COMBINATION THERAPY FOR THE TREATMENT OF SOLID AND HEMATOLOGICAL CANCERS

• US 20190309066A1
• Filed: 06/25/2019
• Published: 10/10/2019
• Est. Priority Date: 03/22/2017
• Status: Active Application

• Current Assignee: Arch Oncology, Inc.
• Original Assignee: Arch Oncology, Inc.
• Inventors: MANNING, Pamela T., PURO, Robyn, ALMAGRO, Juan C., KARR, Robert W., CAPOCCIA, Benjamin J.
• Application Number:
  US16/452,432
• Publication Number:
  US 20190309066A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 5/38 of the suprarenal hormones
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/526 : CH3 domain
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/70 : characterized by effect upon binding to a cell or to an antigen
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Methods are provided for using anti-CD47 mAbs as therapeutics for the prevention and treatment of solid and hematological cancers, with other anti-cancer agents, which include but are not limited to proteasome inhibitors, anthracyclines, platinums, taxols, topisomerase inhibitors, anti-metabolites, anti-tumor antibiotics, mitotic inhibitors, and alkylating agents.

Claims

1. A method of treating a cancer comprising administering an effective amount of a monoclonal antibody or antigen-binding fragment thereof to a subject that specifically binds CD47 and comprises:

a variable heavy chain CDR1 amino acid sequence (HCDR1) amino acid sequence set forth in SEQ ID NO;

3;

a variable heavy chain CDR2 amino acid sequence (HCDR2) amino acid sequence set forth in SEQ ID NO;

6;

a variable heavy chain CDR3 amino acid sequence (HCDR3) amino acid sequence set forth in SEQ ID NO;

10;

a variable light chain CDR1 amino acid sequence (LCDR1) amino acid sequence set forth in SEQ ID NO;

14;

a variable light chain CDR2 amino acid sequence (LCDR2) amino acid sequence set forth in SEQ ID NO;

17;

a variable light chain CDR3 amino acid sequence (LCDR3) amino acid sequence set forth in SEQ ID NO;

18, and

a second anti-cancer agent which results in increased immunogenic cell death (ICD) of tumor cells in the subject compared to the administration of a monoclonal antibody or antigen-binding fragment thereof that specifically binds CD47 alone.

2. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof, further comprises a heavy chain variable domain (V_H) and a light chain variable domain (V_L), selected from:

(i) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

51;

(ii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

36 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

52;

(iii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

51;

(iv) a heavy chain variable domain comprising the amino acid sequence SEQ ID NO;

38 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

52;

(v) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

39 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

51; and

(vi) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO;

39 and a light chain variable domain comprising the amino acid sequence SEQ ID NO;

52.

3. The method of claim 2, wherein the monoclonal antibody or antigen-binding fragment thereof further comprises an IgG isotype selected from IgG1, IgG1-N297Q, IgG2, IgG4, IgG4 S228P, and IgG4 PE.

4. The method of claim 3, wherein the monoclonal antibody or antigen fragment thereof further comprises one heavy chain and one light chain selected from:

(i) a heavy chain comprising the amino acid sequence of SEQ ID NO;

81 and a light chain comprising the amino acid sequence SEQ ID NO;

71;

(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO;

81 and a light chain comprising the amino acid sequence SEQ ID NO;

74;

(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence SEQ ID NO;

71;

(iv) a heavy chain comprising the amino acid sequence of SEQ ID NO;

82 and a light chain comprising the amino acid sequence SEQ ID NO;

74;

(v) a heavy chain comprising the amino acid sequence of SEQ ID NO;

83 and a light chain comprising the amino acid sequence SEQ ID NO;

71; and

(vi) a heavy chain comprising the amino acid sequence of SEQ ID NO;

83 and a light chain comprising the amino acid sequence SEQ ID NO;

74

5. The method of claim 4, wherein the monoclonal antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

82 and a light chain comprising the amino acid sequence SEQ ID NO;

71.

6. The method of claim 1, wherein the immunogenic cell death (ICD) characteristics comprise:

a. an increase in adenosine triphosphate (ATP) release; and

b. an increase in cell surface calreticulin expression on human tumor cells.

7. The method of claim 1, wherein the second anti-cancer agent is a proteasome inhibitor.

8. The method of claim 7, wherein the proteasome inhibitor is bortezomib or carfilzomib.

9. The method of claim 1, wherein the second anti-cancer agent is a chemotherapeutic agent.

10. The method of claim 9, wherein the chemotherapeutic agent can be selected from anthracyclines, platinums, taxols, topisomerase inhibitors, anti-metabolites, anti-tumor antibiotics, mitotic inhibitors, and alkylating agents.

11. The method of claim 10, wherein the chemotherapeutic agent is an anthracycline.

12. The method of claim 11, wherein the anthracycline is selected from doxorubicin, epirubicin, daunorubicin, and idarubicin.

13. The method of claim 10, wherein the platinum is selected from oxaliplatin, cisplatin, and carboplatin.

14. The method of claim 10, wherein the taxol is selected from paclitaxel and docetaxel.

15. The method of claim 10, wherein the topoisomerase inhibitor is selected from irinotecan, topotecan, etoposide, and mitoxantrone.

16. The method of claim 10, wherein the anti-metabolite is selected from 5-FU, capecitabine, cytarabine, gemcitabine, and permetrexed.

17. The method of claim 10, wherein the mitotic inhibitor is selected from vinorelibine, vinblastine, and vincristine.

18. The method of claim 11, wherein the alkylating agent is selected from the group consisting of temzolomide.

19. The method of claim 1, wherein the cancer is a leukemia, a lymphoma, multiple myeloma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and a sarcoma.

20. The method of claim 19, wherein said leukemia is systemic mastocytosis, acute lymphocytic (lymphoblastic) leukemia (ALL), T cell—

ALL, acute myeloid leukemia (AML), myelogenous leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative disorder/neoplasm, myelodysplastic syndrome, monocytic cell leukemia, and plasma cell leukemia;

wherein said lymphoma is histiocytic lymphoma and T cell lymphoma, a B cell lymphoma, including Hodgkin'"'"'s lymphoma and non-Hodgkin'"'"'s lymphoma, such as low grade/follicular non-Hodgkin'"'"'s lymphoma (NHL), cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, and Waldenstrom'"'"'s Macroglobulinemia; and

wherein said sarcoma is selected from the group consisting of osteosarcoma, Ewing'"'"'s sarcoma, leiomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, and chrondrosarcoma.

21. The method of claim 1, wherein the cancer is multiple myeloma.

22. The method of claim 8, wherein the cancer is multiple myeloma.