 804-815)。放射線被ばくの数分以内に、内皮の酸性スフィンゴミエリナーゼ(ASMase)は活性化し、マウス及びヒト内皮の外側の細胞膜上でのセラミド生成を触媒してアポトーシスシグナル伝達を起こす(Stancevic B., Kolesnick R., Ceramide-rich platforms in transmembrane signaling. FEBS Lett. 2010; 584 (9): 1728-1740; Truman J.P., et al. Endothelial membrane remodeling is obligate for anti-angiogenic radio sensitization during tumor radiosurgery. PLoS One. 2010; 5 (9))。内皮は、他の哺乳動物細胞よりも20倍多くほぼ分泌型のみであるASMaseを提示し、そのため特にセラミド誘発性アポトーシスに対して弱い。(Marathe S., et al. Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling. J. Biol. Chem. 1998; 273 (7): 4081-4088; Santana P., et al., Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell. 1996; 86 (2): 189-199.)初期証拠は、内皮細胞のアポトーシスの結果生じる血管の障害により、放射線により傷害を受けたSCCのDNA損傷修復が損なわれ、SCCの死がもたらされることを示す。いくつかのマウス系統において、亜致死的(≦14 Gy)及び致死的(≧15 Gy)GI管損傷(5)のどちらも引き起こす線量を包含する8から15Gyの間で、内皮のアポトーシスは起こり、放射線照射後1時間で始まり、放射線照射後4から6時間で最大になる。(Maj J.G., Paris F., Haimovitz-Friedman A, Venkatraman E., Kolesnick R., Fuks, Z. Microvascular function regulates intestinal crypt response to radiation. Cancer Res. 2003; 63 (15): 4338-4341.)ASMase媒介性セラミド生成の遺伝的不活性化による腸の内皮のアポトーシスの軽減は、SCCの生存を高め、陰窩損傷の修復及びGI致死性から動物を救うことを促進する。(Paris, F., et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001; 293 (5528): 293-297); Rotolo, J.A., et al. Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys. 2008; 70 (3): 804-815.)これらの所見は、中和抗セラミドモノクローナル抗体を潜在的な放射線対策として開発する根拠を提供する。放射線は、胃腸微小血管系及び増殖している陰窩幹細胞の両方を標的とする。絨毛中の微小血管内皮のアポトーシスは、放射線の約4時間後に起こる、GI症候群の重要な病変である。内皮のアポトーシスにより、病変が陰窩クロノゲンに対して亜致死的から致死的なものに変わり、再生陰窩の喪失をもたらし、GI毒性を促進する。また、血管の機能障害と結びつく幹細胞クロノゲンへの直接の損傷がもたらす統合的な事象である、GI致死性をうむ幹細胞区画のDNA損傷の修復と内皮損傷が結びつくことも見出した。
セラミドシグナル伝達は、多くの種間で重要である
セラミド媒介性ラフトクラスタリングは、細菌及び病原体の内在化のシグナル伝達のための場所となる(D. A. Brown及びE. London, Annu Rev Cell Dev Biol 14, 111 (1998); J. C. Fanzo, M. P. Lynch, H. Phee et al., Cancer Biol Ther 2 (4), 392 (2003); S. Lacour, A. Hammann, S. Grazide et al., Cancer Res 64 (10), 3593 (2004); Semac, C. Palomba, K. Kulangara et al., Cancer Res 63 (2), 534 (2003); A. B. Abdel Shakor, K. Kwiatkowska, and 及びA. Sobota, J Biol Chem 279 (35), 36778 (2004); H. Grassme, V. Jendrossek, J. Bock et al., J Immunol 168 (1), 298 (2002); M. S. Cragg, S. M. Morgan, H. T. Chan et al., Blood 101 (3), 1045 (2003); D. Scheel-Toellner, K. Wang, L. K. Assi et al., Biochem Soc Trans 32 (Pt 5), 679 (2004); D. Delmas, C. Rebe, S. Lacour et al., J Biol Chem 278 (42), 41482 (2003); 及びC. Bezombes, S. Grazide, C. Garret et al., Blood 104 (4), 1166 (2004))。セラミド固有の生物物理学の特性により、セラミドは、様々な刺激に対するシグナル伝達において一般的な機能を持つセラミドリッチプラットフォーム(CRP)と称するシグナル伝達ドメインの形成に長けている。この理論は、様々な幾分無関係な細胞の刺激に対し応答して、CRPが形成されるという事実によっても支持されている(表1を参照)。
この新しい治療の方法は、高レベルの内皮のアポトーシス及び/又はセラミドリッチプラットフォーム(CRP)の形成を特徴とする他の状態と同様に、GI症候群、GvHD、放射線疾患、及びGI損傷と関連している特定の自己免疫疾患の治療において、特に有効である。そのような疾患は、表2に一覧表とした。これらの疾患の全てをまとめて列挙された疾患と呼ぶ。
図1に示すとおり、放射線照射の24時間後に精製したモノクローナル2A2抗セラミド抗体を単独で投与した時、マウスの生存は著しく改善した。抗体療法は、すぐに又はできるだけ早く、好ましくは放射線照射に先立ち2時間以内に、供給された場合、最も良く働く。もう一つの実験において、細菌複製の静止期及び増殖期のいずれにおいても、グラム陰性及びグラム陽性細菌のいずれに対しても有効性を実証されたフルオロキノロン、キノロン剤抗生物質エンロフロキサシン(以下「バイトリル」ともいう)で、照射されたマウスを治療した。マウスは、放射線照射の24時間後に0.57 mg/mlバイトリル含有飲水を自由に利用できるようにした。25 g C57BL/6マウスが飲水を約6ml日々消費するという概算量に基づき、日々消費したバイトリルの量は、1日あたり約3mg/動物であった。未治療のマウスは9日目までに死亡した一方で、エンロフロキサシンで治療したマウスの約25%は、80日間の研究の期間生存した。図2。
マウス2A2抗体のヒト化は、下記の実施例に記載されている。ELISA実験は、h2A2が選択的にセラミドに結合し(図5)、セラミドに対するh2A2の結合は、親m2A2抗体の結合を著しく上回り図6、かつ本発明の実施態様に使用され得る抗体でもある市販の抗セラミドモノクローナル IgM MID15B4(Enzo Life Sciences)で観察される結合に相当することを明らかにした。h2A2 IgG1のin vitroでの生物学的活性を、h2A2 IgG1の存在下又は非存在下で10 Gy電離放射線で曝露したヒトJurkat Tリンパ球を用いて決定した。m2A2 IgMは、これらの実験において、陽性コントロールとして使用した。結果は、h2A2が用量依存的にJurkat細胞の放射線誘発性アポトーシスを阻害したことを示した。重要なことに、アポトーシスの阻害は、親マウス2A2 IgMと比較して、左にシフトされており、h2A2組み換え抗体がより強力であることを示す。これらのデータは、h2A2は生物学的に活性であることを実証し、組み換えヒト化IgG1はin vivoで有効であろうことを示唆する。図7。
特定の実施態様は、対象において列挙された疾患を予防又は治療するのに十分な治療上又は予防上有効量の列挙された抗生物質及び抗体の医薬製剤を対象にする。これらの医薬組成物は、予防法又は治療法を必要としている対象に対する投与に適している。対象は、好ましくはヒトであるが、非ヒトでもあり得る。適した対象は、列挙された疾患の1つを有すると疑われる、有すると診断された又は発症する危険性がある個体であり得る。疾患の予防又は治療のため、抗体及び抗生物質の適切な用量は、治療される疾患の種類、重症度及び疾患の経過、予防又は治療の目的で薬剤が投与されるか否か、以前の治療法、投与経路、剤の薬物動態、患者の臨床履歴及び新しい薬剤(2A2抗体、など)への応答及び主治医の裁量に依存するであろう。
本明細書中使用される、抗セラミド抗体の「生物学的に活性な断片」は、セラミドに対する結合親和性を保持する任意の断片を意味する。該断片は、元となる抗体からの1以上のCDR領域を保持する。CDRは、抗原(すなわち、本出願の場合はセラミド)と結合する、抗体の部位であり、多くの場合において、その抗体特有である。断片が抗原との結合を保持するために、これらのCDRの少なくとも1つを有することが必要であろう。変異が、アミノ酸配列において、少なくとも75%、より好ましくは少なくとも80%、90%、95%及び最も好ましくは99%の配列同一性を維持し、セラミドとの結合親和性を保持するならば、生物学的に活性な断片は、微小な変異も含有してもよい。
「抗体」は、完全な免疫グロブリン、又は特異的な結合に対して完全な抗体と競合するその抗原結合部分を指す。抗原結合部分は、組み換えDNA技術により、又は完全な抗体の酵素切断もしくは化学開裂により、うみだされてもよい。本明細書中使用される用語「組み換えヒト抗体」は、(a)ヒト免疫グロブリン遺伝子のトランスジェニックである動物(例、マウス)から単離した抗体、(b)宿主細胞にトランスフェクトされた組み換え発現ベクターを用いて発現させた抗体、(c)組み換えコンビナトリアルヒト抗体ライブラリーから単離した抗体、及び(c)ヒト免疫グロブリン遺伝子配列を他のDNA配列につぎ合わせることを伴う他の任意の手法により、調製、発現、作製又は単離した抗体などの、組み換え手法により、調製、発現、作製又は単離される全てのヒト抗体を含むことを意図する。そのような組み換えヒト抗体は、ヒト生殖系列免疫グロブリン配列に由来する可変領域及び定常領域を有する。特定の実施態様において、しかしながら、そのような組み換えヒト抗体に、in vitro変異誘発(または、ヒトIg配列のトランスジェニックである動物が使用された場合、in vivo体細胞変異誘発)をさせ得、従って組み換え抗体のVH及びVL領域のアミノ酸配列は、ヒト生殖系列VH及びVL配列に由来する及び関連する一方、in vivoでヒト抗体生殖系列レパートリー中に天然に存在しないかもしれない配列である。抗原結合部分は、特にFab、Fab'、F(ab')2、Fv、dAb及び相補性決定領域(CDR)断片、単鎖抗体(scFv)、キメラ抗体、二重特異性抗体、並びに標的セラミドに対する特異的な抗原結合を授けるのに十分である、免疫グロブリンの少なくとも一部分を含有するポリペプチドを含む。T15ペプチドに対して化学的に共役した又はヒトIgG1骨格に遺伝子組み換えされたスーパー抗体を含むスーパー抗体も、抗体の定義に含まれる。(Y. Zhao, D. Lou, J. Burkett and H. Kohler. Enhanced Anti-B-cell Tumor Effects with Anti-CD20 SuperAntibody. J Immunotherapy, 25: 57-62, 2002.を参照。免疫グロブリンサブタイプは、任意のサブタイプであり得る。通常IgG及びIgMを使用するが、IgA、IgEなどが効果的であることがある。
抗体である。本明細書中使用される「単離した抗体」は、異なる抗原特異性を有する他の抗体を実質的に含まない抗体を指すことを意図する。さらに、単離した抗体は、他の細胞の材料及び/又は化学物質を実質的に含まなくてもよい。本発明の1つの実施態様において、異なる特異性を有する「単離した」抗セラミド抗体の組み合わせは、詳細に明らかにされた組成物中で、組み合わせられる。本発明の実施態様は、単離した抗体を使用する。
強力なin vivo活性をもつ新規抗セラミド抗体を作製するために用いられる戦略の流れ図を、図4に示す。2A2を含むモノクローナル抗体は、当技術分野で公知であり、PCT/US08/62789にさらに詳細に記載した方法を用いて作った。該抗体を作るために、接種された宿主から強力な抗体応答を生み出すのに十分な免疫原性である、セラミド抗原を開発した。スフィンゴイド塩基上にBSA共役C16脂肪酸を合成することにより、BSA共役セラミドを作製した。抗原の量を減少させ、プレートに固定して、抗体スクリーニングのための抗原の検証をELISAアッセイにより行った。各ウェルをブロッキング後、Axxora LLC、San Diego、Californiaから市販されている抗セラミドMID15B4抗体(1:100)と共にプレートをインキュベートし、続いて西洋ワサビペルオキシダーゼ(HRP)共役抗マウスIgMと共にインキュベートした。HRP基質の投与後に、650 nmでODを評価した。BSAセラミドELISAにより、カポジ肉腫細胞でマウスに免疫付与した後の上清#3673中に、増強された結合活性を同定した。結合活性は、抗セラミド結合活性をもつモノクローナル2A2 IgMの単離を可能とする、抗体を産生するB細胞の不死化の後にも残存した(図示せず)。カポジ肉腫細胞での免疫付与は、抗体を産生するB細胞のパネルの作製をもたらす強力な免疫応答を生み出すことを意図する。その後、これらのB細胞から生み出されたハイブリドーマからの抗体含有上清を、BSAセラミドELISAに対して、スクリーニングした。アッセイにおいて検査で陽性であった上清を単離し、最終的にクローン2A2の精製がもたらされた。
実施例1: 材料及び方法
TBI(全身放射線照射)は防護研究のためのみに用い、緩和研究用のSBIは、137Csソースを操作するShepherd Mark-Iユニット(モデル68、SN643)を用いて提供された。線量率は、2.12Gy/分であった。小腸の試料を採取するため、高炭酸ガス窒息によりマウスを屠殺し、近位空腸の2.5cmの断片を、トライツ靱帯から2cmにおいて採取した。組織試料を、4%中性緩衝ホルムアルデヒド中での一晩のインキュベーションにより固定し、パラフィンブロックに包埋した。腸組織の放射線に対する応答を評価するため、完全な空腸周囲の横断切片(厚さ5マイクロメートル)を、ミクロトーム法によって、パラフィンブロックから得て、ポリリジン処理したスライドに付着させ、摂氏90度で10分間及び摂氏60度で5分間加熱することにより脱パラフィンさせ、続いて5分間のキシレン洗浄を2回行い、標準プロトコルに従って、ヘマトキシリン及びエオシンを用いて染色した。TBI後に死因を決定するために、動物の死亡から60分以内、又は末期呼吸パターンを示す末期症状の動物を高炭酸ガス窒息により屠殺した時に、剖検を行った。全ての動物から組織標本を採取し、ホルムアルデヒド中で固定し、ヘマトキシリンを用いて染色した。
生命表法による動物の生存を、積極限カプラン・マイヤー方法により算出した。末期呼吸パターンを示す末期症状の動物は、高炭酸ガス窒息により屠殺し、死因を決定するため剖検により評価した。腸の標本をホルムアルデヒド中で固定し、ヘマトキシリンを用いて染色した。小腸が一見すると絨毛(villae)又は陰窩がほとんどない露出粘膜を示す場合、又は粘膜が限られた粘膜修復を示す場合、GI損傷が死因として診断され得る。Kaplan, E.L. and P. Meier, Nonparametic estimation from incomplete observations. J of the American Statistical Association, 1958. 53: p. 457-48; Rotolo, J.A., et al., Bax and Bak do not exhibit functional redundancy in mediating radiation endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys, 2008. 70(3): p. 804-15。
ヒト化2A2抗体の作製方法
モノクローナルマウス2A2抗体の作製方法は、PCT/US08/62789に記載されている。
一番目のイタリック体:: 可変重鎖配列
二番目の下線: CH1配列
二番目のイタリック体: ヒンジ配列
三番目の下線: CH2及びCH3配列
角括弧配列=可変重鎖配列
NYWMH=CDR
LYYGYD=CDR
二番目の下線: CH1配列
二番目のイタリック体: ヒンジ配列
三番目の下線: CH2及びCH3配列
一番目のイタリック体: 可変軽鎖配列
二番目の下線: 欠失したアミノ酸
二番目のイタリック体: 定常kappa軽鎖配列
角括弧=可変軽鎖配列
KSSQSLIDSDGKTFLNW=CDR配列
LVSKLDS = CDR配列
WQGTHFPYT =CDR配列
二番目の下線を引いた配列 = 欠失したアミノ酸
一番目のイタリック体: 定常kappa軽鎖配列
Claims (22)
- 移植片対宿主病、放射線疾患、GI症候群、及びGI損傷と関連している自己免疫疾患、内皮のアポトーシスと関連している疾患、及びセラミドリッチプラットフォームの産生と関連している疾患から成る群より疾患が選択され、抗セラミド抗体又はその生物学的に活性な断片、及びグラム陰性細菌に対して有効な抗生物質を、予防上又は治療上有効量投与することを含む、動物の疾患の予防又は治療の方法。
- 抗生物質が、グラム陰性に対して有効である広域スペクトル抗生物質である請求項1記載の方法。
- 抗生物質が、エンロフロキサシン(バイトリル)、シプロフロキサシン(すなわち、シプロ及びプロキン)、エノキサシン(すなわち、ペネトレックス)、ガチフロキサシン(すなわち、ガチフロ、テキン及びザイマール(Zymar))、ゲミフロキサシン(すなわち、ファクティブ)、レボフロキサシン(すなわち、レバキン)、ロメフロキサシン(すなわち、マキサキン)、モキシフロキサシン(すなわち、アベロックス)、ノルフロキサシン(すなわち、ノロキシン)、オフロキサシン(すなわち、フロキシン(Floxin))、プルリフロキサシン、スパルフロキサシン(すなわち、ザガム)、トロバフロキサシン/アルトロフロキサシン(すなわち、トロバン)、ダノフロキサシン(すなわち、A180)、ジフロキサシン(すなわち、ジクラール)、マルボフロキサシン(すなわち、オーバックス)、オルビフロキサシン(すなわち、ゼニクイン)、ナリジクス酸(Naldixic acid)(すなわち、ネググラム)、シノキサシン(すなわち、シノバック(Cinobac))、フルメキン、ナリジクス酸、オキソリン酸、ピペミド酸、ピロミド酸、ロソキサシン、フレロキサシン ペフロキサシン、ルフロキサシン、バロフロキサシン、グレパフロキサシン、パズフロキサシン、テマフロキサシン、トスフロキサシン、ベシフロキサシン、クリナフロキサシン、ガレノキサシン、シタフロキサシン、イバフロキサシン、プラドフロキサシン及びサラフロキサシンから成る群より選択されるキノロン剤抗生物質である、請求項1記載の方法。
- 抗体がモノクローナル抗体である、請求項1記載の方法。
- モノクローナル抗体が、1H4、15D9及び5H9から成る群より選択される、請求項4記載の方法。
- 抗体が、h2A2ヒト化マウスモノクローナル抗体である、請求項1記載の方法。
- 抗体が、2A2 IgG又はIgMヒト化マウスモノクローナル抗体である、請求項6記載の方法。
- 方法が放射線疾患又はGI症候群の予防又は治療のためであり、動物の放射線照射前又は後のいずれかに抗体及び抗生物質を投与する、請求項1記載の方法。
- 方法が移植片対宿主病(GvHD)の予防であり、動物が移植を受ける前又は後のいずれかに抗体及び抗生物質を投与する、請求項1記載の方法。
- 移植片が造血幹細胞移植である、請求項9記載の方法。
- モノクローナル抗体が、セラミドと交差反応し、かつモノクローナル抗体を分泌するハイブリドーマをつくるために使用される脾臓細胞が全カポジ肉腫(KS)で免疫された動物から得られる、請求項4記載の方法。
- 抗セラミド抗体又はその生物学的に活性な断片、及びグラム陰性細菌に対して有効な抗生物質を含み、医薬上許容される担体中に調合される医薬組成物。
- 抗生物質が、グラム陰性細菌に対して有効な広域スペクトル抗生物質である、請求項12記載の組成物。
- 抗生物質が、エンロフロキサシン(バイトリル)、シプロフロキサシン(すなわち、シプロ及びプロキン)、エノキサシン(すなわち、ペネトレックス)、ガチフロキサシン(すなわち、ガチフロ、テキン及びザイマール(Zymar))、ゲミフロキサシン(すなわち、ファクティブ)、レボフロキサシン(すなわち、レバキン)、ロメフロキサシン(すなわち、マキサキン)、モキシフロキサシン(すなわち、アベロックス)、ノルフロキサシン(すなわち、ノロキシン)、オフロキサシン(すなわち、フロキシン(Floxin))、プルリフロキサシン、スパルフロキサシン(すなわち、ザガム)、トロバフロキサシン/アルトロフロキサシン(すなわち、トロバン)、ダノフロキサシン(すなわち、A180)、ジフロキサシン(すなわち、ジクラール)、マルボフロキサシン(すなわち、オーバックス)、オルビフロキサシン(すなわち、ゼニクイン)、ナリジクス酸(Naldixic acid)(すなわち、ネググラム)、シノキサシン(すなわち、シノバック(Cinobac))、フルメキン、ナリジクス酸、オキソリン酸、ピペミド酸、ピロミド酸、ロソキサシン、フレロキサシン ペフロキサシン、ルフロキサシン、バロフロキサシン、グレパフロキサシン、パズフロキサシン、テマフロキサシン、トスフロキサシン、ベシフロキサシン、クリナフロキサシン、ガレノキサシン、シタフロキサシン、イバフロキサシン、プラドフロキサシン及びサラフロキサシンから成る群より選択されるキノロン剤抗生物質である、請求項12記載の組成物。
- 抗体がモノクローナル抗体である、請求項12記載の組成物。
- モノクローナル抗体が、1H4、15D9、5H9、及び2A2及びそのヒト化型、及びh2A2、 2A2 IgM及び1H4から成る群より選択される一員である、請求項15記載の組成物。
- さらにスタチンを含む、請求項12記載の医薬組成物。
- さらにイミプラミンを含む、請求項12記載の医薬組成物。
- 抗セラミド抗体の予防上及び治療上有効量が約0.1 mg/kgから約100 mg/kgであり、かつ抗生物質の予防上及び治療上有効量が約0.1 mg/kgから約100 mg/kgである、請求項1記載の方法。
- 抗セラミド抗体の量が約100 mg/kgから約1000 mg/kg、かつ抗生物質の予防上及び治療上有効量が約100 ug/mlから約1000 ug/mlである、請求項12記載の医薬組成物。
- セラミドに結合する予防上又は治療上有効量のミモトープ並びにグラム陰性細菌に対して有効である抗生物質を投与することを含み、疾患が、移植片対宿主病、放射線疾患、GI症候群、及びGI損傷と関連している自己免疫疾患、内皮のアポトーシスと関連している疾患、及びセラミドリッチプラットフォームの産生と関連している疾患から成る群より選択される動物の疾患の予防又は治療方法。
- ヒト化抗セラミド抗体h2A2、及びその生物学的に活性な断片。
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