JPWO2020104531A5 - - Google Patents
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- JPWO2020104531A5 JPWO2020104531A5 JP2021527213A JP2021527213A JPWO2020104531A5 JP WO2020104531 A5 JPWO2020104531 A5 JP WO2020104531A5 JP 2021527213 A JP2021527213 A JP 2021527213A JP 2021527213 A JP2021527213 A JP 2021527213A JP WO2020104531 A5 JPWO2020104531 A5 JP WO2020104531A5
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Description
実施形態52は、実施形態28~32のいずれか1つに記載の組み換えMVA、実施形態27に記載のワクチン、実施形態26に記載の医薬組成物、実施形態33~40のいずれか1つに記載の併用医薬であって、がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法で用いるものであり、その方法が、実施形態28~32に記載の組み換えMVA、実施形態27に記載のワクチン、実施形態26に記載の医薬組成物、または実施形態33~40のいずれか1つに記載の併用医薬をその対象に静脈内投与及び腫瘍内投与することを含み、前記静脈内投与及び腫瘍内投与により、1)TAAをコードする第1の核酸と、抗原4-1BBLをコードする第2の核酸とを含む組み換えMVAウイルス、2)TAAをコードする第1の核酸と、抗原CD40Lをコードする第2の核酸とを含む組み換えMVAウイルス、または3)TAAをコードする第1の核酸と、抗原4-1BBLをコードする第2の核酸と、抗原CD40Lをコードする第3の核酸とを含む組み換えMVAウイルスの群から選択したいずれかのMVAを非静脈内投与または非腫瘍内投与する場合と比べて、その対象の腫瘍の縮小が増大し、及び/または全生存率が上昇するものである。前記静脈内投与及び腫瘍内投与は、当業者には明らかなように、同時または異なる時点に行うことができる。
なお、本願は、特許請求の範囲に記載の発明に関するものであるが、他の態様として以下も包含し得る。
1.がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法であって、前記方法が、腫瘍関連抗原(TAA)をコードする第1の核酸と、4-1BBLをコードする第2の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に腫瘍内投与することを含み、前記組み換えMVAを腫瘍内投与すると、TAA及び抗原4-1BBLをコードする第1及び第2の核酸を含む組み換えMVAウイルスを非腫瘍内注射する場合と比べて、前記がん性腫瘍における炎症応答が増強され、前記対象の腫瘍の縮小が増大し、及び/または全生存率が上昇する前記方法。
2.がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法であって、前記方法が、腫瘍関連抗原(TAA)をコードする第1の核酸と、4-1BBLをコードする第2の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に静脈内投与することを含み、前記組み換えMVAを静脈内投与すると、TAA及び抗原4-1BBLをコードする第1及び第2の核酸を含む組み換えMVAウイルスを非静脈内注射する場合と比べて、ナチュラルキラー(NK)細胞応答が増強され、前記TAAに特異的なCD8 T細胞応答が増強される前記方法。
3.がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法であって、前記方法が、腫瘍関連抗原(TAA)をコードする第1の核酸と、4-1BBLをコードする第2の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を含む前記対象に投与することを含み、前記組み換えMVAを投与すると、組み換えMVA及び抗原4-1BBLを単独で投与する場合と比べて、前記対象の腫瘍の縮小が増大し、及び/または全生存率が上昇する前記方法。
4.対象のがん性腫瘍における炎症応答の増強を誘導する方法であって、前記方法が、第1の異種の腫瘍関連抗原(TAA)をコードする第1の核酸と、抗原4-1BBLをコードする第2の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に腫瘍内投与することを含み、前記組み換えMVAを腫瘍内投与すると、異種の腫瘍関連抗原及び抗原4-1BBLをコードする第1及び第2の核酸を含む組み換えMVAウイルスの非腫瘍内注射によって生じる炎症応答と比べて、前記腫瘍における炎症応答が増強される前記方法。
5.前記対象が、ヒトである、上記1に記載の方法。
6.前記TAAが、腫瘍細胞で発現する内在性レトロウイルス(ERV)タンパク質である、上記1に記載の方法。
7.前記ERVタンパク質が、ヒト内在性レトロウイルスK(HERV-K)ファミリーに由来し、HERV-Kエンベロープタンパク質及びHERV-K gagタンパク質から選択されている、上記6に記載の方法。
8.前記TAAが、がん胎児性抗原(CEA)、ムチン1細胞表面関連(MUC-1)、前立腺酸性ホスファターゼ(PAP)、前立腺特異抗原(PSA)、ヒト上皮細胞成長因子受容体2(HER-2)、サバイビン、チロシン関連タンパク質1(TRP1)、チロシン関連タンパク質1(TRP2)、Brachyury、PRAME、FOLR1、HERV-K-env、HERV-K-gag、p15、MEL及びこれらを組み合わせたものからなる群から選択されている、上記1に記載の方法。
9.がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法であって、前記方法が、内在性レトロウイルス(ERV)タンパク質をコードする第1の核酸と、4-1BBLをコードする第2の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に投与することを含み、前記組み換えMVAを投与すると、組み換えMVA及び抗原4-1BBLを単独で投与する場合と比べて、前記対象の腫瘍の縮小が増大し、及び/または全生存率が上昇する前記方法。
10.前記ERVタンパク質が、ヒト内在性レトロウイルスタンパク質K(HERV-K)ファミリー由来である、上記9に記載の方法。
11.前記レトロウイルスタンパク質Kが、HERV-Kエンベロープタンパク質及びHERV-K-gagタンパク質から選択されている、上記10に記載の方法。
12.前記組み換えMVAが、抗原CD40Lをコードする第3の核酸をさらに含む、上記1に記載の方法。
13.少なくとも1つの免疫チェックポイント分子アンタゴニストまたは免疫チェックポイント分子アゴニストを前記対象に投与することをさらに含む、上記1に記載の方法。
14.前記免疫チェックポイント分子アンタゴニストまたは前記免疫チェックポイント分子アゴニストが、CTLA-4、PD-1、PD-L1、LAG-3、TIM-3及びICOSのアンタゴニストまたはアゴニストから選択される、上記13に記載の方法。
15.前記免疫チェックポイント分子アンタゴニストが、抗体である、上記14に記載の方法。
16.がんの治療で用いる組み換え改変ワクシニアアンカラ(MVA)であって、a)腫瘍関連抗原(TAA)をコードする第1の核酸と、b)4-1BBLをコードする第2の核酸とを含み、前記組み換えMVAを腫瘍内投与すると、前記組み換えMVAを非腫瘍内注射する場合と比べて、そのヒト患者のがん性腫瘍における炎症応答が増強され、前記がん性腫瘍のサイズが縮小し、及び/または全生存率が上昇する前記組み換えMVA。
17.c)CD40Lをコードする第3の核酸をさらに含む、上記16に記載の用途用の組み換えMVA。
18.前記TAAが、内在性レトロウイルス(ERV)タンパク質である、上記16に記載の用途用の組み換えMVA。
19.前記ERVタンパク質が、ヒト内在性レトロウイルスK(HERV-K)ファミリーに由来し、HERV-K-env及びHERV-K-gagから選択されている、上記18に記載の用途用の組み換えMVA。
20.前記TAAが、がん胎児性抗原(CEA)、ムチン1細胞表面関連(MUC-1)、前立腺酸性ホスファターゼ(PAP)、前立腺特異抗原(PSA)、ヒト上皮細胞成長因子受容体2(HER-2)、サバイビン、チロシン関連タンパク質1(TRP1)、チロシン関連タンパク質1(TRP2)、Brachyury、FOLR1、PRAME、HERV-K-env、HERV-K-gag、p15、MEL及びこれらを組み合わせたものからなる群から選択されている、上記16に記載の用途用の組み換えMVA。
21.がんである対象を治療するための組み換え改変ワクシニアアンカラ(MVA)であって、(a)腫瘍関連抗原(TAA)をコードする第1の核酸と、(b)4-1BBLをコードする第2の核酸とを含む前記組み換えMVA。
22.前記TAAが、ヒト内在性レトロウイルスK(HERV-K)ファミリーのERVタンパク質である、上記21に記載の組み換えMVA。
23.前記ERVタンパク質が、HERV-K envタンパク質及びHERV-K gagタンパク質から選択されている、上記22に記載の組み換えMVA。
24.c)CD40Lをコードする第3の核酸をさらに含む、上記23に記載の組み換えMVA。
25.(a)上記24に記載の組み換えMVAと、(b)少なくとも1つの免疫チェックポイント分子アンタゴニストまたは免疫チェックポイント分子アゴニストとを含む併用医薬。
26.前記免疫チェックポイント分子アンタゴニストまたは前記免疫チェックポイント分子アゴニストが、CTLA-4、PD-1、PD-L1、LAG-3、TIM-3及びICOSのアンタゴニストまたはアゴニストから選択されている、上記25に記載の併用医薬。
27.がん性腫瘍を有する対象において、腫瘍サイズを縮小させ、及び/または生存率を上昇させる方法であって、前記方法が、腫瘍関連抗原(TAA)をコードする第1の核酸と、4-1BBLをコードする第2の核酸と、CD40Lをコードする第3の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に投与することを含み、前記組み換えMVAを投与すると、組み換えMVA、抗原4-1BBL及び抗原CD40Lを単独で投与する場合と比べて、前記対象の腫瘍の縮小が増大し、及び/または全生存率が上昇する前記方法。
28.対象のがん性腫瘍における炎症応答の増強を誘導する方法であって、前記方法が、第1の異種の腫瘍関連抗原(TAA)をコードする第1の核酸と、抗原4-1BBLをコードする第2の核酸と、抗原CD40Lをコードする第3の核酸とを含む組み換え改変ワクシニアアンカラ(MVA)を前記対象に腫瘍内投与することを含み、前記組み換えMVAを腫瘍内投与すると、異種の腫瘍関連抗原をコードする第1の核酸と、抗原4-1BBLをコードする第2の核酸と、抗原CD40Lをコードする第3の核酸とを含む組み換えMVAウイルスの非腫瘍内注射によって生じる炎症応答と比べて、前記腫瘍における炎症応答が増強される前記方法。
29.前記組み換え改変ワクシニアアンカラ(MVA)を前記対象に静脈内投与することを含む、上記27に記載の方法。
30.前記組み換え改変ワクシニアアンカラ(MVA)を前記対象に腫瘍内投与することを含む、上記27に記載の方法。
31.前記組み換え改変ワクシニアアンカラ(MVA)を前記対象に静脈内投与及び腫瘍内投与することを含む、上記27に記載の方法。
32.前記静脈内投与と前記腫瘍内投与とを異なる時点に行う、上記31に記載の方法。
Embodiment 52 is a recombinant MVA according to any one of embodiments 28-32, a vaccine according to embodiment 27, a pharmaceutical composition according to embodiment 26, any one of embodiments 33-40. A pharmaceutical combination as described for use in a method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, the method comprising any of embodiments 28-32. intravenously and intratumorally administering to the subject recombinant MVA, the vaccine of embodiment 27, the pharmaceutical composition of embodiment 26, or the pharmaceutical combination of any one of embodiments 33-40. wherein the intravenous and intratumoral administration produces 1) a recombinant MVA virus comprising a first nucleic acid encoding a TAA and a second nucleic acid encoding the antigen 4-1BBL, 2) a second nucleic acid encoding a TAA and a second nucleic acid encoding the antigen CD40L, or 3) a first nucleic acid encoding a TAA, a second nucleic acid encoding the antigen 4-1BBL, and the antigen CD40L. increased tumor shrinkage in the subject compared to non-intravenous or non-intratumoral administration of any MVA selected from the group of recombinant MVA viruses comprising a third nucleic acid encoding and/or It increases overall survival. Said intravenous administration and intratumoral administration can be carried out at the same time or at different times, as will be appreciated by those skilled in the art.
Although the present application relates to the invention described in the claims, it can also include the following as other aspects.
1. A method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, said method comprising: a first nucleic acid encoding a tumor-associated antigen (TAA); intratumorally administering to said subject recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid encoding enhanced inflammatory response in said cancerous tumor, increased tumor shrinkage and/or increased overall survival in said subject compared to non-intratumoral injection of a recombinant MVA virus comprising a second nucleic acid the above method.
2. A method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, said method comprising: a first nucleic acid encoding a tumor-associated antigen (TAA); intravenously administering to said subject recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid encoding Said method wherein a natural killer (NK) cell response is enhanced and said TAA-specific CD8 T cell response is enhanced compared to non-intravenous injection of a recombinant MVA virus comprising a second nucleic acid.
3. A method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, said method comprising: a first nucleic acid encoding a tumor-associated antigen (TAA); administering to the subject a recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid encoding wherein said subject has increased tumor shrinkage and/or increased overall survival.
4. A method of inducing an enhanced inflammatory response in a cancerous tumor of a subject, said method comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) and encoding antigen 4-1BBL intratumorally administering to said subject recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid, wherein upon intratumoral administration of said recombinant MVA, a heterologous tumor-associated antigen and a first nucleic acid encoding antigen 4-1BBL and said method wherein an inflammatory response in said tumor is enhanced relative to the inflammatory response produced by non-intratumoral injection of a recombinant MVA virus comprising a second nucleic acid.
5. 2. The method of claim 1, wherein the subject is human.
6. 2. The method of claim 1, wherein the TAA is an endogenous retroviral (ERV) protein expressed in tumor cells.
7. 7. The method of claim 6, wherein said ERV protein is from the human endogenous retrovirus K (HERV-K) family and is selected from HERV-K envelope protein and HERV-K gag protein.
8. The TAAs are carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), human epidermal growth factor receptor 2 (HER-2) ), survivin, tyrosine-related protein 1 (TRP1), tyrosine-related protein 1 (TRP2), Brachyury, PRAME, FOLR1, HERV-K-env, HERV-K-gag, p15, MEL and combinations thereof 1. The method of claim 1, wherein the method is selected from
9. 4. A method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, said method comprising: a first nucleic acid encoding an endogenous retroviral (ERV) protein; - administering to the subject a recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid encoding 1BBL, wherein administering the recombinant MVA and administering the recombinant MVA and the antigen 4-1BBL alone; Said method, wherein said subject's tumor shrinkage is increased and/or overall survival is increased in comparison.
10. 10. The method of claim 9, wherein said ERV protein is from the human endogenous retroviral protein K (HERV-K) family.
11. 11. The method of claim 10, wherein said retroviral protein K is selected from HERV-K envelope protein and HERV-K-gag protein.
12. 2. The method of claim 1, wherein said recombinant MVA further comprises a third nucleic acid encoding the antigen CD40L.
13. 2. The method of claim 1, further comprising administering to said subject at least one immune checkpoint molecule antagonist or immune checkpoint molecule agonist.
14. 14. 14. 14 above, wherein said immune checkpoint molecule antagonist or said immune checkpoint molecule agonist is selected from antagonists or agonists of CTLA-4, PD-1, PD-L1, LAG-3, TIM-3 and ICOS. Method.
15. 15. The method of 14 above, wherein the immune checkpoint molecule antagonist is an antibody.
16. 1. A recombinant modified vaccinia Ankara (MVA) for use in the treatment of cancer, comprising a) a first nucleic acid encoding a tumor-associated antigen (TAA) and b) a second nucleic acid encoding 4-1BBL, intratumoral administration of the recombinant MVA enhances the inflammatory response and reduces the size of the cancerous tumor in the human patient compared to non-intratumoral injection of the recombinant MVA; and /or said recombinant MVA with increased overall survival.
17. c) A recombinant MVA for use according to 16 above, further comprising a third nucleic acid encoding CD40L.
18. 17. A recombinant MVA for use according to claim 16, wherein said TAA is an endogenous retroviral (ERV) protein.
19. 19. A recombinant MVA for use according to claim 18, wherein said ERV protein is from the human endogenous retrovirus K (HERV-K) family and is selected from HERV-K-env and HERV-K-gag.
20. The TAAs are carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), human epidermal growth factor receptor 2 (HER-2) ), survivin, tyrosine-related protein 1 (TRP1), tyrosine-related protein 1 (TRP2), Brachyury, FOLR1, PRAME, HERV-K-env, HERV-K-gag, p15, MEL and combinations thereof 17. A recombinant MVA for use according to 16 above, which is selected from
21. A recombinant modified vaccinia Ankara (MVA) for treating a subject with cancer comprising: (a) a first nucleic acid encoding a tumor-associated antigen (TAA); and (b) a second nucleic acid encoding 4-1BBL. the recombinant MVA comprising a nucleic acid;
22. 22. The recombinant MVA of claim 21, wherein said TAA is an ERV protein of the human endogenous retrovirus K (HERV-K) family.
23. 23. The recombinant MVA of claim 22, wherein said ERV protein is selected from HERV-K env protein and HERV-K gag protein.
24. c) A recombinant MVA according to 23 above, further comprising a third nucleic acid encoding CD40L.
25. A pharmaceutical combination comprising (a) a recombinant MVA according to 24 above and (b) at least one immune checkpoint molecule antagonist or immune checkpoint molecule agonist.
26. 26. The method of claim 25, wherein said immune checkpoint molecule antagonist or immune checkpoint molecule agonist is selected from antagonists or agonists of CTLA-4, PD-1, PD-L1, LAG-3, TIM-3 and ICOS. concomitant medications.
27. A method of reducing tumor size and/or increasing survival in a subject with a cancerous tumor, said method comprising: a first nucleic acid encoding a tumor-associated antigen (TAA); and a third nucleic acid encoding CD40L, wherein administration of the recombinant MVA comprises administering to the subject a recombinant MVA, antigen 4- Said method, wherein said subject has increased tumor shrinkage and/or increased overall survival compared to administration of 1BBL and the antigen CD40L alone.
28. A method of inducing an enhanced inflammatory response in a cancerous tumor of a subject, said method comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) and encoding antigen 4-1BBL intratumorally administering to said subject a recombinant modified vaccinia Ankara (MVA) comprising a second nucleic acid and a third nucleic acid encoding the antigen CD40L, wherein intratumoral administration of said recombinant MVA results in heterologous tumor-associated Compared to the inflammatory response generated by non-intratumoral injection of a recombinant MVA virus comprising a first nucleic acid encoding the antigen, a second nucleic acid encoding the antigen 4-1BBL, and a third nucleic acid encoding the antigen CD40L. , said method wherein an inflammatory response in said tumor is enhanced.
29. 28. The method of Claim 27, comprising intravenously administering said recombinant modified vaccinia Ankara (MVA) to said subject.
30. 28. The method of Claim 27, comprising intratumorally administering said recombinant modified vaccinia Ankara (MVA) to said subject.
31. 28. The method of claim 27, comprising intravenously and intratumorally administering said recombinant modified vaccinia Ankara (MVA) to said subject.
32. 32. The method of 31 above, wherein said intravenous administration and said intratumoral administration are performed at different times.
Claims (24)
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