JP4366080B2 - ガングリオシドを過剰発現する腫瘍を治療するための免疫併用療法 - Google Patents
ガングリオシドを過剰発現する腫瘍を治療するための免疫併用療法 Download PDFInfo
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- JP4366080B2 JP4366080B2 JP2002580025A JP2002580025A JP4366080B2 JP 4366080 B2 JP4366080 B2 JP 4366080B2 JP 2002580025 A JP2002580025 A JP 2002580025A JP 2002580025 A JP2002580025 A JP 2002580025A JP 4366080 B2 JP4366080 B2 JP 4366080B2
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Description
ガングリオシドはほとんどの哺乳動物細胞の形質膜の成分である。これらのグリコスフィンゴリピッドは正常組織に発現した場合であっても、細胞の悪性形質転換の期間の発現パターンのためにそれらは免疫治療の非常に魅力ある標的である(Hakomori, S. Ann. Rev. Biochem. 50; 1981: 733-764; Hakomori, Cancer Res. 45; 1985: 2405-2414; Irie, R.F., et al. In: Therapeutic monoclonal antibodies. Borrebaeck, C.A.K., and Larrick, J. W. (Eds.). M Stockton Press, 1990, pp. 75-94)。
本発明は、癌免疫療法、特にガングリオシドを過剰に発現する腫瘍に対して有用な医薬組成物または医薬組成物の併用に関するものであり、そしてそれは以下の化合物の少なくとも二つを含んでいる:
(A)抗−ガングリオシド抗体(Ab1)を含むイディオタイプワクチン;
(B)抗−ガングリオシド抗体に対する抗−イディオタイプ抗体(Ab2)を含む
イディオタイプワクチン;及び
(C)ガングリオシドを含むワクチン。
ガングリオシドを含むワクチンはEstevezおよび共同研究者の明細書に従って得られる(Vaccine 18; 1999: 190-197及び米国特許5,788,985及び6,149,921)。グラム陰性細菌株、Neisseria meningitidis、の外膜タンパク複合体(OMPC)及び合成または天然ガングリオシドの会合によって得られた極小サイズのプロテオリポソーム(VSSP)をその中に組込んだ(VSSP-G)。このガングリオシドは(NeuGcGM3)、GD3または(NeuAcGM3)であり得た。
医薬組成物は米国特許5,817,513及び6,063,379の明細書にしたがって得た。ワクチンは、MAb P3のようなマウス抗−ガングリオシドモノクロナール抗体または抗−ガングリオシドモノクロナール抗体を認識するMAb 1E10のようなマウス抗−イディオタイプモノクロナール抗体を含んでいる。
言及する方法はマウス及び哺乳動物のその他の種類にも使用することができる。併用する成分はガングリオシドワクチン及びイディオタイプワクチンである;これらは種々の方法で併用することができる。
前に言及した方法を種々の臨床段階にある癌患者に適用することができる。特にガングリオシドを過剰発現している腫瘍並びに肺、乳腺、消化器系、泌尿・生殖器系、黒色腫、肉腫及び神経外胚葉形成異常組織由来のもの。
例1:マウスMAB P3による免疫により誘導された、同系モデルにおける抗−イディオタイプT2及び抗−抗−イディオタイプT3細胞の活性化。
6-8週齢の同じ遺伝的背景の雌Balb/c及びヌードマウスを100μgのマウスMAb P3
及び完全フロイントアジュバント(CFA)で皮下に免疫した。7日後マウスを不完全フロイントアジュバント(IFA)中50μgの抗体で再度免疫した。10日目に吸引したリンパ節を採取し、シリンジで押してリンパ球を得た。細胞懸濁を、3H-チミジン取り込みにより測定する細胞増殖実験に使用した。インビトロリンパ球増殖はMAb P3及びそのAb2 MAb 1E10(寄託番号ECACC97112901)(25から150μg/mLの濃度範囲)の存在下にリンパ球懸濁を培養して測定した。アイソタイプマウスMAbを対照として使用した。刺激指数が3と同じかそれ以上の場合に陽性とした。P3 MAbでBalb/cマウスを免疫して得られたリンパ球はこのMAbの存在下に特異的に増殖したが、マウス対照MAb A3(IgM)(Alfonso M.and col.: Hybridoma 14; 1995: 209-216)の存在下に培養した場合にはこの増殖は観察されなかった。この増殖はT細胞の存在に依存していた;何故なら、P3免疫胸腺欠如nu/nuマウスのリンパ節細胞では認められなかったからである。マウスMAb P3による免疫はこのAb1 MAb(T2)のイディオタイプに対するT細胞の増殖を誘導するのみならず、マウスAb2 MAb 1E10(IgG1)に特異的な抗−抗−イディオタイプT細胞(T3)の増殖も誘導する、が同じアイソタイプ(IgG1)のMAb C5に対するT細胞の増殖は誘導しない(図1)。
その重鎖(VH)及び軽鎖(VL)可変領域のアミノ酸配列が図8及び9にそれぞれ示されているキメラ抗体P3を、6-8週齢のBalb/c雌マウスを免疫するために使用した。最初の皮下投与には100μgの抗体をACF中に乳化して使用した。7日後に動物をAIF中に乳化した50μgの抗体で再免疫した。10日目に吸引してリンパ節(LN)を採取し、LN細胞リンパ増殖能をP3及びAb2 1E10抗体のマウス及びキメラ変異体の存在下に培養して調べた、その抗体の可変領域の配列を図13(重鎖)及び14(軽鎖)に示す。C5マウスMAb及びそのキメラ変異体をアイソタイプ対照として使用した(特許出願WO97/33916 A1)。キメラ抗体P3で免疫したマウスのリンパ球は、この抗体またはキメラ1E10 MAbの存在下に培養した場合に、またこれらの抗体のマウス変異体の存在下に培養した場合に、特異的に増殖した。増殖の特異性はアイソタイプ対照MAbを使用することにより証明された。したがって、キメラP3 MAbは、特異的な抗−イディオタイプ(T2)及び抗−抗−イディオタイプ(T3)T細胞を誘導するマウス変異体の能力を維持している(図2)。
6-8週齢のC57BL/6雌マウスの群を0,14,28及び42日に50μgのマウス1E10 MAbを水酸化アルミニウムに吸着させて皮下投与して免疫した。7,21,35及び49日目にマウスに120μgのGM3-VSSP/Montanide ISA 51を筋肉内に投与した。別の群のマウスを同様に免疫したが、最初にGM3ガングリオシドを含むワクチン製剤で免疫した。別の対照群は各ワクチンの投与間隔と投与回数と同じに接種を行なったが、この群にはリン酸緩衝食塩液のみを投与した。63日目に、全群のマウスにマウス腫瘍B16の10000細胞を皮下に接種した。腫瘍の成長を全群で調べた。
Montanide ISA 51をアジュバントとして使用する(米国特許5,788,985及び6,149,921)NeuGc-GM3/VSSPワクチンによる免疫の安全性及び免疫原性を立証する目的で、この他の癌治療に適さない進行期悪性黒色腫の患者20例においてこのワクチンで免疫して臨床試験を実施した。
表1:
NeuGcGM3/VSSP/Montanide ISA 51ワクチンで免疫された進行期悪性黒色腫の患者におけるNeuGcGM3に対する抗体力価。
マウス抗−イディオタイプMAb 1E10(米国特許5,817,513及び6,063,379)及びアジュバントとして水酸化アルミニウムを含有するイディオタイプワクチンの安全性及び免疫原性を立証する目的で、この他の癌特異的治療に適さない進行期悪性黒色腫の患者20例で臨床試験を実施した。
診断を受け、1ヶ月間外科に入院していた転移を伴う黒色腫の患者に、Ab2 MAb 1E10及び水酸化アルミニウムゲル(MAb投与毎に2 mg)を含むイデオタイプワクチンを6回、0,14,28,42,56日目に投与した。この期間中に、200μgのNeuGcGM3-VSSPガングリオシド及びアジュバントとしてMontanide ISA 51を含むガングリオシドワクチンを7,21,35,49,63日目に患者に投与した。この免疫スケジュールの後に、患者を1ヶ月毎に2ヶ月間両ワクチンで同時に再免疫した。このワクチン接種の期間中は新規の病変は認められず、患者の状態は良好であった。
NeuGcGM3ガングリオシドはMAb 14F7(特許出願WO99/40119)によって認識される。
Claims (4)
- 以下の成分:
(A)寄託番号ECACC97112901を有するハイブリドーマにより産生されるマウス抗−イディオタイプ抗体1E10を含むワクチン;および
(B)その活性成分が、NeuGcGM3ガングリオシドおよびNeuAcGM3ガングリオシドから選ばれるワクチン、
を含む、ガングリオシドを過剰発現している腫瘍の免疫治療用の免疫治療用医薬組成物。 - 該ワクチンA及びBが同時にまたは交互に投与される請求項1に記載の免疫治療用医薬組成物。
- ガングリオシドを過剰に発現している腫瘍を治療する医薬を製造するための請求項1または2に記載の免疫治療用医薬組成物の使用。
- 乳腺、肺、消化器系、泌尿・生殖器系、黒色腫、肉腫及び神経外胚葉形成異常組織のものの腫瘍の治療のための医薬を製造するための請求項3に記載の使用。
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JP2017512759A (ja) * | 2014-04-10 | 2017-05-25 | オービーアイ ファーマ インコーポレイテッド | 抗体、前記抗体を産生するハイブリドーマ、前記抗体を含む薬学的組成物及びその用途 |
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EP0586002B1 (en) * | 1992-08-18 | 2000-01-19 | CENTRO de IMMUNOLOGIA MOLECULAR | Monoclonal antibodies recognizing the epidermal growth factor receptor, cells and methods for their production and compositions containing them |
JPH07101999A (ja) * | 1993-10-06 | 1995-04-18 | Hagiwara Yoshihide | 抗癌ヒトモノクローナル抗体に対する抗イデイオタイプ抗体のアミノ酸配列およびそれをコードするdna塩基配列 |
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