JP2021191793A - Programmed Death 1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 - Google Patents
Programmed Death 1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 Download PDFInfo
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Abstract
Description
(a)KDが1×10−7M以下でヒトPD−1に結合する。
(b)ヒトCD28、CTLA−4またはICOSに実質的に結合しない。
(c)混合リンパ球反応(MLR)アッセイにおいてT細胞増殖を上昇させる。
(d)MLRアッセイにおいてインターフェロン−γ産生を増加させる。
(e)MLRアッセイにおいてIL−2分泌を増加させる。
(f)ヒトPD−1およびカニクイザルPD−1に結合する。
(g)PD−L1および/またはPD−L2のPD−1に対する結合を阻害する。
(h)抗原特異的記憶応答を刺激する。
(i)抗体応答を刺激する。
(j)腫瘍細胞増殖をインビボで阻害する。
(a)配列番号1、2、3、4、5、6および7から構成される群から選択されたアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号8、9、10、11、12、13および14から構成される群から選択されたアミノ酸配列を含むヒト軽鎖可変領域
を含む参考抗体とPD−1に対する結合を交差競合する単離ヒトモノクローナル抗体またはその結合部分を提供する。
(a)配列番号1のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号8のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号2のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号9のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号3のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号10のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号4のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号11のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号5のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号12のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号6のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号13のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または当該参考抗体は、
(a)配列番号7のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号14のアミノ酸配列を含むヒト軽鎖可変領域
を含む。
(a)ヒトVH3−33遺伝子の重鎖可変領域および
(b)ヒトVKL6遺伝子の軽鎖可変領域
を含み、抗体が特異的にPD−1に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
(a)ヒトVH4−39遺伝子の重鎖可変領域および
(b)ヒトVKL15遺伝子の軽鎖可変領域
を含み、抗体が特異的にPD−1に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
CDR1、CDR2およびCDR3配列を含む重鎖可変領域およびCDR1、CDR2およびCDR3配列を含む軽鎖可変領域
を含み、
(a)重鎖可変領域CDR3配列は、配列番号29、30、31、32、33、34および35、およびその保存的修飾体から構成される群から選択されたアミノ酸配列を含み、(b)軽鎖可変領域CDR3配列は、配列番号50、51、52、53、54、55および56、およびその保存的修飾体から構成される群から選択されたアミノ酸配列を含み、(c)当該抗体は特異的にPD−1に結合する、
単離モノクローナル抗体またはその抗原結合部分を提供する。
(a)当該重鎖可変領域は、配列番号1、2、3、4、5、6および7から構成される群から選択されたアミノ酸配列に対して少なくとも80%の相同性を有するアミノ酸配列を含み、
(b)当該軽鎖可変領域は、配列番号8、9、10、11、12、13および14から構成される群から選択されたアミノ酸配列に対して少なくとも80%の相同性を有するアミノ酸配列を含み、
(c)当該抗体は、ヒトPD−1に対してKDが1×10−7M以下で結合し、
(d)当該抗体は、ヒトCD28、CTLA−4またはICOSに対して実質的に結合しない、単離モノクローナル抗体またはその抗原結合部分を提供する。
(b)当該抗体は、MLRアッセイにおいてインターフェロン−γ産生を増大させる。
(c)当該抗体は、MLRアッセイにおいてインターロイキン−2(IL−2)分泌を増大させる。
(a)配列番号15、16、17、18、19、20および21から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR1、
(b)配列番号22、23、24、25、26、27および28から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR2、
(c)配列番号29、30、31、32、33、34および35から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR3、
(d)配列番号36、37、38、39、40、41および42から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR1、
(e)配列番号43、44、45、46、47、48および49から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR2、
(f)配列番号50、51、52、53、54、55および56から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR3
を含み、抗体が、PD−1と特異的に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
(a)配列番号15を含む重鎖可変領域CDR1、
(b)配列番号22を含む重鎖可変領域CDR2、
(c)配列番号29を含む重鎖可変領域CDR3、
(d)配列番号36を含む軽鎖可変領域CDR1、
(e)配列番号43を含む軽鎖可変領域CDR2および
(f)配列番号50を含む軽鎖可変領域CDR3
を含む。
(a)配列番号16を含む重鎖可変領域CDR1、
(b)配列番号23を含む重鎖可変領域CDR2、
(c)配列番号30を含む重鎖可変領域CDR3、
(d)配列番号37を含む軽鎖可変領域CDR1、
(e)配列番号44を含む軽鎖可変領域CDR2および
(f)配列番号51を含む軽鎖可変領域CDR3
を含む。
(a)配列番号17を含む重鎖可変領域CDR1、
(b)配列番号24を含む重鎖可変領域CDR2、
(c)配列番号31を含む重鎖可変領域CDR3、
(d)配列番号38を含む軽鎖可変領域CDR1、
(e)配列番号45を含む軽鎖可変領域CDR2および
(f)配列番号52を含む軽鎖可変領域CDR3
を含む。
(a)配列番号18を含む重鎖可変領域CDR1、
(b)配列番号25を含む重鎖可変領域CDR2、
(c)配列番号32を含む重鎖可変領域CDR3、
(d)配列番号39を含む軽鎖可変領域CDR1、
(e)配列番号46を含む軽鎖可変領域CDR2および
(f)配列番号53を含む軽鎖可変領域CDR3
を含む。
(a)配列番号19を含む重鎖可変領域CDR1、
(b)配列番号26を含む重鎖可変領域CDR2、
(c)配列番号33を含む重鎖可変領域CDR3、
(d)配列番号40を含む軽鎖可変領域CDR1、
(e)配列番号47を含む軽鎖可変領域CDR2および
(f)配列番号54を含む軽鎖可変領域CDR3
を含む。
(a)配列番号20を含む重鎖可変領域CDR1、
(b)配列番号27を含む重鎖可変領域CDR2、
(c)配列番号34を含む重鎖可変領域CDR3、
(d)配列番号41を含む軽鎖可変領域CDR1、
(e)配列番号48を含む軽鎖可変領域CDR2および
(f)配列番号55を含む軽鎖可変領域CDR3
を含む。
(a)配列番号21を含む重鎖可変領域CDR1、
(b)配列番号28を含む重鎖可変領域CDR2、
(c)配列番号35を含む重鎖可変領域CDR3、
(d)配列番号42を含む軽鎖可変領域CDR1、
(e)配列番号49を含む軽鎖可変領域CDR2および
(f)配列番号56を含む軽鎖可変領域CDR3
を含む。
(a)配列番号1、2、3、4、5、6および7から構成される群から選択されたアミノ酸配列を含む重鎖可変領域および
(b)配列番号8、9、10、11、12、13および14から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域
を含み、当該抗体はPD−1に特異的に結合する。
(a)配列番号1のアミノ酸配列を含む重鎖可変領域および
(b)配列番号8のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号2のアミノ酸配列を含む重鎖可変領域および
(b)配列番号9のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号3のアミノ酸配列を含む重鎖可変領域および
(b)配列番号10のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号4のアミノ酸配列を含む重鎖可変領域および
(b)配列番号11のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号5のアミノ酸配列を含む重鎖可変領域および
(b)配列番号12のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号6のアミノ酸配列を含む重鎖可変領域および
(b)配列番号13のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)配列番号7のアミノ酸配列を含む重鎖可変領域および
(b)配列番号14のアミノ酸配列を含む軽鎖可変領域
を含む。
(a)(i)配列番号15、16、17、18、19、20および21から構成される群から選択したCDR1配列および/または配列番号22、23、24、25、26、27および28から構成される群から選択したCDR2配列;および/または配列番号29、30、31、32、33、34および35から構成される群から選択したCDR3配列を含む重鎖可変抗体配列;または(ii)配列番号36、37、38、39、40、41および42から構成される群から選択したCDR1配列および/または配列番号43、44、45、46、47、48および49から構成される群から選択したCDR2配列;および/または配列番号50、51、52、53、54、55および56から構成される群から選択したCDR3配列を含む軽鎖可変抗体配列を提供すること;
(b)重鎖可変領域抗体配列および軽鎖可変領域抗体配列から選択した少なくとも1個の可変領域抗体配列内部の少なくとも1個のアミノ酸残基を改変し、少なくとも1個の改変抗体配列を作成すること;および
(c)当該改変抗体配列をタンパク質として発現させること
を含む、抗PD−1抗体を調製する方法を提供する。
本発明の抗体は、抗体の特定の機能的特徴または性質によって特徴づけられる。例えば、当該抗体は、PD−1に特異的に結合する(例えば、ヒトPD−1に結合し、カニクイザルのような他の種由来のPD−1に交差反応できる)。好適には、本発明の抗体はヒトPD−1に対してKDが1×10−7以下の高親和性で結合する。本発明の抗PD−1抗体は、好適には下記の性質を1個以上示す。
(a)KDが1×10−7M以下でヒトPD−1に結合する。
(b)ヒトCD28、CTLA−4またはICOSに実質的に結合しない。
(c)混合リンパ球反応(MLR)アッセイにおいてT細胞増殖を上昇させる。
(d)MLRアッセイにおいてインターフェロン−γ産生を増加させる。
(e)MLRアッセイにおいてインターロイキン−2(IL−2)分泌を増加させる。
(f)ヒトPD−1およびカニクイザルPD−1に結合する。
(g)PD−L1および/またはPD−L2のPD−1に対する結合を阻害する。
(h)抗原特異的記憶応答を刺激する。
(i)抗体応答を刺激する。
(j)腫瘍細胞増殖をインビボで阻害する。
(a)配列番号1、2、3、4、5、6および7から構成される群から選択されたアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号8、9、10、11、12、13および14から構成される群から選択されたアミノ酸配列を含むヒト軽鎖可変領域
を含み、抗体が、PD−1、好適には、ヒトPD−1に特異的に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
(a)配列番号1のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号8のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号2のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号9のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号3のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号10のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号4のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号11のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号5のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号12のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号6のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号13のアミノ酸配列を含むヒト軽鎖可変領域
を含むか、または
(a)配列番号7のアミノ酸配列を含むヒト重鎖可変領域および
(b)配列番号14のアミノ酸配列を含むヒト軽鎖可変領域
を含む。
(a)配列番号15、16、17、18、19、20および21から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR1;
(b)配列番号22、23、24、25、26、27および28から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR2;
(c)配列番号29、30、31、32、33、34および35から構成される群から選択されたアミノ酸配列を含む重鎖可変領域CDR3;
(d)配列番号36、37、38、39、40、41および42から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR1;
(e)配列番号43、44、45、46、47、48および49から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR2;
(f)配列番号50、51、52、53、54、55および56から構成される群から選択されたアミノ酸配列を含む軽鎖可変領域CDR3
を含み、抗体がPD−1に、好適にはヒトPD−1に特異的に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
(a)配列番号15を含む重鎖可変領域CDR1、
(b)配列番号22を含む重鎖可変領域CDR2、
(c)配列番号29を含む重鎖可変領域CDR3、
(d)配列番号36を含む軽鎖可変領域CDR1、
(e)配列番号43を含む軽鎖可変領域CDR2および
(f)配列番号50を含む軽鎖可変領域CDR3
を含む。
(a)配列番号16を含む重鎖可変領域CDR1、
(b)配列番号23を含む重鎖可変領域CDR2、
(c)配列番号30を含む重鎖可変領域CDR3、
(d)配列番号37を含む軽鎖可変領域CDR1、
(e)配列番号44を含む軽鎖可変領域CDR2および
(f)配列番号51を含む軽鎖可変領域CDR3
を含む。
(a)配列番号17を含む重鎖可変領域CDR1、
(b)配列番号24を含む重鎖可変領域CDR2、
(c)配列番号31を含む重鎖可変領域CDR3、
(d)配列番号38を含む軽鎖可変領域CDR1、
(e)配列番号45を含む軽鎖可変領域CDR2および
(f)配列番号52を含む軽鎖可変領域CDR3
を含む。
(a)配列番号18を含む重鎖可変領域CDR1、
(b)配列番号25を含む重鎖可変領域CDR2、
(c)配列番号32を含む重鎖可変領域CDR3、
(d)配列番号39を含む軽鎖可変領域CDR1、
(e)配列番号46を含む軽鎖可変領域CDR2および
(f)配列番号53を含む軽鎖可変領域CDR3
を含む。
(a)配列番号19を含む重鎖可変領域CDR1、
(b)配列番号26を含む重鎖可変領域CDR2、
(c)配列番号33を含む重鎖可変領域CDR3、
(d)配列番号40を含む軽鎖可変領域CDR1、
(e)配列番号47を含む軽鎖可変領域CDR2および
(f)配列番号54を含む軽鎖可変領域CDR3
を含む。
ある態様において、本発明の抗体は、特定の生殖細胞型重鎖イムノグロブリン遺伝子由来の重鎖可変領域および/または特定の生殖細胞型軽鎖イムノグロブリン遺伝子由来の軽鎖可変領域を含む。
(a)ヒトVH3−33または4−39遺伝子(この遺伝子は、それぞれ配列番号71または73に記載のアミノ酸配列をコードする)の産物であるかまたはそれに由来する重鎖可変領域を含み、
(b)ヒトVKL6またはL15遺伝子(この遺伝子は、それぞれ配列番号72または74に記載のアミノ酸配列をコードする)の産物であるかまたはそれに由来する軽鎖可変領域を含み、
(c)PD−1に特異的に結合する単離モノクローナル抗体またはその抗原結合部分を提供する。
さらに別の態様において、本発明の抗体は、ここに記載の好適な抗体のアミノ酸配列に相同のアミノ酸配列を含む重鎖および軽鎖可変領域を含み、ここで、当該抗体は、本発明の抗PD−1抗体の望ましい機能的性質を保持している。
(a)重鎖可変領域は、配列番号1、2、3、4、5、6および7から構成される群から選択されたアミノ酸配列に対して少なくとも80%相同のアミノ酸配列を含み、
(b)軽鎖可変領域は、配列番号8、9、10、11、12、13および14から構成される群から選択されたアミノ酸配列に対して少なくとも80%相同のアミノ酸配列を含み、当該抗体が下記の性質:
(c)KD1×10−7M以下でヒトPD−1に結合する、
(d)ヒトCD28、CTLA−4またはICOSに実質的に結合しない、
(e)MLRアッセイにおいてT細胞増殖を増大させる、
(f)MLRアッセイにおいてインターフェロン−γ産生を増加させる、
(g)MLRアッセイにおいてIL−2分泌を増加させる、
(h)ヒトPD−1およびカニクイザルPD−1に結合する、
(i)PD−L1および/またはPD−L2のPD−1に対する結合を阻害する、
(j)抗原特異的記憶応答を刺激する、
(k)抗体応答を刺激する、
(l)腫瘍細胞増殖をインビボで阻害する、
のうちの1個以上を示す重鎖可変領域と軽鎖可変領域を含む単離モノクローナル抗体またはその抗原結合部分を提供する。
ある態様において、本発明の抗体は、CDR1、CDR2およびCDR3配列を含む重鎖可変領域とCDR1、CDR2およびCDR3配列を含む軽鎖可変領域を含み、ここで、これらのCDR配列の1つ以上は、ここに記載の好適な抗体に基づく特定のアミノ酸配列(例えば、17D8、2D3、4H1、5C4、4A11、7D3または5F4)またはその保存的修飾体を含み、かつ、当該抗体は、本発明の抗PD−1抗体の望ましい機能的性質を保持している。したがって、本発明は、CDR1、CDR2およびCDR3配列を含む重鎖可変領域とCDR1、CDR2およびCDR3配列を含む軽鎖可変領域を含み、
(a)重鎖可変領域CDR3配列は、配列番号29、30、31、32、33、34および35のアミノ酸配列およびその保存的修飾体から構成される群から選択されたアミノ酸配列を含み、
(b)軽鎖可変領域CDR3配列は、配列番号50、51、52、53、54、55および56のアミノ酸配列およびその保存的修飾体から構成される群から選択されたアミノ酸配列を含み、
抗体が下記の性質:
(c)抗体が、KD1×10−7M以下でヒトPD−1に結合する、
(d)抗体が、ヒトCD28、CTLA−4またはICOSに実質的に結合しない、
(e)抗体が、MLRアッセイにおいてT細胞増殖を上昇させる、
(f)抗体が、MLRアッセイにおいてインターフェロン−γ産生を増加させる、
(g)抗体が、MLRアッセイにおいてIL−2分泌を増加させる、
(h)抗体が、ヒトPD−1およびカニクイザルPD−1に結合する、
(i)抗体が、PD−L1および/またはPD−L2のPD−1に対する結合を阻害する、
(j)抗体が、抗原特異的記憶応答を刺激する、
(k)抗体が、抗体応答を刺激する、
(l)抗体が、腫瘍細胞増殖をインビボで阻害する、
のうちの1個以上を示す単離モノクローナル抗体またはその抗原結合部分を提供する。
別の態様において、本発明は、本発明のPD−1モノクローナル抗体のいずれかと同一のヒトPD−1上エピトープに結合する抗体(すなわち、本発明のモノクローナル抗体のいずれかとPD−1結合を交差競合する能力を有する抗体)を提供する。好適な態様において、交差競合研究の参考抗体は、モノクローナル抗体17D8(それぞれ配列番号1および8に示したようなVHおよびVLを有する)、またはモノクローナル抗体2D3(それぞれ配列番号2および9に示したようなVHおよびVLを有する)、またはモノクローナル抗体4H1(それぞれ配列番号3および10に示したようなVHおよびVLを有する)、またはモノクローナル抗体5C4(それぞれ配列番号4および11に示したようなVHおよびVLを有する)、またはモノクローナル抗体4A11(それぞれ配列番号5および12に示したようなVHおよびVLを有する)、またはモノクローナル抗体7D3(それぞれ配列番号6および13に示したようなVHおよびVLを有する)、またはモノクローナル抗体5F4(それぞれ配列番号7および14に示したようなVHおよびVLを有する)であってもよい。このような交差競合性抗体は、標準的なPD−1結合アッセイにおいて17D8、2D3、4H1、5C4、4A11、7D3または5F4と交差競合する能力に基づいて同定できる。例えば、ビアコア分析、ELISAアッセイまたはフローサイトメトリーを用いて、本発明の抗体との交差競合を明らかにすることもできる。ヒトPD−1に対する17D8、2D3、4H1、5C4、4A11、7D3または5F4の結合を阻害する試験抗体の能力は、試験抗体がヒトPD−1に対する結合を17D8、2D3、4H1、5C4、4A11、7D3または5F4と競合でき、従って、17D8、2D3、4H1、5C4、4A11と同一のヒトPD−1上エピトープに結合することを明らかにする。好適な態様において、17D8、2D3、4H1、5C4、4A11、7D3または5F4と同一のヒトPD−1上エピトープに結合する抗体は、ヒトモノクローナル抗体である。このようなヒトモノクローナル抗体は、実施例に記載のようにして調製して単離できる。
本発明の抗体は、修飾抗体を工学的に作製するための出発物質として、ここに開示した1つ以上のVHおよび/またはVL配列を有する抗体を用いて調製でき、ここで、当該修飾抗体は、当該出発物質から改変された性質を有することがある。抗体は、1つ以上の可変領域(すなわち、VHおよび/またはVL)内部、例えば、1つ以上のCDR領域内部および/または1つ以上のフレームワーク領域内部の1つ以上の残基を修飾することによって工学的に作製できる。さらにまたはこれとは別に、抗体は、例えば、抗体のエフェクター機能を改変するために定常領域内部の残基を修飾することによって工学的に作製できる。
上記にも述べたように、ここに開示したVHおよびVK配列を有する抗PD−1抗体を用いて、VHおよび/またはVK配列またはそれに結合した定常領域を修飾することによって、新しい抗PD−1抗体を作製できる。したがって、本発明の別の面において、本発明の抗PD−1抗体の構造的特徴、例えば、17D8、2D3、4H1、5C4、4A11、7D3または5F4を用いてヒトPD−1に対する結合のような本発明の抗体の少なくとも一つの機能的特徴を保持する構造的に関連した抗PD−1抗体を作製できる。例えば、17D8、2D3、4H1、5C4、4A11、7D3または5F4またはその変異体の1個以上のCDR領域を公知のフレームワーク領域および/または他のCDRと組み換えで組み合わせて、付加的な組み換え工学で作成された本発明の抗体を上述のように作製できる。他の修飾タイプには、前章で述べたものが含まれる。工学的方法の出発物質は、ここで提供したVHおよび/またはVK配列の1個以上またはその1個以上のCDR領域である。工学的抗体を作製するため、VHおよび/またはVK配列の1個以上またはその1個以上のCDR領域を有する抗体を実際に調製(すなわち、タンパク質として発現させる)する必要はない。むしろ、配列に含まれる情報を出発物質として用いて当初の配列に由来する“第二世代”配列を作製し、次に、この“第二世代”配列をタンパク質として調製し発現させる。
(a)(i)配列番号15、16、17、18、19、20および21から構成される群から選択したCDR1配列、配列番号22、23、24、25、26、27および28から構成される群から選択したCDR2配列、および/または配列番号29、30、31、32、33、34および35から構成される群から選択したCDR3配列を含む重鎖可変領域抗体配列、および/または(ii)配列番号36、37、38、39、40、41および42から構成される群から選択したCDR1配列、配列番号43、44、45、46、47、48および49から構成される群から選択したCDR2配列、および/または配列番号50、51、52、53、54、55および56から構成される群から選択したCDR3配列を含む軽鎖可変領域抗体配列を提供すること、
(b)重鎖可変領域抗体配列および/または軽鎖可変領域抗体配列から選択した少なくとも1個の可変領域抗体配列内部の少なくとも1個のアミノ酸残基を改変し、少なくとも1個の改変抗体配列を作成すること;および
(c)当該改変抗体配列をタンパク質として発現させること、
を含む抗PD−1抗体を調製する方法を提供する。
(b)当該抗体は、ヒトCD28、CTLA−4またはICOSに実質的に結合しない。(c)当該抗体は、MLRアッセイにおいてT細胞増殖を増大させる。
(d)当該抗体は、MLRアッセイにおいてインターフェロン−γ産生を増加させる。
(e)当該抗体は、MLRアッセイにおいてIL−2分泌を増加させる。
(f)当該抗体は、ヒトPD−1およびカニクイザルPD−1に結合する。
(g)当該抗体は、PD−L1および/またはPD−L2のPD−1に対する結合を阻害する。
(h)当該抗体は、抗原特異的記憶応答を刺激する。
(i)当該抗体は、抗体応答を刺激する。
(j)当該抗体は、腫瘍細胞増殖をインビボで阻害する。
本発明の別の面は、本発明の抗体をコードする核酸分子に関する。核酸は、細胞溶解物として、細胞全体または部分精製若しくは実質的に純粋な形状で存在できる。核酸は、アルカリ/SDS処理、CsCl結合、カラムクロマトグラフィ、アガロースゲル電気泳動およびその他当該技術の周知の方法を含む標準的技術によって、例えば、他の細胞性核酸またはタンパク質のような他の細胞性成分または他の夾雑物から精製して取り出す際に“単離される”かまたは“実質的に純粋にされる”。F.Ausubelら(1987)Current Protocols in Molecular Biology,Greene Publishing and Wiley Interscience, New Yorkを参照。本発明の核酸は、例えば、DNAまたはRNAであってもよく、イントロン配列を含んでいてもよいし、含まなくてもよい。好適な態様において、当該核酸はcDNA分子である。
本発明のモノクローナル抗体(mAbs)は、例えば、KohlerとMilstein(1975)Nature 256:495の標準的体細胞ハイブリダイゼーション技術のような従来のモノクローナル抗体方法を含む様々な手法によって作製できる。体細胞ハイブリダイゼーション操作が好適であるが、原則的には、モノクローナル抗体作製のための他の技術として、例えば、Bリンパ細胞のウイルス性または癌性形質転換を用いることができる。
ヒトIgマウスを用いて本発明のヒト抗体を作製する場合、Lonberg,N.ら(1994)Nature 368(6474);856−859、Fishwild,D.ら(1996)Nature Biotechnology 14:845−851およびPCT公報WO98/24884およびWO01/14424に記載されているようにして、精製または高含量のPD−1抗原および/または組み換えPD−1またはPD−1融合タンパク質により、このようなマウスを免疫できる。好適には、6−16週齢の当該マウスに対して最初の注入を行う。例えば、PD−1抗原の精製または組み換え調製物(5−50μg)を用いて、腹腔中でヒトIgマウスに免疫できる。
本発明のヒトモノクローナル抗体産生ハイブリドーマ作製のため、免疫したマウス由来の脾臓および/またはリンパ節細胞を単離し、マウス骨髄細胞株のような適切な不死化細胞株に融合できる。得られたハイブリドーマについて、抗原特異的抗体の産生をスクリーニングできる。例えば、免疫したマウス由来の脾臓リンパ球の単細胞懸濁物を、50%PEGにより、6分の1数のP3X63−Ag8.653非分泌マウス骨髄細胞(ATCC、CRL1580)に融合できる。これとは別に、免疫したマウス由来の脾臓リンパ球の単細胞懸濁物を、サイトパルス大型チェンバー細胞融合エレクトロポレータ(Cyto Pulse Sciences,Inc.,Glen Burnie,MD)を用いて電場に基づく電気融合法により融合させることができる。細胞は、約2×105で平底マイクロタイタープレートに播種し、20%胎児クローン血清、18%“653”調製培地、5%オリゲン(IGEN)、4mM L−グルタミン、1mM ピルビン酸ナトリウム、5mM HEPES、0.055mM 2−メルカプトメタノール、50単位/mLペニシリン、50mg/mL ストレプトマイシン、50mg/mL ゲンタマイシンおよび1xHAT(Sigma;HATを、注入24時間後に添加する)を含む選択培地中で2週間インキュベーションする。約2週後、細胞を、HATをHTに置き換えた培地中で培養する。次に、それぞれのウェルをELISAでスクリーニングし、ヒトモノクローナルIgMおよびIgG抗体をスクリーニングする。いったん広範なハイブリドーマ増殖が起こると、培地は、通常、10−14日後に観察できる。抗体分泌ハイブリドーマを再播種し、再度スクリーニングし、もしヒトIgGがまだ陽性であるならば、モノクローナル抗体を少なくとも2回、限定希釈によってサブクローニングする。次に、安定なサブクローンをインビトロで培養し、少量の抗体を組織培地に産生させ、特性解析する。
また、本発明の抗体は、例えば、当該技術において周知の組み換えDNA技術と遺伝子トランスフェクション技術を組み合わせて用いて、宿主細胞中で産生させることができる(例えば、Morrison,S.(1985)Science 229:1202)。
本発明の抗体について、例えば、標準的ELISAによってPD−1への結合を試験できる。簡単に述べると、マイクロタイタープレートをPBS中0.25μg/mLの精製PD−1でコートし、次に、PBS中5%のウシ血清アルブミンでブロックする。抗体希釈物(例えば、PD−1免疫マウス由来の血漿の希釈物)を各ウェルに添加し、37℃で1−2時間インキュベーションする。プレートをPBS/Tweenで洗浄し、次に、アルカリホスファターゼ結合第2試薬(例えば、ヒト抗体用には、ヤギ抗ヒトIgG Fc−特異的ポリクローナル試薬)とともに37℃で1時間、インキュベーションする。洗浄後、プレートをpNPP基質(1mg/mL)で発色させ、OD406−650で分析する。好適には、最大力価を示したマウスを融合用に用いる。
別の面において、本発明は、サイトトキシン、薬物(例えば、免疫抑制剤)または放射性トキシンのような治療分子に複合させた抗PD−1抗体またはその断片を特徴とする。このような複合物は、ここで、“免疫複合物”と称する。1個以上のサイトトキシンを含む免疫複合物は、“イムノトキシン”と称される。サイトトキシン、すなわち、細胞傷害性物質には、細胞に有害な(例えば、死滅させる)いかなる物質も含まれる。例として、タキソール、サイトカラシンB、グラミシジンD、エチジウムブロマイド、エメチン、マイトマイシン、エトポシド、テノポシド、ビンクリスチン、ビンブラスチン、コルヒチン、ドキソルビシン、ダウノルビシン、ジハイドロキシアントラシンジオン、ミトキサントロン、ミトラマイシン、アクチノマイシンD、1−デヒドロテストステロン、グルココルチコイド、プロカイン、テトラカイン、リドカイン、プロプラノロール、およびピューロマイシンおよびそのアナログまたはホモログを含む。また、治療薬には、例えば、代謝拮抗物質(例えば、メトトレキセート、6−メルカプトプリン、6−チオグアニン、シタラビン、5−フルオロウラシルデカルバジン)、アルカリ化剤(例えば、メクロレタミン、チオエパクロラムブチル、メルファラン、カルムスチン(BSNU)およびロムスチン(CCNU)、シクロソスファミド、ブスルファン、ジブロモマンニトール、ストレプトゾトシン、マイトマイシンC、およびシス−ジクロロジアミン白金(II)(DDP)シスプラチン)、アントラサイクリン(例えば、ダウノルビシン(旧ダウノマイシン)およびドキソルビシン)、抗生物質(例えば、ダクチノマイシン(旧アクチノマイシン)、ブレオマイシン、ミトラマイシン、およびアンスラマイシン(AMC))、および有糸分裂剤(例えば、ビンクリスチンおよびビンブラスチン)が含まれる。
別の面において、本発明は、本発明の抗PD−1抗体またはその断片を含む二重特異性分子を特徴とする。本発明の抗体またはその抗原結合部分は、誘導体化することができ、または、例えば、別のペプチドまたはタンパク質(例えば、別の抗体またはレセプターに対するリガンド)のような別の機能分子に連結することによって、少なくとも2つの異なる結合部位または標的分子に結合する二重特異性分子を作製できる。本発明の抗体は、実際に、誘導体化することもできあるいは1つ以上の他の機能分子に連結することによって、2つ以上の異なる結合部位および/または標的分子に結合する多重特異性分子を作製することができる。このような多重特異性分子も、本文中、用語“二重特異性分子”に含まれるものとする。本発明の二重特異性分子を作製するため、二重特異性分子ができるように本発明の抗体を別の抗体、抗体断片、ペプチドまたは結合模倣物のような1つ以上の結合分子に機能的に(例えば、化学的カップリング、遺伝的融合、非共有結合またはその他で)連結することができる。
本発明は、例えば、本発明のモノクローナル抗体またはその抗原結合部分を1種またはその組み合わせを含有し、薬学的に許容できる担体とともに処方された医薬組成物を提供するという側面がある。このような組成物は、本発明の(例えば、2種以上の異なる)抗体、または免疫複合物または二重特異性分子を1個、または、その組み合わせを含んでいてもよい。例えば、本発明の医薬組成物は、標的抗原上の異なるエピトープに結合するかまたは補完的活性を有する抗体(または免疫複合物または二重特異性抗体)の組み合わせを含むことができる。
本発明の抗体、抗体組成物および方法は、例えば、PD−1検出またはPD−1阻害により免疫応答を増強の検出といった、多数のインビトロおよびインビボ用途を有している。好適な態様において、本発明の抗体はヒト抗体である。例えば、これらの分子は、培養細胞に対してインビトロでまたはエクスビボであるいはヒト被験者に対して、例えば、インビボで投与して、様々な状況において免疫性を高めることができる。したがって、一面において、本発明は、被験者の免疫応答が修正されるように本発明の抗体またはその抗原結合部分を当該被験者に投与することを含む、被験者に対する免疫応答を修正する方法を提供する。好適には、当該応答は、増強、刺激または上方制御される。
抗体によるPD−1阻害は、患者において癌性細胞に対する免疫応答を増強できる。PD−1に対するリガンドPD−L1は、正常なヒト細胞では発現されないが、様々なヒト癌には多く発現している(Dongら(2002)Nat Med 8:787−9)。PD−1とPD−L1との相互作用の結果、腫瘍浸潤性リンパ球の減少、T細胞レセプターを介した増殖の低下、癌性細胞による免疫回避が起こる(Dongら(2003)J Mol Med 81:281−7、Blankら(2005)Cancer Immunol.Immunother. 54:307−314、Konishiら(2004)Clin. Cancer Res. 10:5094−100)。免疫抑制は、PD−L1に対するPD−1の局所相互作用を阻害することによって元に戻すことができ、PD−L2に対するPD−1の相互作用を同様に阻害する時、その効果は相加的である(Iwaiら(2002)PNAS 99:12293−7、Brownら(2003)J.Immunol. 170:1257−66)。これまでの研究において、T細胞増殖がPD−L1に対するPD−1の相互作用を阻害することによって回復できることが示されているが、インビボにおいて、PD−1/PD−L1相互作用の阻害による癌腫瘍の増殖に対する直接的な効果については全く報告がない。本発明は、一面において、癌性腫瘍の増殖を阻害するように抗PD−1抗体を用いる、被験者のインビボ治療に関する。抗PD−1抗体だけを用いて癌性腫瘍の増殖を阻害できる。あるいは、抗PD−1抗体を、他の免疫原性物質、標準的癌治療または他の抗体と組み合わせて、下記に記載のように用いることができる。
本発明の他の方法としては、特定の毒素または病原体に暴露した患者を治療するものが挙げられる。したがって、本発明の別の側面においては、被験者に対して抗PD−1抗体またはその抗原結合部分を、当該被験者の感染性疾患を治療できるように投与することを含む、当該被験者における感染性疾患を治療する方法を提供できる。好適には、当該抗体は、(本文で記載のヒト抗PD−1抗体のいずれかのような)ヒト抗ヒトPD−1抗体である。さらにまたはこれとは別に、当該抗体はキメラまたはヒト化抗体であってもよい。
抗PD−1抗体は、自己免疫応答を惹起し増幅できる。実際、腫瘍細胞とペプチドワクチンを用いた抗腫瘍応答の誘発により、多くの抗腫瘍応答には、抗自己反応性を伴う(抗CTLA−4+GM−CSF修飾B16メラノーマに見られる脱色、 van Elsasら、同上、Trp−2ワクチンマウスにおける脱色(Overwijk、W.ら(1999)Proc.Nat.Acad.Sci.USA 96:2982−2987);TRAMP腫瘍細胞ワクチンにより惹起された自己免疫前立腺炎(Hurwitz,A.(2000)同上);メラノーマペプチド抗原ワクチン化およびヒト臨床治験で観察された尋常性白斑(Rosenberg,SAおよびWhite,DE(1996)J.Immunother. Emphasis Tumor Immunol. 19(1):81−4)。
抗PD−1抗体は、抗PD−1抗体を問題となる抗原(例えば、ワクチン)を同時投与することによって抗原特異的応答を刺激することができる。したがって、別の側面において、本発明は、被験者に対して(i)抗原、および(ii)抗PD−1抗体またはその抗原結合部分を投与し、被験者における抗原に対する免疫応答を増強することを含む、被験者における抗原に対する免疫応答を増強する方法を提供することができる。好適には、当該抗体は、ヒト抗ヒトPD−1抗体(上述のヒト抗PD−1抗体のいずれかのような)である。さらにまたはこれとは別に、当該抗体は、キメラまたはヒト化抗体であってもよい。その抗原は、例えば、腫瘍抗原、ウイルス抗原、細菌抗原または病原体由来の抗原であってもよい。このような抗原の例として、上述の腫瘍抗原(または腫瘍ワクチン)若しくは上述のウイルス、細菌または他の病原体由来の抗原が挙げられるが、それらに限定されない。
本発明は、部分的に、下記の実験データに基づいている。マウス腫瘍モデル(MC38結腸癌およびSA1/N線維肉腫)を用いて、免疫刺激治療用抗体−抗CTLA−4および抗PD−1を組み合わせることによって、腫瘍を治療するインビボ効果を検討した。併用免疫療法は、腫瘍細胞移植と同時に(実施例14と17)または形成された腫瘍となるまでに十分な時間腫瘍細胞を移植後(実施例15、16および18)に行われた。抗体治療タイミングにかかわらず、単独での抗CTLA−4抗体治療および単独での抗PD−1抗体(ラット抗マウスPD−1をマウスイムノグロブリンFc領域で修飾したキメラ抗体、実施例1を参照)治療は、MC38腫瘍モデルにおいて腫瘍増殖の低下に中等度の効果を示した(例えば、図21、24および27を参照)。抗CTLA−4抗体は単独でも、SA1/N腫瘍モデルにおいて非常に効果的で(図30Dを参照)、このモデルにおける併用試験では、抗CTLA−4抗体の必要量は低用量であった。にもかかわらず、抗CTLA−4抗体と抗PD−1抗体の併用治療は、腫瘍増殖の低下に対し、いずれかの抗体単独による治療に比較して予想外の極めて高い効果を示した(例えば、図21D、24D、30Fおよび33H−Jを参照)。さらに、実施例14、16および18の結果は、抗CTLA−4抗体と抗PD−1抗体の併用治療が、いずれかの抗体単独に比較して最適治療用量以下でも有意の(相乗的)効果を示すことが明らかである(すなわち、併用療法は、いずれかの単独療法よりも治療用量以下で驚くほど高い効果を示した)。理論にしばられることなく、PD−1およびCTLA−4阻害によるT細胞活性化閾値の上昇によって、抗腫瘍応答を宿主中で活性化することができる。
PD−1に対するヒトモノクローナル抗体の作製
抗原
抗原として、免疫プロトコールでは、(i)PD−1の細胞外部分を含む組み換え融合タンパク質および(ii)膜結合全長PD−1の両者を利用した。両抗原とも、CHO細胞株中で組み換えトランスフェクション方法により作製した。
PD−1に対する完全ヒトモノクローナル抗体を、それぞれがヒト抗体遺伝子を発現するHuMab形質転換マウスのHCo7系と形質転換トランス染色体マウスのKM系を用いて調製した。これらのマウス系のそれぞれにおいて、内因性マウスκ軽鎖遺伝子を、Chenら(1993)EMBO J. 12:811−820に記載のようにホモ接合により破壊し、内因性マウス重鎖遺伝子は、PCT公報WO01/09187の実施例1に記載のように、ホモ接合により破壊した。これらのマウス系のそれぞれは、Fishwildら(1996)Nature Biotechnology 14:845−851に記載されているようにヒトκ軽鎖導入遺伝子KCo5を有している。HCo7系は、米国特許5,545,806、5,625,825、および5,545,807に記載されているように、HCo7ヒト重鎖導入遺伝子を有している。KM系は、PCT公報WO02/43478に記載されているように、SC20トランス染色体を含む。
PD−1に対する完全ヒトモノクローナル抗体を産生させるため、HuMabおよびKMマウス(商標)を、精製組み換えPD−1融合タンパク質およびPD−1移入CHO細胞を抗原として免疫した。HuMabマウスのための一般的免疫スキームは、Lonberg、N.ら(1994)Nature 368(6474):856−859;Fishwild,D.ら(1996)Nature Biotechnology 14:845−851およびPCT公報WO98/24884に記載されている。当該マウスは、第1回抗原注入時に6−16週齢であった。PD−1融合タンパク質抗原と5−10×106細胞の精製組み換え調製物(5〜50μg)を用いて、HuMabマウスおよびKMマウス(商標)を腹腔内、皮下(Sc)または足蹠注入により免疫した。
PD−1に結合する抗体を産生するHuMabまたはKMマウス(商標)を選択するため、免疫マウス由来の血清をFishwild,D.ら(1996)に記載のようにELISAによって試験した。簡単に述べると、マイクロタイタープレートに、PBS中1〜2μg/mLで形質移入CHO細胞由来の精製組み換えPD−1融合タンパク質をコートし、100μL/ウェルを4℃で一晩インキュベーションし、次に、200μL/ウェルのPBS/Tween(0.05%)中5%ウシ胎児血清によりブロックした。PD−1免疫マウス由来の血清希釈物を各ウェルに添加し、室温で1〜2時間インキュベーションした。このプレートをPBS/Tweenで洗浄し、その後、西洋わさびパーオキシダーゼ(HRP)結合ヤギ抗ヒトIgGポリクローナル抗体とともに室温で1時間インキュベーションした。洗浄後、プレートをABTS基質(Sigma,A−1888,0.22mg/mL)で発色させ、分光光度計によりOD415−495で分析した。最大力価の抗PD−1抗体を産生したマウスを融合に使用した。融合は、下記に記載のように実施し、ハイブリドーマ上清を、ELISAにより抗PD−1活性について試験した。
HuMabまたはKMマウスから単離したマウス脾臓細胞を、標準的プロトコールによるPEGまたはCyto Pulse大型チェンバー細胞融合エレクトポレータ(Cyto Pulse Sciences,Inc.,Glen Burnie,MD)を用いる電場に基づくエレクトロフュージョンを用いて、マウス骨髄細胞株に融合させた。生成したハイブリドーマは、次に抗原結合抗体の産生をスクリーニングした。免疫マウスからの脾臓細胞の単細胞懸濁物を、50%PEG(Sigma)により、その4分の1数のSP2/0非分泌性マウス骨髄細胞(ATCC、CRL1581)に融合させた。細胞を、約1×105/ウェルで平底マイクロタイタープレートに接種し、10%胎児クローン血清、10%P388D1(ATCC,CRL TIB−63)調製培地、DMEM(Mediatech,CRL 10013、高グルコース、L−グルタミンおよびピルビン酸ナトリウムを有する)中3〜5%オリゲン(IGEN)及び5mM HEPES、0.055mM 2−メルカプトエタノール、50mg/mL ゲンタマイシン、および1XHAT(Sigma、CRL P−7185)を含む選択培地中で約2週間、インキュベーションした。1〜2週後、細胞を、HATをHTに置き換えた培地中で培養した。次に、それぞれのウェルを、ヒト抗PD−1モノクローナルIgG抗体についてELISA(上記で記載)でスクリーニングした。いったん強いハイブリドーマ増殖が起こったならば、培地を通常10〜14日後にモニタリングした。抗体分泌ハイブリドーマを再度接種し、再度スクリーニングし、もしヒトIgGがまだ陽性であるならば、抗PD−1モノクローナル抗体を少なくとも2回、限定希釈によってサブクローニングした。次に、安定なサブクローンをインビトロで培養し、少量の抗体を組織培地に産生させ、さらに特性解析した。
ヒトモノクローナル抗体17D8、2D3、4H1、5C4、4A11、7D3および5F4の構造特性解析
17D8、2D3、4H1、5C4、4A11、7D3および5F4の重鎖および軽鎖可変領域をコードするcDNA配列を、標準的PCR技術を用いて17D8、2D3、4H1、5C4、4A11、7D3および5F4ハイブリドーマからそれぞれ得て、標準的DNA配列決定技術を用いて配列決定した。
抗PD−1ヒトモノクローナル抗体の結合特性および結合動態の特性解析
この実施例では、抗PD−1抗体の結合特性および結合動態をビアコア分析により調べた。結合特性および交差競合性は、フローサイトメトリーによって調べた。
抗PD−1抗体は、ビアコア分析(Biacore AB、Uppsala、Sweden)によって親和性と結合動態を特性解析した。精製した組み換えヒトPD−1融合タンパク質を、1級アミンによりCM5チップ(カルボキシメチルデキストラン塗布チップ)に標準的アミンカップリング化学およびビアコアが提供しているキットを用いて、共有結合させた。結合は、濃度267nMでかつフロー速度50μL/分でHBS EP緩衝液(ビアコアAB提供)中に抗体を流すことによって測定した。抗原抗体会合動態は、3分間追跡し、解離動態は、7分間追跡した。会合および解離曲線は、BIA評価ソフトウェア(Biacore AB)を用いて、1:1ラングミュア結合モデルに適合した。結合定数推定においてアビィディティ効果を最小とするため、会合および解離相に対応する最初のデータ部分のみを適合に使用した。決定したKD、konおよびkoff値を表2に示した。
細胞表面で組み換えヒトPD−1を発現するチャイニーズハムスター卵巣(CHO)細胞株を作製し、PD−1ヒトモノクローナル抗体の特異性をフローサイトメトリーで決定するために用いた。CHO細胞に、膜型PD−1をコードする全長cDNAを含む発現プラスミドを移入させた。5C4および4H1抗PD−1ヒトモノクローナル抗体の結合を、移入細胞と20μg/mLの抗PD−1ヒトモノクローナル抗体とをインキュベーションすることによって評価した。細胞を洗浄し、結合をFITC−標識抗ヒトIgG Abにより検出した。フローサイトメトリー分析を、FACSスキャンフローサイトメトリー(Becton Dickinson、San Jose,CA)を用いて行った。結果を、図13A(5C4)および13B(4H1)に示した。抗PD−1ヒトモノクローナル抗体は、PD−1移入CHO細胞に結合したが、ヒトPD−1を移入していなかったCHO細胞には結合しなかった。これらのデータは、PD−1に対する抗PD−1ヒトモノクローナル抗体の特異性を明らかにしている。
CD28ファミリーメンバーに対する抗PD−1抗体の結合比較を、4種の異なるCD28ファミリーメンバーを用いる標準的ELISAにより行い、PD−1に対する結合特性を調べた。
ヒトおよびサル細胞表面で発現したPD−1に対する抗PD−1抗体結合の特性解析
抗PD−1抗体について、細胞表面におけるPD−1発現細胞への結合をフローサイトメトリーによって試験した。
混合リンパ球反応における細胞増殖およびサイトカイン産生に及ぼすヒト抗PD−1抗体の効果
混合リンパ球反応を用いて、リンパ球エフェクター細胞へのPD−1経路を阻害する効果を明らかにした。本アッセイにおけるT細胞について、抗PD−1 HuMab抗体存在下または非存在下における増殖、IFN−γ分泌およびIL−2分泌を試験した。
ヒト抗PD−1抗体によるPD−1に対するリガンド結合阻害
抗PD−1 HuMabを、フローサイトメトリー分析を用いることによって移入CHO細胞上で発現したPD−1に対するリガンド、PD−L1およびPD−L2の結合阻害能を試験した。
ヒト血中におけるサイトカイン放出に及ぼすヒト抗PD−1抗体の効果
抗PD−1 HuMabが単独でヒト血球からのサイトカイン放出を刺激するかどうかを決定するため、抗PD−1 HuMabを新鮮ヒト全血と混合した。
T細胞のアポトーシスに及ぼす抗PD−1抗体の効果
T細胞のアポトーシス誘導に及ぼす抗PD−1抗体の効果を、アネキシンV染色試験を用いて測定した。
ウイルス陽性ドナー由来ウイルス刺激PBMC細胞によるサイトカイン分泌に及ぼす抗PD−1抗体の効果
この例では、CMV陽性ドナーから末梢血単核球(PBMC)を単離し、抗PD−1抗体存在下または非存在下CMV溶解物に暴露し、当該抗体の抗原刺激サイトカイン分泌に及ぼす効果を調べた。
抗原に対する二次抗体応答に及ぼす抗PD−1抗体の効果
マウスをTI−抗原(DNP−Ficoll)により免疫し、再度チャレンジし、さらに、ラット抗マウスPD−1抗体または対照抗体により処理し、抗体力価に及ぼす抗PD−1抗体の効果を調べた。
抗PD−1抗体を用いたインビボ腫瘍モデルへの処理
癌性腫瘍を移植したマウスをインビボで、抗PD−1抗体で処理し、腫瘍増殖に及ぼす抗体のインビボ効果を調べた。陽性対象として、抗CTLA−4抗体を用いたが、その理由は、このような抗体が腫瘍増殖をインビボで阻害することが明らかとされているからである。
キメラ(ラット−マウス)抗PD−1抗体4H2の産生
マウスPD−1抗体に対するラットモノクローナル抗体(ラット抗mPD−1)を、標準的ハイブリドーマ作製方法(KohlerおよびMilstein(1975)Nature 256:495、およびHarlowおよびLane(1988)Antibodies,A Laboratory Mnual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor New Yorkを参照)を用いてmPD−1−hFc融合タンパク質で免疫したラットから作製した。ハイブリドーマ8個をサブクローニングし、抗体を単離し、mPD−1に対するマウスPD−L2(mPD−L2)結合を阻害する能力をスクリーニングした。mPD−1に対するmPD−L2結合を阻害できる数種の抗mPD−1抗体を同定し(例えば、4H2活性、図41を参照)、これらの数種のタンパク質のmPD−1−Fc融合タンパク質の結合アフィニティをELISAによって決定した(図42)。
腫瘍形成と増殖に及ぼす併用療法(抗CTLA−4および抗PD−1抗体)のインビボ効果
MC38結直腸癌細胞(PD−L1−)(Dr.N.Restifo,National Cancer Institute,Bethesda、MD、またはJeffrey Schlom,National Institutes of Health,Bethesda,MD)は、C57BL/6マウスに(2×106細胞/マウス)で移植した。第0日(すなわち、マウスにMC38細胞を移植した日)において、それぞれマウス10匹で構成した4群のそれぞれに:(1)マウスIgG(対照)、(2)抗CTLA−4モノクローナル抗体9D9(J.Allison,Memorial Sloan−Kettering Cancer Center,New York、NYから得たマウス抗マウスCTLA−4抗体)、(3)抗PD−1モノクローナル抗体4H2(ラット抗マウスPD−1をマウスFc抗原で修飾したキメラ抗体、実施例6に記載)または(4)抗CTLA−4抗体9D9および抗PD−1抗体4H2のいずれかを、腹腔内(IP)注入した。次に、第3、6および10日に、抗体注入を行った。単独抗体による処理は、10mg/kgで投与し、抗CTLA−4抗体および抗PD−1抗体併用は、各抗体5mg/kgで投与した(すなわち、総抗体10mg/kg)。電子カリパスを用いて、腫瘍を3次元(高さ×幅×長さ)で測定し、腫瘍容積を計算した。腫瘍が指定された腫瘍終点に到達した時、マウスを安楽死させた。その結果を表5および図21に示した。
形成された腫瘍の増殖に及ぼす併用療法(抗CTLA−4および抗PD−1抗体)のインビボ効果
MC38結直腸癌細胞(PD−L1−)をC57BL/6マウスに(2×106細胞/マウスで)腫瘍形成に十分な時間(約6乃至7日)移植した。移植後第6日(第−1日)において腫瘍測定を行い、その後の抗体治療のため、マウスを平均腫瘍容積(約250mm3)に基づき無作為に11群に振り分けた。第0日において(すなわち、MC38細胞を移植後1週)、マウスに(1)マウスIgG(対照)、(2)抗CTLA−4モノクローナル抗体9D9、(3)抗PD−1モノクローナル抗体4H2、または(4)抗CTLA−4モノクローナル抗体9D9および抗PD−1モノクローナル抗体4H2を、濃度10mg/kg/マウスでIP注入した。また、抗体は、第3、6および10日に投与した。使用したモノクローナル抗体組成は、低レベルのエンドトキシンを有し、有意に凝集することはなかった。電子カリパスを用いて、腫瘍を3次元(高さ×幅×長さ)で測定し、腫瘍容積を計算した。腫瘍測定は、第0日(治療開始時点の腫瘍は、容積約125mm3であった)、および抗体注入後第3、6、10、13、17および20日に行った。マウスは、腫瘍が所定の腫瘍終点(1500mm3のような特定の腫瘍容積および/または、マウスが約15%を超える体重減少を示した時)、マウスを安楽死させた。
形成された腫瘍の増殖に及ぼす併用療法(抗CTLA−4および抗PD−1抗体)の投与量測定
実施例3に記載のように、MC38結直腸癌細胞(PD−L1−)をC57BL/6マウスに(2×106細胞/マウスで)腫瘍形成に十分な時間(約6〜7日)移植した。マウス10匹の群に対して、第0、3、6および10日に下記のように腹腔内注入した。(A)群 マウスIgG(対照、20mg/kg)、(B)群 抗PD−1モノクローナル抗体4H2(10mg/kg)およびマウスIgG(10mg/kg)、(C)群 抗CTLA−4モノクローナル抗体9D9(10mg/kg)およびマウスIgG(10mg/kg)、(D)群 抗CTLA−4モノクローナル抗体9D9(10mg/kg)および抗PD−1モノクローナル抗体4H2(10mg/kg)、(E)群 抗CTLA−4モノクローナル抗体9D9(3mg/kg)および抗PD−1モノクローナル抗体4H2(3mg/kg)、または(F)群 抗CTLA−4モノクローナル抗体9D9(1mg/kg)および抗PD−1モノクローナル抗体4H2(1mg/kg)。電子カリパスを用いて、腫瘍を3次元(高さ×幅×長さ)で測定し、腫瘍容積を計算した。腫瘍測定は、処理開始時点(すなわち、第0日において、腫瘍は平均容積約90mm3であった)、および抗体処理後第3、6、10、13、17および20日に行った。マウスを、腫瘍が所定の腫瘍終点(1500mm3のような特定の腫瘍容積および/またはマウスが約15%を超える体重減少を示した時)に達した時、安楽死させた。
線維肉腫形成および増殖に及ぼす併用療法(抗CTLA−4と抗PD−1抗体)のインビボ効果
SA1/N線維肉腫細胞(PD−L1−)(Leachら(1996)Science 271:1734−1736)を、第0日にA/Jマウスに皮下移植した(2×106細胞/マウス)。移植後第1、4、7および11日に、下記:(A)群 PBS(“溶媒”と称する)単独、(B)群 マウスIgG(対照、マウス当たり10mg/kg)、(C)群 抗PD−1モノクローナル抗体4H2(マウス当たり10mg/kg)、(D)群 抗CTLA−4モノクローナル抗体9D9(マウス当たり10mg/kgまたは0.2mg/kg)、(E)群 抗CTLA−4モノクローナル抗体9D9(マウス当たり0.2mg/kg)と併用した抗PD−1モノクローナル抗体4H2(マウス当たり10mg/kg)のようにマウスに腹腔内投与した。本試験を41日間継続し、本試験過程での様々な時点で腫瘍測定を行った(図29参照)。腫瘍容積は、電子カリパスを用いて3次元(高さ×幅×長さ)で腫瘍を測定し、計算した。腫瘍が1500mm3の所定の腫瘍終点に到達したかあるいは潰瘍化腫瘍になった時に、マウスを安楽死させた。
PD−L1−線維肉腫の増殖に及ぼす併用療法(抗CTLA−4と抗PD−1抗体)のインビボ効果と用量測定
SA1/N線維肉腫細胞(PD−L1−)を、第0日に腫瘍形成に十分な時間(約7日)、A/Jマウスに皮下移植した(2×106細胞/マウス)。移植後第7、10、13および16日に、平均110mm3の腫瘍容積を有するマウス8匹の10群に、下記:(A)群 PBS(“溶媒”と称する)単独、(B)群 マウスIgG(対照、10mg/kg/マウス)、(C)群 抗CTLA−4モノクローナル抗体9D9(0.25mg/kg/マウス)、(D)群 抗CTLA−4モノクローナル抗体9D9(0.5mg/kg/マウス)、(E)群 抗CTLA−4モノクローナル抗体9D9(5mg/kg/マウス)、(F)群 抗PD−1モノクローナル抗体4H2(3mg/kg/マウス)、(G)群 抗PD−1モノクローナル抗体4H2(10mg/kg/マウス)、(H)群 抗CTLA−4モノクローナル抗体9D9(0.25mg/kg/マウス)と抗PD−1モノクローナル抗体4H2(10mg/kg/マウス)との併用、(I)群 抗CTLA−4モノクローナル抗体9D9(0.5mg/kg/マウス)と抗PD−1モノクローナル抗体4H2(10mg/kg/マウス)との併用、および(J)群 抗CTLA−4モノクローナル抗体9D9(0.5mg/kg/マウス)と抗PD−1モノクローナル抗体4H2(3mg/kg/マウス)との併用、のようにIP投与した。
抗PD−1抗体処理およびPD−L1−線維肉腫細胞の再チャレンジ後のマウスにおける腫瘍免疫
腫瘍細胞によるチャレンジと抗PD−1抗体処理(すなわち、実施例5および6に記載の有効性試験に類似の処理)でも腫瘍を有さず生き延びたマウスを、次に、腫瘍細胞で再チャレンジし、このような処理後の腫瘍形成に対する免疫性を調べた。簡単に述べると、最初のチャレンジにおいて、SA1/N線維肉腫細胞(PD−L1−)を、第0日にA/Jマウスに皮下移植した(1×106細胞/マウス)。各群に、移植後第1、4、7、10、14、17日および20日に、マウスIgG(対照、マウス当たり10mg/kg)または様々な用量の抗PD−1モノクローナル抗体4H2(30、10、3、1、および0.3mg/kg)の一つを腹腔内注入した。腫瘍形成および容積を、試験完了まで週2回、精密電子カリパスを用いてモニタリングした。マウス8匹の群は、抗PD1抗体処理後も無腫瘍であった(4匹は30mg/kgで処理し、2匹は3mg/kgで処理し、1匹は0.3mg/kgで処理した)。
結直腸癌細胞で再チャレンジしたマウスにおける単一抗体療法(抗PD−1)または併用抗体療法(抗CTLA−4および抗PD−1)後のPD−L1−腫瘍免疫性
腫瘍細胞によるチャレンジと抗PD−1抗体単独または抗CTLA−4抗体と抗PD−1抗体との併用(すなわち、実施例2−4に記載の有効性試験に類似の処理)による治療でも腫瘍を有さず生き延びたマウスを、次に、腫瘍細胞で再チャレンジし、このような処理後の腫瘍形成に対する免疫性を調べた。簡単に述べると、最初のチャレンジにおいて、MC38結直腸癌細胞(PD−L1−)を、第0日にC57BL/6マウスに皮下移植した(2×106細胞/マウス)。各群に、移植後第0、3、6および10日に下記の一つを腹腔内注入した。(1)マウスIgG(対照、10mg/kg/マウス)、抗PD−1モノクローナル抗体4H2、または(3)抗CTLA−4モノクローナル抗体9D9と抗PD−1モノクローナル抗体4H2との併用。腫瘍増殖は、精密電子カリパスにより実施例15に記載のようにしてモニタリングした。11匹のマウス群は、抗PD−1抗体処理後(総計2匹)または併用抗PD−1/抗CTLA−4抗体処理後(総計9匹)も無腫瘍であった。
形成された腫瘍の増殖に及ぼす併用療法(抗CTLA−4および抗PD−1抗体)のインビボ効果
CT26結直腸癌細胞を、BALB/Cマウスに腫瘍形成できる十分な時間(約10日)移植した(2×106細胞/マウス)。移植後第10日において、腫瘍測定を行い、マウスを平均腫瘍容積(約250mm3)に基づき無作為に5群に分け、次に抗体療法を行った。第0日(すなわち、CT26細胞を移入10日後)において、マウスに(1)マウスIgG(対照)、(2)抗CTLA−4モノクローナル抗体9D9、(3)抗PD−1モノクローナル抗体4H2または(4)マウス当たり濃度10mg/kgの抗CTLA−4モノクローナル抗体9D9と抗PD−1モノクローナル抗体4H2を腹腔注入した。抗体注入は、第3、6および10日にも行った。使用したモノクローナル抗体組成物は、低レベルのエンドドキシンを有しており、有意に凝集することはなかった。電子カリパスを用いて、腫瘍を3次元(高さ×幅×長さ)で測定し、腫瘍容積を計算した。腫瘍測定は、第0日(処理開始時点における腫瘍は、約125mm3の容積を有していた)に行い、抗体注入後3、6、10、13、17および20日にも行った。腫瘍が所定の腫瘍終点(1500mm3のような特定腫瘍容積および/またはマウスが約15%の体重減少を示した時点)に到達した時に、マウスを安楽死させた。結果は図50に示されている。本試験では、マウス腫瘍モデルにおいて、CTLA−4抗体およびPD−1抗体の併用処理が、腫瘍がすでに十分に確立している時でさえもいずれかの抗体単独よりもはるかに高い効果を腫瘍増殖に対して有することを示唆している。
制御性T細胞機能に及ぼすヒト抗PD−1抗体の効果
制御性T細胞は、免疫応答を抑制するリンパ球である。この実施例において、制御性T細胞を、抗PD−1ヒトモノクローナル抗体の存在下または非存在下においてCD4+CD25−T細胞の増殖およびIFN−γ分泌その阻害機能について試験した。
ヒト抗PD−1抗体のT細胞活性化に及ぼす効果
この実施例において、抗PD−1抗体5C4によるPD−1経路の阻害がT細胞活性化に及ぼす効果を調べた。精製ヒトCD4+T細胞(Dynal CD4 T細胞精製キット)を1μg/mLの可溶性抗CD3抗体(BD)により、自己単球または単球由来樹状細胞(DCs)存在下において活性化した。単球を、Miltenyi CD14単球精製キットを用いて精製し、単球をGM−CSFおよびIL−4(Pepro Tech)とともに7日間培養後、DCをインビトロで産生させた。力価検定した抗PD−1抗体または関連のないアイソタイプ対照mAbの存在下または非存在下3日間活性化した後、培養上清を採取し、IFNγ分泌のELISA分析と行い、一方、T細胞増殖を測定するため、トリチウム化チミジンをアッセイ中、最終18時間時点で添加した。図52Aおよび52Bに示した結果は、抗PD−1抗体によるPD−1阻害の結果、T細胞増殖とIFN−γ分泌が増強された。単球存在下における抗PD−1抗体と抗CTLA−4抗体によるT細胞活性化に及ぼす(特に、IFN−γ分泌に及ぼす)相乗的効果もまた、観察された。
抗PD−1抗体のADCC活性評価
この実施例において、抗体依存性細胞傷害(ADCC)アッセイを実施し、抗PD−1抗体が標的細胞に対してADCCを誘発できるか評価した。5C4の2種のバージョンであるヒトIgG1のFc領域を有するもの(5C4−IgG1)とヒトIgG4のFc領域を有するもの(5C4−IgG4)を本アッセイで評価した。Perkin ElmerのDelfia Cell Cytotoxicity Kitを本アッセイに用いた。簡単に述べると、精製ヒトCD4 T細胞(Dynal CD4 T細胞精製キット)を、プレート結合抗CD3抗体(BD)により活性化し、PD−1発現を誘発させた。次に、標的活性化CD4 T細胞をBATDA試薬で標識した。標識CD4 T細胞を、V底96ウェルプレートに添加し、ヒトPBMC(標的(E/T)細胞に対するエフェクターの比は50:1)に添加し、抗体を設計した。37℃で1時間インキュベーションした後、プレートをスピンダウンした。上清を平底96ウェルプレートに移し、プレートをRubyStar プレートリーダーで読み取った。その結果は、5C4−IgG4が活性化CD4 T細胞においてADCCを媒介せず、一方、5C4−IgG1は、活性化CD4 T細胞においてADCCを媒介した(図53)が、このことは、ADCC活性が抗PD−1抗体のFc領域に関連していることを示唆している。
抗PD−1抗体の補体依存性細胞傷害活性の評価
この実施例において、抗PD−1抗体の補体依存性細胞傷害(CDC)を調べた。5C4の2種のバージョンであるヒトIgG1(5C4−IgG1)のFc領域を有するものとヒトIgG4のFc領域を有するもの(5C4−IgG4)を本アッセイで評価した。簡単に述べると、精製ヒトCD4 T細胞(Dynal CD4 T細胞精製キット)を、プレート結合抗CD3抗体(BD)により活性化し、PD−1発現を誘発させた。抗PD−1抗体(5C4)および対照抗体の50μg/mLから640pg/mLまでの系列希釈を、ヒト補体(Quidel−A113)存在下においてCDCについて試験した。Alamar blue(Biosource Internationals)を用いて細胞傷害を測定した。プレートを蛍光プレートリーダ(EX530 EM590)により測定した。生細胞数は、蛍光単位に比例している。その結果は、5C4−IgG1または5C4−IgG4のいずれも活性化CD4 T細胞上でCDCを媒介せず、一方、陽性対照抗体(抗HLA−A−ABC抗体)は媒介した(図54)。
ヒトT細胞上におけるPD−1発現の評価
この実施例では、異なるドナー由来ヒトPBMCを、様々な細胞サブセット上でのPD−1発現について、FACSにより調べた。ビオチン化抗PD−1は、細胞表面におけるPD−1分子検出時に、市販の抗PD−1抗体よりもはるかに高い感度を示し、それを本アッセイに用いた。結合抗体を、PE結合ストレプトアビジンを用いて検出した。フローサイトメトリー分析を、FACSスキャンフローサイトメトリー(Becton Dickinson)およびFlowjoソフトウェア(Tree Star)を用いて実施した。PD−1発現は、いくつかの末梢ヒトT細胞上で検出されたが、B細胞または単球上では検出されなかった。T細胞サブセットをさらに調べ、CD4およびCD8記憶およびエフェクターT細胞上でPD−1が発現するが、未処理のCD4またはCD8 T細胞にはないことを示唆している。
[1] 配列番号18のアミノ酸配列からなる重鎖可変領域CDR1、配列番号25のアミノ酸配列からなる重鎖可変領域CDR2、配列番号32のアミノ酸配列からなる重鎖可変領域CDR3、配列番号39のアミノ酸配列からなる軽鎖可変領域CDR1、配列番号46のアミノ酸配列からなる軽鎖可変領域CDR2および配列番号53のアミノ酸配列からなる軽鎖可変領域CDR3を含む抗体であって、ヒトPD−1と特異的に結合する単離ヒト抗ヒトPD−1モノクローナル抗体を有効成分として含む腫瘍細胞増殖阻害剤。
[2] 単離ヒト抗ヒトPD−1モノクローナル抗体が、配列番号4のアミノ酸配列からなる重鎖可変領域および配列番号11のアミノ酸配列からなる軽鎖可変領域を含む抗体である[1]の腫瘍細胞増殖阻害剤。
[3] 腫瘍細胞が、メラノーマ、腎癌、前立腺癌、乳癌、結腸癌、卵巣癌、膵癌、食道癌および肺癌から選択される癌細胞である[1]または[2]の腫瘍細胞増殖阻害剤。
[4] 腫瘍細胞が、骨癌、皮膚癌、頭頚部癌、皮膚または眼窩内悪性メラノーマ、子宮癌、直腸癌、肛門部癌、胃癌、精巣癌、子宮癌、卵管のカルシノーマ、子宮内膜カルシノーマ、子宮頚部カルシノーマ、膣カルシノーマ、外陰部カルシノーマ、ホジキン病、非ホジキンリンパ腫、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、柔組織肉腫、尿道癌、陰茎癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を含む慢性または急性白血病、小児固形癌、リンパ球性リンパ腫、膀胱癌、腎臓または尿管の癌、腎盂カルシノーマ、中枢神経系(CNS)腫瘍、原発性CNSリンパ腫、腫瘍新脈管形成、脊椎腫瘍、脳幹グリオーム、脳下垂体アデノーマ、カポシ肉腫、扁平上皮癌、扁平細胞癌、T細胞リンパ腫、アスベスト誘発癌類を含む環境誘発癌および上記癌の組み合わせからなる群から選択される癌細胞である[1]または[2]の腫瘍細胞増殖阻害剤。
[5] 配列番号18のアミノ酸配列からなる重鎖可変領域CDR1、配列番号25のアミノ酸配列からなる重鎖可変領域CDR2、配列番号32のアミノ酸配列からなる重鎖可変領域CDR3、配列番号39のアミノ酸配列からなる軽鎖可変領域CDR1、配列番号46のアミノ酸配列からなる軽鎖可変領域CDR2および配列番号53のアミノ酸配列からなる軽鎖可変領域CDR3を含む抗体であって、ヒトPD−1と特異的に結合する単離ヒト抗ヒトPD−1モノクローナル抗体を有効成分として含むT細胞増殖促進剤。
[6] 配列番号18のアミノ酸配列からなる重鎖可変領域CDR1、配列番号25のアミノ酸配列からなる重鎖可変領域CDR2、配列番号32のアミノ酸配列からなる重鎖可変領域CDR3、配列番号39のアミノ酸配列からなる軽鎖可変領域CDR1、配列番号46のアミノ酸配列からなる軽鎖可変領域CDR2および配列番号53のアミノ酸配列からなる軽鎖可変領域CDR3を含む抗体であって、ヒトPD−1と特異的に結合する単離ヒト抗ヒトPD−1モノクローナル抗体を有効成分として含むIFN−γおよび/またはIL−2分泌促進剤。
[7] 抗PD−1モノクローナル抗体を有効成分とする、抗CTLA−4モノクローナル抗体と併用するための癌治療剤。
Claims (2)
- (a)(i)配列番号15、16、17、18、19、20および21から構成される群から選択されるCDR1配列、配列番号22、23、24、25、26、27および28から構成される群から選択されるCDR2配列、および配列番号29、30、31、32、33、34および35から構成される群から選択されるCDR3配列を含む重鎖可変領域抗体配列または(ii)配列番号36、37、38、39、40、41および42から構成される群から選択されるCDR1配列、配列番号43、44、45、46、47、48および49から構成される群から選択されるCDR2配列、および配列番号50、51、52、53、54、55および56から構成される群から選択されるCDR3配列を含む軽鎖可変領域抗体配列を提供すること、
(b)重鎖可変領域抗体配列および軽鎖可変領域抗体配列から選択した少なくとも1個の可変領域抗体配列内部の少なくとも1個のアミノ酸残基を改変し、少なくとも1個の改変抗体配列を作成すること、および
(c)前記改変抗体配列をタンパク質として発現させること
を含む、抗PD−1抗体調製方法。 - 請求項1記載の抗PD−1抗体調製方法により調製された抗PD-1抗体の有効量を癌患者に投与することからなる癌治療法。
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JP2012106662A Active JP5872377B2 (ja) | 2005-05-09 | 2012-05-08 | ProgrammedDeath1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 |
JP2014010140A Pending JP2014077015A (ja) | 2005-05-09 | 2014-01-23 | ProgrammedDeath1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 |
JP2015213586A Active JP6185971B2 (ja) | 2005-05-09 | 2015-10-30 | ProgrammedDeath1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 |
JP2016220640A Pending JP2017052784A (ja) | 2005-05-09 | 2016-11-11 | Programmed Death 1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 |
JP2019018345A Active JP6975733B2 (ja) | 2005-05-09 | 2019-02-05 | Programmed Death 1(PD−1)に対するヒトモノクローナル抗体および抗PD−1抗体単独または他の免疫療法と併用した癌治療方法 |
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