PREVENTION OR ALLEVIATION OF T-CELL ACTIVATOR-ASSOCIATED ADVERSE EVENTS

Claims

1. The use of a T cell activator in the manufacture of a medicinal product for the treatment of a disease in an individual, said treatment comprising: (a) administering to the individual a T cell activator, and (b) administering an NLRP3 inhibitor to the individual.

2. The use according to claim 1, wherein the administration of the NLRP3 inhibitor is intended to prevent or alleviate an adverse event associated with the administration of the T cell activator.

3. Use of an NLRP3 inhibitor in the manufacture of a medicinal product for the prevention or amelioration of an adverse event associated with the administration of a T cell activator.

4. The use according to any of the preceding paragraphs, wherein the NLRP3 inhibitor is MCC950 or a derivative thereof.

5. The use according to any one of the preceding paragraphs, wherein the NLRP3 inhibitor is selected from the group consisting of MCC950, selnoflast, emlenoflast, CY-09, IZD334, IZD174, DFV890, IFM-632, IFM-514, JT194, JT349, NT-0167, NT-0796, NT-0249, VENT-01, VTX3232, VTX2735, BT032, BT132, OLT1177, ADS-032, ZYIL1, HY209, AC-201, AC-203 and tranilast.

6. The use according to any of the preceding paragraphs, wherein (administration of) the NLRP3 inhibitor causes inhibition of an adverse event associated with the administration of a T cell activator.

7. The use according to any of the preceding paragraphs, wherein (administration) of the NLRP3 inhibitor does not cause inhibition of the desired effect associated with the administration of the T cell activator.

8. Use according to claim 6 or 7, wherein the inhibition is complete inhibition or clinically significant and / or statistically significant inhibition.

9. Use according to any of paragraphs 2-8, wherein the undesirable effect is: (i) cytokine release syndrome (CRS); (ii) fever, hypotension and / or hypoxia; and / or (iii) an elevated serum level of one or more cytokines, in particular one or more cytokines selected from the group consisting of IL-1β, IL-6 and IL-8.

10. The use according to any one of claims 2-9, wherein the administration of the NLRP3 inhibitor is carried out upon (clinical) manifestation of an adverse event (in an individual).

11. The use according to any of the preceding paragraphs, wherein the administration of the NLRP3 inhibitor occurs: (i) before, simultaneously and / or after administration of a T cell activator; (ii) periodically or continuously; and / or (iii) orally or parenterally, in particular intravenously.

12. The use according to any of the preceding paragraphs, wherein the administration of the NLRP3 inhibitor is associated with the first administration of the T cell activator, and does not necessarily occur before, simultaneously and / or after the first administration of the T cell activator.

13. The use according to any of the preceding paragraphs, wherein the administration of the T-cell activator is carried out: (i) in an effective dose; (ii) parenterally, in particular intravenously; and / or (iii) as the first administration of a T cell activator to an individual.

14. The use according to any of the preceding paragraphs, wherein the T cell activator is a T cell bispecific antibody or a CAR-T cell.

15. The use according to claim 14, wherein the T-cell bispecific antibody binds to CD3 and the target cell antigen.

16. The use according to claim 14 or 15, wherein the T-cell bispecific antibody comprises an antigen-binding fragment that binds to CD3 and an antigen-binding fragment that binds to an antigen of a target cell.

17. The use according to claim 15 or 16, wherein the target cell antigen is CD20.

18. The use according to claim 17, wherein the T-cell bispecific antibody comprises: (i) a first antigen-binding fragment that binds to CD3 and comprises a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9; and (ii) a second antigen-binding fragment that binds to CD20 and comprises a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 14, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 15, LCDR2 of SEQ ID NO: 16, and LCDR3 of SEQ ID NO:

17.

19. The use according to claim 17 or 18, wherein the T-cell bispecific antibody comprises a third antigen-binding fragment that binds to CD20 and / or an Fc domain consisting of a first and second subunits.

20. The use according to any one of paragraphs 17-19, wherein the T-cell bispecific antibody comprises: (i) a first antigen-binding fragment that binds to CD3, comprising a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, wherein the first antigen-binding fragment is a crossover Fab molecule in which either the variable or constant regions of a Fab light chain and a Fab heavy chain are exchanged; (ii) a second and a third antigen-binding fragment that binds to CD20, comprising a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 14, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 15, LCDR2 of SEQ ID NO: 16, and LCDR3 of SEQ ID NO: 17, wherein each of the second and third antigen-binding fragments is a Fab molecule, in particular a standard Fab molecule; (iii) the Fc domain, consisting of the first and second subunits, wherein the second antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen-binding fragment, and the first antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.

21. Use according to any of paragraphs. 17-20, wherein the first antigen-binding fragment of the T-cell bispecific antibody comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10, and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11, and / or the second and (if present) third antigen-binding fragment of the T-cell bispecific antibody comprise a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

19.

22. Use according to any of paragraphs. 17-21, wherein the first antigen-binding fragment of the T-cell bispecific antibody is a crossover Fab molecule in which the variable regions of the Fab light chain and the Fab heavy chain are replaced, and wherein the second and (if present) third antigen-binding fragment of the T-cell bispecific antibody is a standard Fab molecule in which in the CL constant domain the amino acid at position 124 is independently replaced by lysine (K), arginine (R) or histidine (H) (Kabat numbering) and the amino acid at position 123 is independently replaced by lysine (K), arginine (R) or histidine (H) (Kabat numbering), and in the CH1 constant domain the amino acid at position 147 is independently replaced by glutamic acid (E) or aspartic acid (D) (numbering in accordance with the EU index according to Kabat) and the amino acid at position 213 independently replaced by glutamic acid (E) or aspartic acid (D) (numbering according to the EU index according to Kabat).

23. The use or method according to any one of claims 19-22, wherein the Fc domain of the T-cell bispecific antibody comprises a modification that facilitates the association of the first and second subunits of the Fc domain, and / or the Fc domain comprises one or more amino acid substitutions that reduce binding to the Fc receptor and / or effector function.

24. The use according to any one of claims 14-23, wherein the T-cell bispecific antibody is glofitamab.

25. The use according to any of the preceding claims, wherein the disease (to be treated with the T-cell activator) is a cancer, in particular a cancer expressing the target cell antigen of the T-cell activator.

26. The use according to claim 25, wherein the cancer is: (i) CD20-expressing cancer, (ii) B-cell carcinoma, and / or (iii) selected from the group consisting of non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

27. A method for treating a disease in an individual, said method comprising: (a) administering to the individual a T cell activator, and (b) administering an NLRP3 inhibitor to the individual.

28. The method of claim 27, wherein the administration of the NLRP3 inhibitor is intended to prevent or alleviate an adverse event associated with the administration of the T cell activator.

29. A method for preventing or alleviating an adverse event associated with the administration of a T cell activator to an individual, comprising administering to the individual an NLRP3 inhibitor.

30. The method according to any one of claims 27-29, wherein the NLRP3 inhibitor is MCC950 or a derivative thereof.

31. The method according to any one of claims 27-30, wherein the NLRP3 inhibitor is selected from the group consisting of MCC950, selnoflast, emlenoflast, CY-09, IZD334, IZD174, DFV890, IFM-632, IFM-514, JT194, JT349, NT-0167, NT-0796, NT-0249, VENT-01, VTX3232, VTX2735, BT032, BT132, OLT1177, ADS-032, ZYIL1, HY209, AC-201, AC-203 and tranilast.

32. The method according to any one of claims 27-31, wherein (administration) of the NLRP3 inhibitor causes inhibition of an adverse event associated with the administration of a T cell activator.

33. The method according to any one of claims 27-32, wherein (administration) of the NLRP3 inhibitor does not cause inhibition of the desired effect associated with the administration of the T cell activator.

34. The method according to claim 32 or 33, wherein the inhibition is complete inhibition or clinically significant and / or statistically significant inhibition.

35. The method according to any one of paragraphs 28-34, wherein the undesirable phenomenon is: (i) cytokine release syndrome (CRS); (ii) fever, hypotension and / or hypoxia; and / or (iii) an elevated serum level of one or more cytokines, in particular one or more cytokines selected from the group consisting of IL-1β, IL-6 and IL-8.

36. The method according to any one of claims 28-35, wherein the administration of the NLRP3 inhibitor is carried out upon (clinical) manifestation of an adverse event (in an individual).

37. The method according to any one of claims 27-36, wherein the administration of the NLRP3 inhibitor occurs: (i) before, simultaneously and / or after administration of a T cell activator; (ii) periodically or continuously; and / or (iii) orally or parenterally, in particular intravenously.

38. The method according to any one of claims 27-37, wherein the administration of the NLRP3 inhibitor is associated with the first administration of the T cell activator, and optionally occurs before, simultaneously with and / or after the first administration of the T cell activator.

39. The method according to any one of paragraphs 27-38, wherein the administration of the T-cell activator is carried out: (i) in an effective dose; (ii) parenterally, in particular intravenously; and / or (iii) as the first administration of a T cell activator to an individual.

40. The method according to any one of claims 27-39, wherein the T cell activator is a T cell bispecific antibody or a CAR-T cell.

41. The method according to claim 40, wherein the T-cell bispecific antibody binds to CD3 and an antigen of the target cell.

42. The method according to claim 40 or 41, wherein the T-cell bispecific antibody comprises an antigen-binding fragment that binds to CD3 and an antigen-binding fragment that binds to an antigen of a target cell.

43. The method according to claim 41 or 42, wherein the target cell antigen is CD20.

44. The method according to claim 43, wherein the T-cell bispecific antibody comprises: (i) a first antigen-binding fragment that binds to CD3 and comprises a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9; and (ii) a second antigen-binding fragment that binds to CD20 and comprises a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 14, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 15, LCDR2 of SEQ ID NO: 16, and LCDR3 of SEQ ID NO:

17.

45. The method according to claim 43 or 44, wherein the T-cell bispecific antibody comprises a third antigen-binding fragment that binds to CD20 and / or an Fc domain consisting of a first and second subunits.

46. The method according to any one of claims 43-45, wherein the T-cell bispecific antibody comprises: (i) a first antigen-binding fragment that binds to CD3, comprising a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, wherein the first antigen-binding fragment is a crossover Fab molecule in which either the variable or constant regions of a Fab light chain and a Fab heavy chain are exchanged; (ii) a second and a third antigen-binding fragment that binds to CD20, comprising a heavy chain variable region comprising a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 14, and a light chain variable region comprising a light chain CDR (LCDR) 1 of SEQ ID NO: 15, LCDR2 of SEQ ID NO: 16, and LCDR3 of SEQ ID NO: 17, wherein each of the second and third antigen-binding fragments is a Fab molecule, in particular a standard Fab molecule; (iii) the Fc domain, consisting of the first and second subunits, wherein the second antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen-binding fragment, and the first antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen-binding fragment is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.

47. The method according to any of paragraphs. 43-46, wherein the first antigen-binding fragment of the T-cell bispecific antibody comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10, and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11, and / or the second and (if present) third antigen-binding fragment of the T-cell bispecific antibody comprise a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

19.

48. The method according to any of paragraphs. 43-47, wherein the first antigen-binding fragment of the T-cell bispecific antibody is a crossover Fab molecule in which the variable regions of the Fab light chain and the Fab heavy chain are replaced, and wherein the second and (if present) third antigen-binding fragment of the T-cell bispecific antibody is a standard Fab molecule in which in the CL constant domain the amino acid at position 124 is independently replaced by lysine (K), arginine (R) or histidine (H) (Kabat numbering) and the amino acid at position 123 is independently replaced by lysine (A), arginine (R) or histidine (H) (Kabat numbering), and in the CH1 constant domain the amino acid at position 147 is independently replaced by glutamic acid (E) or aspartic acid (D) (numbering in accordance with the EU index according to Kabat) and the amino acid at position 213 independently replaced by glutamic acid (E) or aspartic acid (D) (numbering according to the EU index according to Kabat).

49. The method according to any one of claims 45-48, wherein the Fc domain of the T-cell bispecific antibody comprises a modification that facilitates the association of the first and second subunits of the Fc domain, and / or the Fc domain comprises one or more amino acid substitutions that reduce binding to the Fc receptor and / or effector function.

50. The method according to any one of claims 40-49, wherein the T-cell bispecific antibody is glofitamab.

51. The method according to any one of claims 27-50, wherein the disease (to be treated with the T cell activator) is a cancer, in particular a cancer expressing a target cell antigen of the T cell activator.

52. The method according to claim 51, wherein the cancer is: (i) CD20-expressing cancer, (ii) B-cell carcinoma, and / or (iii) selected from the group consisting of non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).