Use of targeted radiotherapy (TRT) to promote the antitumor immune response to immunotherapy

Abstract

This invention provides a method for systemic immunotherapy for malignant solid tumors. [Solution] The present invention provides a method comprising the steps of administering a targeted radiotherapy (TRT) agent to a target and performing immunotherapy by systemically administering an immunostimulant to a target. For example, a radiophospholipid metal chelate compound that is a TRT agent has formula (I), where R1 comprises a chelating agent chelated to a metal atom, and the metal atom is an alpha, beta, or Auger-emitting metal isotope having a half-life of more than 6 hours and less than 30 days, or R1 comprises a radiohalogen isotope. Equation (I) JPEG2026102802000061.jpg30167 (a is 1, n is 18, m is 0, b is 1) Yes, R2 is -N + (CH3)3.

Claims

1. A method for treating cancer including one or more malignant solid tumors in the subject, (a) Differentially incorporated by malignant solid tumor tissue The immunomodulatory dose of targeted radiotherapy (TRT) agents is maintained, and (b) One or more immunostimulants, This includes administering it systemically, A method of treating cancer in a given subject.

2. One or more immunostimulants have the ability to target one or more checkpoint molecules. The method according to claim 1, wherein the checkpoint inhibitor is used.

3. One or more checkpoint molecules that can be targeted by a checkpoint inhibitor are A2AR ( Adenosine A2a receptor), BTLA (B and T lymphocyte attenuators), CTLA 4 (Cytotoxic T lymphocyte-associated protein 4), KIR (Killer cell immunoglobulin-like receptor) (Condition), LAG3 (Lymphocyte Activation Gene 3), PD-1 (Programmed Cell Death Receptor 1) PD-L1 (programmed cell death ligand 1), CD40 (differentiation antigen group 40), CD27 (differentiation antigen group 27), CD28 (differentiation antigen group 28), CD137 (differentiation antigen group 137), OX40 (CD134; differentiation antigen group 134), OX40L (OX40 ligand; differentiation antigen) Group 252), GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein), GITRL (Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand), I COS (inducible T cell costimulatory), ICOSL (inducible T cell costimulatory ligand), B7H3 (CD276; differentiation antigen group 276), B7H4 (VT CN1; V-set domain-containing T cell activation inhibitor 1), IDO (indoleamine 2) ,3-dioxygenase), TIM-3 (T cell immunoglobulin domain and mucindo Main 3), Gal-9 (Galectin-9), and VISTA (V-dominant for T cell activation) The method according to claim 2, selected from the group consisting of (in-Ig suppressor).

4. One or more immune checkpoint inhibitors, one or more anti-immune checkpoint molecular antibodies, Or one or more small molecule immune molecules that act to block one or more immune checkpoint molecules. The method according to claim 2 or 3, comprising a checkpoint inhibitor.

5. One or more anti-immune checkpoint molecule antibodies, anti-CTLA4 antibody, anti-PD-1 antibody, anti PD-L1 antibody, anti-LAG3 antibody, anti-KIR antibody, anti-A2AR antibody, and anti-BTLA antibody body, anti-CD40 antibody, anti-CD27 antibody, anti-CD28 antibody, anti-CD137 antibody, anti-OX40 Antibody, anti-OX40L antibody, GITR antibody, GITRL antibody, ICOS antibody, ICOSL anti- Body, B7H3 antibody, B7H4 antibody, IDO antibody, TIM-3 antibody, Gal-9 antibody, and Selected from a group consisting of VISTA antibodies, or one or more immune checkpoints One or more small molecule immune checkpoint inhibitors that act to block molecules, small molecule P The method according to claim 4, comprising a D-L1 inhibitor.

6. TRT drugs, (1) Metaiodobenzylguani, in which the iodine atom in MIBG is a radioactive iodine isotope. Jin (MIBG), (2) Radiolabeled tumor-targeting antibodies, (3) Radioactive radium isotopes; or (4) The following formula: 【Chemistry 1】 [During the ceremony, R １ (a) A chelating agent chelated to a metal atom, wherein the metal atom has been chelated for 6 hours Alpha, beta, or Auger-emitting metal isotopes with half-lives longer than 30 days; or (b) containing a radioactive halogen isotope, a is either 0 or 1, n is an integer between 12 and 30. m is either 0 or 1. Y is a group consisting of -H, -OH, -COOH, -COOX, -OCOX, and -OX. Selected from, where X is an alkyl or arylalkyl, R ２ is selected from the group consisting of -N ＋ H ３ , -N ＋ H ２ Z, -N ＋ HZ ２ , and -N ＋ Z ３ selected from the group consisting of Selected, each Z is independently alkyl or aryl, and b is 1 or 2, however R １ If it contains radioactive halogen isotopes, then b is 1. be〕 Phospholipid ether metal chelates or radioactive halogenated phospholipid ethers having The method according to any one of claims 1 to 5, wherein the salt is the salt thereof.

7. (1) Metal isotopes are Sc-47, Lu-177, Y-90, Ho-166, Re-1 86, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac- Selected from the group consisting of 225, Pb-212, and Th-227, (2) Radioactive halogen isotopes, １２３ I, １２４ I, １２５ I, １３１ I, ２１１ A t, ７７ Br, and ７６ Selected from the group consisting of Br, or (3) The method according to claim 6, wherein the radioactive radium isotope is Ra-223.

8. The chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid ( DO3A) and its derivatives, 1,4,7-triazacyclononane-1,4-diacetic acid (N ODA) and its derivatives, 1,4,7-triazacyclononane-1,4,7-triacetic acid ( NOTA) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid (DOTA) and its derivatives, 1,4,7-triazacyclononane, 1-Glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives, 1, 4, 7, 10 - Tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11 -Tetraacetic acid (TETA) and its derivatives, 1,4,8,11-tetraazabicyclo[6. 6.2] Hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives, dieth Lentriamin pentaacetic acid (DTPA), its diesters, and their derivatives, 2-cyclohex Xyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA) and its derivatives, def Eroxamine (DFO) and its derivatives, 1,2-[[6-carboxypyridine-2- [Iyl]methylamino]ethane (H ２ dedpa) and its derivatives, as well as DADA Selected from the group consisting of and its derivatives, DADA has the following structure: 【Chemistry 2】 The method according to claim 6 or claim 7, including the method according to claim 6 or 7.

9. (a) m is 0, or (b) b is 1, or (c) n is 18, or (d) R ２ ga-N ＋ Z ３ is, or (e) Any two or more combinations of (a) to (d), The method according to any one of claims 6 to 8.

10. Each Z independently -CH ２ CH ３ or -CH ３ The method according to claim 9.

11. Each Z is -CH ３ The method according to claim 10.

12. A chelating agent chelated to a metal atom, 【Transformation 3】 【change】 【change】 【change】 【change】 A method according to any one of claims 6 to 11, selected from the group consisting of the following.

13. Radioactive phospholipid ether metal chelates 【Chemistry 4】 【change】 【change】 【change】 【change】 The formula is selected from the group consisting of, The selected compound is chelated to a metal atom. The method according to any one of claims 6 to 11.

14. a is 1, b is 1, m is 0, n is 18, R ２ ga-N ＋ (CH ３ ) ３ The method according to any one of claims 6 to 12.

15. The radioactive phospholipid ether metal chelate is NM600, which has metal atoms chelated into it. or the radioactive halogenated phospholipid ether is NM404, according to claim 14. method.

16. Radioactive phospholipid ether metal chelates ９０ Y-NM600 or １７７ Lu-NM The method according to claim 15, wherein the value is 600.

17. Radioactive halogenated phospholipid ethers, １２３ I]-NM404, [ １２４ I]-N M404、[ １２５ I]-NM404、[ １３１ I]-NM404、[ ２１１ At]-N M404, [ ７７ Br]-NM404, or [ ７６ Claim is Br-NM404. Method 15.

18. TRT agents, immune checkpoint inhibitors, or both are administered intravenously, claim The method described in any one of items 1 to 17.

19. The method according to any one of claims 1 to 18, wherein the subject is a human.

20. The cancers treated include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, and pre- Standal cancer, liver cancer, subcutaneous cancer, squamous cell carcinoma of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer Glioma, breast cancer, pancreatic cancer, soft tissue sarcoma, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, Wi A selection from the group consisting of Lums tumor and pediatric brain tumors, any one of claims 1 to 19 The method described in section [section number].

21. Cancer can be treated without targeting antibodies against tumor antigens that are not checkpoint molecules. The method according to any one of claims 1 to 20, which is used for treatment.

22. Any one of claims 1 to 21, in which cancer is treated without administering an anti-GD2 antibody to the subject. The method described in item 1.

23. (a) Standard immunomodulatory dose for treating cancer including one or more malignant solid tumors in the subject (b) Use of targeted radiotherapy (TRT) agents and one or more immunostimulants, wherein the TRT agent However, it is selectively incorporated and preserved by malignant solid tumor tissue. It can be maintained, and both the TRT agent and one or more immunostimulants are administered systemically to the subject. The use of this method to treat cancer in the target population.

24. One or more immunostimulants have the ability to target one or more checkpoint molecules. The use according to claim 23, which is a checkpoint inhibitor.

25. One or more checkpoint molecules that can be targeted by a checkpoint inhibitor are A2AR ( Adenosine A2a receptor), BTLA (B and T lymphocyte attenuators), CTLA 4 (Cytotoxic T lymphocyte-associated protein 4), KIR (Killer cell immunoglobulin-like receptor) (Condition), LAG3 (Lymphocyte Activation Gene 3), PD-1 (Programmed Cell Death Receptor 1) PD-L1 (programmed cell death ligand 1), CD40 (differentiation antigen group 40), CD27 (differentiation antigen group 27), CD28 (differentiation antigen group 28), CD137 (differentiation antigen group 137), OX40 (CD134; differentiation antigen group 134), OX40L (OX40 ligand; differentiation antigen) Group 252), GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein), GITRL (Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand), I COS (inducible T cell costimulatory), ICOSL (inducible T cell costimulatory ligand), B7H3 (CD276; differentiation antigen group 276), B7H4 (VT CN1; V-set domain-containing T cell activation inhibitor 1), IDO (indoleamine 2) ,3-dioxygenase), TIM-3 (T cell immunoglobulin domain and mucindo Main 3), Gal-9 (Galectin-9), and VISTA (V-dominant for T cell activation) The use according to claim 24, selected from the group consisting of (in-Ig suppressor).

26. One or more immune checkpoint inhibitors are used in conjunction with one or more anti-immune checkpoint molecular antibodies. or one or more small molecule immune checkpoints that act to block one or more immune checkpoint molecules The use according to claim 24 or claim 25, comprising a checkpoint inhibitor.

27. One or more anti-immune checkpoint molecule antibodies, anti-CTLA4 antibody, anti-PD-1 antibody, anti PD-L1 antibody, anti-LAG3 antibody, anti-KIR antibody, anti-A2AR antibody, and anti-BTLA antibody body, anti-CD40 antibody, anti-CD27 antibody, anti-CD28 antibody, anti-CD137 antibody, anti-OX40 Antibody, anti-OX40L antibody, GITR antibody, GITRL antibody, ICOS antibody, ICOSL anti- Body, B7H3 antibody, B7H4 antibody, IDO antibody, TIM-3 antibody, Gal-9 antibody, and Selected from a group consisting of VISTA antibodies, or one or more immune checkpoints One or more small molecule immune checkpoint inhibitors that act to block molecules, small molecule P The use according to claim 26, comprising a D-L1 inhibitor.

28. TRT drugs, (1) Metaiodobenzylguani, in which the iodine atom in MIBG is a radioactive iodine isotope. Jin (MIBG), (2) Radiolabeled tumor-targeting antibodies, (3) Radioactive radium isotopes, or (4) The following formula: 【Transformation 5】 [During the ceremony, R １ (a) A chelating agent chelated to a metal atom, wherein the metal atom has been chelated for 6 hours Alpha, beta, or Auger-emitting metal isotopes with half-lives longer than 30 days. (b) containing radioactive halogen isotopes, a is either 0 or 1, n is an integer between 12 and 30. m is either 0 or 1. Y is a group consisting of -H, -OH, -COOH, -COOX, -OCOX, and -OX. Selected from, where X is an alkyl or arylalkyl, R ２ is, -N ＋ H ３ , -N ＋ H ２ Z, -N ＋ HZ ２ , and -N ＋ Z ３ From a group consisting of Selected, each Z is independently alkyl or aryl, and b is either 1 or 2. However, R １ If it contains a radioactive halogen isotope, then b is 1. Phospholipid ether metal chelates or radioactive halogenated phospholipid ethers having The use according to any one of claims 23 to 27, wherein the salt is the salt.

29. (1) Metal isotopes are Sc-47, Lu-177, Y-90, Ho-166, Re-1 86, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac- Selected from the group consisting of 225, Pb-212, and Th-227, (2) Radioactive halogen isotopes, １２３ I, １２４ I, １２５ I, １３１ I, ２１１ A t, ７７ Br, and ７６ Selected from the group consisting of Br, or (3) The use according to claim 28, wherein the radioactive radium isotope is Ra-223.

30. The chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid ( DO3A) and its derivatives, 1,4,7-triazacyclononane-1,4-diacetic acid (N ODA) and its derivatives, 1,4,7-triazacyclononane-1,4,7-triacetic acid ( NOTA) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid (DOTA) and its derivatives, 1,4,7-triazacyclononane, 1-Glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives, 1, 4, 7, 10 - Tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11 -Tetraacetic acid (TETA) and its derivatives, 1,4,8,11-tetraazabicyclo[6. 6.2] Hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives, dieth Lentriamin pentaacetic acid (DTPA), its diesters, and their derivatives, 2-cyclohex Xyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA) and its derivatives, def Eroxamine (DFO) and its derivatives, 1,2-[[6-carboxypyridine-2- [Iyl]methylamino]ethane (H ２ dedpa) and its derivatives, as well as DADA Selected from the group consisting of and its derivatives, DADA has the following structure: 【Transformation 6】 The use according to claim 28 or claim 29, including the use described in claim 28 or claim 29.

31. (a) m is 0, or (b) b is 1, or (c) n is 18, or (d) R ２ ga-N ＋ Z ３ is, or (e) Any two or more combinations of (a) to (d), The use described in any one of claims 28 to 30.

32. Each Z independently -CH ２ CH ３ or -CH ３ The use described in claim 31.

33. Each Z is -CH ３ The use described in claim 32.

34. A chelating agent chelated to a metal atom, 【Transformation 7】 【change】 【change】 【change】 A use according to any one of claims 28 to 33, selected from the group consisting of the following.

35. Radioactive phospholipid ether metal chelates 【Transformation 8】 【change】 【change】 【change】 【change】 The formula is selected from the group consisting of, The selected compound is chelated to a metal atom. The use described in any one of claims 28 to 34.

36. a is 1, b is 1, m is 0, n is 18, R ２ ga-N ＋ (CH ３ ) ３ The use according to any one of claims 28 to 35.

37. The radioactive phospholipid ether metal chelate is NM600, which has metal atoms chelated into it. or the radioactive halogenated phospholipid ether is NM404, according to claim 36. use.

38. Radioactive phospholipid ether metal chelates ９０ Y-NM600 or １７７ Lu-NM The use according to claim 37, which is 600.

39. Radioactive halogenated phospholipid ethers, １２３ I]-NM404, [ １２４ I]-N M404、[ １２５ I]-NM404、[ １３１ I]-NM404、[ ２１１ At]-N M404, [ ７７ Br]-NM404, or [ ７６ Claim is Br-NM404. Use as described in 37.

40. TRT agents, immune checkpoint inhibitors, or both are administered intravenously, claim Use as described in any one of paragraphs 23 to 39.

41. The use according to any one of claims 23 to 40, wherein the subject is a human.

42. The cancers treated include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, and pre- Standal cancer, liver cancer, subcutaneous cancer, squamous cell carcinoma of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer Glioma, breast cancer, pancreatic cancer, soft tissue sarcoma, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, Wi Any one of claims 23 to 41, selected from the group consisting of Lums tumor and pediatric brain tumors. Use as described in item 1.

43. Cancer can be treated without targeting antibodies against tumor antigens that are not checkpoint molecules. The use according to any one of claims 23 to 42, which is used for treatment.

44. Any of claims 23 to 43, wherein cancer is treated without administering an anti-GD2 antibody to the subject. Use as described in item 1.

45. In the manufacture of drugs for treating cancer including one or more malignant solid tumors in the subject (a (b) Use of immunomodulatory doses of targeted radiotherapy (TRT) agents or (b) use of one or more immunostimulants And, TRT agents are selectively removed by malignant solid tumor tissue. The drug can be absorbed and retained, and is administered systemically to the subject.

46. One or more immunostimulants have the ability to target one or more checkpoint molecules. The use according to claim 45, which is a checkpoint inhibitor.

47. One or more checkpoint molecules that can be targeted by a checkpoint inhibitor are A2AR ( Adenosine A2a receptor), BTLA (B and T lymphocyte attenuators), CTLA 4 (Cytotoxic T lymphocyte-associated protein 4), KIR (Killer cell immunoglobulin-like receptor) (Condition), LAG3 (Lymphocyte Activation Gene 3), PD-1 (Programmed Cell Death Receptor 1) PD-L1 (programmed cell death ligand 1), CD40 (differentiation antigen group 40), CD27 (differentiation antigen group 27), CD28 (differentiation antigen group 28), CD137 (differentiation antigen group 137), OX40 (CD134; differentiation antigen group 134), OX40L (OX40 ligand; differentiation antigen) Group 252), GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein), GITRL (Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand), I COS (inducible T cell costimulatory), ICOSL (inducible T cell costimulatory ligand), B7H3 (CD276; differentiation antigen group 276), B7H4 (VT CN1; V-set domain-containing T cell activation inhibitor 1), IDO (indoleamine 2) ,3-dioxygenase), TIM-3 (T cell immunoglobulin domain and mucindo Main 3), Gal-9 (Galectin-9), and VISTA (V-dominant for T cell activation) The method according to claim 46, selected from the group consisting of (in-Ig suppressor).

48. One or more immune checkpoint inhibitors are used in conjunction with one or more anti-immune checkpoint molecular antibodies. or one or more small molecule immune checkpoints that act to block one or more immune checkpoint molecules The use according to claim 46 or claim 47, comprising a checkpoint inhibitor.

49. One or more anti-immune checkpoint molecule antibodies, anti-CTLA4 antibody, anti-PD-1 antibody, anti PD-L1 antibody, anti-LAG3 antibody, anti-KIR antibody, anti-A2AR antibody, and anti-BTLA antibody body, anti-CD40 antibody, anti-CD27 antibody, anti-CD28 antibody, anti-CD137 antibody, anti-OX40 Antibody, anti-OX40L antibody, GITR antibody, GITRL antibody, ICOS antibody, ICOSL anti- Body, B7H3 antibody, B7H4 antibody, IDO antibody, TIM-3 antibody, Gal-9 antibody, and Selected from a group consisting of VISTA antibodies, or one or more immune checkpoints One or more small molecule immune checkpoint inhibitors that act to block molecules, small molecule P The use according to claim 48, comprising a D-L1 inhibitor.

50. TRT drugs, (1) Metaiodobenzylguani, in which the iodine atom in MIBG is a radioactive iodine isotope. Jin (MIBG), (2) Radiolabeled tumor-targeting antibodies, (3) Radioactive radium isotopes, or (4) The following formula: 【Chemistry 9】 [During the ceremony, R １ (a) A chelating agent chelated to a metal atom, wherein the metal atom has been chelated for 6 hours Alpha, beta, or Auger-emitting metal isotopes with half-lives longer than 30 days. (b) containing radioactive halogen isotopes, a is either 0 or 1, n is an integer between 12 and 30. m is either 0 or 1. Y is a group consisting of -H, -OH, -COOH, -COOX, -OCOX, and -OX. Selected from, where X is an alkyl or arylalkyl, R ２ is, -N ＋ H ３ , -N ＋ H ２ Z, -N ＋ HZ ２ , and -N ＋ Z ３ From a group consisting of Selected, each Z is independently alkyl or aryl, and b is either 1 or 2. However, R １ If it contains a radioactive halogen isotope, then b is 1. Phospholipid ether metal chelates or radioactive halogenated phospholipid ethers having The use according to any one of claims 45 to 49, wherein the salt is the salt.

51. (1) Metal isotopes are Sc-47, Lu-177, Y-90, Ho-166, Re-1 86, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac- Selected from the group consisting of 225, Pb-212, and Th-227, (2) The radioactive halogen isotope is １２３ I, １２４ I, １２５ I, １３１ I, ２１１ A t, ７７ Br, and ７６ Selected from the group consisting of Br, or (3) The use according to claim 50, wherein the radioactive radium isotope is Ra-223.

52. The chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid ( DO3A) and its derivatives; 1,4,7-Triazacyclononane-1,4-diacetic acid (N ODA) and its derivatives; 1,4,7-Triazacyclononane-1,4,7-triacetic acid ( NOTA) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid (DOTA) and its derivatives; 1,4,7-triazacyclononane, 1-Glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives; 1, 4, 7, 10 - Tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11 -Tetraacetic acid (TETA) and its derivatives; 1,4,8,11-tetraazabicyclo[6. 6.2] Hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives; dieth Lentriamin pentaacetic acid (DTPA), its diesters, and their derivatives; 2-cyclohex Xyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA) and its derivatives; def Eroxamine (DFO) and its derivatives; 1,2-[[6-carboxypyridine-2- [Ill]methylamino]ethane (H ２ dedpa) and its derivatives; and DADA and Selected from the group consisting of and its derivatives, DADA has the following structure: 【Chemistry 10】 The use according to claim 50 or claim 51, including the use according to claim 50 or claim 51.

53. (a) m is 0; or (b) b is 1; or (c) n is 18; or (d) R ２ ga-N ＋ Z ３ is; or (e) Any two or more combinations of (a) to (d), The use described in any one of claims 50 to 52.

54. Each Z independently -CH ２ CH ３ or -CH ３ The use described in claim 53.

55. Each Z is -CH ３ The use described in claim 54.

56. A chelating agent chelated to a metal atom, 【Chemistry 11】 【change】 【change】 【change】 A use according to any one of claims 50 to 55, selected from the group consisting of the following.

57. Radioactive phospholipid ether metal chelates 【Chemistry 12】 【change】 【change】 【change】 【change】 The formula is selected from the group consisting of, Any one of claims 50 to 56, wherein the selected compound is chelated to a metal atom. Use as described in the section.

58. a is 1, b is 1, m is 0, n is 18, R ２ ga-N ＋ (CH ３ ) ３ The use according to any one of claims 50 to 57.

59. The radioactive phospholipid ether metal chelate is NM600, which has metal atoms chelated into it. or the radioactive halogenated phospholipid ether is NM404, according to claim 58. use.

60. Radioactive phospholipid ether metal chelates ９０ Y-NM600 or １７７ Lu-NM The use according to claim 59, wherein the value is 600.

61. Radioactive halogenated phospholipid ethers, １２３ I]-NM404, [ １２４ I]-N M404、[ １２５ I]-NM404、[ １３１ I]-NM404、[ ２１１ At]-N M404, [ ７７ Br]-NM404, or [ ７６ Claim is Br-NM404. Use as described in 59.

62. TRT agents; immune checkpoint inhibitors; or both; are administered intravenously, claim Use as described in any one of paragraphs 45 to 61.

63. The use according to any one of claims 45 to 62, wherein the subject is a human.

64. The cancers treated include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, and pre- Standal cancer, liver cancer, subcutaneous cancer, squamous cell carcinoma of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer Glioma, breast cancer, pancreatic cancer, soft tissue sarcoma, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, Wi Any one of claims 45 to 63, selected from the group consisting of Lums tumor and pediatric brain tumors. Use as described in item 1.

65. Cancer can be treated without targeting antibodies against tumor antigens that are not checkpoint molecules. The use according to any one of claims 45 to 64, which is used for treatment.

66. Any of claims 45 to 65, in which cancer is treated without administering an anti-GD2 antibody to the subject. Use as described in item 1.

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