JP2020524675A - Cd38抗体薬物コンジュゲート - Google Patents
Cd38抗体薬物コンジュゲート Download PDFInfo
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- JP2020524675A JP2020524675A JP2019569931A JP2019569931A JP2020524675A JP 2020524675 A JP2020524675 A JP 2020524675A JP 2019569931 A JP2019569931 A JP 2019569931A JP 2019569931 A JP2019569931 A JP 2019569931A JP 2020524675 A JP2020524675 A JP 2020524675A
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- igg antibody
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Abstract
Description
本特許出願は、2017年6月20日に出願された米国仮特許出願第62/522,516号および2017年9月1日に出願された米国仮特許出願第62/553,438号からの優先権を主張する。
先行技術の抗体の一部は、CD38+B細胞においてアポトーシスを誘発できることが示されている。しかし、それらは間質細胞または間質由来サイトカインの存在下でのみ、誘発を行うことができる。作動性抗CD38抗体(IB4)は、ヒト胚中心(GC)B細胞のアポトーシスを阻止し(Zupo et al. 1994, Eur. J. Immunol., 24:1218-1222)、かつKG−1およびHL−60AML細胞の増殖を誘導するが(Konopleva et al. 1998, J. Immunol., 161:4702-4708)、ジャーカットTリンパ芽球性細胞においてアポトーシスを誘導する(Morra et al. 1998, FASEB J., 12:581-592)ことが報告されている。別の抗CD38抗体T16は、ALL患者由来の未成熟リンパ球細胞および白血病リンパ芽球細胞(Kumagai et al. 1995, J. Exp. Med., 181:1101-1110)、およびAML患者由来の白血病骨髄芽球細胞(Todisco et al. 2000, Blood, 95:535-542)のアポトーシスを誘導したが、T16は、間質細胞または間質由来サイトカイン(IL−7、IL−3、幹細胞因子)の存在下でのみアポトーシスを誘導した。
(a)抗CD38 IgG抗体C38A2(本明細書における重/軽鎖可変領域に関する配列番号1/2)またはC38D8(本明細書における重/軽鎖可変領域に関する配列番号3/4);
(b)チューブリン阻害剤またはドキソルビシン類似体である薬物または毒素部分;および
(c)IgG抗体のヒンジ領域の単一のCys残基へ結合しているコンジュゲーションリンカー部分であって、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む、抗CD38 ADC組成物を提供する。
(a)抗CD38 IgG抗体C38A2−SV(本明細書における重/軽鎖可変領域に関する配列番号1/3)またはC38A2(本明細書における重/軽鎖可変領域に関する配列番号1/2);
(b)チューブリン阻害剤またはドキソルビシン類似体である、薬物または毒素部分;および
(c)コンジュゲーションリンカーが、リンカーと、IgG抗体のヒンジ領域の単一のCys残基に共有結合しているコンジュゲーション部分とを含み、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む、抗CD38 ADC組成物が提供される。
(a)抗CD38 IgG抗体C38A2(本明細書における重/軽鎖可変領域に関する配列番号1/2)またはC38D8(本明細書における重/軽鎖可変領域に関する配列番号3/4);
(b)チューブリン阻害剤またはドキソルビシン類似体である薬物または毒素部分;および
(c)IgG抗体のヒンジ領域の単一のCys残基へ結合しているコンジュゲーションリンカー部分であって、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む、抗CD38 ADC組成物の有効量を投与することを含む方法をさらに提供する。
好ましくは、コンジュゲーションリンカー部分のリンカー部分は、
(a)抗CD38 IgG抗体C38A2−SV(本明細書における重/軽鎖可変領域に関する配列番号1/3)またはC38A2野生型(本明細書における重/軽鎖可変領域に関する配列番号1/2);
(b)チューブリン阻害剤またはドキソルビシン類似体である薬物または毒素部分;および
(c)コンジュゲーションリンカーが、リンカーと、IgG抗体のヒンジ領域の単一のCys残基に共有結合しているコンジュゲーション部分とを含み、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む抗CD38 ADC組成物の治療有効量を供することを含む方法が提供される。
本明細書において使用する一般的な有機物質の略語を以下のとおりに定義する:
化合物18の合成:
化合物13の合成:
化合物14の合成:
化合物16の合成:
化合物18の合成:
化合物22の合成:
化合物22の合成:
化合物27の合成:
化合物27の合成:
化合物31の合成:
化合物31の合成:
化合物34の合成:
化合物34の合成:
化合物39の合成:
化合物37の合成:
化合物39の合成:
化合物52の合成:
化合物52の合成:
ADC調製例1
ADC46の調製
ADC41の調製
アッセイ例1
a.U87細胞を、10%FBS U87培地(EMEM)を用いて培養し、0.05%トリプシンを用いて採取した。細胞を無血清EMEMで2回洗浄し、計数し、0.2mL中5×106細胞、または無血清EMEMおよびマトリゲルの1:1の混合物中25×106細胞/mLで再懸濁し、各マウスの右上側腹部へ皮下注射した。
b.デジタルキャリパーを使用して、接種してから6〜9日目に開始し、その後1週間に2回および研究が終了する前に腫瘍体積を測定することによって腫瘍成長をモニターした。
c.デジタルキャリパーを用いて腫瘍を測定した。長さ(最も長い寸法)および幅(長さに対して垂直なかつ同一の平面内の距離)を測定した。腫瘍体積を算出するための式は、TV(mm3)=1/2×L×W2であった。
a.腫瘍を所望の体積(平均200〜300mm3)へ分類し、動物を無作為化し、非常に大きいまたは小さい腫瘍を有するマウスを処分した。マウスを、腫瘍体積によって無作為化された、各10匹のマウスの8つの群に分けた。
b.マウスを、図4に従ってビヒクルまたは被験物品のいずれかで処置した。マウスには、合計5回の用量が与えられた。
c.明確な処置傾向が確立されたら、および/またはビヒクル処置マウスに負荷された腫瘍がIACUCプロトコール限界(2000mm3)に達したときに、腫瘍応答をモニターし、研究を終了した。
アッセイ例2
研究デザインおよび投薬レジメンを以下の表に示す。
Claims (9)
- CD38に結合するIgG抗体、1つのCys残基のみを有するように突然変異したIgG抗体のヒンジ領域の1つのCys残基にコンジュゲートしているリンカー部分、および前記リンカー部分にコンジュゲートしている毒素部分を含む、抗体薬物コンジュゲート(ADC)組成物。
- (a)抗CD38 IgG抗体C38A2−SV(本明細書における重/軽鎖可変領域に関する配列番号1/3)またはC38A2(本明細書における重/軽鎖可変領域に関する配列番号1/2);
(b)チューブリン阻害剤またはドキソルビシン類似体である薬物または毒素部分;および
(c)コンジュゲーションリンカーが、リンカーと、IgG抗体のヒンジ領域の単一のCys残基に共有結合しているコンジュゲーション部分とを含み、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、前記重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む、抗CD38 ADC組成物。 - 前記薬物または毒素部分が、D1、D2、D3、D4、D5、およびこれらの組合せからなる群から選択され、D1、D2、D3、D4およびD5の構造が
- リンカーが、
- 前記コンジュゲーション部分が、
- 多発性骨髄腫を治療するための方法であって、
(a)抗CD38 IgG抗体C38A2−SV(本明細書における重/軽鎖可変領域に関する配列番号1/3)またはC38A2野生型(本明細書における重/軽鎖可変領域に関する配列番号1/2);
(b)チューブリン阻害剤またはドキソルビシン類似体である薬物または毒素部分;および
(c)リンカーと、IgG抗体のヒンジ領域の単一のCys残基に共有結合しているコンジュゲーション部分とを含むコンジュゲーションリンカー部分であって、IgG抗体の重鎖ヒンジ領域が1つのCys残基のみを含むように、前記重鎖ヒンジ領域が突然変異していてもよい、コンジュゲーションリンカー部分
を含む、抗CD38 ADC組成物の治療有効量を供することを含む方法。 - 前記薬物または毒素部分が、D1、D2、D3、D4、D5、およびこれらの組合せからなる群から選択され、構造が
- 前記リンカーが、
- 前記コンジュゲーション部分が
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