JP5856744B2 - クロロトキシンとの併用化学療法 - Google Patents
クロロトキシンとの併用化学療法 Download PDFInfo
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- JP5856744B2 JP5856744B2 JP2011052039A JP2011052039A JP5856744B2 JP 5856744 B2 JP5856744 B2 JP 5856744B2 JP 2011052039 A JP2011052039 A JP 2011052039A JP 2011052039 A JP2011052039 A JP 2011052039A JP 5856744 B2 JP5856744 B2 JP 5856744B2
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- cancer
- chlorotoxin
- amino acid
- therapeutic agent
- cancer therapeutic
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
- C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
- C07K14/43522—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from scorpions
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Description
本出願は、どちらも参照によりその全体が本明細書に組み入れられている、米国仮出願第60/406,033号(2002年8月27提出)及び米国仮出願第60/384,171号(2002年5月31日提出)の利益を請求する。
[発明の分野]
[発明の背景]
[発明の概要]
[詳細な説明]
本発明は、化学療法薬と組合された、異常な細胞増殖の阻害において化学療法薬の効果を向上させるのに有効である(すなわち、化学療法薬のためのアジュバントとして作用する)クロロトキシン又はクロロトキシン誘導体の量及び薬学的に許容される担体を含む、ヒトを含む哺乳動物における異常な細胞増殖の治療のための医薬組成物を含む。
HHHHHHMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR(配列番号2)、
YMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR(配列番号3)、
YSYMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR(配列番号4)。
MCMPCFTTDHQMARKCDDCCGGKGRGKCFGPQCLCR(配列番号5)、
RCKPCFTTDPQMSKKCADCCGGKGKGKCYGPQCLC(配列番号6)、
RCSPCFTTDQQMTKKCYDCCGGKGKGKCYGPQCICAPY(配列番号7)。
クロロトキシン誘導体の別のクラスにおいて、本発明は、クロロトキシンの三次元構造を模倣するペプチドミメティクスを含む。そのようなペプチドミメティクスは、例えばより経済的な生産、より大きい化学安定性、向上した薬理特性(半減期、吸収、効力、有効性など)、変化した特異性(例えば広範囲の生物活性)、低下した抗原性及びその他を含む、自然発生ペプチドに勝る顕著な利点を有することがある。
本発明の医薬組成物は、非経口、皮下、静脈内、筋肉内、腹腔内、経皮又は頬部経路を通じて投与することができる。例えば薬剤は、マイクロインジェクションにより腫瘍に局所投与される。代わりに、又は同時に、投与は経口経路によって投与される。例えばクロロトキシン又はその誘導体は、腫瘍の部位に局所的に投与可能であり、少なくとも1つの化学療法薬の経口投与が続く。クロロトキシンの事前投与は、好結果の処置に必要な化学療法薬の量を減少させ、それゆえ化学療法薬に関連する重篤な副作用を減少させる効果を有する。投与される投薬量は、レシピエントの年齢、健康状態及び体重、もしあれば同時治療の種類、治療の頻度、及び所望の効果の性質に依存するであろう。
本発明は、通常、自然に見られる原子質量又は質量数とは異なる原子質量又は質量数を有する原子によって置換される1つ以上の原子を有する、同位体標識クロロトキシン又はその誘導体も含む。本発明の化合物中に組み入れることができる同位体の例は、水素、炭素、フッ素、リン、ヨウ素、銅、レニウム、インジウム、イットリウム、テクネチウム及びルテチウム(すなわち3H、14C、18F、19F、31P、32P、35S、131I、125I、123I、64Cu、187Re、111In、90Y、99mTc、177Lu)を含む。一部の実施形態において、金属(例えば銅、レニウム、インジウム、イットリウム、テクネチウム及びルテチウム)である同位体は、クロロトキシン又はその誘導体にキレート化によって非共有結合的に結合している。本発明に含まれるキレート化の例は、クロロトキシン又はその誘導体に融合されるポリヒスチジン(polyHis)領域への金属同位体のキレート化である。非金属同位体は、許容されるいずれかの手段を使用して、クロロトキシン又はその誘導体に共有結合される。
本発明は、上記哺乳動物に、化学療法薬の前に、又はそれに続いて投与されるときに化学療法薬の効果を向上させるのに有効である(すなわち化学療法薬のアジュバントとして作用する)クロロトキシン又はその誘導体の量、或いはクロロトキシン又はその誘導体の量を含む医薬組成物を投与することを含む、ヒトを含む哺乳動物における異常な細胞増殖の治療のための方法も含む。この方法の1つの実施形態において、異常な細胞増殖は、これに限定されるわけではないが、肺癌、骨肉腫、肝臓癌、膵臓癌、皮膚癌、頭頚部癌、皮膚又は眼内メラノーマ、子宮癌、卵巣癌、直腸癌、肛門部の癌、胃癌、大腸癌、乳癌、子宮癌、卵管癌、子宮内膜癌、子宮頚癌、膣癌、外陰癌、ホジキン病、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、軟部組織肉腫、尿道癌、陰茎癌、前立腺癌、慢性又は急性白血病、リンパ球性リンパ腫、膀胱癌、腎臓又は尿管の癌、腎細胞癌、腎盂癌、中枢神経系(CNS)の腫瘍、神経外胚葉性癌、脊髄軸腫瘍、神経膠腫、髄膜腫、下垂体腺腫、或いは上述の癌の1つ以上の組合せを含む、癌である。上記方法の別の実施形態において、上記の異常な細胞増殖は、これに限定されるわけではないが、良性前立腺肥大、過形成又は再狭窄を含む良性増殖性疾患である。
本発明は、癌などの異常細胞増殖に関連する疾患の治療のための、放射線治療と併用したクロロトキシン又はその誘導体の投与を含む治療方法を含む。特に、治療は、癌細胞でのアポトーシス(細胞死)を誘導するように設計されているが、転移の発生又は回数の減少、及び腫瘍サイズの減少も考慮される。放射線治療剤に対する腫瘍細胞の抵抗力は、臨床腫瘍学において主要な問題となっている。それゆえ本発明に照らして、クロロトキシンとの併用療法は、放射線治療の有効性を向上させるために放射線耐性腫瘍に対して使用できることが、考慮される。
本発明は、患者の臓器又は体の部分における異常な細胞増殖の存在及び位置の決定のための診断方法を含む。本方法の実施形態において、異常な細胞増殖は、これに限定されるわけではないが、肺癌、骨肉腫、肝臓癌、膵臓癌、皮膚癌、頭頚部癌、皮膚又は眼内メラノーマ、子宮癌、卵巣癌、直腸癌、肛門部の癌、胃癌、大腸癌、乳癌、子宮癌、卵管癌、子宮内膜癌、子宮頚癌、膣癌、外陰癌、ホジキン病、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、軟部組織肉腫、尿道癌、陰茎癌、前立腺癌、慢性又は急性白血病、リンパ球性リンパ腫、膀胱癌、腎臓又は尿管の癌、腎細胞癌、腎盂癌、中枢神経系(CNS)の腫瘍、神経外胚葉性癌、脊髄軸腫瘍、神経膠腫、髄膜腫、下垂体腺腫、或いは上述の癌の1つ以上の組合せを含む、癌である。
インビトロでの化学療法薬活性の決定
各種の化学療法薬の、複数の癌細胞系(表1を参照)に対する効果を試験するために、組織培養方法を最適化した。細胞は、具体的な細胞系に応じて、96ウェルマイクロタイター組織培養プレートに1ウェル当たり約1000〜2000細胞の密度で播種した。細胞は、5%の二酸化炭素を供給した37℃の加湿細胞培養インキュベータ内で付着させた。各細胞系での各薬物の用量反応曲線を得るために、細胞を、特定の細胞毒性化合物の減少する濃度によって2〜5日間処置した。処置の後、薬物の細胞毒性効果は、メーカーの説明書に従って、細胞カウントキット−8(CCK−8)(Dojindo Inc.)を用いて定量した。手短に言えば、細胞毒性薬による処置期間の後、細胞はCCK−8試薬とインキュベートし、特定の細胞種に応じて1〜4時間に渡って37℃にてインキュベートした。インキュベーションの後、プレートをマイクロプレートリーダーで波長490nmにて読取った。各薬物のIC50を薬物の負の対数濃度対平均光学密度のX−Y分散プロットから計算した(表2)。
インビトロでの化学療法薬活性に対するクロロトキシンの効果
化学療法薬に対するクロロトキシンの薬理効果の測定のために、実施例1の細胞培養方法を、以下の修正を行い利用した:IC50に接近しているが、通常そのすぐ下である、化学療法薬の濃度を各アッセイで使用した。次に、クロロトキシンの各種の量をそのIC50の付近又はそれ以下の化学療法薬の濃度と併用して測定し、化学療法薬の細胞毒性効果に対するクロロトキシンの効果を投与の2〜3日後に測定した。このアッセイで利用したクロロトキシンの濃度は、マイクロモルからナノモル濃度の範囲であった。
インビボでの化学療法薬の活性に対するクロロトキシンの効果
この研究の目的は、神経膠腫細胞系を用いたインビトロでの研究から示されるように、クロロトキシンと併用したヒドロキシウレア又はテモダールが腫瘍成長を阻害するのに十分であるかどうかを判断することである。他の研究は、ヒト癌細胞系とプレインキュベートされたクロロトキシンが細胞を、化学療法的腫瘍細胞死滅剤であるテモダールに対して大きく感作させることを示した。神経膠腫脇腹腫瘍を有するマウスにおける、クロロトキシンを用いたヒドロキシウレア又はテモダールとの併用処置を、ヒドロキシウレア又はテモダール単独及び生理食塩水単独の処置群と比較した。ヒドロキシウレア及びテモダール投薬量は、ヌードマウスでの鎌状細胞死の典型例の処置における体からのクリアランスを決定するために前の研究で使用した最低投薬量(10mg/kg体重)に基づいていた(Iyamu et al.(2001) Chemotherapy 47,270−278)。
標識クロロトキシンを用いたPET撮影研究
以下の例示的な手順は、診療所内の患者に対してPET撮影研究を実施するときに利用できる。患者は、水分摂取は随意にさせて少なくとも12時間絶食させ、実験日に筋肉内注射されたアセプロマジン0.3〜0.4mlを前投与する。放射性標識クロロトキシンの投与のために、20ゲージ、2インチの静脈内カテーテルを対側尺骨静脈に挿入する。
D54グリア芽腫細胞を96ウェル平底プレートに約1000細胞/ウェルの濃度で播種し、5%CO2中37℃にてインキュベートした。24時間後に、クロロトキシンを1:4制限希釈にて、最終濃度20、5、1.25、0.313、0.078、0.0195、0.0049、0.0012、0.00031又は0.00008nMまで添加した。対照細胞にはビークルのみ与えた。処置の24時間後、クロロトキシンの効果は、メーカーの説明書に従って、細胞カウントキット−8(CCK−8)(Dojindo Inc.)によりMTTミトコンドリア酵素基質を用いて定量した。手短に言えば、クロロトキシンによる処置期間の後、細胞をCCK−8試薬とインキュベートした。インキュベーションの後、プレートをマイクロプレートリーダーで波長490nmにて読取り、より高い吸収はより高い細胞生存能力を示した。図4は、クロロトキシンのインキュベーションが、より小さい数の生存細胞/ウェル対PBS対照によって証明されるように、0.00120nMまでの試験したすべての濃度においてD54細胞の増殖を阻害したことを示す。
D54グリア芽腫細胞を96ウェル平底プレートに約1000細胞/ウェルの濃度で播種し、5%CO2中37℃にてインキュベートした。24時間後に、クロロトキシンを1:4制限希釈にて、最終濃度20、5、1.25、0.313、0.078、0.02、0.0049、0.0012、0.0003又は0.00008nMまで添加した。対照細胞にはビークルのみ与えた。24時間後、細胞の半分をクロロトキシンがないように洗浄し、培地を新しい培地と交換した。クロロトキシンが残っている及びクロロトキシンを除去した両方の条件の細胞を、更に4日間インキュベートした。インキュベーションの後、実施例1と同様にCCK−8によりMTTミトコンドリア酵素基質を用いて、クロロトキシンの効果を定量した。図5は、長いインキュベーション時間が、追加の増殖日数によって細胞にクロロトキシンの効果を克服させ、この例ではクロロトキシンが細胞増殖を阻害するように見えないことを示している。
PC3前立腺癌細胞を96ウェル平底プレートに約1000細胞/ウェルの濃度で播種し、5%CO2中37℃にてインキュベートした。24時間後に、クロロトキシンを1:2制限希釈にて、最終濃度(nM)20、10、5、2.5、1.25、0.625、0.313、0.156、0.078、及び0.039まで添加した。対照細胞にはPBSビークルのみ与えた。処置の24時間後、実施例1と同様にCCK−8によりMTTミトコンドリア酵素基質を用いて、クロロトキシンの効果を定量した。図6は、クロロトキシンのインキュベーションが、より小さい数の生存細胞/ウェル対PBS対照によって証明されるように、試験したすべての濃度においてD54細胞の増殖を阻害したことを示す。
胸腺欠損ヌードマウス8匹の3つのグループに、右脇腹にヒトD54グリア芽腫細胞5×107の皮下注射を与えて、これらのマウスにヒト神経膠腫の脇腹への異種移植を生じさせた。グループI及びIIIの動物には、D54注射の14、21、28、35、42及び49日後に100μlのリン酸緩衝生理食塩水中のクロロトキシン(配列番号1)2.6μgを静脈内に与えた。グループII及びIIIの動物には、D54注射の15、22、29、36、43及び50日後に2Gy60C全身照射を与えた。腫瘍サイズは、週3回測定し、図7に示す。
胸腺欠損ヌードマウスでの頭蓋内D54MG神経膠腫異種移植は、被験者の脳へのD54MG細胞1×106個の移植によって確立させた。処置計画は、移植の14日後に、尾静脈内注射によって週2回で開始した。マウス7匹の対照グループには生理食塩水ビークルのみを投与した。動物8匹を含むマウスの第二のグループにはそれぞれ、0.2μg/用量の、低用量のクロロトキシンを投与し、動物8匹を含むマウスの第三のグループには、2.0μg/用量の、高用量のクロロトキシンを投与した。動物は死まで追跡し、生存時間をKaplan−Meierチャートにプロットして、生存期間の中央値を示した(図8)。これらの結果は、クロロトキシン単独での処置が、実質的に頭蓋内モデルの被験者の生存を延長させること、及びこの延長した生存が用量依存性であることを示している。クロロトキシンの投与は静脈内であることは注目に値し、クロロトキシンは血液脳関門を通過してその効果を発揮することが証明される。
別個の調査で、D54MG神経膠腫異種移植は、胸腺欠損ヌードマウスの脇腹にD54MG細胞1×106個を移植することにより、末梢的に確立した。腫瘍は14日目に触診可能であり、個々の腫瘍の体積は約43mm3であった。再び処置計画は、移植の14日後に、尾静脈内注射によって週2回で開始した。マウス7匹の対照グループには生理食塩水ビークルのみを投与した。動物8匹を含むマウスの第二のグループには、それぞれ0.2μg/用量の低用量のクロロトキシンを投与した。各注射時に腫瘍サイズを測定し、元の腫瘍サイズのパーセントとしてプロットした(図9)。静脈内処置は42日目に終了し、腫瘍の測定を数週間継続した。これらの結果は、低用量クロロトキシンが単独で、この脇腹モデルでの腫瘍成長を劇的に減少できることを証明している。
クロロトキシンのコア結合部位配列を同定するために、図10に示すようにペプチドのC末端から開始する、配列番号1に由来する27の重複10merを合成した。各ペプチドは、検出を促進するためにアミノ末端に結合したビオチンを有しており、架橋を防止するために各システイン残基はセリンと置換された。
これらの同定された結合領域のインビボ活性を決定するために、配列番号1の10merペプチド5(アミノ酸残基23−32)、12(アミノ酸残基16−25;陰性対照として)及び21(アミノ酸残基7−16)を、クロロトキシンの生物活性を決定するために一般に使用されるアッセイである、ザリガニ麻痺アッセイで使用した(DeBin et al.(1993)Am.J.Physiol.264,C361−369を参照)。ペプチド5及び12は、ザリガニを麻痺させることができなかったが、一方ペプチド21は有効であり、クロロトキシンの麻痺効果に関与する部位がペプチド21によって定義された領域であることを示唆した。
クロロトキシンは、8つのシステインを備えた36アミノ酸ペプチドであり、以下に下線を付けた実施例12の重複10merを使用して同定された、ペプチド番号8(ベータ領域ペプチド)及びペプチド番号21(アルファ領域ペプチド)の配列を用いてボールド体で以下に表す:
MCMPCFTTDHQMARKCDDCCGGKGRCKCYGPQCLCR(配列番号1)
アルファペプチドの結合特性への各残基の寄与を決定するために、アラニン走査変種を、表7に示すように9merペプチドTDHQMARKS(配列番号10)の各アミノ酸を順次置換することによって合成した。ペプチド21、自然コア9mer、及び各アラニン置換9merペプチドは、アミノ末端におけるビオチンによって合成し、それらの結合対U251及びPC3細胞の両方について評価した(図13)。
MCMPCFTTAHAMARKCDDCCGGKGRCKCYGPQCLCR(配列番号12)
ショートスコーピオントキシンの結合を比較するために、スモールトキシン及び考えられる毒素(Probable toxin)LQH−8/6のペプチド21に相同である領域を合成し、クロロトキシン結合アッセイでの解析のためにビオチン化した(ペプチドのアミノ酸配列については表8を参照)。
この実験の目的は、D54MGグリア芽腫細胞の増殖が、3H−チミジン取込みによって測定されるように、全長クロロトキシン配列の断片である、ペプチド21によって実施されるかどうかを判定することであった。ペプチド21の配列及びそのクロロトキシンとの関係を以下の配列に示す:
クロロトキシン: MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
ペプチド21: TTDHQMARK(配列番号82)
Claims (16)
- 癌治療剤であって、
単離されたポリペプチドを第1の薬剤として、有子分裂阻害剤を第2の薬剤として含み、
前記単離されたポリペプチドのアミノ酸配列は、配列番号1の全長とは異なるが、少なくとも90%のアミノ酸配列同一性を示し、アミノ酸配列TDHQMARKS(配列番号10)、アミノ酸配列KGRGKSY(配列番号8)又はこれらの変異体を含み、前記変異体は1〜3個のアミノ酸の挿入又は置換を含み、前記単離されたポリペプチドは、正常細胞と比較して癌細胞に対して特異的に結合するというクロロトキシン生物活性を有し、
2つの薬剤は同時に投与されるか、又は同時に作用するように独立に投与されるためのものであり、少なくとも前記単離されたポリペプチドは静脈内投与されるものであり、
癌は、多形性グリア芽腫及び前立腺癌からなる群のひとつである、
癌治療剤。 - 有糸分裂阻害剤が、チューブリン重合崩壊剤又は安定化剤である、請求項1に記載の癌治療剤。
- チューブリン重合崩壊剤又は安定化剤が、タキサンである、請求項2に記載の癌治療剤。
- タキサンが、パクリタキセル、ドセタキセル及びこれらの組合せからなる群より選択される、請求項3に記載の癌治療剤。
- タキサンがパクリタキセルである、請求項4に記載の癌治療剤。
- 有糸分裂阻害剤が、ビンカアルカロイドである、請求項1に記載の癌治療剤。
- ビンカアルカロイドが、ビンクリスチン又はビンブラスチンである、請求項6に記載の癌治療剤。
- 癌治療剤であって、
単離されたポリペプチドを第1の薬剤として、ピリミジン拮抗剤を第2の薬剤として含み、
前記単離されたポリペプチドのアミノ酸配列は、配列番号1の全長とは異なるが、少なくとも90%のアミノ酸配列同一性を示し、アミノ酸配列TDHQMARKS(配列番号10)、アミノ酸配列KGRGKSY(配列番号8)又はこれらの変異体を含み、前記変異体は1〜3個のアミノ酸の挿入又は置換を含み、前記単離されたポリペプチドは、正常細胞と比較して癌細胞に対して特異的に結合するというクロロトキシン生物活性を有し、
2つの薬剤は同時に投与されるか、又は同時に作用するように独立に投与されるためのものであり、少なくとも前記単離されたポリペプチドは静脈内投与されるものであり、
癌は、多形性グリア芽腫及び前立腺癌からなる群のひとつである、
癌治療剤。 - ピリミジン拮抗剤がゲムシタビンである、請求項8に記載の癌治療剤。
- 癌治療剤であって、
単離されたポリペプチドを第1の薬剤として、白金化学療法剤を第2の薬剤として含み、
前記単離されたポリペプチドのアミノ酸配列は、配列番号1の全長とは異なるが、少なくとも90%のアミノ酸配列同一性を示し、アミノ酸配列TDHQMARKS(配列番号10)、アミノ酸配列KGRGKSY(配列番号8)又はこれらの変異体を含み、前記変異体は1〜3個のアミノ酸の挿入又は置換を含み、前記単離されたポリペプチドは、正常細胞と比較して癌細胞に対して特異的に結合するというクロロトキシン生物活性を有し、
2つの薬剤は同時に投与されるか、又は同時に作用するように独立に投与されるためのものであり、少なくとも前記単離されたポリペプチドは静脈内投与されるものであり、
癌は、多形性グリア芽腫及び前立腺癌からなる群のひとつである、
癌治療剤。 - 白金化学療法剤がシスプラチンである、請求項10に記載の癌治療剤。
- シスプラチンが、シス−プラチン、シス−ジアミンジクロロプラチナ、プラチノール(商標)及びこれらの組合せから選択される、請求項11に記載の癌治療剤。
- 第1の薬剤が、第2の薬剤の投与と同時に投与されるためのものである、請求項1〜12のいずれか一項に記載の癌治療剤。
- 第1の薬剤が、第2の薬剤とコンジュゲートを形成している、請求項13に記載の癌治療剤。
- 第1の薬剤が、第2の薬剤の投与の前に投与されるためのものである、請求項1〜12のいずれか一項に記載の癌治療剤。
- 第1の薬剤が、第2の薬剤の投与に続いて投与される、請求項1〜12のいずれか一項に記載の癌治療剤。
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SK282452B6 (sk) * | 1993-01-14 | 2002-02-05 | Cancer Research Campaign Technology Limited | Kombinovaný farmaceutický prostriedok na liečbu ľudských nádorových buniek, použitie O6-benzylguanínu a temozolomidu na jeho prípravu a farmaceutický kit |
US5626862A (en) * | 1994-08-02 | 1997-05-06 | Massachusetts Institute Of Technology | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
US5756340A (en) * | 1995-05-08 | 1998-05-26 | The Regents Of The University Of California | Insect control with multiple toxins |
JP3809502B2 (ja) * | 1995-05-30 | 2006-08-16 | 二郎 有川 | ハンタウィルス抗原蛋白質およびモノクローナル抗体 |
JPH0971599A (ja) * | 1995-09-06 | 1997-03-18 | Nippon Seibutsu Kagaku Kenkyusho | 鶏貧血ウイルス(cav)感染鶏血清と高い反応性を示すポリペプチド及びこのポリペプチドに対する抗体、鶏貧血ウイルス感染の診断法及びワクチン |
US5905027A (en) * | 1995-12-27 | 1999-05-18 | Uab Research Foundation | Method of diagnosing and treating gliomas |
US6667156B2 (en) * | 1995-12-27 | 2003-12-23 | Uab Research Foundation | Diagnosis and treatment of neuroectodermal tumors |
CA2312289A1 (en) * | 1997-12-05 | 1999-06-17 | Kyogo Itoh | Tumor antigen peptide derivatives |
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MXPA04011871A (es) | 2005-07-26 |
AU2003237347B2 (en) | 2009-07-23 |
AU2003240496A1 (en) | 2003-12-19 |
CA2494451A1 (en) | 2003-12-11 |
EP1553962A1 (en) | 2005-07-20 |
EP1553962A4 (en) | 2008-01-02 |
US20060166892A1 (en) | 2006-07-27 |
EP2431385A3 (en) | 2012-07-04 |
EP2182004A1 (en) | 2010-05-05 |
WO2003101475A1 (en) | 2003-12-11 |
ES2341767T3 (es) | 2010-06-28 |
AU2003237347A1 (en) | 2003-12-19 |
EP1539207A1 (en) | 2005-06-15 |
AU2003240496B2 (en) | 2008-01-10 |
WO2003101474A1 (en) | 2003-12-11 |
EP2431385A2 (en) | 2012-03-21 |
DE60331458D1 (de) | 2010-04-08 |
EP1553962B1 (en) | 2010-02-24 |
EP1539207A4 (en) | 2008-01-02 |
JP2011153149A (ja) | 2011-08-11 |
JP2015214562A (ja) | 2015-12-03 |
ATE458751T1 (de) | 2010-03-15 |
JP2005537234A (ja) | 2005-12-08 |
CA2487425A1 (en) | 2003-12-11 |
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