Antigen vaccination and treatment including a binder that binds to PD-L1 and CD137.

JP2026094342APending Publication Date: 2026-06-09BIONTECH SE
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
BIONTECH SE
Filing Date
2026-03-04
Publication Date
2026-06-09

AI Technical Summary

Benefits of technology

【0012】 本発明者らは、驚くべきことに、ワクチン接種(例えば、ワクチン接種に使用されるペプチドまたはタンパク質をコードするRNA(抗原をコードするRNA)を投与することによる)の有効性が、少なくともPD-L1およびCD137に結合する多重特異性(例えば二重特異性、三重特異性など)結合剤を同時投与することによって増大され得ることを見出した。ヒトでは、CD137は、CD8+T細胞およびCD4+T細胞などの活性化T細胞上に発現されるが、PD-L1は、樹状細胞または腫瘍細胞などの抗原提示細胞(APC)上に主に発現される。一実施形態では、結合剤は、そのPD-L1結合領域を介してPD-L1発現腫瘍細胞または抗原提示細胞(APC)に結合し、そのCD137結合領域を介してT細胞に結合して活性化し、T細胞の条件付き活性化をもたらす。理論に拘束されるものではないが、本発明による結合剤は、結合剤がPD-L1およびCD137に同時に結合する場合、CD137のクラスタ化を媒介し得る。結合剤によるCD137のクラスタ化は、この受容体の十分な活性化およびT細胞のCD137媒介共刺激のために必要である。一実施形態では、本発明による二重特異性抗体などの結合剤は、細胞上のPD-L1およびCD137の同時結合によってAPCとT細胞との間の細胞間相互作用を媒介し得る。したがって、これは抗原特異的T細胞の増殖をもたらし得る。一実施形態では、結合剤は、T細胞を腫瘍細胞に近接させ、それによってT細胞による腫瘍細胞の死滅を促進する。一実施形態では、PD-L1発現腫瘍細胞とCD8+T細胞などのエフェクタT細胞とを互いに近接させることにより、インターフェロンγの放出を開始させ得、これは次に腫瘍細胞上のPD-L1を上方制御することができ、したがって腫瘍へのより多くの結合剤の動員を促進し、その死滅をさらに増強する。したがって、これは、T細胞上のCD137の結合によって腫瘍細胞の存在下でT細胞のさらなる活性化をもたらし得るが、腫瘍細胞上のPD-L1の結合はT細胞と腫瘍細胞とを近接させる。したがって、腫瘍細胞の存在下でのT細胞の活性化は、T細胞による腫瘍細胞の死滅の増強をもたらし得る。さらに、本発明による結合剤の、PD-L1抗原結合領域が腫瘍細胞上のPD-L1とT細胞上のPD-1との結合を阻害する能力は、腫瘍細胞がT細胞阻害を誘導することができ、それによって活性化T細胞の抗腫瘍効果を回避することを防止する。活性化T細胞上に発現されたPD1へのPD-L1結合は、T細胞阻害をもたらし得る。一実施形態では、結合剤は、ヒトPD-1へのヒトPD-L1の結合を阻害し、したがってPD-L1がPD-1を介した抗腫瘍免疫を妨げるのを防止する。したがって、結合剤は、T細胞がPD-1/PD-L1相互作用を介して阻害シグナルを受け取ることを防止する一方で、CD137分子への結合を介して活性化シグナルを受け取り、T細胞の増殖、活性化、エフェクタおよびメモリ機能を強化するシグナル伝達をもたらす。二重特異性抗体などの結合剤は、PD1(PD-L1)阻害シグナル伝達を遮断し、同時に、活性化T細胞上に発現されるCD137分子へのトランス結合を介してT細胞を共刺激することができ、活性化はトランス結合を介して起こる。本明細書に記載される少なくともPD-L1およびCD137に結合する結合剤は、不活性Fc領域を有していてもよく、あるいはFc結合領域を有していなくてもよく、それにより、CD137に結合するときに補体依存性細胞傷害(CDC)またはT細胞上の他のFc媒介性エフェクタ機能を誘導しない。本明細書に記載される少なくともPD-L1およびCD137に結合する結合剤は、T細胞を活性化し得る。本明細書に記載される少なくともPD-L1およびCD137に結合する結合剤は、腫瘍浸潤T細胞などの腫瘍特異的T細胞を活性化するのに適し得る。

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Abstract

This provides strategies to enhance the effectiveness of vaccines, especially cancer vaccines. [Solution] This disclosure relates to methods and compositions for inducing an immune response in a subject, including providing a peptide or protein vaccine and a binder that binds to PD-L1 and CD137, such as human PD-L1 and human CD137, such as a bispecific antibody, by co-administering to the subject, for example, a peptide or protein used for vaccination, or a polynucleotide, particularly RNA, encoding a peptide or protein used for vaccination, and a binder that binds to PD-L1 and CD137, or a polynucleotide, particularly RNA, encoding a binder that binds to PD-L1 and CD137. This disclosure further relates to pharmaceutical formulations useful in the methods disclosed herein.
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Claims

1. A method for treating the subject, a. A peptide or protein containing an epitope for inducing an immune response to an antigen in the subject, or a polynucleotide encoding the peptide or protein; and b. A binder comprising a first antigen-binding region that binds to PD-L1 and a second antigen-binding region that binds to CD137, or a polynucleotide encoding the binder. A method comprising administering the above to the subject.

2. The method according to claim 1, wherein the subject is a human.

3. The method according to claim 1 or 2, wherein the PD-L1 is human PD-L1 and / or the CD137 is human CD137.

4. The method according to any one of claims 1 to 3, wherein the first antigen-binding region that binds to PD-L1 inhibits the binding of human PD-L1 to human PD-1.

5. The method according to any one of claims 1 to 4, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH) containing HCDR3 having the sequence shown in SEQ ID NO:

13.

6. The method according to any one of claims 1 to 5, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH) containing HCDR2 having the sequence shown in SEQ ID NO:

12.

7. The method according to any one of claims 1 to 6, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH) containing HCDR1 having the sequence shown in SEQ ID NO:

11.

8. The method according to any one of claims 1 to 7, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH) containing HCDR1, HCDR2, and HCDR3 sequences, and the HCDR1, HCDR2, and HCDR3 sequences each contain the sequences shown in SEQ ID NOs: 11, 12, and 13, respectively.

9. The method according to any one of claims 1 to 8, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL) having an LCDR3 having the sequence shown in SEQ ID NO:

16.

10. The method according to any one of claims 1 to 9, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL) containing an LCDR2 having a sequence DDN.

11. The method according to any one of claims 1 to 10, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL) having an LCDR1 having the sequence shown in SEQ ID NO:

15.

12. The method according to any one of claims 1 to 11, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences, and the LCDR1, LCDR2, and LCDR3 sequences each include the sequences shown in SEQ ID NOs. 15, DDN, and 16, respectively.

13. The method according to any one of claims 1 to 12, wherein the first antigen-binding region that binds to PD-L1 comprises a heavy chain variable region (VH) containing HCDR1, HCDR2, and HCDR3 sequences, and a light chain variable region (VL) containing LCDR1, LCDR2, and HCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs. 11, 12, and 13, and the LCDR1, LCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs. 15, DDN, and 16, respectively.

14. The method according to any one of claims 1 to 13, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VH sequence shown in SEQ ID NO:

10.

15. The method according to any one of claims 1 to 14, wherein the first antigen-binding region that binds to PD-L1 includes a heavy chain variable region (VH), and the VH includes the sequence shown in SEQ ID NO:

10.

16. The method according to any one of claims 1 to 15, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VL sequence shown in SEQ ID NO:

14.

17. The method according to any one of claims 1 to 16, wherein the first antigen-binding region that binds to PD-L1 includes a light chain variable region (VL), and the VL includes the sequence shown in SEQ ID NO:

14.

18. The method according to any one of claims 1 to 17, wherein the first antigen-binding region that binds to PD-L1 comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the sequence shown in SEQ ID NO: 10 and the VL comprises the sequence shown in SEQ ID NO:

14.

19. The method according to any one of claims 1 to 18, wherein the first antigen-binding region that binds to PD-L1 competes for PD-L1 binding with an antibody comprising a heavy chain variable region (VH) and / or a light chain variable region (VL) as described in any one of claims 5 to 18, and / or comprises a heavy chain variable region and a light chain variable region of an antibody having specificity for PD-L1.

20. The method according to any one of claims 1 to 19, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) having the sequence shown in SEQ ID NO:

4.

21. The method according to any one of claims 1 to 20, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) containing HCDR2 having the sequence shown in SEQ ID NO:

3.

22. The method according to any one of claims 1 to 21, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) having HCDR1 having the sequence shown in SEQ ID NO:

2.

23. The method according to any one of claims 1 to 22, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences, and the HCDR1, HCDR2, and HCDR3 sequences each comprise the sequences shown in Sequence ID No. 2, 3, and 4, respectively.

24. The method according to any one of claims 1 to 23, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) having an LCDR3 having the sequence shown in SEQ ID NO:

7.

25. The method according to any one of claims 1 to 24, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) containing an LCDR2 having the sequence GAS.

26. The method according to any one of claims 1 to 25, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) having an LCDR1 having the sequence shown in SEQ ID NO:

6.

27. The method according to any one of claims 1 to 26, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences, and the LCDR1, LCDR2, and LCDR3 sequences each include the sequences shown in SEQ ID NOs: 6, GAS, and 7, respectively.

28. The method according to any one of claims 1 to 27, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region (VH) containing HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) containing LCDR1, LCDR2, and HCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs: 2, 3, and 4, and the LCDR1, LCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs: 6, GAS, and 7.

29. The method according to any one of claims 1 to 28, wherein the second antigen-binding region bound to CD137 includes a heavy chain variable region (VH) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VH sequence shown in SEQ ID NO: 1 or 8.

30. The method according to any one of claims 1 to 29, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH), and the VH includes the sequence shown in SEQ ID NO: 1 or 8.

31. The method according to any one of claims 1 to 30, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VL sequence shown in SEQ ID NO: 5 or 9.

32. The method according to any one of claims 1 to 31, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL), and the VL includes the sequence shown in SEQ ID NO: 5 or 9.

33. The method according to any one of claims 1 to 32, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising the sequence shown in SEQ ID NO: 1, and the VL comprising the sequence shown in SEQ ID NO:

5.

34. The method according to any one of claims 1 to 32, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising the sequence shown in SEQ ID NO: 8, and the VL comprising the sequence shown in SEQ ID NO:

9.

35. The method according to any one of claims 1 to 19, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) containing HCDR3 having the sequence shown in SEQ ID NO:

27.

36. The method according to any one of claims 1 to 19 and 35, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) containing HCDR2 having the sequence shown in SEQ ID NO:

26.

37. The method according to any one of claims 1 to 19, 35, and 36, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) containing HCDR1 having the sequence shown in SEQ ID NO:

25.

38. The method according to any one of claims 1 to 19 and 35 to 37, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences, and the HCDR1, HCDR2, and HCDR3 sequences comprise sequences shown in SEQ ID NOs. 25, 26, and 27, respectively.

39. The method according to any one of claims 1 to 19 and 35 to 38, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) comprising an LCDR3 having the sequence shown in SEQ ID NO:

30.

40. The method according to any one of claims 1 to 19 and 35 to 39, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) containing an LCDR2 having the sequence SAS.

41. The method according to any one of claims 1 to 19 and 35 to 40, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) having an LCDR1 having the sequence shown in SEQ ID NO:

29.

42. The method according to any one of claims 1 to 19 and 35 to 41, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences, and the LCDR1, LCDR2, and LCDR3 sequences each include the sequences shown in SEQ ID NOs. 29, SAS, and 30, respectively.

43. The method according to any one of claims 1 to 19 and 35 to 42, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region (VH) containing HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) containing LCDR1, LCDR2, and HCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs. 25, 26, and 27, and the LCDR1, LCDR2, and HCDR3 sequences each comprise the sequences shown in SEQ ID NOs. 29, SAS, and 30, respectively.

44. The method according to any one of claims 1 to 19 and 35 to 43, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VH sequence shown in SEQ ID NO:

24.

45. The method according to any one of claims 1 to 19 and 35 to 44, wherein the second antigen-binding region that binds to CD137 includes a heavy chain variable region (VH), and the VH includes the sequence shown in SEQ ID NO:

24.

46. The method according to any one of claims 1 to 19 and 35 to 45, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL) having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity with the amino acid sequence of the VL sequence shown in SEQ ID NO:

28.

47. The method according to any one of claims 1 to 19 and 35 to 46, wherein the second antigen-binding region that binds to CD137 includes a light chain variable region (VL), and the VL includes the sequence shown in SEQ ID NO:

28.

48. The method according to any one of claims 1 to 19 and 35 to 47, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising the sequence shown in SEQ ID NO: 24, and the VL comprising the sequence shown in SEQ ID NO:

28.

49. The method according to any one of claims 1 to 48, wherein the second antigen-binding region that binds to CD137 comprises a heavy chain variable region and a light chain variable region of an antibody that competes for CD137 binding with an antibody comprising a heavy chain variable region and / or a light chain variable region according to any one of claims 20 to 48, and / or has specificity for CD137 of the antibody.

50. The method according to any one of claims 1 to 49, wherein the binder is in the form of a full-length antibody.

51. The method according to any one of claims 1 to 49, wherein the binder is in the form of an antibody fragment.

52. The method according to any one of claims 1 to 51, wherein the binder is a multispecific antibody such as a bispecific antibody.

53. The method according to any one of claims 1 to 52, wherein the peptide or protein containing an epitope for inducing an immune response to an antigen, or the polynucleotide encoding the peptide or protein, and the binder or the polynucleotide encoding the binder are administered sequentially to the subject.

54. The method according to any one of claims 1 to 53, wherein the binder or the polynucleotide encoding the binder is administered after administration of the peptide or protein containing an epitope for inducing an immune response to an antigen in the subject, or the polynucleotide encoding the peptide or protein.

55. The method according to any one of claims 1 to 54, wherein the binder or the polynucleotide encoding the binder is administered 6 hours, 12 hours, or 24 hours after the administration of the peptide or protein containing an epitope for inducing an immune response to an antigen in the subject, or the polynucleotide encoding the peptide or protein.

56. The method according to any one of claims 1 to 55, wherein the binder or the polynucleotide encoding the binder is administered between 12 and 48 hours after administration of the peptide or protein containing an epitope for inducing an immune response to an antigen in the subject, or the polynucleotide encoding the peptide or protein.

57. The method according to any one of claims 1 to 56, wherein the polynucleotide encoding the peptide or protein containing an epitope for inducing an immune response to an antigen in the subject and / or the polynucleotide encoding the binder is RNA.

58. a. RNA encoding the peptide or protein containing an epitope for inducing an immune response to the antigen in the subject; and b. The binder The method according to any one of claims 1 to 57, comprising administering to the subject.

59. The method according to any one of claims 1 to 58, wherein administration of the binder or the polynucleotide encoding the binder increases the number of CD8-positive T cells specific to the antigen or cells expressing the antigen.

60. The method according to any one of claims 1 to 59, which is a method for inducing an immune response in the subject.

61. The method according to any one of claims 1 to 60, which is a method for inducing an immune response against the antigen or cells expressing the antigen in the subject.

62. A method for treating or preventing cancer in the subject, wherein the antigen is a tumor-associated antigen, according to any one of claims 1 to 61.

63. It is a pharmaceutical preparation, a. A peptide or protein containing an epitope for inducing an immune response to an antigen in a subject, or a polynucleotide encoding said peptide or protein; and b. A binder comprising a first antigen-binding region that binds to PD-L1 and a second antigen-binding region that binds to CD137, or a polynucleotide encoding the binder. A pharmaceutical preparation containing the above.

64. a. RNA encoding the peptide or protein containing an epitope for inducing an immune response to an antigen in a subject; and b. The binder A pharmaceutical preparation according to claim 63, including the above.

65. A pharmaceutical preparation according to claim 63 or 64, which is a kit.

66. A pharmaceutical preparation according to any one of claims 63 to 65, comprising components a and b in separate containers.

67. A pharmaceutical preparation according to any one of claims 63 to 66, further comprising instructions for use of the pharmaceutical preparation for treating or preventing cancer, wherein the antigen is a tumor-associated antigen.

68. A pharmaceutical preparation according to any one of claims 63 to 67, for pharmaceutical use.

69. The pharmaceutical formulation according to claim 68, wherein the pharmaceutical use includes a therapeutic or preventive measure for a disease or disorder.

70. A pharmaceutical preparation according to any one of claims 63 to 69, for use in a method for treating or preventing cancer in a subject, wherein the antigen is a tumor-associated antigen.