METHODS OF TREATING SKIN CANCER BY ADMINISTERING A PD-1 INHIBITOR

• US 20170327590A1
• Filed: 05/12/2017
• Published: 11/16/2017
• Est. Priority Date: 05/13/2016
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: LOWY, Israel, SIMS, Tasha N., FURY, Matthew G.
• Granted Patent: US 10,457,725 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 2039/545 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 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39575 against materials from other living beings excluding bacteria and viruses, e.g. protozoa, fungi, plants
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 51/1045 against animal or human tumor cells or tumor cell determinants
• CPC Class Codes: A61N 2005/0604 Lungs and/or airways
• CPC Class Codes: A61N 2005/0605 Ear
• CPC Class Codes: A61N 2005/0606 Mouth
• CPC Class Codes: A61N 2005/0607 Nose
• CPC Class Codes: A61N 2005/0608 Rectum
• CPC Class Codes: A61N 2005/0609 Stomach and/or esophagus
• CPC Class Codes: A61N 2005/061 Bladder and/or urethra
• CPC Class Codes: A61N 2005/0611 Vagina
• CPC Class Codes: A61N 2005/1098 Enhancing the effect of the particle by an injected agent or implanted device
• CPC Class Codes: A61N 5/06 using light
• CPC Class Codes: A61N 5/0603 : for treatment of body cavities
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/3053 : Skin, nerves, brain
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention provides methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., skin cancer). The methods of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of a programmed death 1 (PD-1) antagonist (e.g., an anti-PD-1 antibody). In certain embodiments, the skin cancer is cutaneous squamous cell carcinoma or basal cell carcinoma.

Claims

1. A method of treating or inhibiting the growth of a tumor comprising:

(a) selecting a patient with a skin cancer; and

(b) administering to the subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds PD-1;

wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO;

1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

2.

2. The method of claim 1, wherein the anti-PD-1 antibody is administered as a monotherapy.

3. The method of claim 1, wherein said skin cancer is an UV-associated skin cancer.

4. The method of claim 1, wherein said skin cancer is selected from the group consisting of cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma and melanoma.

5. The method of claim 1, with the proviso that said skin cancer is not a squamous cell carcinoma of head and neck.

6. The method of claim 1, wherein said skin cancer is a metastatic, unresectable and/or locally advanced cancer.

7. The method of claim 6, wherein said skin cancer is BCC, and wherein said patient is intolerant to or progresses after treatment with a hedgehog pathway inhibitor.

8. The method of claim 6, wherein said skin cancer is CSCC, and wherein said patient is intolerant to or progresses after prior treatment with an anti-cancer therapy.

9. The method of claim 8, wherein said skin cancer is metastatic CSCC, and wherein said patient has been treated with at least one prior systemic anti-cancer therapy selected from the group consisting of surgery, radiation, chemotherapy, and another anti-PD-1 antibody.

10. The method of claim 8, wherein said skin cancer is locally advanced CSCC, and wherein said patient is not amenable to curative surgery.

11. The method of claim 1, wherein the anti-PD-1 antibody is administered as one or more doses, wherein each dose is administered 0.5 to 4 weeks after the immediately preceding dose.

12. The method of claim 11, wherein each dose is administered 2 weeks after the immediately preceding dose.

13. The method of claim 11, wherein each dose is administered 3 weeks after the immediately preceding dose.

14. The method of claim 11, wherein each dose comprises 1, 3 or 10 mg/kg of patient'"'"'s body weight.

15. The method of claim 14, wherein each dose comprises 3 mg/kg of the patient'"'"'s body weight.

16. The method of claim 11, wherein each dose comprises 50-600 mg of the anti-PD-1 antibody.

17. The method of claim 16, wherein each dose comprises 200, 250 or 350 mg of the anti-PD-1 antibody.

18. The method of claim 8, wherein the anti-PD-1 antibody is administered as one or more doses wherein each dose is administered 0.5 to 4 weeks after the immediately preceding dose.

19. The method of claim 18, wherein each dose comprises 1, 3 or 10 mg/kg of the patient'"'"'s body weight.

20. The method of claim 18, wherein each dose comprises 50-600 mg of the anti-PD-1 antibody.

21. The method of claim 1, wherein the subject is resistant or inadequately responsive to, or relapsed after prior therapy.

22. The method of claim 1, wherein the administration leads to at least one effect selected from the group consisting of inhibition of tumor growth, tumor regression, reduction in the size of a tumor, reduction in tumor cell number, delay in tumor growth, abscopal effect, inhibition of tumor metastasis, reduction in metastatic lesions over time, reduced use of chemotherapeutic or cytotoxic agents, reduction in tumor burden, increase in progression-free survival, increase in overall survival, complete response, partial response, and stable disease.

23. The method of claim 1 further comprising administering to the subject an additional therapeutic agent or therapy, wherein the additional therapeutic agent or therapy is selected from the group consisting of surgery, radiation, a chemotherapeutic agent, a cancer vaccine, a programmed death ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG3) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor, a T-cell immunoglobulin and mucin-domain containing-3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a bispecific anti-CD3/anti-CD20 antibody, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFβ

) inhibitor, a CD38 inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, granulocyte-macrophage colony-stimulating factor (GM-CSF), cyclophosphamide, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-15, an antibody-drug conjugate, an anti-inflammatory drug, and a dietary supplement.

24. The method of claim 1, wherein the anti-PD-1 antibody is administered intravenously, subcutaneously, or intraperitoneally.

25. The method of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:

3;

HCDR2 comprises the amino acid sequence of SEQ ID NO;

4;

HCDR3 comprises the amino acid sequence of SEQ ID NO;

5;

LCDR1 comprises the amino acid sequence of SEQ ID NO;

6;

LCDR2 comprises the amino acid sequence of SEQ ID NO;

7; and

LCDR3 comprises the amino acid sequence of SEQ ID NO;

8.

26. The method of claim 22, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:

1 and the LCVR comprises the amino acid sequence of SEQ ID NO;

2.

27. The method of claim 1, wherein the anti-PD-1 antibody comprises a HCVR with 90% sequence identity to SEQ ID NO:

1.

28. The method of claim 1, wherein the anti-PD-1 antibody comprises a LCVR with 90% sequence identity to SEQ ID NO:

2.

29. The method of claim 1, wherein the anti-PD-1 antibody comprises a HCVR with 90% sequence identity to SEQ ID NO:

1 and a LCVR with 90% sequence identity to SEQ ID NO;

2.

30. The method of claim 1, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

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

10.