HUMAN MONOCLONAL ANTIBODIES TO PROGRAMMED DEATH LIGAND 1 (PD-L1)

• US 20130122014A1
• Filed: 01/22/2013
• Published: 05/16/2013
• Est. Priority Date: 07/01/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Korman, Alan J., Selby, Mark J., Wang, Changyu, Srinivasan, Mohan, Passmore, David B., Huang, Haichun, Chen, Haibin
• Granted Patent: US 9,102,725 B2
• Time in Patent Office: Days
• US Class Current: 424/143.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6825 Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/10 : Anthelmintics
• 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 37/04 : Immunostimulants
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.

Claims

1. An anti-PD-L1 monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody, or antigen-binding portion thereof, exhibits at least one of the following properties:

(a) binds to human PD-L1 with a K_D of 1×

10<sup>−

7</sup> M or less;

(b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;

(c) increases interferon-γ

production in an MLR assay; and

(d) increases interleukin-2 (IL-2) secretion in an MLR assay.

2. The antibody, or antigen-binding portion thereof, of claim 1, which is a chimeric antibody or antigen-binding portion thereof, a humanized antibody or antigen-binding portion thereof, or a fully human antibody or antigen-binding portion thereof.

4. The antibody, or antigen-binding portion thereof, of claim 1, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 domains;

and a light chain variable region comprising CDR1, CDR2, and CDR3 domains, wherein;

(a) the heavy chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof; and

(b) the light chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof;

wherein the antibody, antigen-binding portion thereof, binds to PD-L1.

5. The antibody, or antigen-binding portion thereof, of claim 4, wherein the heavy chain variable region CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:

31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and

the light chain variable region CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof.

6. The antibody, or antigen-binding portion thereof, of claim 5, wherein the heavy chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:

21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and

the light chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.

7. The antibody, or antigen-binding portion thereof, of claim 1, comprising:

(a) a heavy chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;

(b) a heavy chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;

(c) a heavy chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;

(d) a light chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;

(e) a light chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and

(f) a light chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.

8. The antibody, or antigen binding portion thereof, of claim 1, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

(b) a light chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

9. An isolated nucleic acid molecule encoding the antibody, or antigen-binding portion thereof, of claim 1.

10. A transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses the antibody, or antigen-binding portion thereof, of claim 1.

11. A method of modulating an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 1 such that the immune response in the subject is modulated.

12. A method of inhibiting growth of tumor cells in a subject, comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 1, such that growth of tumor cells in the subject is inhibited.

13. The method of claim 12, wherein the tumor cells are of a cancer selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer.

14. The method of claim 12, wherein the tumor cells are of a cancer selected from the list consisting of bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'"'"'s Disease, non-Hodgkin'"'"'s lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'"'"'s sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

15. A method of treating an infectious disease in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 1 such that the subject is treated for the infectious disease.

16. The method of claim 15, wherein the infectious disease is selected from the list consisting of:

HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, the pathogenic infection by the virus Hepatitis (A, B, &

C), herpes virus, adenovirus, influenza virus, Flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme'"'"'s disease bacteria, pathogenic infection by the fungi Candida, Cryptococcus neoformans, Aspergillus, Genus Mucorales, Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma Bondi, Nippostrongylus brasiliensis.

17. A method of enhancing an immune response to an antigen in a subject, comprising administering to the subject:

(i) the antigen; and

(ii) the antibody, or antigen-binding portion thereof, of claim 1 such that an immune response to the antigen in the subject is enhanced.

18. The method of claim 17, wherein the antigen is a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.

19. A method of treating or preventing an inflammatory disease in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 1 such that the subject is treated for the inflammatory disease.

3. A monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody, or antigen-binding portion thereof, cross-competes for binding to PD-L1 with a reference antibody or reference antigen-binding portion thereof, comprising:

(a) a heavy chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

(b) a light chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

20. A method for preparing an anti-PD-L1 antibody comprising:

(a) providing a nucleic acid encoding an antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 domains; and

a light chain variable region comprising CDR1, CDR2 and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;

the heavy chain variable CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;

the heavy chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;

the light chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;

the light chain variable region CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and

the light chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs;

71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;

(b) altering the nucleic acid encoding at least one amino acid residue within at least one variable region to create a nucleic acid encoding an altered antibody sequence or antigen-binding portion thereof comprising at least one amino acid alteration; and

(c) expressing the altered antibody sequence or antigen-binding portion thereof as a protein.