Dosing Strategy that Mitigates Cytokine Release Syndrome for Therapeutic Antibodies

• US 20200129617A1
• Filed: 08/30/2019
• Published: 04/30/2020
• Est. Priority Date: 08/31/2018
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Brownstein, Carrie, Lowy, Israel, Adriaens, Lieve Lucille
• Granted Patent: US 11,590,223 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/7051 : T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2866 : against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment

Abstract

Administration regimens for therapeutic proteins (e.g., T cell-activating bispecific antibodies) that mitigate cytokine release syndrome and infusion-related reaction are disclosed. The methods employ initial fractional dosing with optional administration of additional agents such as steroids or cytokine antagonists that are discontinued with maximal weekly dosing over the course of the dosing regimen.

Claims

1. A method of administering a therapeutic protein to a subject in a dosing regimen to mitigate adverse effects of cytokine release syndrome or infusion-related reaction, comprising:

administering fractions of a primary dose (D1) of the therapeutic protein in week 1 of the dosing regimen, wherein the primary dose comprises no more than 10 mg of the therapeutic protein, a first dose fraction (F1D1) comprises 40% to 60% of the total primary dose and is administered to the subject on day 1 of week 1, and a second dose fraction (F2D1) comprises the remaining 40% to 60% of the total primary dose and is administered to the subject from 12 to 96 hours following administration of the F1D1;

administering fractions of a secondary dose (D2) of the therapeutic protein in week 2 of the dosing regimen, wherein the secondary dose is no more than one-half of a maximum weekly dose of the therapeutic protein, a first dose fraction (F1D2) comprises 40 to 60% of the total secondary dose, a second dose fraction (F2D2) comprises the remaining 40% to 60% of the total secondary dose, and the F2D2 is administered to the subject from 12 to 96 hours following administration of the F1D2 during week 2 of the dosing regimen; and

administering the maximum weekly dose of the therapeutic protein to the subject as a single dose in a subsequent week of the dosing regimen.

2. The method of claim 1, wherein the F2D1 is administered to the subject from 24 to 96 hours following administration of the F1D1, or from 18 to 72 hours following administration of the F1D1.

4. The method of claim 1, wherein the F2D2 is administered to the subject from 24 to 96 hours following administration of the F1D2, or from 18 to 72 hours following administration of the F1D2.

6. The method of claim 1, wherein the subsequent week is week 3 of the dosing regimen, the subsequent week is week 4 of the dosing regimen, or the subsequent week is week 14 of the dosing regimen.

10. The method of claim 1, further comprising:

administering fractions of a tertiary dose (D3) of the therapeutic protein in week 3 of the dosing regimen, wherein the tertiary dose is no less than one-half of the maximum weekly dose of the therapeutic protein and no more than the maximum weekly dose of the therapeutic protein, a first dose fraction (F1D3) comprises 40% to 60% of the total tertiary dose, a second dose fraction (F2D3) comprises the remaining 40% to 60% of the total tertiary dose, and the F2D3 is administered to the subject from 12 to 96 hours following administration of the F1D3 during week 3 of the dosing regimen; and

administering the maximum weekly dose of the therapeutic protein to the subject as a single dose in a subsequent week of the dosing regimen.

11. The method of claim 10, wherein the F2D3 is administered to the subject from 24 to 96 hours following administration of the F1D3, or from 18 to 72 hours following administration of the F1D3.

13. The method of claim 10, wherein the subsequent week is week 4 of the dosing regimen, the subsequent week is any one of weeks 4 to 36 of the dosing regimen, or the tertiary dose is administered as a single dose in weeks 4 to 12 of the dosing regimen.

18. The method of claim 1, wherein the maximum weekly dose of the therapeutic protein is administered to the subject as a single dose during a weekly phase of the dosing regimen.

19. The method of claim 1, further comprising administering the maximum weekly dose of the therapeutic protein to the subject as a single dose once every two weeks, one every three weeks, or one every four weeks during a maintenance phase of the dosing regimen, which follows completion of a weekly phase of the dosing regimen, wherein the maximum weekly dose is from 80 mg to 320 mg.

24. The method of claim 1, wherein the primary dose (D1) is 1 mg.

25. The method of claim 1, wherein the secondary dose (D2) is 20 mg.

26. The method of claim 10, wherein the tertiary dose is 40 mg, 80 mg, 160 mg, or 320 mg.

30. The method of claim 1, wherein the F1D1 comprises 50% of the total primary dose, and the F2D1 comprises 50% of the total primary dose.

31. The method of claim 1, wherein the F1D2 comprises 50% of the total secondary dose, and the F2D2 comprises 50% of the total secondary dose.

32. The method of claim 10, wherein the F1D3 comprises 50% of the total tertiary dose, and the F2D3 comprises 50% of the total tertiary dose.

33. The method of claim 1, wherein the maximum weekly dose of the therapeutic protein is from 5 mg to 320 mg.

35. The method of claim 1, wherein the maximum weekly dose is 80 mg, 160 mg, or 320 mg.

39. The method of claim 1, wherein the subject has been diagnosed with a cancer.

40. The method of claim 39, wherein the cancer is a B-cell malignancy.

41. The method of claim 40, wherein the B-cell malignancy is a CD20+ B-cell malignancy.

42. The method of claim 40, wherein the cancer is non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, primary mediastinal B-cell lymphoma, lymphoblastic lymphoma, or Waldenstrom macroglobulinemia.

43. The method of claim 1, wherein the subject has been diagnosed with follicular lymphoma (FL).

44. The method of claim 43, wherein the FL is grade 1-3a.

45. The method of claim 1, wherein the subject has been diagnosed with diffuse large B-cell lymphoma (DLBCL).

46. The method of claim 45, wherein the subject has failed prior CAR-T therapy.

47. The method of claim 1, wherein the subject has been diagnosed with mantle cell lymphoma (MCL).

48. The method of claim 47, wherein the subject has failed prior Bruton tyrosine kinase (BTK) inhibitor therapy.

49. The method of claim 1, wherein the subject has been diagnosed with marginal zone lymphoma (MZL).

50. The method of claim 39, wherein the cancer is selected from pancreatic carcinoma, head and neck cancer, prostate cancer, malignant gliomas, osteosarcoma, colorectal cancer, gastric cancer, malignant mesothelioma, multiple myeloma, ovarian cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, melanomaglioma, breast cancer, squamous cell carcinoma, esophageal cancer, clear cell renal cell carcinoma, chromophobe renal cell carcinoma, oncocytoma, transitional cell carcinoma, urothelial carcinoma, bladder adenocarcinoma, or bladder small cell carcinoma.

52. The method of claim 1, wherein the therapeutic protein is an antibody or an antigen-binding fragment thereof.

54. The method of claim 52, wherein the antibody is a bispecific antibody or antigen-binding fragment thereof.

55. The method of claim 54, wherein a first antigen-binding arm of the bispecific antibody or antigen-binding fragment binds to a T-cell antigen.

56. The method of claim 55, wherein the T-cell antigen is CD3, or CD28.

58. The method of claim 54, wherein a second antigen-binding arm of the bispecific antibody or antigen-binding fragment binds to a tumor cell antigen, or binds to a tumor cell antigen selected from the group consisting of AFP, ALK, BAGE proteins, BCMA, BIRC5 (survivin), BIRC7, β

-catenin, brc-abl, BRCA1, BORIS, CA9, carbonic anhydrase IX, caspase-8, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD40, CD70, CDK4, CEA, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE proteins (e.g., GAGE-1, -2), GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, LMP2, MAGE proteins (e.g., MAGE-1, -2, -3, -4, -6, and -12), MART-1, mesothelin, ML-IAP, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1, NA17, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, STEAP1, STEAP2, TAG-72, TGF-β

, TMPRSS2, Thompson-nouvelle antigen (Tn), TRP-1, TRP-2, tyrosinase, and uroplakin-3.

60. The method of claim 58, wherein the tumor cell antigen is CD20.

61. The method of claim 60, wherein the bispecific antibody is an anti-CD20×

anti-CD3 antibody.

62. The method of claim 61, wherein the anti-CD20×

anti-CD3 antibody is REGN1979, or an antibody comprising the HCVRs/LCVRs of REGN1979, or an antibody comprising the CDRs of REGN1979.

63. The method of claim 58, wherein:

(a) the tumor cell antigen is BCMA;

(b) the bispecific antibody is an anti-BCMA×

anti-CD3 antibody;

(c) the tumor cell antigen is PSMA;

(d) the bispecific antibody is an anti-PSMA×

anti-CD3 antibody;

(e) the tumor cell antigen is MUC16;

(f) the bispecific antibody is an anti-MUC16×

anti-CD3 antibody;

(g) the tumor cell antigen is STEAP2;

or

(h) the bispecific antibody is an anti-STEAP2×

anti-CD3 antibody.

71. The method of claim 1, wherein the therapeutic protein is maintained at a serum concentration at or above about 2000 mcg/L, at or above about 2600 mcg/L, or at least about 3700 mcg/L following administration of the maximum weekly dose for the duration of the dosing regimen.

74. The method of claim 1, wherein the therapeutic protein is administered to the subject in combination with a second agent selected from a steroid, an anti-histamine, acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), an IL-6 antagonist, or an IL-6R antagonist.

75. The method of claim 74, wherein the steroid is dexamethasone, or the NSAID is indomethacin.

78. The method of claim 75, wherein the dexamethasone is administered to the subject about one to three hours prior to at least one of the F1D1, the F2D1, the F1D2, the F2D2, the F1D3, and the F2D3.

79. The method of claim 74, wherein the IL-6 antagonist is an anti-IL-6 antibody, or the IL-6R antagonist is an anti-IL-6R antibody, or the anti-IL-6R antagonist is sarilumab.

81. The method of claim 74, wherein administration of the second agent is eliminated following a first administration of the maximum weekly dose for the duration of the dosing regimen.

82. The method of claim 1, wherein the therapeutic protein is administered to the subject in combination with a second therapeutic agent, wherein the second therapeutic agent comprises at least one of rituximab, obinutuzumab, cyclophophamide, doxorubicin, vincristine, prednisone, prednisolone, bendamustine, lenalidomide, chlorambucil, ibritumomab tiuxetan, idelalisib, copanlisib, duvelisib, etoposide, methylprednisolone, cytarabine, cisplatin, mesna, ifosfamide, mitoxantrone, and procarbazine.

90. The method of claim 39, wherein the subject has been treated previously with an anti-cancer therapy.

91. The method of claim 90, wherein the subject is refractory to previous treatment or has relapsed after previous treatment.

92. The method of claim 41, wherein the subject has previously been treated with an anti-CD20 antibody therapy.

95. The method of claim 1, wherein the incidence of grade 3 CRS and IRR is less than 10%.

96. The method of claim 95, wherein the incidence of grade 3 CRS and IRR is less than 7.5% or less than 7%.

99. The method of claim 92, wherein the anti-CD20 antibody therapy comprises rituximab.

3. (canceled)

5. (canceled)

7-9. -9. (canceled)

12. (canceled)

14-17. -17. (canceled)

20-23. -23. (canceled)

27-29. -29. (canceled)

34. (canceled)

36-38. -38. (canceled)

51. (canceled)

53. (canceled)

57. (canceled)

59. (canceled)

64-70. -70. (canceled)

72-73. -73. (canceled)

76-77. -77. (canceled)

80. (canceled)

83-89. -89. (canceled)

93-94. -94. (canceled)

97-98. -98. (canceled)