Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, a PD-1 Inhibitor, and/or a PD-L1 Inhibitor

• US 20170239351A1
• Filed: 08/11/2015
• Published: 08/24/2017
• Est. Priority Date: 08/11/2014
• Status: Abandoned Application

• Current Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Original Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Inventors: Hamdy, Ahmed, Rothbaum, Wayne, Izumi, Raquel, Lannutti, Brian, Covey, Todd, Ulrich, Roger, Johnson, Dave, Barf, Tjeerd, Kaptein, Allard
• Application Number:
  US15/503,233
• Publication Number:
  US 20170239351A1
• Time in Patent Office: Days
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• 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 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/3046 Stomach, Intestines
• CPC Class Codes: C07K 16/3061 Blood cells
• CPC Class Codes: C07K 16/3069 : Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

Therapeutic compositions and methods of using the compositions, including combinations of a Bruton'"'"'s tyrosine kinase (BTK) inhibitor, a phosphomositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both y- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ, a programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor, and/or a Janus kinase-2 (JAK-2) inhibitor are described. In certain embodiments, the invention includes therapeutic methods of using a PD-1 monoclonal antibody and a BTK inhibitor. In other embodiments, the invention includes therapeutic methods of using a PD-L1 monoclonal antibody and a BTK inhibitor. In other embodiments, the invention includes therapeutic methods of using a PD-1 inhibitor, a BTK inhibitor, and a PI3K˜δ inhibitor. In other embodiments, the invention includes therapeutic methods of using a PD-L1 inhibitor, a BTK inhibitor, and a PI3K˜δ inhibitor.

Claims

1-59. -59. (canceled)

60. A method of treating a cancer, comprising the steps of co-administering, to a human in need thereof, a therapeutically effective amount of (1) a programmed death 1 (PD-1) inhibitor or a programmed death ligand 1 (PD-L1) inhibitor, or an antigen-binding fragment, variant, conjugate, or biosimilar thereof, and (2) a Bruton'"'"'s tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the BTK inhibitor is selected from the group consisting of:

62. The method of claim 61, further comprising the step of administering to the human a therapeutically effective dose of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ¹³¹I-tositumomab, ibritumomab, ⁹⁰Y-ibritumomab, ¹¹¹In-ibritumomab, ibritumomab tiuxetan, and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, and biosimilars thereof.

63. The method of claim 61, wherein the PD-1 inhibitor is an antibody comprising a heavy chain region comprising SEQ ID NO:

1 and a light chain region comprising SEQ ID NO;

2, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

64. The method of claim 61, wherein the PD-1 inhibitor is an antibody comprising a heavy chain region comprising SEQ ID NO:

12 and a light chain region comprising SEQ ID NO;

14, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

65. The method of claim 61, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain region comprising SEQ ID NO:

21 and a light chain region comprising SEQ ID NO;

22, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

66. The method of claim 61, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain region comprising SEQ ID NO:

53 and a light chain region comprising SEQ ID NO;

54, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

67. The method of claim 61, wherein the PD-L1 inhibitor is an antibody comprising a heavy chain region comprising SEQ ID NO:

61 and a light chain region comprising SEQ ID NO;

62, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

68. The method of claim 61, wherein the PD-1 inhibitor is an anti-PD-1 monoclonal antibody selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

69. The method of claim 61, wherein the PD-L1 inhibitor is an anti-PD-L1 monoclonal antibody selected from the group consisting of durvalumab, atezolizumab, avelumab, or antigen-binding fragments, variants, conjugates, or biosimilars thereof.

70. The method of claim 61, wherein the cancer is a hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin'"'"'s lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin'"'"'s lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt'"'"'s lymphoma, Waldenströ

m'"'"'s macroglobulinemia (WM), Burkitt'"'"'s lymphoma, multiple myeloma (MM), myelodysplastic syndrome, or myelofibrosis.