JP2013501740A - ベンダムスチンとのアフコシル化cd20抗体の併用療法 - Google Patents
ベンダムスチンとのアフコシル化cd20抗体の併用療法 Download PDFInfo
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Abstract
Description
モノクローナル抗体の細胞媒介性エフェクター機能は、Umana, P.等, Nature Biotechnol. 17 (1999) 176-180及び米国特許第6602684号に記載されているように、そのオリゴ糖成分を操作することによって亢進せしめることができる。癌免疫療法において最もよく使用される抗体であるIgG1型抗体は、保存されたN結合型グリコシル化部位を各CH2ドメインのAsn297に有する糖タンパク質である。Asn297に結合した2つの複合型二分岐オリゴ糖は、CH2ドメイン間に埋もれて、ポリペプチド主鎖との広範囲の接触面を形成し、その存在は、抗体が抗体依存性細胞傷害性(ADCC)のようなエフェクター機能を媒介するために必須である(Lifely, M.R.等, Glycobiology 5 (1995) 813-822;Jefferis, R.等, Immunol. Rev. 163 (1998) 59-76;Wright, A.及びMorrison, S.L., Trends Biotechnol. 15 (1997) 26-32)。Umana, P.等, Nature Biotechnol. 17 (1999) 176-180及び国際公開第99/154342号は、2つに分岐したオリゴ糖の形成を触媒するグリコシルトランスフェラーゼであるβ(1,4)-N-アセチルグルコサミニルトランスフェラーゼIII(「GnTIII」)のチャイニーズハムスター卵巣(CHO)細胞における過剰発現が、抗体のインビトロでのADCC活性を有意に増大せしめることを示した。N297炭水化物の組成の改変又はその除去もまたFcγR及びC1qへの結合、Fcへの結合に影響を及ぼす(Umana, P.等, Nature Biotechnol. 17 (1999) 176-180;Davies, J.等, Biotechnol. Bioeng. 74 (2001) 288-294;Mimura, Y.等, J. Biol. Chem. 276 (2001) 45539-45547;Radaev, S.等, J. Biol. Chem. 276 (2001) 16478-16483;Shields, R.L.等, J. Biol. Chem. 276 (2001) 6591-6604;Shields, R.L.等, J. Biol. Chem. 277 (2002) 26733-26740;Simmons, L.C.等, J. Immunol. Methods 263 (2002) 133-147)。
CD20分子(ヒトBリンパ球限定分化抗原又はBp35とも称される)は、広く開示されているプレB細胞及び成熟Bリンパ球上に位置する疎水性膜貫通タンパク質である(Valentine, M.A.等, J. Biol. Chem. 264 (1989) 11282-11287;及びEinfeld, D.A.等, EMBO J. 7 (1988) 711-717;Tedder, T.F.等, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 208-12;Stamenkovic, I.等, J. Exp. Med. 167 (1988) 1975-80;Tedder, T.F.等, J. Immunol. 142 (1989) 2560-8)。CD20は、90%を越えるB細胞非ホジキンリンパ腫(NHL)で発現している(Anderson, K.C.等, Blood 63 (1984) 1424-1433)が、造血幹細胞、プロB細胞、正常形質細胞、又は他の正常組織には見いだせない(Tedder, T.F.等, J, Immunol. 135(2) (1985) 973- 979)。
ベンダムスチン(商品名リボムスチン及びトレンダ(Treanda);SDX−105としても知られている)は慢性リンパ性白血病(CLL)(Kath, R.等, J. Cancer Res. Clin. Oncol. 127 (2001) 48-54)及び非ホジキンリンパ腫(NHL)の治療に使用されるナイトロジェンマスタードである。それはアルキル化剤と呼ばれる薬剤のファミリーに属する。それはまた肉腫の治療について研究されている(Bagchi, S., Lancet Oncol. 8 (2007) 674)。
本発明は、ベンダムスチンと併用される癌治療医薬の製造のための、Asn297においてフコース量がオリゴ糖(糖)全量の60%以下であるIgG1又はIgG3アイソタイプ(好ましくはIgG1アイソタイプ)のアフコシル化抗CD20抗体の使用を含む。一実施態様では、アフコシル化抗CD20抗体は、10−9Mから10−13mol/lのKDでCD20に結合する。
Kabat等, Sequences of Proteins of Immunological Interest, 5版 Public Health Service, National Institutes of Health, Bethesda, MD (1991)に報告されたEUインデックス)。
増加した抗体依存性細胞傷害性(ADCC)を有する「アフコシル化抗CD20抗体」は、該用語がここで定義されるように、当業者に知られる任意の適切な方法により決定されて増加したADCCを有するアフコシル化抗CD20抗体を意味する。一つの許容されるインビトロADCCアッセイは、次の通りである:
1)該アッセイは、抗体の抗原結合領域により認識される標的抗原を発現することが知られている標的細胞を使用する;
2)該アッセイは、エフェクター細胞として、無作為に選択された健常なドナーの血液から単離されたヒト末梢血単核細胞(PBMC)を使用する;
3)該アッセイは、次のプロトコルに従って実施される:
i)標準的な密度遠心分離手順を使用してPBMCを単離し、5×106細胞/mlの濃度でRPMI細胞培養培地に懸濁させる;
ii)標準的な組織培養法により標的細胞を増殖させ、生存率が90%以上の対数増殖期に回収し、RPMI細胞培養培地中で洗浄し、100マイクロキュリーの51Crで標識し、細胞培養培地で2回洗浄し、105細胞/mlの密度で細胞培養培地に懸濁させる;
iii)上記100マイクロリットルの最終的な標的細胞懸濁物を96ウェルのマイクロタイタープレートの各ウェルに移す;
iv)抗体を細胞培養培地で4000ng/mからl0.04ng/mlに連続希釈し、50マイクロリットルの得られた抗体溶液を96ウェルマイクロタイタープレート中の標的細胞に添加し、上記の全濃度範囲をカバーする様々な抗体濃度で3回試験する;
v)最大放出(MR)コントロールに対して、標識された標的細胞を含むプレート中の更なる3つのウェルに、抗体溶液(上記のiv項)に代えて、50マイクロリットルの非イオン性洗浄剤(Nonidet, Sigma, St. Louis)の2%(VN)水溶液を添加する;
vi)自然放出(SP)コントロールに対して、標識された標的細胞を含むプレート中の更なる3つのウェルに、抗体溶液(上記のiv項)に代えて、50マイクロリットルのRPMI細胞培養培地を添加する;
vii)ついで、96ウェルマイクロタイタープレートを50xgで1分間遠心分離し、1時間4℃でインキュベートする;
viii)エフェクター:標的細胞の比率が25:1となるように各ウェルに50マイクロリットルのPBMC懸濁液(上記のi項)を添加して、該プレートを37℃、5%CO2のインキュベーター中に4時間配する;
ix)各ウェルから無細胞の上清を回収し、ガンマカウンターを使用して、実験的に放出された放射能(ER)を定量する;
x)特定の細胞溶解の割合を、各抗体濃度について、式(ER−MR)/(MR−SR)×100に従って計算する。ここで、ERは、各抗体濃度で定量(上記のix項)された平均放射能であり、MRは、MRコントロール(上記のv項)において定量(上記のix項)された平均放射能であり、SRは、SRコントロール(上記のvi項)において定量(上記のix項)された平均放射能である;
4)「増加したADCC」は、上記の試験された抗体濃度範囲内で観察される特定の細胞溶解の最大割合の増加、及び/又は上記の試験された抗体濃度範囲内で観察される特定の細胞溶解の最大割合の半分を達成するのに必要な抗体濃度の減少の何れかとして定義される。ADCCの増加は、上記アッセイで測定され、当業者に知られている同じ標準的な生産、精製、製剤化及び保存法を使用して同じ種類の宿主細胞により産生された同じ抗体により媒介されるものであるが、GnTIIIを過剰発現するように操作された宿主細胞により産生されたものではないADCCと比較したものである。
薬学的組成物は、この発明に係る抗CD20抗体及び/又はベンダムスチンを、薬学的に許容可能な無機又は有機担体とプロセシングすることによって得ることができる。ラクトース、コーンスターチ又はその誘導体、タルク、ステアリン酸又はその塩等を、例えば錠剤、被覆錠剤、糖衣錠及び硬質ゼラチンカプセルのかかる担体として使用することができる。軟質ゼラチンカプセルのための適切な担体は、例えば植物油、ロウ、脂肪、半固形及び液体ポリオール等である。しかしながら、活性物質の性質に応じて、軟質ゼラチンカプセルの場合、通常は担体は必要とされない。溶液及びシロップの製造のための適切な担体は例えば水、ポリオール、グリセロール、植物油等である。坐薬に対して適切な担体は例えば天然又は硬化油、脂肪、半液体又は液体ポリオール等である。
上記薬学的組成物は一又は複数の薬学的に許容可能な担体を更に含有しうる。
本発明の更なる一実施態様では、アフコシル化抗CD20抗体及びベンダムスチンが二つの別個の製剤に処方される。
一実施態様では、フコース量は40%と60%の間である。
好ましくは、上記癌はCD20発現癌である。
好ましくは、上記CD20発現癌はB細胞非ホジキンリンパ腫(NHL)である。
好ましくは、上記アフコシル化抗CD20抗体はII型抗CD20抗体である。
好ましくは、上記抗体はヒト化B−Ly1抗体である。
好ましくは、上記ヒト化B−Ly1抗体は、6週投薬サイクルの1、8、15日目に800から1200mg、ついで5回までの4週投薬サイクルの1日目に800から1200mgの投薬量で投与され、ベンダムスチンが6回までの4週投薬サイクルの1日目と2日目に80mg/m2から110mg/m2の投薬量で投与される。
本発明は、癌の治療に使用するためにフコースの量が60%以下であるアフコシル化抗CD20抗体とベンダムスチンを更に含む。
好ましくは、上記アフコシル化抗CD20抗体はヒト化B−Ly1抗体である。
好ましくは、癌はCD20発現癌、より好ましくはB細胞非ホジキンリンパ腫(NHL)である。
好ましくは、上記ヒト化B−Ly1抗体は、6週投薬サイクルの1、8、15日目に800から1200mg、ついで5回までの4週投薬サイクルの1日目に800から1200mgの投薬量で投与され、ベンダムスチンが6回までの4週投薬サイクルの1日目と2日目に80mg/m2から110mg/m2の投薬量で投与される。
配列番号1:マウスモノクローナル抗CD20抗体B−Ly1の重鎖の可変領域(VH)のアミノ酸配列。
配列番号2:マウスモノクローナル抗CD20抗体B−Ly1の軽鎖の可変領域(VL)のアミノ酸配列。
配列番号3−19:ヒト化B−Ly1抗体(B−HH2からB−HH9、B−HL8、及びB−HL10からB−HL17)の重鎖の可変領域(VH)のアミノ酸配列。
配列番号20:ヒト化B−Ly1抗体B−KV1の軽鎖の可変領域(VL)のアミノ酸配列。
II型抗CD20抗体(リツキシマブ)とII型抗CD20抗体(B−HH6−B−KV1 GE)との組合せ治療の抗腫瘍活性
アフコシル化抗CD20抗体B−HH6−B−KV1 GE(アフコシル化ヒト化B−Ly1,糖操作B−HH6−B−KV1,国際公開第2005/044859号及び国際公開第2007/031875号を参照)は、ストック液(9.4mg/ml)としてGlycArt, Schlieren, Switzerlandから提供された。抗体バッファーは、ヒスチジン、トレハロース及びポリソルベート20を含んでいた。抗体溶液は先の注入のために原液からPBSで適宜希釈した。
ヒトZ138マントル細胞リンパ腫細胞株を10%ウシ胎仔血清(PAA Laboratoris, Austria)及び2mMのL−グルタミンを補填したDMEM中で、37℃で、8%CO2の水飽和雰囲気中で常套的に培養した。継代4を移植に使用した。細胞をMatrigelと共に同時注入した。
雌のSCIDベージュマウス;到着時3〜4週齢(Charles River, Sulzfeld, Germanyから購入)を、コミットされたガイドライン(GV-Solas; Felasa; TierschG)に従って特定の病原体不含有条件下で、毎日12時間/12時間の明暗サイクルで維持した。実験の試験プロトコルは、地方自治体により調査され承認された。到着後、動物を新しい環境に馴れさせ、観察のために、動物施設の検疫部に1週間維持した。連続的な健康モニタリングを定期的に実施した。食餌(Provimi Kliba 3337)と水(pH2.5〜3に酸性化)は自由に与えた。
臨床症状と有害作用の検出のために、動物を毎日管理した。実験を通してのモニタリングのために、動物の体重を週2回記録し、腫瘍体積をステージ分類後、ノギスで測定した。
腫瘍細胞接種の19日後のランダム化した日に動物の処置を開始した。ヒト化アフコシル化抗CD20抗体B−HH6−B−KV1 GE又はリツキシマブを、1mg/kgの示された投薬量で研究19日及び26日目に単一薬剤をq7dで腹腔内投与した。対応するビヒクルを同じ日に投与した。ベンダムスチンを3mg/kgで19、20、21、及び22日目に腹腔内投与した。併用治療群では、化学療法剤を19日目に両抗体後に8時間投与した。
腫瘍細胞接種後の33日目の実験の終了時に、コントロール群と比較して、リツキシマブ、抗CD20抗体B−HH6−B−KV1 GE、リツキシマブとベンダムスチンの組み合わせ、又は抗CD20抗体とベンダムスチンの組み合わせをそれぞれ投与した動物において表1に与えたように腫瘍増殖阻害(TGI)があった。ベンダムスチン単独での処置は本実験では抗腫瘍活性を示さなかった。
抗CD20抗体B−HH6−B−KV1 GE/ベンダムスチン併用群を抗CD20抗体B−HH6−B−KV1 GE単独の処置と比較することによって相加効果以上の効果があった。
実験を33日目に終了させた。統計的評価はsAUCに基づいた。腫瘍増殖は、ビヒクル群(1群)と比較して、0.72(CI0.59−0.86)のTCRによって示された2群(B−HH6−B−KV1 GE,1mg/kg,毎週1回,腹腔内)、0.78(CI0.65−0.93)のTCRによって示された3群(リツキシマブ,1mg/kg,毎週1回,腹腔内)、0.46(CI0.34−0.59)のTCRによって示された5群(B−HH6−B−KV1 GE,1mg/kg,毎週1回,腹腔内と、ベンダムスチン,3mg/kg,研究日19−22,腹腔内との併用)及び0.67(CI0.54−0.81)のTCRによって示された6群(リツキシマブ,1mg/kg,毎週1回,腹腔内と、ベンダムスチン,3mg/kg,研究日19−22,腹腔内との併用)において統計的に有意に阻害された。
4群(ベンダムスチン,3mg/kg,研究日19−22,腹腔内)は研究の終了時にコントロール群として匹敵する腫瘍増殖を示した。
B−HH6−B−KV1 GEとベンダムスチンの併用は、Tukey−Kramer 検定(p<0.001)によって解析した単一処置と比較して腫瘍増殖阻害に対して相加的以上(相乗的)で統計的に有意な効果を示した(表1及び図1を参照)。
Claims (11)
- ベンダムスチンと併用される癌治療医薬の製造のための、Asn297においてフコース量がオリゴ糖(糖)全量の60%以下であるアフコシル化抗CD20抗体の使用。
- フコース量が40%から60%であることを特徴とする請求項1に記載の使用。
- フコース量が50%以下であることを特徴とする請求項1に記載の使用。
- 上記癌がCD20発現癌であることを特徴とする請求項1から3の何れか一項に記載の使用。
- 上記CD20発現癌が、B細胞非ホジキンリンパ腫(NHL)であることを特徴とする請求項4に記載の使用。
- 上記アフコシル化抗CD20抗体がII型抗CD20抗体であることを特徴とする請求項1から5の何れか一項に記載の使用。
- 上記抗体がヒト化B−Ly1抗体であることを特徴とする請求項6に記載の使用。
- 一又は複数の更なる他の細胞傷害、化学療法又は抗癌剤、又は該薬剤の効果を亢進する化合物又は電離放射線が投与されることを特徴とする請求項1から7の何れか一項に記載の使用。
- 上記ヒト化B−Ly1抗体が、6週投薬サイクルの1、8、15日目に800から1200mgの投薬量で、ついで5回までの4週投薬サイクルの1日目に800から1200mgの投薬量で投与され、ベンダムスチンが6回までの4週投薬サイクルの1日目と2日目に80mg/m2から110mg/m2の投薬量で投与されることを特徴とする請求項1から8の何れか一項に記載の使用。
- Asn297においてフコース量がオリゴ糖(糖)全量の60%以下であるアフコシル化抗CD20抗体とベンダムスチンを含有する癌治療のための組成物。
- 上記抗アフコシル化CD20抗体がヒト化B−Ly1抗体であることを特徴とする請求項10に記載の組成物。
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JP2012515217A (ja) * | 2009-01-16 | 2012-07-05 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | ベンダムスチンおよび抗−cd20抗体の組合せを用いた癌治療 |
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JPN7013004327; UMANA, P. et al: 'Novel 3rd generation humanized type IICD20 antibody with glycoengineered fc and modified elbow hinge' BLOOD Vol.108, No.11, 2009, Abstract 229 * |
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