Anti-pd-1 antibody and use thereof

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.

1 - 14 . (canceled) 
     
     
         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-11, 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-I 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.
 wherein the antibody or a functional fragment thereof that can bind to the programmed cell death 1 (PD-1) protein having an amino acid sequence of SEQ ID NO: 43, wherein the antibody or a functional fragment thereof comprises: 
 i) a heavy chain CDR1 having the amino acid sequence of Asp Tyr Glu Met His (SEQ ID NO: 1), 
 ii) a heavy chain CDR2 having the amino acid sequence of Val Ile Glu Ser Glu Thr Gly Thr Ala Tyr Asn Gin Lys Phe Lys (SEQ ID NO: 2), 
 iii) a heavy chain CDR3 having the amino acid sequence of Glu Gly Ile Thr Val Ala Thr Tyr Trp Tyr Phe Asp Val (SEQ ID NO: 3), 
 iv) a light chain CDR1 having the amino acid sequence of Arg Ser Gin Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu (SEQ ID NO: 10), 
 v) a light chain CDR2 having the amino acid sequence of Lys Val Ser Asn Arg Phe Ser (SEQ ID NO: 11), and 
 vi) a light chain CDR3 having the amino acid sequence of Phe Gin Gly Ser His Val Pro Leu Thr (SEQ ID NO: 12). 
 
     
     
         16 . The method of  claim 15 , wherein the antibody or a functional fragment thereof comprises:
 (i) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 19, or an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 19, and/or   (ii) a light chain variable region having the amino acid sequence of SEQ ID NO: 22, or an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 22.   
     
     
         17 . The method of  claim 15 , wherein the antibody or functional fragment thereof is a chimeric antibody or a humanized antibody. 
     
     
         18 . The method of  claim 15 , wherein the antibody or functional fragment thereof comprises:
 i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that has at least 95% sequence identity with SEQ ID NO: 35, and/or   ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 37 or an amino acid sequence that has at least 95% sequence identity with SEQ ID NO: 37.   
     
     
         19 . The method of  claim 15 , wherein the antibody or functional fragment thereof comprises
 (i) a heavy chain variable region comprising SEQ ID NO: 35 or an amino acid sequence that has at least 95% sequence identity with SEQ ID NO: 35 and   (ii) a light chain variable region comprising SEQ ID NO: 37 or an amino acid sequence that has at least 95% sequence identity with SEQ ID NO: 37.   
     
     
         20 . The method of  claim 15 , wherein the antibody or functional fragment thereof is coupled with a therapeutic agent, wherein said therapeutic agent is a toxin, radioisotope, drug, or cytotoxic agent.