ANTI-PD-1 ANTIBODY AND USE THEREOF

• US 20160272708A1
• Filed: 02/26/2014
• Published: 09/22/2016
• Est. Priority Date: 06/26/2013
• Status: Active Grant

• Current Assignee: Junmeng Biosciences Co., Ltd.
• Original Assignee: Junmeng Biosciences Co., Ltd., Shanghai Junshi Biosciences Inc.
• Inventors: CHEN, Bo
• Granted Patent: US 10,066,013 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• 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 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• 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 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

This invention provides antibodies or functional fragments thereof that bind to PD-1 with high affinity. The invention provides nucleic acid molecules encoding the antibodies or the fragments thereof according to the present invention, expression vectors and host cells for expressing the antibodies or the functional fragments thereof according to the present invention, as well as methods for producing the antibodies or the functional fragments thereof according to the present invention. The present invention also provides immunoconjugates and pharmaceutical compositions comprising the antibodies or the functional fragments thereof according to the present invention. The present invention additionally provides methods for treating a plurality of diseases (comprising cancers, infectious diseases and inflammatory diseases) by using the antibodies or the functional fragments thereof disclosed herein.

Claims

1. An antibody or a functional fragment thereof that can bind to the programmed cell death 1 (PD-1) protein and comprises a heavy-chain comprising a heavy-chain complementarity-determining region (CDR) having an amino acid sequence selected from the group consisting of SEQ ID NO:

1, 2, 3, 7, 8, 9, 13, 14 and 15, and/or a light-chain comprising a light-chain CDR having an amino acid sequence selected from the group consisting of SEQ ID NO;

4, 5, 6, 10, 11, 12, 16, 17 and 18.

2. The antibody or functional fragment thereof according to claim 1, wherein:

the amino acid sequences of CDR1, CDR2 and CDR3 of said heavy chain CDR are selected from any of the following groups of amino acid sequences;

3. The antibody or functional fragment thereof according to claim 1, whose amino acid sequences of CDR1, CDR2 and CDR3 of the heavy chain and CDR1, CDR2 and CDR3 of the light chain are selected from any of the following groups of amino acid sequences;

4. The antibody or functional fragment thereof according to claim 1, which comprises a variable region of the heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO:

19, 21 and 23 or a variant having at least 95% sequence identity with SEQ ID NO;

19, 21 or 23, and/or a variable region of the light chain having an amino acid sequence selected from the group consisting of SEQ ID NO;

20, 22, 24, and a variant having at least 95% sequence identity with SEQ ID NO;

20, 22, or 24.

5. The antibody or functional fragment thereof according claim 4, wherein said variable region of the heavy chain is SEQ ID NO:

19 or a variant that has at least 95% sequence identity with SEQ ID NO;

19, and said variable region of the light chain is SEQ ID NO;

20 or a variant that has at least 95% sequence identity with SEQ ID NO;

20, or

wherein said variable region of the heavy chain is SEQ ID NO;

21 or a variant that has at least 95% sequence identity with SEQ ID NO;

21 and said variable region of the light chain is SEQ ID NO;

22 or a variant that has at least 95% sequence identity with SEQ ID NO;

22, or

wherein said variable region of the heavy chain is SEQ ID NO;

23 or a variant that has at least 95% sequence identity with SEQ ID NO;

23 and said variable region of the light chain is SEQ ID NO;

24 or a variant that has at least 95% sequence identity with SEQ ID NO;

24.

6. The antibody or functional fragment thereof according to claim 1, wherein the antibody or functional fragment thereof is a chimeric antibody, a humanized antibody or a fully human antibody.

7. The antibody or functional fragment thereof according to claim 1, comprising a variable region of the heavy chain having a sequence selected from the group consisting of SEQ ID NO:

33, 35, 36, and a variant that has at least 95% sequence identity with SEQ ID NO;

33, 35, or 36, and/or a variable region of the light chain having a sequence selected from the group consisting of SEQ ID NO;

34, 37, and a variant that has at least 95% sequence identity with SEQ ID NO;

33, 35, or 36.

8. The antibody or functional fragment thereof according to claim 1, wherein said variable region of the heavy chain is SEQ ID NO:

33 or a variant that has at least 95% sequence identity with SEQ ID NO;

33 and said variable region of the light chain is SEQ ID NO;

34 or a variant that has at least 95% sequence identity with SEQ ID NO;

34;

or

wherein said variable region of the heavy chain is SEQ ID NO;

35 or a variant that has at least 95% sequence identity with SEQ ID NO;

35 and said variable region of the light chain is SEQ ID NO;

34 or a variant that has at least 95% sequence identity with SEQ ID NO;

34 or

wherein said variable region of the heavy chain is SEQ ID NO;

36 or a variant that has at least 95% sequence identity with SEQ ID NO;

36 and said variable region of the light chain is SEQ ID NO;

34 or a variant that has at least 95% sequence identity with SEQ ID NO;

34 or

wherein said variable region of the heavy chain is SEQ ID NO;

35 or a variant that has at least 95% sequence identity with SEQ ID NO;

35 and said variable region of the light chain is SEQ ID NO;

37 or a variant that has at least 95% sequence identity with SEQ ID NO;

37.

9. A isolated nucleic acid molecule, which encodes said antibody or functional fragment thereof according to claim 1.

10. An expression vector, which comprises said nucleic acid molecule according to claim 9.

11. A host cell, which comprises said expression vector according to claim 10.

12. A method of producing an anti-PD-1 antibody or a functional fragment thereof comprising:

culturing a host cell according to claim 11 under conditions that allow production of said antibody or functional fragment thereof, and recovering said antibody or functional fragment thereof so produced.

13. An immunoconjugate, comprising said antibody or functional fragment thereof according to claim 1 that is coupled with a therapeutic agent, wherein said therapeutic agent is a toxin, radioisotope, drug, or cytotoxic agent.

14. A pharmaceutical composition comprising the antibody or functional fragment thereof according to claim 1 and a pharmaceutical carrier.

15. A method used to prevent or treat diseases or conditions through removing, inhibiting or lowering the activity of PD-1, which comprises administration of effective treatment dose of the antibody or functional fragment thereof according to claim 1 or a pharmaceutical composition comprising the antibody or functional fragment thereof to a subject in need, where said diseases or conditions are selected from the group consisting of cancers, infectious diseases or inflammatory diseases, said cancers are preferably selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, esophagus cancer, small intestinal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, chronic or acute leukemia which includes acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors during childhood, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system vegetation, primary central nervous system lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi'"'"'s sarcoma, epidermoid carcinoma, squamous cell cancer, T cell lymphoma, environmentally induced cancers which include those induced by asbestos and the combination of said cancers, said infectious diseases are preferably selected from HIV, influenza, herpes, giardiasis, malaria, leishmaniasis, pathogenic infections caused by the following viruses:

hepatitis viruses (hepatitis A, B and C), herpes virus (such as VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, polio virus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infections by the following bacteria;

chlamydia, rickettsia, mycobacteria, staphylococcus, streptococcus, pneumococcus, meningococcus and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, tuberculosis, cholera, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease bacteria, pathogenic infections by the following fungi;

Candida (Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, aspergillus (fumigatus, aspergillus niger, etc.), genus of Mucor (mucor, absidia, rhizopus), Sporothrix schenckii, dermatitis yeast bud, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, pathogenic infections by the following parasites;

Entamoeba histolytica, Colon balantidium, fernando'"'"'s worms, amoeba spine, suction blow Giardia, cryptosporidium, Pneumocystis carinii, P. vivax, voles Babesia, Trypanosoma brucei, Cruz trypanosoma, Leishmania donovani, Toxoplasma gondii and Nippostrongylus brasiliensis, said inflammatory diseases are preferably selected from acute disseminated encephalomyelitis, Addison'"'"'s disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, arthritis, Behcet'"'"'s disease, bullous blistering day sores, celiac disease, Chagas disease, Crohn'"'"'s disease, dermatomyositis, type-1 diabetes, pulmonary hemorrhage—

nephritic syndrome, graft versus host disease, Graves'"'"' disease, Guillain-Barre syndrome, Hashimoto'"'"'s disease, hyperimmunoglobulin E syndrome, idiopathic thrombocytopenic purpura, lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis disease, rheumatoid arthritis, Sjogren'"'"'s syndrome, temporal arteritis, vasculitis and Wegener'"'"'s granulomatosis.