TREATMENT OF CAR T-CELL TOXICITY

Abstract

The present disclosure relates to methods for improving the safety profile of adoptive cell transfer therapies. In particular, the present disclosure relates to methods for improving the safety profile of CAR T-cell therapies. Disclosed is an anti-CD25 antibody-drug-conjugate for use in a method of treatment or prevention of CAR immune cell toxicity in an individual.

Claims

1.-28. (canceled)

29. A method for treating or preventing CAR immune cell toxicity in an individual, the method comprising administering to the individual an effective amount of an anti-CD25 antibody drug conjugate (ADC).

30. The method according to claim 29, wherein a CAR immune cell has been administered to the individual prior to administration of the ADC.

31. The method according to claim 29, wherein a CAR immune cell has been administered to the individual at least 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 4 weeks, 3 months, 6 months, 12 months, 2 years, or 5 years prior to administration of the ADC.

32. The method according to claim 29, wherein the individual has CAR immune cell toxicity or has been determined to have CAR immune cell toxicity.

33. The method according to claim 29, wherein the individual does not have CAR immune cell toxicity or has not been determined to have CAR immune cell toxicity.

34. The method according to claim 29, wherein the individual had a disorder, or had been determined to have a disorder, wherein the individual has reached complete response (CR) to the disorder or has been determined to have reached complete response (CR) to the disorder.

35. The method according to claim 34, wherein the disorder is selected from the group consisting of: (i) a proliferative disease; (ii) cancer; (iii) a haematological cancer; and (iv) Hodgkin's and non-Hodgkin's Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph−ALL).

36. The method according to claim 29, wherein the anti-CD25 ADC is administered in a dosage regime sufficient to eliminate or inactivate CAR immune cells in the individual.

37. The method according to claim 29, wherein the anti-CD25 ADC is administered as a single dose.

38. The method according to claim 29, wherein the anti-CD25 ADC is administered as two doses.

39. The method according to claim 38, wherein the second dose is administered 1 week or 3 weeks after the first dose.

40. The method according to claim 29, wherein each dose of anti-CD25 ADC is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, or 300 μg/kg.

41. The method according to claim 29, wherein each dose of anti-CD25 ADC is about 1 to 10 μg/kg, 11 to 20 μg/kg, 21 to 30 μg/kg, 31 to 40 μg/kg, 41 to 50 μg/kg, 51 to 60 μg/kg, 61 to 70 μg/kg, 71 to 80 μg/kg, 81 to 90 μg/kg, 91 to 100 μg/kg, 101 to 120 μg/kg, 121 to 140 μg/kg, 141 to 160 μg/kg, 161 to 180 μg/kg, 181 to 200 μg/kg, 201 to 220 μg/kg, 221 to 240 μg/kg, 241 to 260 μg/kg, 261 to 280 μg/kg, or 281 to 300 μg/kg.

42. The method according to claim 29, wherein the individual is human.

43. The method according to claim 29, wherein the CAR immune cell toxicity is one or more disorder selected from the following: (a) Cytokine Release syndrome (CRS), such as elevated IL-6, elevated interferon gamma, elevated tumour necrosis factor, pyrexia, fatigue, nausea, tachycardia, hypotension, dyspnea, shortness of breath, pulmonary edema, or cardiac dysfunction; bh) Neurotoxicity, such as cerebral oedema, confusion, delirium, aphasia, or encephalopathy; (c) Tumour Lysis Syndrome (TLS), such as hyperuricemia, or hyperkalemia; (d) Cellular and/or humoral immune responses, such as anaphylaxis; (e) On-target, off-tumour recognition; or (f) Off-target, off-tumour recognition.

44. The method according to claim 30, wherein the administered CAR immune cell expresses a CAR that specifically binds a tumour associated antigen, and/or the administered CAR immune cell expresses a CAR that specifically binds CD19, CD20, or CD22.

45. The method according to claim 29, wherein the CAR immune cell is a CAR T-cell.

46. The method according to claim 46, wherein the CAR T-cell is a 1st generation CAR T-cell, a 2nd generation CAR T-cell, a 3rd generation CAR T-cell, a 4th generation CAR T-cell, a TRUCK, a smart CAR, or an iCAR.

47. The method according to claim 29, wherein the anti-CD25 ADC is ADCx25, ADCT 301, or Camidanlumab tesirine.

48. The method of claim 29, wherein the ADC is administered in combination with: (i) a therapeutic agent; (ii) a corticosteroid; (iii) dexamethasone; (iv) an IL-6 antagonist; and/or (v) tocilizumab.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0236] Embodiments and experiments illustrating the principles of the disclosure will now be discussed with reference to the accompanying FIGURES in which:

[0237] FIG. 1. Sequences

[0238] The disclosure includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0239] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0240] Aspects and embodiments of the present disclosure will now be illustrated, by way of example, with reference to the accompanying FIGURES. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0241] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0242] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.

SOME EMBODIMENTS

[0243] 1. A method for treating or preventing CAR T-cell toxicity in an individual, the method comprising administering to the individual an effective amount of ADCx25, ADCT 301, or Camidanlumab tesirine.

[0244] 2. An ADC for use in a method of treatment or prevention of CAR T-cell toxicity in an individual, wherein the treatment comprises administration of the ADCx25, ADCT 301, or Camidanlumab tesirine to the individual.

[0245] 3. A pharmaceutical composition comprising ADCx25, ADCT 301, or Camidanlumab tesirine for use in a method of treating or preventing CAR T-cell toxicity in an individual, wherein the treatment comprises administration of ADCx25, ADCT 301, or Camidanlumab tesirine to the individual; optionally wherein the composition comprises a pharmaceutically acceptable excipient

[0246] 4. Use of ADCx25, ADCT 301, or Camidanlumab tesirine in the manufacture of a medicament for treating or preventing CAR T-cell toxicity in an individual, wherein the medicament comprises ADCx25, ADCT 301, or Camidanlumab tesirine, and wherein the treatment comprises administration of the medicament to the individual.

[0247] 5. A kit comprising: [0248] a first medicament comprising ADCx25, ADCT 301, or Camidanlumab tesirine; [0249] a package insert comprising instructions for administration of the first medicament to an individual for the treatment or prevention of CAR T-cell toxicity.

[0250] 6. The method, ADC, use, or kit according to any previous paragraph, wherein a CAR T-cell has been administered to the individual prior to administration of the ADC.

[0251] 7. The method, ADC, use, or kit according to any preceding paragraph, wherein the individual has CAR T-cell toxicity or has been determined to have CAR T-cell toxicity.

[0252] 8. The method, ADC, use, or kit according to any preceding paragraph, wherein the individual had cancer, or had been determined to have cancer, wherein the individual has reached complete response (CR) or has been determined to have reached complete response (CR).

[0253] 9. The method, ADC, use, or kit according to any preceding paragraph, wherein the ADC is administered as a single dose, or two separate doses.

[0254] 10. The method, ADC, use, or kit according to paragraph 17, wherein the second dose is administered 1 week or 3 weeks after the first dose.

[0255] 11. The method, ADC, use, or kit according to any preceding paragraph, wherein each dose is about 1 to 10 μg/kg, 11 to 20 μg/kg, 21 to 30 μg/kg, 31 to 40 μg/kg, 41 to 50 μg/kg, 51 to 60 μg/kg, 61 to 70 μg/kg, 71 to 80 μg/kg, 81 to 90 μg/kg, 91 to 100 μg/kg, 101 to 120 μg/kg, 121 to 140 μg/kg, 141 to 160 μg/kg, 161 to 180 μg/kg, 181 to 200 μg/kg, 201 to 220 μg/kg, 221 to 240 μg/kg, 241 to 260 μg/kg, 261 to 280 μg/kg, or 281 to 300 μg/kg.

[0256] 12. The method, ADC, use, or kit according to any previous paragraph, wherein the individual is human.

[0257] 13. The method, ADC, use, or kit according to any previous paragraph, wherein the CAR immune cell toxicity is one or more disorder selected from the following: [0258] (a) Cytokine Release syndrome (CRS), such as elevated IL-6, elevated interferon gamma, elevated tumour necrosis factor, pyrexia, fatigue, nausea, tachycardia, hypotension, dyspnea, shortness of breath, pulmonary edema, or cardiac dysfunction; [0259] (b) Neurotoxicity, such as cerebral oedema, confusion, delirium, aphasia, or encephalopathy; [0260] (c) Tumour Lysis Syndrome (TLS), such as hyperuricemia, or hyperkalemia; [0261] (d) Cellular and/or humoral immune responses, such as anaphylaxis; [0262] (e) On-target, off-tumour recognition; or [0263] (f) Off-target, off-tumour recognition.

[0264] 14. The method, ADC, use, or kit according to any previous paragraph wherein the administered CAR immune cell expresses a CAR that specifically binds CD19, CD20, or CD22.

[0265] 15. A method, ADC, use, or kit according to any previous paragraph, wherein the ADC is administered in combination with a corticosteroid such as dexamethasone, and/or an IL-6 antagonist such as tocilizumab.

STATEMENTS OF INVENTION

[0266] 1. A method for treating or preventing CAR immune cell toxicity in an individual, the method comprising administering to the individual an effective amount of an ADC.

[0267] 2. An ADC for use in a method of treatment or prevention of CAR immune cell toxicity in an individual, wherein the treatment comprises administration of the ADC to the individual.

[0268] 3. A pharmaceutical composition comprising an ADC for use in a method of treating or preventing CAR immune cell toxicity in an individual, wherein the treatment comprises administration of the ADC to the individual; optionally wherein the composition comprises a pharmaceutically acceptable excipient

[0269] 4. Use of an ADC in the manufacture of a medicament for treating or preventing CAR immune cell toxicity in an individual, wherein the medicament comprises an ADC, and wherein the treatment comprises administration of the medicament to the individual.

[0270] 5. A kit comprising: [0271] a first medicament comprising an ADC; [0272] a package insert comprising instructions for administration of the first medicament to an individual for the treatment or prevention of CAR immune cell toxicity.

[0273] 6. The method, ADC, use, or kit according to any previous paragraph, wherein a CAR immune cell has been administered to the individual prior to administration of the ADC.

[0274] 7. The method, ADC, use, or kit according to paragraph 6, wherein a CAR immune cell has been administered to the individual at least 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 4 weeks, 3 months, 6 months, 12 months, 2 years, or 5 years prior to administration of the ADC.

[0275] 8. The method, ADC, use, or kit according to any preceding paragraph, wherein the individual has CAR immune cell toxicity or has been determined to have CAR immune cell toxicity.

[0276] 9. The method, ADC, use, or kit according to any one of paragraphs 1 to 8, wherein the individual does not have CAR immune cell toxicity or has not been determined to have CAR immune cell toxicity.

[0277] 10. The method, ADC, use, or kit according to any preceding paragraph, wherein the individual had a disorder, or had been determined to have a disorder, wherein the individual has reached complete response (CR) to the disorder or has been determined to have reached complete response (CR) to the disorder.

[0278] 11. The method, ADC, use, or kit according to paragraph 10, wherein the disorder is a proliferative disease.

[0279] 12. The method, ADC, use, or kit of paragraph 10, wherein the disorder is cancer.

[0280] 13. The method, ADC, use, or kit of paragraph 10, wherein the cancer is a haematological cancer.

[0281] 14. The method, ADC, use, or kit of paragraph 10, wherein the disorder is selected from the group comprising: Hodgkin's and non-Hodgkin's Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph−ALL).

[0282] 15. The method, ADC, use, or kit according to any preceding paragraph, wherein the ADC is administered in a dosage regime sufficient to eliminate or inactivate CAR immune cells in the individual.

[0283] 16. The method, ADC, use, or kit according to any preceding paragraph, wherein the ADC is administered as a single dose.

[0284] 17. The method, ADC, use, or kit according to any one of paragraphs 1 to 15, wherein the ADC is administered as two doses.

[0285] 18. The method, ADC, use, or kit according to paragraph 17, wherein the second dose is administered 1 week after the first dose.

[0286] 19. The method, ADC, use, or kit according to paragraph 17, wherein the second dose is administered 3 weeks after the first dose.

[0287] 20. The method, ADC, use, or kit according to any preceding paragraph, wherein each dose is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, or 300 μg/kg.

[0288] 21. The method, ADC, use, or kit according to any preceding paragraph, wherein each dose is about 1 to 10 μg/kg, 11 to 20 μg/kg, 21 to 30 μg/kg, 31 to 40 μg/kg, 41 to 50 μg/kg, 51 to 60 μg/kg, 61 to 70 μg/kg, 71 to 80 μg/kg, 81 to 90 μg/kg, 91 to 100 μg/kg, 101 to 120 μg/kg, 121 to 140 μg/kg, 141 to 160 μg/kg, 161 to 180 μg/kg, 181 to 200 μg/kg, 201 to 220 μg/kg, 221 to 240 μg/kg, 241 to 260 μg/kg, 261 to 280 μg/kg, or 281 to 300 μg/kg.

[0289] 22. The method, ADC, use, or kit according to any previous paragraph, wherein the individual is human.

[0290] 23. The method, ADC, use, or kit according to any previous paragraph, wherein the CAR immune cell toxicity is one or more disorder selected from the following: [0291] (g) Cytokine Release syndrome (CRS), such as elevated IL-6, elevated interferon gamma, elevated tumour necrosis factor, pyrexia, fatigue, nausea, tachycardia, hypotension, dyspnea, shortness of breath, pulmonary edema, or cardiac dysfunction; [0292] (h) Neurotoxicity, such as cerebral oedema, confusion, delirium, aphasia, or encephalopathy; [0293] (i) Tumour Lysis Syndrome (TLS), such as hyperuricemia, or hyperkalemia; [0294] (j) Cellular and/or humoral immune responses, such as anaphylaxis; [0295] (k) On-target, off-tumour recognition; or [0296] (l) Off-target, off-tumour recognition.

[0297] 24. The method, ADC, use, or kit according to any previous paragraph wherein the administered CAR immune cell expresses a CAR that specifically binds a tumour associated antigen.

[0298] 25. The method, ADC, use, or kit according to paragraph 24, wherein the administered CAR immune cell expresses a CAR that specifically binds CD19, CD20, or CD22.

[0299] 26. The method, ADC, use, or kit according to any previous paragraph, wherein the CAR immune cell is a CAR T-cell.

[0300] 27. The method, ADC, use, or kit according to paragraph 26, wherein the CAR T-cell is a 1.sup.st generation CAR T-cell, a 2.sup.nd generation CAR T-cell, a 3.sup.rd generation CAR T-cell, a 4.sup.th generation CAR T-cell, a TRUCK, a smart CAR, or an iCAR.

[0301] 28. A method, ADC, use, or kit according to any previous paragraph, wherein the ADC is an anti-CD25 ADC.

[0302] 29. A method, ADC, use, or kit according to paragraph 28, wherein the anti-CD25 ADC is ADCx25, ADCT 301, or Camidanlumab tesirine.

[0303] 30. A method, ADC, use, or kit according to any previous paragraph, wherein the ADC is administered in combination with a therapeutic agent.

[0304] 31. A method, ADC, use, or kit according to paragraph 30, wherein the therapeutic agent is a corticosteroid such as dexamethasone, or an IL-6 antagonist such as tocilizumab.

EXAMPLES

Example 1: In Vitro Demonstration of CAR T-Cell Killing on Treatment with an Anti-CD25 ADC

[0305] CAR-T cells are placed in culture with appropriate aliquots [suggested range of 1 μg/ml to 1 pg/ml] of CD25-ADC to confirm binding of the ADC to CD25 on the CAR-T cell surface, and to determine that killing of the CAR-T cells occurs upon release of the PBD moiety from the ADC.

Example 2: In Vivo Treatment of Acute CAR-T Toxicity

[0306] A patient treated with CD19 CAR-T exhibits acute toxicity within few hours of administration of CAR-T: shortness of breath, confusion, hypotension. The patient is transferred to ICU for general management of consequences of “cytokine storm” and specifically for treatment with tocilizumab.

[0307] The patient's condition does not improve despite receiving tocilizumab and intensive care. Administration of CD25-ADC [suggested range 10-50 μg/kg] leads to significant improvement of patient's status, and to eventual full recovery from acute toxic effects of CAR-T administration. Complete elimination of CAR-T cells is confirmed by FACS analysis of patient's blood.

Example 3: In Vivo Treatment of Chronic CAR-T Toxicity

[0308] A patient treated with CD19 CAR-T is considered to be good responder to CAR-T treatment.

[0309] Several weeks after cessation of CAR-T dosing, the patient experiences symptoms consistent with chronic depletion of CD-19 positive B-cells. FACS analysis reveals significant clonal expansion of CD19/CD25 positive T-cells. It is determined that depletion of B-cells in this patient is most likely caused by clonal expansion of CD25 positive CAR-T cells.

[0310] Administration of CD25-ADC [suggested range 10-50 μg/kg] leads to significant improvement of patient's status, and to eventual full recovery from chronic toxic effects of CAR-T administration. Complete elimination of CAR-T cells is confirmed by FACS analysis of patient's blood.