JP6072854B2 - Cd38を特異的に認識する抗体とシタラビンを含有する抗腫瘍性組合せ剤 - Google Patents
Cd38を特異的に認識する抗体とシタラビンを含有する抗腫瘍性組合せ剤 Download PDFInfo
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- JP6072854B2 JP6072854B2 JP2015111127A JP2015111127A JP6072854B2 JP 6072854 B2 JP6072854 B2 JP 6072854B2 JP 2015111127 A JP2015111127 A JP 2015111127A JP 2015111127 A JP2015111127 A JP 2015111127A JP 6072854 B2 JP6072854 B2 JP 6072854B2
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Description
log10細胞死滅=T−C(日数)/3.32×Td
式中、T−Cは腫瘍増殖の遅延を表し、腫瘍があらかじめ定めた値(例えば、1g)に達するまでの日数の、治療群についての中央値(T)および対照群についての中央値(C)であり、Tdは、対照動物で腫瘍体積が2倍になるのに必要な日数を表す[T.H.Corbett et al.,Cancer,40:2660−2680(1977);F.M.Schabel et al.,Cancer Drug Development,Part B,Methods in Cancer Research,17:3−51,New York,Academic Press Inc.(1979)]。log10細胞死滅が0.7以上であれば、この完成品は活性であると判断される。log10細胞死滅が2.8より大きければ、この完成品は非常に活性が高いと判断される。
0日目、実験に供される動物(一般にマウス)に、腫瘍断片30から60mgを両側に皮下移植する。腫瘍を持たされた動物を、この腫瘍の大きさに関して無作為に割り振って様々な治療と対照に供する。移植後、腫瘍があらかじめ定めた大きさに到達したら、腫瘍の種類に依存して、化学療法を開始し、動物を毎日観察する。治療中、それぞれの動物群の重さを、重さの減少が最大になり、続いて重さが完全に回復するまで、毎日測定する。次いで、試験終了まで、動物群の重さを週に1回か2回測定する。
この実施例では、腫瘍増殖阻害について本発明の抗CD38抗体/シタラビン組合せ剤の有効性をin vivoで実証した。
・≧20%体重減少または≧10%薬物死を誘導する投薬量では毒性であるとした、
・Iog10細胞死滅=(T−C)/[3.32×(腫瘍が2倍になる日数)]を見積もることにより抗腫瘍効力を求めた
(Tは、処置したマウスで750mgに達するまでの時間の中央値を意味し、Cは対照マウスで同じ大きさに達するまでの時間の中央値(26.9日)を意味する;無再発生存個体はこれらの計算から排除し別々に集計する。)。log細胞死滅<0.7では抗腫瘍活性はないものとした。log細胞死滅≧2.8では治療が非常に活性が高いとした
・無再発生存個体(TFS):研究の全期間(最後の処置から100日後以降)について触診限界(63mg)未満の完全回復に相当する。
Claims (18)
- CD38を特異的に認識する抗体および少なくともシタラビンとを含む癌治療のための薬学的組合せ剤であって、前記癌はCD38を発現し、前記抗体が、アポトーシス、抗体依存性細胞媒介性細胞傷害(ADCC)および補体依存性細胞傷害(CDC)によりCD38+細胞を死滅させることができ、
前記抗体が、少なくとも1本の重鎖および少なくとも1本の軽鎖を含み、
(i)前記重鎖が配列番号:1、2および3で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号:4、5、6で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(ii)前記重鎖が配列番号7、8および9で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号10、11および12で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(iii)前記重鎖が配列番号13、81および15で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号16、17および18で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(vi)前記重鎖が配列番号19、20および21で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号22、23および24で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(v)前記重鎖が配列番号25、26および27で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号28、29および30で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、または
(vi)前記重鎖が配列番号31、32および33で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号34、35および36で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含む、薬学的組合せ剤。 - 前記抗体が、キメラ抗体またはヒト化抗体である、請求項1に記載の薬学的組合せ剤。
- 前記重鎖が配列番号66で表されるアミノ酸配列を含み、前記軽鎖が配列番号:62および64からなる群より選択されるアミノ酸配列を含む、請求項1または2に記載の組合せ剤。
- 前記重鎖が配列番号72で表されるアミノ酸配列を含み、前記軽鎖が配列番号:68および70からなる群より選択されるアミノ酸配列を含む、請求項1または2に記載の組合せ剤。
- CD38を発現する癌が造血器癌である、請求項1〜4のいずれか一項に記載の組合せ剤。
- 前記造血器癌が、多発性骨髄腫、白血病、急性および慢性リンパ性白血病、急性および慢性リンパ様白血病、急性および慢性リンパ芽球性白血病、B細胞リンパ腫、T細胞リンパ腫、非ホジキンリンパ腫;急性および慢性骨髄性白血病、ならびに前骨髄球性白血病からなる群より選択される、請求項5に記載の組合せ剤。
- CD38を発現する癌の治療用医薬を製造するための請求項1に記載の薬学的組合せ剤の使用。
- 抗体がキメラ抗体またはヒト化抗体である、請求項7に記載の使用。
- 前記重鎖が配列番号66で表されるアミノ酸配列を含み、前記軽鎖が配列番号:62および64からなる群より選択されるアミノ酸配列を含む、請求項7または8に記載の使用。
- 前記抗体が、少なくとも1本の重鎖および少なくとも1本の軽鎖を含み、前記重鎖が配列番号72で表されるアミノ酸配列を含み、前記軽鎖が配列番号:68および70からなる群より選択されるアミノ酸配列を含む、請求項7〜9のいずれか一項に記載の使用。
- CD38を特異的に認識する抗体および少なくともシタラビンを含む、CD38を発現する癌の治療のための薬学的組合せ剤であって、前記抗体が
配列番号62で表されるアミノ酸配列を含む軽鎖;および
配列番号66で表されるアミノ酸配列を含む重鎖からなる抗体である、薬学的組合せ剤。 - 癌の治療において同時または別々に使用するための、請求項11に記載の薬学的組合せ剤。
- 癌の治療において、成分を同時に使用するための、請求項7〜10のいずれか一項に記載の使用。
- 癌の治療において、成分を別々に使用するための、請求項7〜10のいずれか一項に記載の使用。
- 前記CD38を発現する癌が造血器癌である、請求項7〜10および13〜14のいずれか一項に記載の使用。
- 前記造血器癌が、多発性骨髄腫、白血病、急性および慢性リンパ性白血病、急性および慢性リンパ様白血病、急性および慢性リンパ芽球性白血病、B細胞リンパ腫、T細胞リンパ腫、非ホジキンリンパ腫;急性および慢性骨髄性白血病、ならびに前骨髄球性白血病からなる群より選択される、請求項15に記載の使用。
- 少なくともシタラビンと組み合わせた癌治療のための医薬の製造のためのCD38を特
異的に認識する抗体の使用であって、前記癌はCD38を発現し、そして前記抗体が、アポトーシス、抗体依存性細胞媒介性細胞傷害(ADCC)および補体依存性細胞傷害(CDC)によりCD38 + 細胞を死滅させることができ、
前記抗体が、少なくとも1本の重鎖および少なくとも1本の軽鎖を含み、
(i)前記重鎖が配列番号:1、2および3で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号:4、5、6で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(ii)前記重鎖が配列番号7、8および9で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号10、11および12で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(iii)前記重鎖が配列番号13、81および15で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号16、17および18で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(vi)前記重鎖が配列番号19、20および21で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号22、23および24で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(v)前記重鎖が配列番号25、26および27で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号28、29および30で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、または
(vi)前記重鎖が配列番号31、32および33で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号34、35および36で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含む、使用。 - CD38を特異的に認識する抗体を含む、少なくともシタラビンと組み合わせた癌治療のための薬学的組成物であって、前記癌はCD38を発現し、前記抗体が、アポトーシス、抗体依存性細胞媒介性細胞傷害(ADCC)および補体依存性細胞傷害(CDC)によりCD38 + 細胞を死滅させることができ、
前記抗体が、少なくとも1本の重鎖および少なくとも1本の軽鎖を含み、
(i)前記重鎖が配列番号:1、2および3で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号:4、5、6で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(ii)前記重鎖が配列番号7、8および9で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号10、11および12で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(iii)前記重鎖が配列番号13、81および15で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号16、17および18で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(vi)前記重鎖が配列番号19、20および21で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号22、23および24で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、
(v)前記重鎖が配列番号25、26および27で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号28、29および30で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、または
(vi)前記重鎖が配列番号31、32および33で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含み、前記軽鎖が配列番号34、35および36で表されるアミノ酸配列を有する3つの連続した相補性決定領域を含む、薬学的組成物。
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