JPWO2020043683A5 - - Google Patents
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- JPWO2020043683A5 JPWO2020043683A5 JP2021510824A JP2021510824A JPWO2020043683A5 JP WO2020043683 A5 JPWO2020043683 A5 JP WO2020043683A5 JP 2021510824 A JP2021510824 A JP 2021510824A JP 2021510824 A JP2021510824 A JP 2021510824A JP WO2020043683 A5 JPWO2020043683 A5 JP WO2020043683A5
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- her2 bispecific
- her2
- system inhibitor
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- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 63
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 63
- 239000003112 inhibitor Substances 0.000 claims description 49
- 206010028980 Neoplasm Diseases 0.000 claims description 36
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 102000019298 Lipocalin Human genes 0.000 claims description 15
- 108050006654 Lipocalin Proteins 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 5
- 229960003852 atezolizumab Drugs 0.000 claims description 2
- 229950002916 avelumab Drugs 0.000 claims description 2
- 229940121420 cemiplimab Drugs 0.000 claims description 2
- 229950009791 durvalumab Drugs 0.000 claims description 2
- 230000001394 metastastic effect Effects 0.000 claims description 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 2
- 229960003301 nivolumab Drugs 0.000 claims description 2
- 229960002621 pembrolizumab Drugs 0.000 claims description 2
- 229950007123 tislelizumab Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 16
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 1
- 238000002483 medication Methods 0.000 claims 1
- 230000000750 progressive effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 description 27
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000037455 tumor specific immune response Effects 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
Description
本明細書において使用される場合、「約(about)」または「約（approximately)」という用語とは、所与の値または範囲から20%以内、好ましくは15%以内、好ましくは10%以内、およびより好ましくは5%以内を意味する。また、その実際の数も含む。すなわち、「約20」には、20という数も含まれる。
[本発明1001]
(a)(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、CD137/HER2二重特異性物質、ならびに
(b)PD-1系阻害物質
を対象に投与する段階を含む、該対象においてがんを治療する方法。
[本発明1002]
(a)対象にCD137/HER2二重特異性物質を投与する段階であって、PD-1系阻害物質も対象に与えられ、その結果、対象が両方による治療を受ける、該段階、または
(b)対象にPD-1系阻害物質を投与する段階であって、CD137/HER2二重特異性物質も対象に与えられ、その結果、対象が両方による治療を受ける、該段階
を含む、該対象においてがんを治療する方法であって、
該CD137/HER2二重特異性物質が、(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、該方法。
[本発明1003]
前記がんがHER-2陽性かつ/またはPD-L1陽性である、本発明1001または1002の方法。
[本発明1004]
増強された抗腫瘍効果をもたらすことができる、本発明1001～1003のいずれかの方法。
[本発明1005]
単独の前記CD137/HER2二重特異性物質または前記PD-1系阻害物質と比べて、相加的な抗腫瘍効果をもたらすことができる、本発明1001～1004のいずれかの方法。
[本発明1006]
単独の前記CD137/HER2二重特異性物質または前記PD-1系阻害物質と比べて、相乗的な抗腫瘍効果をもたらすことができる、本発明1001～1004のいずれかの方法。
[本発明1007]
前記抗腫瘍効果が、
(a)腫瘍に関係する免疫応答の刺激;
(b)IL-2分泌の増大;
(c)腫瘍微小環境におけるIL-2分泌の増大;
(d)IFN-γ分泌の増大；
(e)腫瘍微小環境におけるIFN-γ分泌の増大;
(f)CD4
+
T細胞の増殖;
(g)腫瘍微小環境におけるCD4
+
T細胞の増殖;
(h)CD8
+
T細胞の増殖;
(i)腫瘍微小環境におけるCD8
+
T細胞の増殖;
(j)腫瘍浸潤リンパ球の増殖;
(k)NK細胞の活性化、および抗体依存性細胞媒介性細胞障害（ADCC)の増大；
(l)腫瘍微小環境における、NK細胞の活性化およびADCCの増大;
(m)腫瘍微小環境におけるCD4レベルの上昇;
(n)腫瘍微小環境におけるCD4レベルの低下;
(o)腫瘍微小環境におけるCD8レベルの上昇;
(p)腫瘍微小環境におけるCD8レベルの低下;
(q)腫瘍微小環境におけるPD-L1レベルの上昇;
(r)腫瘍微小環境におけるPD-L1レベルの低下;
(s)腫瘍微小環境におけるKi67レベルの上昇;
(t)腫瘍微小環境におけるKi67レベルの低下;
(u)腫瘍微小環境におけるCD137レベルの上昇;
(v)腫瘍微小環境におけるCD137レベルの低下;
(w)腫瘍微小環境におけるHER2レベルの上昇;
(x)腫瘍微小環境におけるHER2レベルの低下;
(y)腫瘍微小環境におけるIL-8レベルの上昇;
(z)腫瘍微小環境におけるIL-8レベルの低下;
(aa)腫瘍微小環境におけるFoxP3レベルの上昇;
(ab)腫瘍微小環境におけるFoxP3レベルの低下;
(ac)腫瘍サイズの縮小；
(ad)腫瘍増殖の抑制；
(ae)腫瘍転移の抑制；
(af)再発の遅延；または
(ag)全生存期間の改善
からなる群より選択される、本発明1004～1006のいずれかの方法。
[本発明1008]
少なくとも1回の投与サイクルを含み、該サイクルが約3週間の期間であり、該少なくとも1回のサイクルのそれぞれについて、少なくとも1用量の前記CD137/HER2二重特異性物質が投与され、かつ少なくとも1用量の前記PD-1系阻害物質が投与される、本発明1001～1007のいずれかの方法。
[本発明1009]
前記CD137/HER2二重特異性物質および前記PD-1系阻害物質が連続的または同時に投与される、本発明1001～1008のいずれかの方法。
[本発明1010]
前記CD137/HER2二重特異性物質が、約0.05mg/kg、約0.15mg/kg、約0.5mg/kg、約1.0mg/kg、約2.5mg/kg、約5.0mg/kg、または約8.0mg/kgの用量で投与される、本発明1001～1009のいずれかの方法。
[本発明1011]
前記PD-1系阻害物質が抗PD-L1抗体である、本発明1001～1010のいずれかの方法。
[本発明1012]
前記抗PD-L1抗体が、SEQ ID NO: 76およびSEQ ID NO: 77に示す配列を有する、本発明1011の方法。
[本発明1013]
前記抗PD-L1抗体が約1200mgの用量で投与される、本発明1011または1012の方法。
[本発明1014]
前記PD-1系阻害物質が抗PD-1抗体である、本発明1001～1010のいずれかの方法。
[本発明1015]
前記PD-1系阻害物質が、SEQ ID NO: 72およびSEQ ID NO: 73にまたはSEQ ID NO: 74およびSEQ ID NO: 75に示す配列を有する抗体である、本発明1001～1010のいずれかの方法。
[本発明1016]
前記PD-1系阻害物質が、アテゾリズマブ、デュルバルマブ、アベルマブ、ニボルマブ、ペムブロリズマブ、チスレリズマブ、またはセミプリマブである、本発明1001～1010のいずれかの方法。
[本発明1017]
前記CD137/HER2二重特異性物質および前記PD-1系阻害物質が、以下の用量で投与される、本発明1001～1016のいずれかの方法:
(a)約0.05mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(b)約0.15mg/kgのCD137/HR2二重特異性物質および約1200mgのPD-1系阻害物質、
(c)約0.5mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(d)約1.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(e)約2.5mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(f)約5.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、または
(g)約8.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質。
[本発明1018]
少なくとも1回の投与サイクル、例えば、2サイクル、3サイクル、4サイクル、5サイクル、10サイクル、15サイクル、20サイクル、25サイクル、および30サイクルを含み、該サイクルが約3週間の期間である、本発明1001～1017のいずれかの方法。
[本発明1019]
1用量の前記CD137/HER2二重特異性物質および1用量の前記PD-1系阻害物質を互いに連続的に、各3週間サイクルの1日目に投与する段階を含む、本発明1001～1018のいずれかの方法。
[本発明1020]
1用量の前記CD137/HER2二重特異性物質および1用量の前記PD-1系阻害物質を互いに連続的に、30回の3週間サイクルの間、各サイクルの1日目に投与する段階を含む、本発明1001～1019のいずれかの方法。
[本発明1021]
前記CD137/HER2二重特異性物質が、CD137に特異的なリポカリンムテインを含み、該リポカリンムテインが、N末端においてリンカーを介して抗HER2抗体の各重鎖のC末端に融合されている、本発明1001～1020のいずれかの方法。
[本発明1022]
CD137に特異的な前記リポカリンムテインが、SEQ ID NO: 22に示す配列を有する、本発明1021の方法。
[本発明1023]
前記抗HER2抗体が、SEQ ID NO: 79およびSEQ ID NO: 80に示す配列を有する、本発明1022の方法。
[本発明1024]
前記CD137/HER2二重特異性物質が、SEQ ID NO: 81およびSEQ ID NO: 80に、SEQ ID NO: 79およびSEQ ID NO: 82に、SEQ ID NO: 83およびSEQ ID NO: 80に、またはSEQ ID NO: 79およびSEQ ID NO: 84に示す配列を有する、本発明1001～1023のいずれかの方法。
[本発明1025]
前記がんが、進行性または転移性のHER-2陽性固形腫瘍である、本発明1001～1024のいずれかの方法。
[本発明1026]
前記対象が以前に治療されている、本発明1001～1025のいずれかの方法。
[本発明1027]
前記対象が抗HER2療法によって以前に治療されている、本発明1001～1026のいずれかの方法。
[本発明1028]
前記対象がPD-1系阻害物質療法によって以前に治療されている、本発明1001～1027のいずれかの方法。
[本発明1029]
前記治療が、腫瘍特異的免疫応答の刺激、腫瘍サイズの縮小、腫瘍細胞増殖の抑制、転移の抑制、完全寛解、部分寛解、疾患の安定、再発前の期間の延長、生存期間の延長、完全奏功、および部分奏功より選択される少なくとも1つの効果をもたらす、本発明1001～1028のいずれかの方法。
[本発明1030]
CD137/HER2二重特異性物質抗体およびPD-1系阻害物質を含み、該CD137/HER2二重特異性物質抗体が、(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、組合せであって、
該組合せが、少なくとも1回のサイクルにおいて対象に投与されるのに適しており、
各サイクルについて、該CD137/HER2二重特異性物質が、約0.05mg/kg、約0.15mg/kg、約0.5mg/kg、約1.0mg/kg、約2.5mg/kg、約5.0mg/kg、または約8.0mg/kgの用量で投与され、かつ該抗PD-L1系阻害物質が約1200mgの用量で投与される、
該組合せ。
[本発明1031]
前記CD137/HER2二重特異性物質および前記抗PD-L1抗体が連続的または同時に投与される、本発明1030の組合せ。
[本発明1032]
HER2陽性かつ/またはPD-L1陽性の腫瘍を治療するために使用することができる、本発明1030または1031の組合せ。
[本発明1033]
増強された抗腫瘍効果をもたらすことができる、本発明1030～1032のいずれかの組合せ。
[本発明1034]
単独の前記CD137/HER2二重特異性物質または前記PD-1系阻害物質と比べて、相加的な抗腫瘍効果をもたらすことができる、本発明1030～1033のいずれかの組合せ。
[本発明1035]
単独の前記CD137/HER2二重特異性物質または前記PD-1系阻害物質と比べて、相乗的な抗腫瘍効果をもたらすことができる、本発明1030～1033のいずれかの組合せ。
[本発明1036]
(a)CD137/HER2二重特異性物質抗体を含み、該CD137/HER2二重特異性物質抗体が、(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CD2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、薬学的組成物；ならびに
(b)PD-1系阻害物質を含む薬学的組成物
を含む、キット・オブ・パーツ。
[本発明1037]
前記CD137/HER2二重特異性物質が、約0.05mg/kg、約0.15mg/kg、約0.5mg/kg、約1.0mg/kg、約2.5mg/kg、約5.0mg/kg、または約8.0mg/kgの単位投与量で存在し、かつ前記抗PD-L1系阻害物質が約1200mgの単位投与量で存在する、本発明1036のキット・オブ・パーツ。
[本発明1038]
CD137/HER2二重特異性物質を含む前記薬学的組成物、およびPD-1系阻害物質を含む前記薬学的組成物が、相加的または相乗的な抗腫瘍効果をもたらすことができる、本発明1036または1037のキット・オブ・パーツ。
As used herein, the term "about" or "approximately" means within 20%, preferably within 15%, preferably within 10%, of a given value or range, and more preferably within 5%. It also includes its actual number. That is, "about 20" includes the number 20.
[Invention 1001]
(a) (i) the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:64, (ii) the CDR1 domain of a light chain variable region having the sequence set forth in SEQ ID NO:65 , a CDR2 domain, a CDR3 domain, and (iii) a lipocalin mutein having a sequence set forth in any one of SEQ ID NOs: 21-39; and
(b) PD-1 system inhibitor
to the subject.
[Invention 1002]
(a) administering a CD137/HER2 bispecific agent to a subject, wherein a PD-1 system inhibitor is also given to the subject, so that the subject is treated with both, or
(b) administering a PD-1 system inhibitor to the subject, wherein the CD137/HER2 bispecific is also given to the subject, so that the subject is treated with both
A method of treating cancer in the subject comprising
The CD137/HER2 bispecific comprises (i) the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 64, (ii) the sequence set forth in SEQ ID NO: 65. and (iii) a lipocalin mutein having a sequence set forth in any one of SEQ ID NOs: 21-39.
[Invention 1003]
The method of invention 1001 or 1002, wherein said cancer is HER-2 positive and/or PD-L1 positive.
[Invention 1004]
The method of any of inventions 1001-1003, which can provide enhanced anti-tumor effects.
[Invention 1005]
1004. The method of any of inventions 1001-1004, wherein said CD137/HER2 bispecific agent or said PD-1 system inhibitor alone can provide an additive anti-tumor effect.
[Invention 1006]
1004. The method of any of inventions 1001-1004, which is capable of producing a synergistic anti-tumor effect compared to said CD137/HER2 bispecific agent or said PD-1 system inhibitor alone.
[Invention 1007]
The antitumor effect is
(a) stimulation of tumor-associated immune responses;
(b) increased IL-2 secretion;
(c) increased IL-2 secretion in the tumor microenvironment;
(d) increased IFN-γ secretion;
(e) increased IFN-γ secretion in the tumor microenvironment;
(f) proliferation of CD4 + T cells;
(g) proliferation of CD4 + T cells in the tumor microenvironment ;
(h) proliferation of CD8 + T cells;
(i) proliferation of CD8 + T cells in the tumor microenvironment ;
(j) proliferation of tumor-infiltrating lymphocytes;
(k) activation of NK cells and increased antibody-dependent cell-mediated cytotoxicity (ADCC);
(l) activation of NK cells and increased ADCC in the tumor microenvironment;
(m) elevated CD4 levels in the tumor microenvironment;
(n) reduced CD4 levels in the tumor microenvironment;
(o) elevated CD8 levels in the tumor microenvironment;
(p) reduction of CD8 levels in the tumor microenvironment;
(q) elevated PD-L1 levels in the tumor microenvironment;
(r) reduced PD-L1 levels in the tumor microenvironment;
(s) increased Ki67 levels in the tumor microenvironment;
(t) reduced Ki67 levels in the tumor microenvironment;
(u) elevated CD137 levels in the tumor microenvironment;
(v) reduction of CD137 levels in the tumor microenvironment;
(w) elevated HER2 levels in the tumor microenvironment;
(x) reduced HER2 levels in the tumor microenvironment;
(y) elevated levels of IL-8 in the tumor microenvironment;
(z) reduction of IL-8 levels in the tumor microenvironment;
(aa) increased FoxP3 levels in the tumor microenvironment;
(ab) decreased FoxP3 levels in the tumor microenvironment;
(ac) reduction in tumor size;
(ad) inhibition of tumor growth;
(ae) inhibition of tumor metastasis;
(af) delayed recurrence; or
(ag) improved overall survival
The method of any of the inventions 1004-1006, selected from the group consisting of:
[Invention 1008]
comprising at least one dosing cycle, said cycle being about three weeks in duration, wherein for each of said at least one cycle, at least one dose of said CD137/HER2 bispecific agent is administered; and at least one The method of any of inventions 1001-1007, wherein a dose of said PD-1 system inhibitor is administered.
[Invention 1009]
The method of any of inventions 1001-1008, wherein said CD137/HER2 bispecific agent and said PD-1 system inhibitor are administered sequentially or simultaneously.
[Invention 1010]
said CD137/HER2 bispecific agent is about 0.05 mg/kg, about 0.15 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.5 mg/kg, about 5.0 mg/kg, or about 8.0 The method of any of invention 1001-1009 administered at a dose of mg/kg.
[Invention 1011]
The method of any one of inventions 1001-1010, wherein said PD-1 system inhibitor is an anti-PD-L1 antibody.
[Invention 1012]
1012. The method of invention 1011, wherein said anti-PD-L1 antibody has the sequences shown in SEQ ID NO:76 and SEQ ID NO:77.
[Invention 1013]
The method of invention 1011 or 1012, wherein said anti-PD-L1 antibody is administered at a dose of about 1200 mg.
[Invention 1014]
The method of any one of inventions 1001-1010, wherein said PD-1 system inhibitor is an anti-PD-1 antibody.
[Invention 1015]
1010. Any of the inventions 1001-1010, wherein said PD-1 system inhibitor is an antibody having a sequence shown in SEQ ID NO: 72 and SEQ ID NO: 73 or SEQ ID NO: 74 and SEQ ID NO: 75 the method of.
[Invention 1016]
The method of any of Inventions 1001-1010, wherein said PD-1 system inhibitor is atezolizumab, durvalumab, avelumab, nivolumab, pembrolizumab, tislelizumab, or cemiplimab.
[Invention 1017]
The method of any of Inventions 1001-1016, wherein said CD137/HER2 bispecific agent and said PD-1 system inhibitor are administered at the following doses:
(a) about 0.05 mg/kg CD137/HER2 bispecific and about 1200 mg PD-1 system inhibitor;
(b) about 0.15 mg/kg CD137/HR2 bispecific and about 1200 mg PD-1 system inhibitor;
(c) about 0.5 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
(d) about 1.0 mg/kg CD137/HER2 bispecific and about 1200 mg PD-1 system inhibitor;
(e) about 2.5 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
(f) about 5.0 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor, or
(g) about 8.0 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
[Invention 1018]
at least one dosing cycle, including, for example, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 10 cycles, 15 cycles, 20 cycles, 25 cycles, and 30 cycles, wherein the cycles are about 3 weeks in duration; The method of any one of inventions 1001-1017.
[Invention 1019]
of inventions 1001-1018, comprising administering one dose of said CD137/HER2 bispecific agent and one dose of said PD-1 system inhibitor to each other sequentially on day 1 of each three-week cycle. either way.
[Invention 1020]
administering 1 dose of said CD137/HER2 bispecific agent and 1 dose of said PD-1 system inhibitor to each other sequentially for 30 3-week cycles on day 1 of each cycle. , the method of any of the inventions 1001-1019.
[Invention 1021]
The CD137/HER2 bispecific substance comprises a CD137-specific lipocalin mutein, and the lipocalin mutein is fused at the N-terminus to the C-terminus of each heavy chain of the anti-HER2 antibody via a linker. The method of any of Inventions 1001-1020.
[Invention 1022]
1021. The method of invention 1021, wherein said lipocalin mutein specific for CD137 has the sequence shown in SEQ ID NO:22.
[Invention 1023]
1023. The method of invention 1022, wherein said anti-HER2 antibody has the sequences shown in SEQ ID NO:79 and SEQ ID NO:80.
[Invention 1024]
wherein said CD137/HER2 bispecific agent is SEQ ID NO: 81 and SEQ ID NO: 80, SEQ ID NO: 79 and SEQ ID NO: 82, SEQ ID NO: 83 and SEQ ID NO: 80; or the method of any of the inventions 1001-1023 having the sequences shown in SEQ ID NO:79 and SEQ ID NO:84.
[Invention 1025]
The method of any of inventions 1001-1024, wherein said cancer is an advanced or metastatic HER-2 positive solid tumor.
[Invention 1026]
The method of any of inventions 1001-1025, wherein said subject has been previously treated.
[Invention 1027]
The method of any of inventions 1001-1026, wherein said subject has been previously treated with anti-HER2 therapy.
[Invention 1028]
The method of any of inventions 1001-1027, wherein said subject has been previously treated with PD-1 system inhibitor therapy.
[Invention 1029]
said treatment stimulates a tumor-specific immune response, reduces tumor size, inhibits tumor cell proliferation, inhibits metastasis, complete remission, partial remission, stable disease, prolongs time before recurrence, prolongs survival, complete The method of any of the inventions 1001-1028, which results in at least one effect selected from response and partial response.
[Invention 1030]
a CD137/HER2 bispecific antibody and a PD-1 system inhibitor, wherein the CD137/HER2 bispecific antibody comprises (i) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO: 64; a CDR2 domain, a CDR3 domain, (ii) a CDR1 domain, a CDR2 domain, a CDR3 domain of a light chain variable region having the sequence set forth in SEQ ID NO: 65, and (iii) any one of SEQ ID NOs: 21-39 A combination comprising a lipocalin mutein having the sequence shown in
Suitably the combination is administered to the subject in at least one cycle;
For each cycle, the CD137/HER2 bispecific is about 0.05 mg/kg, about 0.15 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.5 mg/kg, about 5.0 mg/kg or at a dose of about 8.0 mg/kg, and the anti-PD-L1 system inhibitor is administered at a dose of about 1200 mg,
the combination.
[Invention 1031]
The combination of invention 1030, wherein said CD137/HER2 bispecific agent and said anti-PD-L1 antibody are administered sequentially or simultaneously.
[Invention 1032]
A combination according to the invention 1030 or 1031 which can be used to treat HER2-positive and/or PD-L1-positive tumors.
[Invention 1033]
Any combination of the invention 1030-1032 that can provide an enhanced anti-tumor effect.
[Invention 1034]
The combination of any of inventions 1030-1033, which is capable of providing an additive anti-tumor effect compared to said CD137/HER2 bispecific agent or said PD-1 system inhibitor alone.
[Invention 1035]
The combination of any of inventions 1030-1033, which is capable of producing a synergistic anti-tumor effect compared to said CD137/HER2 bispecific agent or said PD-1 system inhibitor alone.
[Invention 1036]
(a) a CD137/HER2 bispecific antibody, wherein the CD137/HER2 bispecific antibody (i) a heavy chain variable region CDR1 domain, a CDR2 domain having the sequence set forth in SEQ ID NO: 64 , the CDR3 domain, (ii) the CDR1 domain, the CD2 domain, the CDR3 domain of the light chain variable region having the sequence set forth in SEQ ID NO: 65, and (iii) the sequence set forth in any one of SEQ ID NOs: 21-39. a pharmaceutical composition comprising a lipocalin mutein having
(b) a pharmaceutical composition containing a PD-1 system inhibitor
Kit of parts, including
[Invention 1037]
said CD137/HER2 bispecific agent is about 0.05 mg/kg, about 0.15 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.5 mg/kg, about 5.0 mg/kg, or about 8.0 The kit of parts of Invention 1036, present in a unit dose of mg/kg and wherein said anti-PD-L1 system inhibitor is present in a unit dose of about 1200 mg.
[Invention 1038]
The present invention, wherein said pharmaceutical composition comprising a CD137/HER2 bispecific agent and said pharmaceutical composition comprising a PD-1 system inhibitor can provide additive or synergistic anti-tumor effects. 1036 or 1037 kit of parts.
Claims (24)
(b)PD-1系阻害物質
とを組み合わせてなる、対象においてがんを治療するための医薬。 (a) (i) the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:64, (ii) the CDR1 domain of a light chain variable region having the sequence set forth in SEQ ID NO:65 , a CDR2 domain, a CDR3 domain, and (iii) a lipocalin mutein having a sequence set forth in any one of SEQ ID NOs: 21-39 ;
(b) PD-1 system inhibitor
A medicament for treating cancer in a subject , in combination with
(a)CD137/HER2二重特異性物質を含み、PD-1系阻害物質も対象に与えられ、その結果、対象が両方による治療を受ける、または
(b)PD-1系阻害物質を含み、CD137/HER2二重特異性物質も対象に与えられ、その結果、対象が両方による治療を受け、
該CD137/HER2二重特異性物質が、(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、
該医薬。 A medicament for treating cancer in a subject, comprising:
(a) comprising a CD137/HER2 bispecific agent and a PD - 1 system inhibitor is also given to the subject so that the subject is treated with both , or
(b) a CD137/HER2 bispecific agent comprising a PD - 1 system inhibitor is also given to the subject so that the subject is treated with both ;
The CD137/HER2 bispecific comprises (i) the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 64, (ii) the sequence set forth in SEQ ID NO: 65. and (iii) a lipocalin mutein having a sequence set forth in any one of SEQ ID NOs: 21-39,
the medicament .
(b)CD137/HER2二重特異性物質と組み合わせて使用される、PD-1系阻害物質を含む、(b) a PD-1 system inhibitor used in combination with a CD137/HER2 bispecific agent,
対象においてがんを治療するための医薬であって、A medicament for treating cancer in a subject, comprising:
該CD137/HER2二重特異性物質が、(i)SEQ ID NO: 64に示す配列を有する重鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、(ii)SEQ ID NO: 65に示す配列を有する軽鎖可変領域のCDR1ドメイン、CDR2ドメイン、CDR3ドメイン、および(iii)SEQ ID NO: 21～39のいずれか1つに示す配列を有するリポカリンムテインを含む、The CD137/HER2 bispecific comprises (i) the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:64, (ii) the sequence set forth in SEQ ID NO:65. and (iii) a lipocalin mutein having a sequence set forth in any one of SEQ ID NOs: 21-39,
該医薬。the medicament.
(a)約0.05mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(b)約0.15mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(c)約0.5mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(d)約1.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(e)約2.5mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、
(f)約5.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質、または
(g)約8.0mg/kgのCD137/HER2二重特異性物質および約1200mgのPD-1系阻害物質。 Any one of claims 1-6 or 8-13 , characterized in that said CD137/HER2 bispecific substance and said PD-1 system inhibitor are used to be administered at the following doses: Medications listed:
(a) about 0.05 mg/kg CD137/HER2 bispecific and about 1200 mg PD-1 system inhibitor;
(b) about 0.15 mg/kg CD137/H E R2 bispecific and about 1200 mg PD-1 system inhibitor;
(c) about 0.5 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
(d) about 1.0 mg/kg CD137/HER2 bispecific and about 1200 mg PD-1 system inhibitor;
(e) about 2.5 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
(f) about 5.0 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor, or
(g) about 8.0 mg/kg of a CD137/HER2 bispecific and about 1200 mg of a PD-1 system inhibitor;
該組合せが、少なくとも1回のサイクルにおいて対象に投与されるのに適しており、
各サイクルについて、該CD137/HER2二重特異性物質が、約0.05mg/kg～約8mg/kg、約0.05mg/kg、約0.15mg/kg、約0.5mg/kg、約1.0mg/kg、約2.5mg/kg、約5.0mg/kg、または約8.0mg/kgの用量で投与され、かつ該抗PD-1系阻害物質が約1200mgの用量で投与される、
該組合せ。 a CD137/HER2 bispecific and a PD-1 system inhibitor, wherein the CD137/HER2 bispecific antibody comprises (i) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO: 64; a CDR2 domain, a CDR3 domain, (ii) a CDR1 domain, a CDR2 domain, a CDR3 domain of a light chain variable region having the sequence set forth in SEQ ID NO: 65, and (iii) any one of SEQ ID NOs: 21-39 A combination comprising a lipocalin mutein having the sequence shown in
Suitably the combination is administered to the subject in at least one cycle;
For each cycle, the CD137/HER2 bispecific is about 0.05 mg/kg to about 8 mg/kg, about 0.05 mg/kg, about 0.15 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, administered at a dose of about 2.5 mg/kg, about 5.0 mg/kg, or about 8.0 mg/kg, and the anti-PD- 1 system inhibitor is administered at a dose of about 1200 mg;
the combination.
(b)PD-1系阻害物質を含む薬学的組成物
を含む、キット・オブ・パーツ。 (a) a CD137/HER2 bispecific antibody , wherein the CD137/HER2 bispecific antibody comprises (i) a heavy chain variable region CDR1 domain, a CDR2 domain having the sequence set forth in SEQ ID NO: 64; a CDR3 domain, (ii) a CDR1 domain, a CDR2 domain, a CDR3 domain of a light chain variable region having the sequence set forth in SEQ ID NO: 65, and (iii) set forth in any one of SEQ ID NOs: 21-39 a pharmaceutical composition comprising a lipocalin mutein having a sequence;
(b) a kit of parts containing a pharmaceutical composition comprising a PD-1 system inhibitor;
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| EP18191041.5 | 2018-08-27 | ||
| PCT/EP2019/072754 WO2020043683A1 (en) | 2018-08-27 | 2019-08-27 | Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof |
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| CN116745309A (en) * | 2021-01-25 | 2023-09-12 | 柳韩洋行 | Method for purifying anti-4-1 BB/anti-HER 2 bispecific antibodies |
| EP4313099A2 (en) | 2021-03-23 | 2024-02-07 | Pieris Pharmaceuticals GmbH | Her2/4-1bb bispecific fusion proteins for the treatment of cancer |
| WO2023146394A1 (en) * | 2022-01-25 | 2023-08-03 | Merus N.V. | Combination therapy for the treatment of cancer |
| CN116120461B (en) * | 2022-04-29 | 2023-09-29 | 德琪(杭州)生物有限公司 | Novel anti-drug antibodies and uses thereof |
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