JP2021525248A - 併用のためのbcma及びcd3に対する抗増殖性化合物及び二重特異性抗体 - Google Patents
併用のためのbcma及びcd3に対する抗増殖性化合物及び二重特異性抗体 Download PDFInfo
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- 239000008215 water for injection Substances 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- LKCUKVWRIAZXDU-UHFFFAOYSA-L zinc;hydron;phosphate Chemical compound [Zn+2].OP([O-])([O-])=O LKCUKVWRIAZXDU-UHFFFAOYSA-L 0.000 description 1
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Abstract
Description
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
別段の定義がない限り、本明細書中で使用するすべての技術用語及び科学用語は、当業者によって一般的に理解されている意味と同じ意味を有する。すべての特許、出願、公開出願及び他の刊行物は、その全体が参照により援用される。本明細書の用語に複数の定義がある場合、特に明記しない限り、本節における定義が優先する。
aすべての効果判定カテゴリは、任意の新規療法を実施する前の任意の時点で行う2つの連続評価を必要とし;すべてのカテゴリはまた、X線検査を実施していた場合に、進行性病変または新規骨病変の既知のエビデンスが存在していなかったことも必要である。これらの効果判定要件を満たすためにX線検査は必要ない。
b骨髄生検を繰り返すことによる確認は必要ない。
cクローン細胞の有無は、κ/λ比に基づく。κ/λ比の異常を免疫組織化学検査及び/または免疫蛍光法により分析するためには、最低でも100個の形質細胞を必要とする。異常なクローンの存在を反映する異常な比率は、κ/λが4:1超または1:2未満である。
d以下の測定値の少なくとも1つによって定義される測定可能な疾患:骨髄形質細胞が30%以上;血清Mタンパク質が1g/dl以上(10gm/l以上)[10g/l];尿中Mタンパク質が200mg/24時間以上;血清FLCアッセイ:腫瘍由来FLCレベルが10mg/dl以上(100mg/l以上);ただし、血清FLC比が異常である場合。
本明細書中の方法で使用するための、「化合物1」と呼ばれる、化合物4−(4−(4−(((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)オキシ)メチル)ベンジル)ピペラジン−1−イル)−3−フルオロベンゾニトリル:
本明細書中で提供する方法で使用するための化合物は、当業者に公知の方法、及び本明細書の実施例の節に記載されている手順と同様の手順及びその日常的な改変によって調製することができる。化合物を調製するための例示的な反応スキームを、以下において、化合物1、化合物2及び化合物3についてはスキーム1、ならびに化合物2についてはスキーム2に示す。
本明細書の方法で使用するための、ヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体を提供する。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
a)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
b)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
a)配列番号21のCDR1H領域及び配列番号22のCDR2H領域、配列番号23のCDR1L領域、及び配列番号24のCDR2L領域、b)配列番号21のCDR1H領域及び配列番号22のCDR2H領域、配列番号25のCDR1L領域、及び配列番号26のCDR2L領域、c)配列番号21のCDR1H領域及び配列番号22のCDR2H領域、配列番号27のCDR1L領域、及び配列番号28のCDR2L領域、d)配列番号29のCDR1H領域及び配列番号30のCDR2H領域、配列番号31のCDR1L領域、及び配列番号32のCDR2L領域、e)配列番号34のCDR1H領域及び配列番号35のCDR2H領域、配列番号31のCDR1L領域、及び配列番号32のCDR2L領域、ならびにf)配列番号36のCDR1H領域及び配列番号37のCDR2H領域、配列番号31のCDR1L領域、及び配列番号32のCDR2L領域の群から選択されるCDR1H、CDR2H、CDR1L、及びCDR2L領域の組み合わせを含むことを特徴とする。
a)前記標的であるCD3及びBCMAのうちの1つに特異的に結合する抗体の軽鎖及び重鎖;ならびに
b)前記標的の他方の1つに特異的に結合する抗体の軽鎖及び重鎖を含むことを特徴とし、その場合、可変ドメインVL及びVHまたは定常ドメインCL及びCH1は互いに置換されている。
a)BCMAに特異的に結合する一次抗体の第1の軽鎖及び第1の重鎖;及び
b)CD3に特異的に結合する二次抗体の第2の軽鎖及び第2の重鎖を含み、二次抗体の第2の軽鎖及び第2の重鎖の可変ドメインVL及びVHが互いに置換され;ならびに
c)a)の下の第1の軽鎖の定常ドメインCLにおいて、124位のアミノ酸は、独立して、リジン(K)、アルギニン(R)またはヒスチジン(H)(Kabatによるナンバリング)に置換され、a)の下の第1の重鎖の定常ドメインCH1において、147位のアミノ酸及び213位のアミノ酸は、独立して、グルタミン酸(E)またはアスパラギン酸(D)(Kabatによるナンバリング)に置換されていることを特徴とする(例えば、図1A、2A、2C、3A、3Cを参照のこと)。
a)BCMAに特異的に結合する一次抗体の第1の軽鎖及び第1の重鎖;及び
b)CD3に特異的に結合する二次抗体の第2の軽鎖及び第2の重鎖を含み、二次抗体の第2の軽鎖及び第2の重鎖の可変ドメインVL及びVHが互いに置換され;ならびに
c)b)の下の第2の軽鎖の定常ドメインCLにおいて、124位のアミノ酸は、独立して、リジン(K)、アルギニン(R)またはヒスチジン(H)(Kabatによるナンバリング)に置換され、b)の下の第2の重鎖の定常ドメインCH1において、147位のアミノ酸及び213位のアミノ酸は、独立して、グルタミン酸(E)またはアスパラギン酸(D)(Kabatによるナンバリング)に置換されていることを特徴とする。
a)一方の重鎖のCH3ドメインを改変し、それにより、二重特異性抗体内の他方の重鎖のCH3ドメインの元の界面と接触する一方の重鎖のCH3ドメインの元の界面内で、アミノ酸残基をより大きな側鎖体積を有するアミノ酸残基に置換し、それにより、一方の重鎖のCH3ドメインの界面内に、他方の重鎖のCH3ドメインの界面内の空洞に配置可能な隆起を生成し、そして
b)他方の重鎖のCH3ドメインを改変し、それにより、二重特異性抗体内の第1のCH3ドメインの元の界面と接触する第2のCH3ドメインの元の界面内で、アミノ酸残基をより小さな側鎖体積を有するアミノ酸残基に置換し、それにより、第2のCH3ドメインの界面内に、第1のCH3ドメインの界面内の隆起を配置可能な空洞を生成する。
i)配列番号48、配列番号49、配列番号50、及び配列番号51(2×)(抗体21のセット1 TCB)、
ii)配列番号48、配列番号52、配列番号53、及び配列番号54(2×)(抗体22のセット2 TCB)、ならびに
iii)配列番号48、配列番号55、配列番号56、及び配列番号57(2×)(抗体42のセット3 TCB)。
表1A:抗体の配列
表1B:抗体の配列(一覧表)
83A10−TCBcv:45、46、47(×2)、48(図2A)
21−TCBcv:48、49、50、51(×2)(図2A)
22−TCBcv:48、52、53、54(×2)(図2A)
42−TCBcv:48、55、56、57(×2)(図2A)
本明細書に提供する化合物1、2及び3、ならびにそのエナンチオマー、エナンチオマーの混合物、互変異性体、アイソトポログ、または薬学的に許容される塩を、本明細書に提供するヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体と組み合わせて、本明細書に提供するすべての治療方法で使用することができる。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。
特定の実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約25mg/日、約0.01〜約10mg/日、約0.01〜約5mg/日、約0.01〜約2mg/日、約0.01〜約1mg/日、約0.01〜約0.5mg/日、約0.01〜約0.25mg/日、約0.1〜約25mg/日、約0.1〜約10mg/日、約0.1〜約5mg/日、約0.1〜約2mg/日、約0.1〜約1mg/日、約0.1〜約0.5mg/日、約0.1〜約0.25mg/日、約0.5〜約25mg/日、約0.5〜約10mg/日、約0.5〜約5mg/日、約0.5〜約2mg/日、約0.5〜約1mg/日、約1〜約25mg/日、約1〜約10mg/日、約1〜約5mg/日、約1〜約2.5mg/日、または約1〜約2mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約10mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約2mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約1mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約0.5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.01〜約0.25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約10mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約2mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約1mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約0.5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.1〜約0.25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.5〜約25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.5〜約10mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.5〜約5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.5〜約2mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約0.5〜約1mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約1〜約25mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約1〜約10mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約1〜約5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約1〜約2.5mg/日である。一実施形態では、化合物の治療有効量または予防有効量は、約1〜約2mg/日である。一実施形態では、化合物1、化合物2または化合物3の治療有効量または予防有効量は、約0.1mg/日〜約0.4mg/日である。
一実施形態では、二重特異性抗体を、週1回または週2回、一実施形態では皮下投与を介して投与する(例えば、一実施形態では0.1〜2.5、一実施形態では25mg/m2/週の用量範囲で、一実施形態では250mg/m2/週で)。二重特異性抗体の優れた細胞傷害性活性により、従来の単一特異性抗体またはT細胞二重特異性ではない(すなわち、片方のアーム上のCD3に結合しない)従来の二重特異性抗体と比較して、少なくとも同程度の臨床用量範囲(またはさらに低い)で投与することができる。二重特異性抗体の場合、臨床設定では皮下投与が好ましいと考えられる(例えば、0.1〜250mg/m2/週の用量範囲で)。さらに、血清APRIL及びBAFFのレベルが高い患者(例えば、多発性骨髄腫患者)では、リガンド競合の影響を受けない可能性があるため、二重特異性抗体の用量を増やす必要がない場合がある。対照的に、他のリガンド遮断/競合型抗BCMA抗体の用量は、これらの患者で増やす必要がある場合がある。二重特異性抗体の別の利点は、約4〜12日の消失半減期であり、これにより、少なくとも週1回または週2回、投与することができる。
本明細書に提供する化合物1、化合物2もしくは化合物3、またはそのエナンチオマー、エナンチオマーの混合物、互変異性体、アイソトポログ、もしくは薬学的に許容される塩、ならびに本明細書に提供するヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)はまた、手術、生物学的療法(例えば、チェックポイント阻害剤による免疫療法を含む)、放射線療法、化学療法、幹細胞移植、細胞療法、または多発性骨髄腫の治療、予防、もしくは管理に現在使用されている他の非薬物ベースの療法を含むがこれらに限定されない従来の療法と組み合わせるかまたは併用することができる(例えば、前、中、または後に)。本明細書に提供する化合物と従来の療法との併用は、特定の患者に予想外に有効であるユニークな治療レジメンを提供し得る。理論に拘泥するものではないが、本明細書に提供する化合物1、化合物2または化合物3、ならびにヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体による治療は、従来の療法と同時に投与する場合に、相加的または相乗的効果を提供し得ると考えられる。
本明細書に提供する医薬組成物は、本明細書に提供する治療有効量の1つ以上の化合物、及び場合により薬学的に許容される担体、希釈剤、または賦形剤を含む。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。一実施形態では、組成物は、多発性骨髄腫の治療において併用するための組成物である。
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域、
ならびに薬学的に許容される賦形剤。一実施形態では、組成物は、多発性骨髄腫の治療において併用するための組成物である。
化合物を試験して、抗多発性骨髄腫増殖活性及び十分な安全特性を含む所望の特性を有する化合物を特定するために、標準的な生理学的、薬理学的、及び生化学的手順が利用可能である。そのようなアッセイには、生化学的アッセイ、例えば、結合アッセイ、放射能組込みアッセイ、及び様々な細胞系アッセイが含まれる。
好ましくは、抗CD3抗体は、それぞれ重鎖CDR1、CDR2及びCDR3として配列番号1、2及び3の重鎖CDRを含む可変ドメインVH、ならびにそれぞれ軽鎖CDR1、CDR2及びCDR3として配列番号4、5及び6の軽鎖CDRを含む可変ドメインVLを含む。好ましくは、抗体は、配列番号7(VH)及び配列番号8(VL)の可変ドメインを含む。上記のような抗CD3抗体を使用して、以下の実施例に従ってT細胞二重特異性抗体を生成した。
対応する抗BCMA IgG1抗体の完全重鎖及び軽鎖をコードするcDNA、ならびに抗CD3 VH及びVL cDNAを出発物質として使用した。各二重特異性抗体について、対応する抗BCMA抗体の重鎖及び軽鎖、ならびに上記の抗CD3抗体の重鎖及び軽鎖をそれぞれ含む4つのタンパク質鎖が関与していた。ミスペアリングした重鎖、例えば、抗CD3抗体の2つの重鎖を有する副産物の形成を最小限に抑えるために、WO2009080251及びWO2009080252に記載されるように、「knob−into−hole変異」及び改変型ジスルフィド結合を有する変異型ヘテロ二量体Fc領域を使用する。ミスペアリングした軽鎖を有する、例えば、抗BCMA抗体の2つの軽鎖を有する副産物の形成を最小限に抑えるために、WO2009080251及びWO2009080252に記載されている方法論を用いて、CH1×定常κクロスオーバーを抗CD3抗体の重鎖と軽鎖に適用する。
T細胞活性化及びサイトカインの放出。精製したT細胞を、10%FBS及び1ng/mLのヒトIL−7を含有するRPMI1640培地で解凍する。細胞を、VI−CELL細胞カウンターで計数し、細胞培地で2×106細胞/mLに希釈する。T細胞を、37℃、5%CO2インキュベーター中で一晩回復させた。本明細書に提供するヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体で、または化合物1、化合物2もしくは化合物3を単剤として単独で、または併用して、T細胞を24、48、及び72時間処理する。細胞を各時点で収集し、CD3+CD4+及びCD3+CD8+サブセット上のT細胞活性化マーカー(CD25、CD69、及びHLA−DR)のFACS分析によって特性決定する。培地も各時点で収集し、MesoScale DiscoveryまたはLuminexプラットフォームによってサイトカインについて分析する。
化合物で前処理した後のエフェクターT細胞(E)と標的細胞(T)の共培養。CD3+T細胞を、磁気活性化セルソーティングを使用して、健康なドナーの末梢血単核細胞画分から分離した。10%(v/v)ウシ胎仔血清(FBS)、非必須アミノ酸及びピルビン酸ナトリウムを添加したRPMI1640培地中で細胞を解凍した。すべての細胞培養及び細胞処置を、37℃、5%CO2インキュベーター内で、指定の期間実施した。次いで、T細胞をCFSE(カルボキシフルオレセインスクシンイミジルエステル)で製造元の指示に従って標識し、1ng/mLのヒトIL−7の存在下で一晩回復させた。T細胞をDMSO(対照)または単剤としての化合物2で16時間処理した後、共培養した。多発性骨髄腫H929及びOPM−2細胞株または形質細胞白血病(PCL)細胞株L363をCellTrace(商標)Violetで標識し、DMSO(対照)または単剤として化合物2で72時間前処理した。次いで、T細胞と標的細胞を洗浄して化合物を除去し、本明細書に記載のヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体の濃度を増加させながら、異なるエフェクターT細胞(E)対標的細胞(T)の比率で、72時間共培養した。共培養の最後に、製造元の指示(BioLegend)に従って、7−AADを備えたAPCアネキシンVアポトーシス検出キットを使用したフローサイトメトリーによる標的細胞のアポトーシスと壊死を分析するために細胞を回収した。結果は、化合物2による標的細胞の前処理が、二重特異性抗体の効力(H929細胞とL363細胞の両方)、及び試験した二重特異性抗体によって誘導される最大の標的細胞死滅(H929細胞)を有意に増加させたことを示した(図4A及び4B)。OPM−2細胞を用いた細胞傷害性アッセイでは、化合物2によるエフェクターT細胞または標的細胞のみの処理により、試験した二重特異性抗体による標的細胞殺傷の効力と有効性が増加することが結果から示された(図4C)。OPM−2細胞傷害性アッセイの場合、エフェクターT細胞前処理と化合物2による標的細胞前処理の併用により、試験した二重特異性抗体の最大の増強及び有効性の増加が得られた(図4C)。
化合物で前処理した後のエフェクターT細胞(E)とレナリドマイド耐性多発性骨髄腫標的細胞(T)の共培養。CD3+T細胞を、3人の異なる健康なドナー(ドナーD、E及びF)の末梢血単核細胞画分から磁気活性化セルソーティングを使用して分離した。細胞を、10%(v/v)ウシ胎仔血清(FBS)、非必須アミノ酸、ピルビン酸ナトリウム、ペニシリン/ストレプトマイシンを添加したRPMI1640培地中で解凍した。すべての細胞培養及び細胞処置を、37℃、5%CO2インキュベーター内で、指定の期間実施した。次いで、T細胞をCFSE(カルボキシフルオレセインスクシンイミジルエステル)で製造元の指示に従って標識し、1ng/mLのヒトIL−7の存在下で一晩回復させた。レナリドマイド耐性多発性骨髄腫細胞株H929−1051は、以前に記載されているように(Ghandi et al.Br.J.Haematol.2014 Jan;164(2):233−44) 、記載の方法(Lopez−Girona et al. Leukemia.2012 Nov;26(11):2326−35)を用いて、漸増濃度のレナリドマイドの存在下での長時間培養により生成した。H929−1051細胞を、CellTrace(商標)Violetで標識し、次いで、単剤として、DMSO(対照)、ポマリドミド、または化合物2で72時間前処理した。次いで、T細胞と標的細胞を洗浄して化合物を除去し、本明細書に記載のヒトB細胞成熟抗原(BCMA)及びヒトCD3ε(CD3)に特異的に結合する二重特異性抗体の濃度を増加させながら、エフェクターT細胞(E)対標的細胞(T)比を1:3に固定して72時間共培養した。共培養の最後に、製造元の指示(BioLegend)に従って、7−AADを備えたAPCアネキシンVアポトーシス検出キットを使用したフローサイトメトリーによって標的細胞のアポトーシスと壊死を分析するために細胞を回収した。結果は、化合物2によるレナリドマイド耐性H929−1051標的細胞の前処理により、試験した二重特異性抗体によって誘導される効力及び最大の標的細胞死が増加し、ポマリドミドによる前処理では増加しなかったことを示した(図6)。データは、細胞株がポマリドミド耐性であることも示唆している。
Claims (22)
- 多発性骨髄腫の治療方法であって、それを必要とする患者に、治療有効量の式1の化合物
ヒトB細胞成熟抗原(BCMA)に特異的に結合する第1の結合部分と、ヒトCD3ε(CD3)に特異的に結合する第2の結合部分とを含み、前記第1の結合部分が、配列番号21のCDR1H領域、配列番号22のCDR2H領域及び配列番号17のCDR3H領域を含むVH領域、ならびに配列番号20のCDR3L領域及び以下の群から選択されるCDR1L及びCDR2L領域の組み合わせを含むVL領域を含むことを特徴とする二重特異性抗体と併用して投与することを含む、前記方法:
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。 - 多発性骨髄腫の治療方法であって、それを必要とする患者に、治療有効量の式2の化合物
ヒトB細胞成熟抗原(BCMA)に特異的に結合する第1の結合部分と、ヒトCD3ε(CD3)に特異的に結合する第2の結合部分とを含み、前記第1の結合部分が、配列番号21のCDR1H領域、配列番号22のCDR2H領域及び配列番号17のCDR3H領域を含むVH領域、ならびに配列番号20のCDR3L領域及び以下の群から選択されるCDR1L及びCDR2L領域の組み合わせを含むVL領域を含むことを特徴とする二重特異性抗体と併用して投与することを含む、前記方法:
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。 - 前記多発性骨髄腫が、再発性、難治性または抵抗性である、請求項1または2に記載の方法。
- 前記多発性骨髄腫が、レナリドマイドに対して難治性または抵抗性である、請求項3に記載の方法。
- 前記多発性骨髄腫が、ポマリドミドに対して難治性または抵抗性である、請求項3に記載の方法。
- 前記多発性骨髄腫が、新規診断された多発性骨髄腫である、請求項1または2に記載の方法。
- 前記多発性骨髄腫が形質細胞白血病である、請求項1または2に記載の方法。
- 前記化合物を、前記二重特異性抗体の前に投与する、請求項1〜7のいずれか一項に記載の方法。
- 前記化合物を、前記二重特異性抗体と同時に投与する、請求項1〜7のいずれか一項に記載の方法。
- 前記化合物を、前記二重特異性抗体の後に投与する、請求項1〜7のいずれか一項に記載の方法。
- 追加の活性薬剤を投与することをさらに含む、請求項1〜10のいずれか一項に記載の方法。
- 多発性骨髄腫の治療方法で使用するための化合物であって、前記化合物が、式1の化合物
前記方法が、それを必要とする患者に、治療有効量の式1の化合物、またはその互変異性体、アイソトポログ、もしくは薬学的に許容される塩を、ヒトB細胞成熟抗原(BCMA)に特異的に結合する第1の結合部分及びヒトCD3ε(CD3)に特異的に結合する第2の結合部分を含み前記第1の結合部分が、配列番号21のCDR1H領域、配列番号22のCDR2H領域及び配列番号17のCDR3H領域を含むVH領域、ならびに配列番号20のCDR3L領域及び以下の群から選択されるCDR1L領域とCDR2L領域の組み合わせを含むVL領域を含むことを特徴とする二重特異性抗体と併用して投与することを含む、前記化合物:
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。 - 多発性骨髄腫の治療方法で使用するための化合物であって、前記化合物が、式2の化合物
前記方法が、それを必要とする患者に、治療有効量の式2の化合物、またはその互変異性体、アイソトポログ、もしくは薬学的に許容される塩を、ヒトB細胞成熟抗原(BCMA)に特異的に結合する第1の結合部分及びヒトCD3ε(CD3)に特異的に結合する第2の結合部分を含み、前記第1の結合部分が、配列番号21のCDR1H領域、配列番号22のCDR2H領域及び配列番号17のCDR3H領域を含むVH領域、ならびに配列番号20のCDR3L領域及び以下の群から選択されるCDR1L領域とCDR2L領域の組み合わせを含むVL領域を含むことを特徴とする二重特異性抗体と併用して投与することを含む、前記化合物:
i)配列番号23のCDR1L領域及び配列番号24のCDR2L領域、
ii)配列番号25のCDR1L領域及び配列番号26のCDR2L領域、または
iii)配列番号27のCDR1L領域及び配列番号28のCDR2L領域。 - 前記多発性骨髄腫が、再発性、難治性または抵抗性である、請求項12または13に記載の使用のための化合物。
- 前記多発性骨髄腫が、レナリドマイドに対して難治性または抵抗性である、請求項14に記載の使用のための化合物。
- 前記多発性骨髄腫が、ポマリドミドに対して難治性または抵抗性である、請求項14に記載の使用のための化合物。
- 前記多発性骨髄腫が、新規診断された多発性骨髄腫である、請求項12または13に記載の使用のための化合物。
- 前記多発性骨髄腫が形質細胞白血病である、請求項12または13に記載の使用のための化合物。
- 前記化合物を、前記二重特異性抗体の前に投与する、請求項12〜18のいずれか一項に記載の使用のための化合物。
- 前記化合物を、前記二重特異性抗体と同時に投与する、請求項12〜18のいずれか一項に記載の使用のための化合物。
- 前記化合物を、前記二重特異性抗体の後に投与する、請求項12〜18のいずれか一項に記載の使用のための化合物。
- 前記方法が、追加の活性薬剤を投与することをさらに含む、請求項12〜21のいずれか一項に記載の使用のための化合物。
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EP4218762A3 (en) | 2023-08-16 |
EP4218762A2 (en) | 2023-08-02 |
US11439637B2 (en) | 2022-09-13 |
RS64189B1 (sr) | 2023-06-30 |
CN113713095A (zh) | 2021-11-30 |
LT3796912T (lt) | 2023-06-12 |
JP2023116613A (ja) | 2023-08-22 |
CA3101050A1 (en) | 2019-11-28 |
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EP3796912A1 (en) | 2021-03-31 |
EP3796912B1 (en) | 2023-02-15 |
KR20210021996A (ko) | 2021-03-02 |
CY1126060T1 (el) | 2023-11-15 |
CN112399848A (zh) | 2021-02-23 |
DK3796912T3 (da) | 2023-05-15 |
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