CN1461310B - 结合人白介素-18的抗体及制备和使用方法 - Google Patents

结合人白介素-18的抗体及制备和使用方法 Download PDF

Info

Publication number
CN1461310B
CN1461310B CN018077358A CN01807735A CN1461310B CN 1461310 B CN1461310 B CN 1461310B CN 018077358 A CN018077358 A CN 018077358A CN 01807735 A CN01807735 A CN 01807735A CN 1461310 B CN1461310 B CN 1461310B
Authority
CN
China
Prior art keywords
antibody
antigen
binding portion
human
place
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN018077358A
Other languages
English (en)
Other versions
CN1461310A (zh
Inventor
T·哈于尔
R·W·迪克松
M·罗古斯卡
M·怀特
B·拉布科夫斯基
J·萨菲尔德
A·R·敦坎
S·M·布洛克勒胡尔斯特
J·曼科维奇
C·P·索尔罗克
J·E·汤普森
S·N·伦纳德
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22665007&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1461310(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Publication of CN1461310A publication Critical patent/CN1461310A/zh
Application granted granted Critical
Publication of CN1461310B publication Critical patent/CN1461310B/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Reproductive Health (AREA)
  • Pulmonology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)

Abstract

本发明提供结合人白介素-18(hIL-18)的抗体、尤其是结合人IL-18表位的抗体。所述抗体可以是例如完整的人抗体、重组抗体或单克隆抗体。优选抗体对hIL-18具有高亲和力并且在体外和体内均中和hIL-18活性。本发明的抗体可以全长抗体或其抗原结合部分。本发明也提供本发明抗体的制备方法和应用方法。本发明的抗体或抗体部分可用来检测hIL-18和可用来抑制hIL-18活性，例如抑制罹患其中hIL-18活性是有害的疾病的病人体内的hIL-18活性。

Description

结合人白介素-18的抗体及制备和使用方法
相关申请 
本申请要求于2000年2月10日申请的、题目是“结合人白介素-18的抗体及制备和使用方法”的美国临时专利申请顺序号60/181,608的非临时专利申请的优先权，该专利申请的内容通过引用结合到本文中。另外，整个本申请引用的包括参考文献、授予的专利和公布的专利申请的所有引用参考文献的内容均通过引用结合到本文中。 
发明背景 
白介素-18(IL-18)最早于1989年被描述为干扰素-γ诱导因子(IGIF)，它是除了能够诱导干扰素γ外还具有各种功能的促炎细胞因子。这些生物学特性包括激活NF-κb、Fas配体表达、诱导CC趋化因子和CXC趋化因子以及增加产生感受态人免疫缺陷病毒。 
由于IL-18能够诱导T细胞和巨噬细胞内产生干扰素γ，因此它在Th1型免疫应答中起重要作用且参与先天性免疫和获得性免疫。IL-18在结构和功能上与IL-1家族有关。有关IL-18结构、功能和生物活性的综述，参见例如Dinarello，C.等(1998)J.Leukoc.Biol. 63：658-654；Dinarello，C.A.(1999)Methods 19：121-132和Dinarello，C.A.(1999)J.Allergy Clin.Immunol.103：11-24。 
特别需要调节各种各样的人免疫应答中的IL-18。具体来说，与IL-18结合并中和IL-18的抗体是特别理想的。此外，由于存在小鼠抗体给予人体的相关问题，例如血清半寿期短、不能触发某些人类效应子功能并且在人体内诱发针对小鼠抗体不需要的免疫应答(“人抗小鼠抗体”(HAMA)反应)，因此小鼠IL-18抗体的体内应用受到限 制。 
一般而言，尝试克服与将完全小鼠抗体用于人类相关的问题，已经涉及对所述抗体进行基因工程改造以使其更“人样化(human-like)”。例如，已经制备出这样的嵌合抗体：其中所述抗体链的可变区来源于小鼠，而所述抗体链的恒定区来源于人(Junghans等(1990)Cancer Res.50：1495-1502；Brown等(1991)Proc.Natl.Acad.Sci.88：2663-2667；Kettleborough等(1991)Protein Engineering.4：773-783)。然而，因为这些嵌合人源化抗体仍保留某些小鼠序列，所以它们仍可能诱发不需要的免疫反应、人抗嵌合抗体(HAMA)反应，当长期给予时情况尤其如此。 
针对小鼠抗体或其衍生物(例如嵌合抗体或人源化抗体)的优选IL-18抑制剂将完全是人抗IL-18抗体，由于这样的药物不会诱发HAMA反应，因此即使长期应用也不会诱发HAMA反应。然而，这样的抗体本领域尚未见介绍，因此仍然需要这样的抗体。 
发明概述 
本发明涉及结合人IL-18的诸如抗体的化合物以及制备和应用这类化合物或抗体的方法。 
一方面，本发明涉及能够结合人IL-18氨基酸序列或其部分的化合物，其中所述氨基酸包含SEQ ID NO：70或SEQ ID NO：71提供的人IL-18的N末端部分或C末端部分。在一个实施方案中，所述化合物是一种小分子、肽、多肽、抗体或抗体片段，例如完全人抗体或片段。 
另一方面，本发明涉及能够与人IL-18结合的人单克隆抗体或其抗原结合部分。在其它实施方案，根据表面等离子体共振(surface plasmon resonance)测定，所述抗体或其片段与人IL-18解离的koff速率常数为0.1s-1或以下、1x 10E-2 s-1或以下、1x 10E-3 s-1或以下、1x 10E-4 s-1或以下、1x 10E-5 s-1或以下、1x 10E-6 s-1或以下； 或者抑制人IL-18活性的IC50为1x 10E-6或以下、1x 10E-7或以下、1x 10E-8或以下、1x 10E-9或以下、1x 10E-10或以下、或1x 10E-11或以下。 
另一方面，本发明涉及这样的分离抗体或其抗原结合部分：它结合包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)或二者任何一个的一部分的人IL-18表位。所述抗体最好是中和抗体。所述抗体最好是人抗体。在各种实施方案中，所述抗体是重组抗体(例如单链抗体(scFv))或单克隆抗体。 
在其它实施方案中，所述分离抗体或其抗原结合部分与人IL-18表位或二者任何一个的一部分结合，其中根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为0.1s-1或以下；或者其抑制人IL-18活性的IC50为1x 10-6M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-2s-1或以下；或者抑制人IL-18活性的IC50为1x 10-7M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分可以与人IL-18解离，其koff速率常数为1x 10-3s-1或以下；或者可以抑制人IL-18活性，其IC50为1x 10-8M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-4s-1或以下；或者抑制人IL-18活性的IC50为1x 10-9M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-5s-1或以下；或者抑制人IL-18活性的IC50为1x 10-10M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-6s-1或以下；或者抑制人IL-18活性的IC50为1x 10-11M或以下。 
本发明的另一方面涉及含有能够结合IL-18表位的至少一个可变区CDR结构域的分离的人抗体或其抗原结合部分。在相关实施方案中，所述分离抗体或其抗原结合部分的可变区含有如表6或表9所 示的重链和/或轻链CDR1结构域、CDR2结构域或CDR3结构域，所述结构域可以在表7-8和表10-11中所示的任一Kabat位置上或邻近所述位置具有例如一个或多个氨基酸取代或***。在一个优选实施方案中，所述分离抗体或其抗原结合部分含有一个含氨基酸序列SEQ ID NO：29的轻链可变区(LCVR)和一个含氨基酸序列SEQ ID NO：26的重链可变区(HCVR)。在另一个优选实施方案中，所述分离抗体或其抗原结合部分含有一个具有氨基酸序列SEQ ID NO：29的轻链可变区(LCVR)和一个具有氨基酸序列SEQ ID NO：27的重链可变区(HCVR)。 
本发明的另一方面涉及包含本发明的抗体或其抗原结合部分和药学上可接受的载体的药用组合物。在一个实施方案中，所述药用组合物还包含至少一种另外的治疗其中IL-18活性是有害的疾病的治疗药物。 
本发明的另一方面涉及制备结合人白介素-18(IL-18)的抗体的方法。本发明提供的方法包括将抗体库(antibody repertoire)暴露于包含含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)或二者任何一个的一部分的人IL-18表位的抗原；并且从所述抗体库选择结合包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQID NO：33)或者二者任何一个的一部分的人IL-18表位的抗体。 
在一个实施方案中，所述抗体库是动物体内的体内抗体库，所述方法包括用包含以下组分的抗原免疫所述动物：包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQID NO：33)的人IL-18表位、人IL-18的N末端部分或C末端部分(SEQID NO：70-71)或这些表位中任一表位的一部分。在另一个实施方案中，所述抗体库是重组抗体文库，所述方法包括用含有以下组分的抗原筛选所述文库：具有氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)的人IL-18表位、SEQ ID NO： 31-32和SEQ ID NO：34-60表示的肽或任一前述组分的一部分。所述文库最好是人抗体文库。 
另一方面，本发明提供编码任一上述方面的抗体(例如重链和/或轻链可变区)或其部分的分离核酸。在相关实施方案中，所述编码抗IL-18抗体或其部分的分离核酸位于重组表达载体中，例如在宿主细胞中表达。 
因此，另一方面，本发明涉及采用已经导入所述重组表达载体中的前述宿主细胞合成结合人IL-18的抗体的方法，所述方法包括在培养基中培养所述宿主细胞直到所述细胞合成结合人IL-18的抗体。 
本发明的另一方面涉及抑制人IL-18活性的方法，所述方法包括将人IL-18与本发明的抗体或其抗原结合部分接触，使得人IL-18活性被抑制。 
本发明的再一方面涉及抑制罹患其中人IL-18活性是有害的疾病的病人体内的人IL-18活性的方法，所述方法包括给予所述病人本发明的抗体或其抗原结合部分，使得所述病人体内的人IL-18活性被抑制。在一个实施方案中，可以例如在给予另外的药物之前、同时或之后，给予所述抗IL-18抗体，所述另外的药物例如抗IL-12抗体或其抗原结合片段、氨甲蝶呤、抗TNF抗体或其抗原结合片段、皮质类固醇、环孢菌素、雷帕霉素、FK506或非甾体消炎药。 
附图简述 
图1显示与IL-1β(左)和IL1RA(右)相比的IL-18(中间)的结构模型。 
图2显示与IL-18受体复合的IL-18的结构模型，其中IL-18的包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)的肽表位以深灰色表示。该肽表位被抗IL-18抗体2E1结合。 
图3显示与IL-18受体复合的IL-18的结构模型，其中IL-18的包含氨基酸VIRNLNDQVLFIDQ(SEQ ID NO：33)的肽表位以深灰色 表示。该肽表位被抗IL-18抗体LT28结合。 
图4显示与IL-18受体复合的全长IL-18的结构模型。球形浅灰色和深灰色表位代表IL-18的N末端和C末端接触表位(分别为SEQID NO：70和71)。 
图5显示三种不同的抗IL-18抗体中和IL-18的生物效应的效价与抑制KG1细胞内IFN-γ诱导作用的关系。抗体125H(方框)和2E1IgG抗体(圆形)或2E1单链抗体(三角形)的IC50值分别为2.1E-10、9.0E-10和3.3E-9。 
发明详述 
本发明涉及选择能够对IL-18介导的信号转导产生中和作用的抗体的肽表位、制备抗这些表位的抗体以及这些抗体的应用，包括用来治疗涉及IL-18的疾病。选择表位的策略必须构建IL-18蛋白及其相应的受体的同源性模型。然后组合应用目测和计算估计选择用于合成和抗体产生的代表性肽区段。本文所示的氨基酸序列运用标准单字母缩写代码。 
IL-18表位的选择
运用程序Modeler(Sali，A.等，通过MODELLER评价比较性蛋白质建模(Evaluation of comparative protein modeling by MODELLER)。Proteins：Struct.，Funct.，Genet.(1995)，23(3)，第318-26页。CODEN：PSFGEY；ISSN：0887-3585)产生用于IL-18和IL-18受体两者的同源性模型。IL-1β(Priestle，J.等，人白介素-1β的三维结构精确到2.0.ANG.分辨率(The three-dimensional structure of human interleukin-1.beta.refined to 2.0.ANG.resolution)。Prog.Clin.Biol.Res.(1990)，349(Cytokines Lipocortins Inflammation Differ.)，第297-307页)和IL-1RA(Schreuder，H.等，白介素-1受体拮抗剂的精细晶体结构：二硫键和顺式脯氨酸的存在(Refined crystal structure of the interleukin-1 receptor antagonist：presence of a disulfide link and a cis-proline)。Eur.J.Biochem.(1995))，227(3)，第838-47页)的X射线晶体结构是可得到的并且用作IL-18模型构建的参考坐标。应用IL-1受体结构(Viger，G.等，与白介素-1β复合的I型白介素-1受体的晶体结构(Crystal structure of thetype-1 interleukin-1-receptor complexed with interleukin-1.beta)。Nature(London)(1997)，386(6621)，第190-194页)对IL-18受体建模。 
下文进一步描述IL-18和IL-18受体的结构模型建立。 
IL-18模型建立
与所述两种蛋白质(即IL-1β和IL-18)的总体序列同源性低，然而，令人信服的证据是IL-18是IL-1家族成员(参见Dinarello，C.A.IL-18：一种TH1诱导型促炎细胞因子及IL-1家族新成员(IL-18：aTH1-inducing，proinflammatory cytokine and new member of the IL-1family)。J.Allergy Clin.Immunol.(1999))，103(1，Pt.1)，第11-24页)，并且总体蛋白质折叠非常相似。和IL-1β一样，IL-18最初以前体形式分泌出来。前体IL-1β(pro-IL-1β)和前体IL-18(pro-IL-18)两者均被IL-1β转化酶(ICE)激活(Fantuzzi，G.和Dinarello，C.A.白介素-18和白介素-1β：ICE(caspase-1)的两种细胞因子底物(Interleukin-18 andInterleukin-1β：two cytokine substrates for ICE(caspase-1))。J.Clin.Immunol.(1999))，19(1)，第1-11页)。还知道IL-1受体和IL-18受体相似(Dinarello，C.A.等，白介素-18的综述：不止是一种干扰素γ诱导因子(Overview of interleukin-18：more than an interferon-γinducingfactor)。J.Leukocyte Biol.(1998)，63(6)，658-664)。IL-1β能够与IL-18受体结合。虽然这两种蛋白质间的总体序列同源性和IL-18的序列同源性相同，但是作为最终论证，IL-1β和IL-1RA显示出相同的折叠。对这三种蛋白质(即IL-18、IL-1β和IL1-RA)间的序列比对运用程序InsightII人工进行。该序列比对可以参见表1： 
表1：IL-18与IL-1β和IL-1RA的序列比对 
Figure DEST_PATH_GWB00000013830100091
  H96   A，R，E，Q，S，Y，V，H，P，W，or C
  H97   A，R，E，Q，S，Y，V，H，P，W，or C
  H98   A，R，E，Q，S，Y，V，H，P，W，or C
  H99   A，R，E，Q，S，Y，V，H，P，W，or C
  H100   A，R，E，Q，S，Y，V，H，P，W，or C
  H100a   A，R，E，Q，S，Y，V，H，P，W，or C
  H101   A，R，E，Q，S，Y，V，H，P，W，or C
  H102   A，R，E，Q，S，Y，V，H，P，W，or C
[0155] 表11.引入LT28的轻链氨基酸取代 
如上所述引入取代。然后对得自每个诱变反应的多个代表性克隆测序，并将代表来自亲代LT28单链抗体序列改变的那些克隆在细菌中表达，然后将其纯化，供如下所述的进一步测试用。 
实施例3 
人抗体与IL-18的结合活性
采用BIAcore***(Pharmacia Biosensor，Piscataway，NJ)，通过表面等离子体共振(SPR)，测定配体(固定在生物传感器基体上的生物素化重组人IL-18(rhIL-18))和分析物(抗体溶液)之间的实时结合相互作用。所述***利用SPR的光学性能检测葡聚糖生物传感器基体中的蛋白质浓度改变。使蛋白质以已知浓度与所述葡聚糖基体共价结合。将抗体通过所述葡聚糖基体注入，在注入抗体和固定配体间的特异性结合导致基体蛋白质浓度增加和SPR信号产生变化。SPR信号变化以共振单位(RU)记录，并相对于时间沿sensorgram的y轴显示。 
为了有利于将生物素化rhIL-18固定在生物传感器基体上，首先用100mM N-羟基琥珀酰亚胺(NHS)和400mM N-乙基-N’-(3-二乙基氨基丙基)碳二亚胺盐酸盐(EDC)，使链霉抗生物素蛋白通过游离氨基与所述基体共价连接。接下来，穿过所述活化基体注入链霉抗生物素蛋白。穿过所述活化生物传感器注入35μl在乙酸钠、pH 4.5中稀释的链霉抗生物素蛋白(25μg/ml)，所述蛋白上的游离胺直接与所述活化羧基结合。未反应的基体EDC-酯通过注射1M乙醇胺而去活化。另外，链霉抗生物素蛋白偶联的生物传感器芯片是可商业性获得的(Pharmacia BR-1000-16，Pharmacia Biosensor，Piscataway，NJ)。 
生物素化rhIL-18如下制备：首先将5.0mg生物素(D-生物素基-ε-氨基己酸N-羟基琥珀酰亚胺酯；Boehringer Mannheim Cat.No.1008960)溶于500μl二甲亚砜中，制备10mg/ml溶液。每毫升rhIL-18加入10μl生物素(2.65mg/ml)，生物素与rhIL-18的摩尔比为2∶1。将反应物温和地混合，然后于室温下避光孵育2小时。将PD-10柱子Sephadex G-25M(Pharmacia Catalog No.17-0851-01)用25ml冷PBS平衡，然后每个柱子上样2ml rhIL-18-生物素。用10x1ml冷PBS洗脱所述柱子。收集流分，然后在OD280读数(1.0 OD＝1.25mg/ml)。合并合适流分，然后于-80℃贮藏待用。 
将需通过链霉抗生物素蛋白固定在所述基体上的生物素化rhIL-18在补充0.05％(BIAcore)表面活性剂P20(Pharmacia BR-1000-54，Pharmacia Biosensor，Piscataway，NJ)的PBS运行缓冲液(Gibco Cat.No.14190-144，Gibco BRL，Grand Island，NY)中稀释。为了测定rhIL-18特异性抗体结合固定化rhIL-18的能力，如下进行结合测定。等份生物素化rhIL-18(25nM；10μl等份样品)以流速5μl/min注射通过链霉抗生物素蛋白偶联的葡聚糖基体。注入所述蛋白之前和不久以后，PBS缓冲液单独流过每个流式测定池。在基线和完成生物素化rhIL-18注入后约30秒之间信号的净差值代表结合值。测定直接与固定生物素化rhIL-18结合的rhIL-18特异性抗体。将抗体(20μg/ml)在PBS运行缓冲液中稀释，将25μl等份样品以流速5μl/min注射通过所述固定化蛋白质基体。注入抗体之前和不久以后，PBS缓冲液单独流过每个流式测定池。在基线信号和完成抗体注入后的信号的净差值代表所述特定样品的结合值。在注入下一个样品前，生物传感器基体用100mM HCl再生。为了测定解离速率(Koff)常数、缔合速率(Kon)常数、缔合速率(Ka)常数和解离速率(Kd)常数，运用BIAcore动力学评价软件(version 2.1)。 
与亲代抗体2E1和LT28(和小鼠对照)相比，改进候选抗IL-18抗体与生物素化rhIL-18结合的代表性结果示于下表12中。为了比较，也包括基于细胞的中和测定的IC50值，这些均在实施例4中有描述。所有克隆均作为单链Fv抗体制备，用以采用Biacore分析进行测试，基于细胞的测定如下所述。列出的亲代克隆包含未突变的亲代重链和轻链，而单链突变体含有一条亲代链和一条突变链，其中所述突变链以重(H)链或轻(L)链显示，其后氨基酸取代的Kabat位置和性质。 
表12.来源于2E1和LT28的抗IL-18抗体的结合 
Figure G01807735819950825D000441
*某些数值为与亲代相比改进的倍数。 
                    实施例4 
            抗IL-18抗体的中和活性
为了检查本发明的抗人IL-18抗体的中和活性，使用本领域公知的测定来监测IL-18活性。 
概括地讲，所述测定利用按照标准技术培养的KG1细胞(ATCC#CCL-246，髓性白血病骨髓细胞)(例如使用RPMI 1640培养基Gibco#21870-076；(补充10％胎牛血清(BioWhittaker#14-501F)；2mM L谷氨酰胺(Gibco#25030-081)；50单位/ml青霉素，50μg/ml链霉素(Gibco#15070-063)和075％碳酸氢钠)。 
为了测试对IL-18的中和作用，用20ng/ml hTNF-α(Lot#19130132)刺激的3x10E5 KG-1细胞与50μl抗IL-18抗体(4x Conc.)和50μl IL-18(4xConc.＝8ng/ml)一起孵育并且于37℃孵育1小时或16-20小时。为了测定随诱导的hIFN-γ产生而发生中和作用的IL-18含量，采用市售Elisa Kit(R&D#DIF00/Endogen#EH-IFNG)，按照生产商的说明，进行ELISA，然后根据标准曲线计算hIFN-γ的产量(pg/ml)。 
总之，4种突变抗体，即2E1衍生的L34S、H53R、H53Y和H58Q比亲代2E1抗体显示更强的IL-18中和效力(参见表12)。采用KG-1测定IC50值改进2-5倍，并且采用BIAcore分析测得相似的改进结合结果。 
也制备出各种突变组合的克隆，并对其进行测试，该数据概述于表12中。最佳组合克隆L34S-H53R在基于KG-1细胞的测定和采用BIAcore分析两者显示比亲代抗体2E1有10倍改进。将所得抗体命名为2E1RS。 
根据采用KG-1测定确定，2E1的几个其它突变克隆显示效能增强，即IL-18中和作用增强。突变体L95Y比亲代2E1抗体IC50值增加5-8倍。几个其它突变体提高2-3倍，它们是2E1突变体H96A、 H96Q、H96S、H98S、L90C、L90W、L93C、L94P、L94P、L94Q、L94R、L94W、L95R、L95aA、L95aH、L95aP、L95aR、L95aW、L95bE、L95bW、L95bY、L97C和L97E。 
也比较了2E1以ScFv抗体或IgG抗体形式的结合(参见图5)。 
再者，衍生自LT28亲代的两个突变体与所述亲代抗体相比，其IL-18中和活性改善。 
这些结果证明完全人IL-18中和抗体可以采用本发明的方法和组合物获得。 
                   等同实施方案 
本领域技术人员知道，或者采用常规实验能够确定与本文所述的本发明的具体实施方案等同的许多实施方案。下文的权利要求将包括这样的等同实施方案。 
Figure IYZ000004607658000031
Figure IYZ000004607658000041
Figure IYZ000004607658000051
Figure IYZ000004607658000091
Figure IYZ000004607658000101
Figure IYZ000004607658000111
Figure IYZ000004607658000121
Figure IYZ000004607658000131
Figure IYZ000004607658000141
Figure IYZ000004607658000161
Figure IYZ000004607658000171
Figure IYZ000004607658000191
Figure IYZ000004607658000221
Figure IYZ000004607658000231
Figure IYZ000004607658000241
Figure IYZ000004607658000251

Claims (18)

1.一种分离的抗体或其抗原结合部分，其中所述抗体或其抗原结合部分包含重链可变区和轻链可变区，
所述重链可变区包含：
由SEQ ID NO：9所示的氨基酸序列组成的重链CDR1结构域；
由SEQ ID NO：10所示的氨基酸序列组成的重链CDR2结构域；
由SEQ ID NO：11所示的氨基酸序列组成的重链CDR3结构域；
所述轻链可变区包含：
由SEQ ID NO：12所示的氨基酸序列组成的轻链CDR1结构域；
由SEQ ID NO：13所示的氨基酸序列组成的轻链CDR2结构域；
由SEQ ID NO：14所示的氨基酸序列组成的轻链CDR3结构域；以及
其中所述抗体或其抗原结合部分任选地具有选自下述的一组置换：在Kabat位置L34处的S；在Kabat位置H53处的R；在Kabat位置H53处的Y；在Kabat位置H58处的Q；在Kabat位置L34处的S和在Kabat位置H53处的R；在Kabat位置L34处的S和在Kabat位置H58处的Q；在Kabat位置L34处的S和在Kabat位置H53处的Y；在Kabat位置H53处的R和在Kabat位置H58处的Q；在Kabat位置H53处的Y和在Kabat位置H58处的Q；在Kabat位置L34处的S、在Kabat位置H53处的R和Kabat位置H58处的Q；在Kabat位置L34处的S、在Kabat位置H53处的Y和在Kabat位置H58处的Q；在Kabat位置L90处的C；在Kabat位置L93处的C；在Kabat位置L94处的P；在Kabat位置L94处的Q；在Kabat位置L94处的R；在Kabat位置L95处的R；在Kabat位置L95处的Y；在Kabat位置L95b处的E；或在Kabat位置L95b处的W。
2.权利要求1的抗体或其抗原结合部分，其中所述抗体是中和抗体。
3.权利要求1的抗体或其抗原结合部分，所述抗体是重组抗体。
4.权利要求1的抗体或其抗原结合部分，所述抗体是单克隆抗体。
5.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-2s-1或1x10-2s-1以下；或者它抑制人IL-18活性的IC50为1x10-7M或1x10-7M以下。
6.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-3s-1或1x10-3s-1以下；或者它抑制人IL-18活性的IC50为1x10-8M或1x10-8M以下。
7.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-4s-1或1x10-4s-1以下；或者它抑制人IL-18活性的IC50为1x10-9M或1x10-9M以下。
8.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-5s-1或1x10-5s-1以下；或者它抑制人IL-18活性的IC50为1x10-10M或1x10-10M以下。
9.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-6s-1或1x10-6s-1以下；或者它抑制人IL-18活性的IC50为1x10-11M或1x10-11M以下。
10.一种分离的抗体或其抗原结合部分，其中所述抗体或其抗原结合部分包含重链可变区和轻链可变区，
所述重链可变区包含：
由SEQ ID NO：20所示的氨基酸序列组成的重链CDR1结构域；
由SEQ ID NO：21所示的氨基酸序列组成的重链CDR2结构域；
由SEQ ID NO：22所示的氨基酸序列组成的重链CDR3结构域；
所述轻链可变区包含：
由SEQ ID NO：23所示的氨基酸序列组成的轻链CDR1结构域；
由SEQ ID NO：24所示的氨基酸序列组成的轻链CDR2结构域；
由SEQ ID NO：25所示的氨基酸序列组成的轻链CDR3结构域；
其中所述抗体或其抗原结合部分任选地具有选自下述的一种置换：在Kabat位置H54处的Q或在Kabat位置H58处的W。
11.权利要求10的抗体或其抗原结合部分，其中所述抗体是中和抗体。
12.权利要求10的抗体或其抗原结合部分，所述抗体是重组抗体。
13.权利要求10的抗体或其抗原结合部分，所述抗体是单克隆抗体。
14.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-2s-1或1x10-2s-1以下；或者它抑制人IL-18活性的IC50为1x10-7M或1x10-7M以下。
15.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-3s-1或1x10-3s-1以下；或者它抑制人IL-18活性的IC50为1x10-8M或1x10-8M以下。
16.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-4s-1或1x10-4s-1以下；或者它抑制人IL-18活性的IC50为1x10-9M或1x10-9M以下。
17.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-5s-1或1x10-5s-1以下；或者它抑制人IL-18活性的IC50为1x10-10M或1x10-10M以下。
18.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-6s-1或1x10-6s-2以下；或者它抑制人IL-18活性的IC50为1x10-11M或1x10-11M以下。
CN018077358A 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法 Expired - Fee Related CN1461310B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US18160800P 2000-02-10 2000-02-10
US60/181,608 2000-02-10
PCT/US2001/004170 WO2001058956A2 (en) 2000-02-10 2001-02-09 Antibodies that bind human interleukin-18 and methods of making and using

Related Child Applications (2)

Application Number Title Priority Date Filing Date
CN2011100884013A Division CN102206277A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法
CN2011103115323A Division CN102504024A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法

Publications (2)

Publication Number Publication Date
CN1461310A CN1461310A (zh) 2003-12-10
CN1461310B true CN1461310B (zh) 2013-06-12

Family

ID=22665007

Family Applications (3)

Application Number Title Priority Date Filing Date
CN2011103115323A Pending CN102504024A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法
CN018077358A Expired - Fee Related CN1461310B (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法
CN2011100884013A Pending CN102206277A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN2011103115323A Pending CN102504024A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN2011100884013A Pending CN102206277A (zh) 2000-02-10 2001-02-09 结合人白介素-18的抗体及制备和使用方法

Country Status (22)

Country Link
US (3) US7767207B2 (zh)
EP (4) EP2360184A3 (zh)
JP (2) JP2004500086A (zh)
KR (4) KR101111103B1 (zh)
CN (3) CN102504024A (zh)
AR (2) AR027404A1 (zh)
AU (3) AU2001236807A1 (zh)
BG (2) BG107045A (zh)
BR (1) BR0108188A (zh)
CA (2) CA2800450A1 (zh)
CL (1) CL2012001063A1 (zh)
HU (1) HUP0300423A3 (zh)
IL (2) IL151044A0 (zh)
MX (1) MXPA02007756A (zh)
MY (1) MY146017A (zh)
NO (1) NO20023788L (zh)
NZ (1) NZ520392A (zh)
PL (1) PL356836A1 (zh)
SK (1) SK12942002A3 (zh)
TW (3) TWI335336B (zh)
WO (1) WO2001058956A2 (zh)
ZA (1) ZA200206266B (zh)

Families Citing this family (163)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7109308B1 (en) 1994-03-08 2006-09-19 Human Genome Sciences, Inc. Antibodies to human vascular endothelial growth factor 2
US6608182B1 (en) 1994-03-08 2003-08-19 Human Genome Sciences, Inc. Human vascular endothelial growth factor 2
US7153827B1 (en) 1994-03-08 2006-12-26 Human Genome Sciences, Inc. Vascular endothelial growth factor 2 and methods of use
US5932540A (en) 1994-03-08 1999-08-03 Human Genome Sciences, Inc. Vascular endothelial growth factor 2
ATE309360T1 (de) 1994-03-08 2005-11-15 Human Genome Sciences Inc Vaskularer endothelialer wachstumsfaktor 2
US7186688B1 (en) 1994-03-08 2007-03-06 Human Genome Sciences, Inc. Methods of stimulating angiogenesis in a patient by administering vascular endothelial growth factor 2
US6040157A (en) 1994-03-08 2000-03-21 Human Genome Sciences, Inc. Vascular endothelial growth factor 2
US7223724B1 (en) 1999-02-08 2007-05-29 Human Genome Sciences, Inc. Use of vascular endothelial growth factor to treat photoreceptor cells
WO2001058956A2 (en) * 2000-02-10 2001-08-16 Abbott Laboratories Antibodies that bind human interleukin-18 and methods of making and using
DK1257292T3 (da) * 2000-02-21 2011-07-18 Merck Serono Sa Anvendelse af IL-18-inhibitorer
US20020025317A1 (en) * 2000-07-20 2002-02-28 Schering Ag Bispecific monoclonal antibodies to IL-12 and IL-18
CA2435466C (en) * 2001-01-29 2012-04-03 Applied Research Systems Ars Holding N.V. Use of il-18 inhibitors for the treatment and/or prevention of heart disease
WO2002083704A1 (en) 2001-04-13 2002-10-24 Human Genome Sciences, Inc. Vascular endothelial growth factor 2
US7402312B2 (en) 2001-04-13 2008-07-22 Human Genome Sciences, Inc. Antibodies to vascular endothelial growth factor 2 (VEGF-2)
ES2334773T3 (es) * 2001-05-16 2010-03-16 Yeda Research And Development Co. Ltd. Uso de inhibidores de il-18 para el tratamiento o prevencion de la sepsis.
US20040213786A1 (en) * 2001-08-24 2004-10-28 Rappaport Family Institute For Research In The Medical Sciences Compositions and methods for treating T-cell mediated autoimmune diseases
EP2308888B1 (en) 2001-11-14 2017-03-01 Janssen Biotech, Inc. Anti-IL-6 antibodies, compositions, methods and uses
EP1494710A4 (en) * 2002-03-26 2007-03-21 Centocor Inc DIABETES-RELEVANT IMMUNOGLOBULIN-BASED PROTEINS, COMPOSITIONS, PROCESSES AND USES
WO2003082922A1 (en) * 2002-03-28 2003-10-09 Markus Fritzsche Antibody against an epitope of the b. burgdorferi flagellar basal rod protein (fbrp)
US7253260B2 (en) * 2002-04-17 2007-08-07 Smithkline Beecham Corporation Human IL-18 crystal structure
US7601351B1 (en) 2002-06-26 2009-10-13 Human Genome Sciences, Inc. Antibodies against protective antigen
EP1539235A2 (en) 2002-07-01 2005-06-15 Human Genome Sciences, Inc. Antibodies that specifically bind to reg iv
US9415102B2 (en) 2002-09-06 2016-08-16 Alexion Pharmaceuticals, Inc. High concentration formulations of anti-C5 antibodies
US20050271660A1 (en) 2002-09-06 2005-12-08 Alexion Pharmaceuticals, Inc. Nebulization of monoclonal antibodies for treating pulmonary diseases
AR047392A1 (es) 2002-10-22 2006-01-18 Wyeth Corp Neutralizacion de anticuerpos contra gdf 8 y su uso para tales fines
JP2006519763A (ja) 2002-11-08 2006-08-31 アブリンクス エン．ヴェー． 治療用ポリペプチドの投与法およびそのためのポリペプチド
US9320792B2 (en) 2002-11-08 2016-04-26 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
EP2267032A3 (en) * 2002-11-08 2011-11-09 Ablynx N.V. Method of administering therapeutic polypeptides, and polypeptides therefor
US20060034845A1 (en) 2002-11-08 2006-02-16 Karen Silence Single domain antibodies directed against tumor necrosis factor alpha and uses therefor
KR100988129B1 (ko) * 2003-04-30 2010-10-18 쥬리디컬 파운데이션 더 케모-세로-쎄라퓨틱 리서치 인스티튜트 인간 항인간 인터루킨-18 항체와 그 단편, 및 이들의이용방법
GB0323965D0 (en) * 2003-10-13 2003-11-19 Glaxosmithkline Biolog Sa Immunogenic compositions
AU2011224023C1 (en) * 2003-11-12 2013-08-29 Abbvie Inc. IL-18 binding proteins
US7968684B2 (en) * 2003-11-12 2011-06-28 Abbott Laboratories IL-18 binding proteins
US20050100965A1 (en) * 2003-11-12 2005-05-12 Tariq Ghayur IL-18 binding proteins
US20050227289A1 (en) 2004-04-09 2005-10-13 Reilly Edward B Antibodies to erythropoietin receptor and uses thereof
NZ552908A (en) * 2004-06-30 2009-11-27 Atsuo Sekiyama Indicator agent for noninflammatory stress response and use thereof
US7141382B1 (en) 2004-10-12 2006-11-28 Parikh Chirag R Methods for detection of IL-18 as an early marker for diagnosis of acute renal failure and predictor of mortality
PE20061324A1 (es) 2005-04-29 2007-01-15 Centocor Inc Anticuerpos anti-il-6, composiciones, metodos y usos
KR20130108481A (ko) 2005-08-19 2013-10-02 아보트 러보러터리즈 이원 가변 도메인 면역글로불린 및 이의 용도
EP2500356A3 (en) 2005-08-19 2012-10-24 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
CN101277974A (zh) 2005-09-30 2008-10-01 阿伯特有限及两合公司 排斥性引导分子(rgm)蛋白质家族的蛋白质的结合结构域及其功能性片段和它们的用途
CN110776566A (zh) * 2005-12-20 2020-02-11 Sbi 生物技术有限公司 抗ilt7抗体
TWI417301B (zh) * 2006-02-21 2013-12-01 Wyeth Corp 對抗人類介白素-２２（ｉｌ-２２）之抗體及其用途
MY157173A (en) * 2006-05-25 2016-05-13 Glaxo Group Ltd Modified humanised anti-interleukin-18
EP2500414A1 (en) 2006-09-13 2012-09-19 Abbott Laboratories Cell culture improvements
US8911964B2 (en) 2006-09-13 2014-12-16 Abbvie Inc. Fed-batch method of making human anti-TNF-alpha antibody
CN103397065A (zh) 2006-09-13 2013-11-20 雅培制药有限公司 细胞培养改良
JP5167275B2 (ja) 2007-01-04 2013-03-21 エスケー ケミカルズ カンパニー リミテッド 明るさに優れたポリアリーレンスルフィド樹脂の製造方法
EP2164517A4 (en) * 2007-05-29 2011-03-09 Univ Yale IL-18 AND PROTEIN KINASE-R INHIBITION FOR THE TREATMENT OF COPD
CL2008002153A1 (es) 2007-07-24 2009-06-05 Amgen Inc Anticuerpo aislado o fragmanto de unión de antigeno del mismo que se une al receptor de il-18 (il-18r); molecula de ácido nucleico codificante; celula huesped que la comprende; composición farmaceutica; uso médico para tratar o prevenir una condición asociada con il-18r; método in vitro para inhibir la unión de il-18 al il-18r.
CA3023889A1 (en) 2007-12-27 2009-07-09 Abbott Laboratories Anti-t. cruzi antibodies and methods of use
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
AU2009241589B2 (en) 2008-04-29 2013-10-10 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
UY31861A (es) 2008-06-03 2010-01-05 Abbott Lab Inmunoglobulina con dominio variable dual y usos de la misma
MX2010013239A (es) 2008-06-03 2011-02-24 Abbott Lab Inmunoglobulinas de dominio variable doble y usos de las mismas.
US8188235B2 (en) 2008-06-18 2012-05-29 Pfizer Inc. Antibodies to IL-6 and their uses
RU2011104348A (ru) 2008-07-08 2012-08-20 Эбботт Лэборетриз (Us) Иммуноглобулины с двойным вариабельным доменом против простагландина е2 и их применение
RU2011120178A (ru) * 2008-10-20 2012-11-27 Эбботт Лэборетриз Антитела, которые связываются с il-12, и способы их очистки
WO2010141039A1 (en) * 2008-10-20 2010-12-09 Abbott Laboratories Isolation and purification of antibodies using protein a affinity chromatography
SG10201702951RA (en) * 2008-10-20 2017-06-29 Abbvie Inc Viral inactivation during purification of antibodies
US20100150864A1 (en) * 2008-10-20 2010-06-17 Abbott Laboratories, Inc. Antibodies that bind to il-18 and methods of purifying the same
RU2481824C2 (ru) 2008-10-29 2013-05-20 Аблинкс Н.В Препараты однодоменных антигенсвязывающих молекул
KR20110079693A (ko) 2008-10-29 2011-07-07 와이어쓰 엘엘씨 단일 도메인 항원 결합 분자의 정제 방법
US8349325B2 (en) 2008-12-23 2013-01-08 Abbott Laboratories Soluble FMS-like tyrosine kinase-1 (sFLT-1) antibody and related composition, kit, methods of using, and materials and method for making
US8168165B2 (en) 2008-12-23 2012-05-01 Abbott Laboratories Alkylated interleukin-18 compositions
MX2012002651A (es) 2009-09-01 2012-05-22 Abbott Lab Inmunoglobulinas de dominio variable doble y usos de las mismas.
CA2775959A1 (en) 2009-10-15 2011-04-21 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof
UY32979A (es) 2009-10-28 2011-02-28 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
CN102656190A (zh) 2009-12-08 2012-09-05 雅培股份有限两合公司 用于在视网膜神经纤维层变性治疗中使用的针对rgm a蛋白质的单克隆抗体
WO2011098424A2 (en) 2010-02-09 2011-08-18 Glaxo Group Limited Treatment of a metabolic disorder
US20110229921A1 (en) 2010-03-18 2011-09-22 Abbott Laboratories METHODS OF ASSAYING URINARY NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (uNGAL) IN THE PROGNOSIS OF CADAVERIC KIDNEY TRANSPLANT FUNCTION IN A PATIENT, INCLUDING A PATIENT DIAGNOSED WITH DELAYED GRAFT FUNCTION (DGF), A METHOD OF ASSAYING uNGAL IN THE ASSESSMENT OF RISK OF DGF IN A PATIENT DIAGNOSED WITH EARLY GRAFT FUNCTION (EGF), AND RELATED KITS
MX341579B (es) 2010-08-03 2016-08-25 Abbvie Inc * Inmunoglobulinas de dominio variable doble y usos de las mismas.
SG187938A1 (en) 2010-08-26 2013-04-30 Abbvie Inc Dual variable domain immunoglobulins and uses thereof
BR112013007501B1 (pt) * 2010-09-30 2022-04-19 Chengdu Kanghong Biotechnologies Co., Ltd. Anticorpo humanizado anti-fator de necrose tumoral a, ou um fragmento de ligação ao antígeno do mesmo, uso e composição farmacêutica
US20120115244A1 (en) 2010-11-09 2012-05-10 Abbott Laboratories Materials and methods for immunoassay of pterins
US9255144B2 (en) * 2010-12-20 2016-02-09 Medimmune Limited Anti-IL-18 antibodies and their uses
WO2012088247A2 (en) * 2010-12-22 2012-06-28 Medimmune, Llc Anti-c5/c5a/c5adesr antibodies and fragments
WO2012096264A1 (ja) 2011-01-11 2012-07-19 Jsr株式会社 感放射線性樹脂組成物及び感放射線性酸発生剤
WO2012149197A2 (en) 2011-04-27 2012-11-01 Abbott Laboratories Methods for controlling the galactosylation profile of recombinantly-expressed proteins
JP6336397B2 (ja) 2011-12-14 2018-06-06 アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー 鉄関連障害を診断および治療するための組成物および方法
CN107459576A (zh) 2011-12-14 2017-12-12 艾伯维德国有限责任两合公司 用于诊断和治疗铁相关病症的组合物和方法
WO2013102042A2 (en) 2011-12-30 2013-07-04 Abbvie Inc. Dual specific binding proteins directed against il-13 and/or il-17
US8993248B2 (en) 2011-12-31 2015-03-31 Abbott Laboratories Truncated human vitamin D binding protein and mutation and fusion thereof and related materials and methods of use
CN104487455A (zh) 2012-01-27 2015-04-01 艾伯维德国有限责任两合公司 用于诊断和治疗与神经突变性相关的疾病的组合物和方法
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
US9150645B2 (en) 2012-04-20 2015-10-06 Abbvie, Inc. Cell culture methods to reduce acidic species
WO2013176754A1 (en) 2012-05-24 2013-11-28 Abbvie Inc. Novel purification of antibodies using hydrophobic interaction chromatography
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
BR112015004467A2 (pt) 2012-09-02 2017-03-21 Abbvie Inc método para controlar a heterogeneidade de proteínas
JOP20200308A1 (ar) 2012-09-07 2017-06-16 Novartis Ag جزيئات إرتباط il-18
TWI601745B (zh) 2012-11-01 2017-10-11 艾伯維有限公司 抗－ｖｅｇｆ／ｄｌｌ４雙重可變區域免疫球蛋白及其用途
EP2924117B1 (en) * 2012-11-21 2019-08-14 KM Biologics Co., Ltd. Novel human antibody against il-18
DE112013006579T5 (de) 2013-02-02 2016-03-10 Duke University Verfahren zum Isolieren zirkulierender Tumorzellen
EP2830651A4 (en) 2013-03-12 2015-09-02 Abbvie Inc HUMAN ANTIBODIES THAT BIND TNF-ALPHA AND PREPARATION METHODS
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
WO2014159579A1 (en) 2013-03-14 2014-10-02 Abbvie Inc. MUTATED ANTI-TNFα ANTIBODIES AND METHODS OF THEIR USE
WO2014151878A2 (en) 2013-03-14 2014-09-25 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosacharides
WO2014144280A2 (en) 2013-03-15 2014-09-18 Abbvie Inc. DUAL SPECIFIC BINDING PROTEINS DIRECTED AGAINST IL-1β AND / OR IL-17
US9469686B2 (en) 2013-03-15 2016-10-18 Abbott Laboratories Anti-GP73 monoclonal antibodies and methods of obtaining the same
JP6581572B2 (ja) 2013-06-07 2019-09-25 デューク ユニバーシティ 補体因子ｈ阻害薬
WO2015031626A1 (en) 2013-08-28 2015-03-05 Abbvie Inc. Soluble cmet assay
HUE055608T2 (hu) 2013-09-05 2021-12-28 Ab2 Bio Sa IL-18-kötõ fehérje (IL-18BP) gyulladásos betegségekben
CN105793284A (zh) 2013-09-17 2016-07-20 大学健康网络(Uhn):技术开发和商业化公司 针对顺式RGMa/再生蛋白相互作用或脂筏的试剂及其在治疗方法中的应用
WO2015051293A2 (en) 2013-10-04 2015-04-09 Abbvie, Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
US20150139988A1 (en) 2013-11-15 2015-05-21 Abbvie, Inc. Glycoengineered binding protein compositions
WO2016044736A1 (en) * 2014-09-18 2016-03-24 Cell Signaling Technology, Inc. Altered antibodies and methods of making the same
AU2015336946A1 (en) * 2014-10-23 2017-04-13 La Trobe University Fn14-binding proteins and uses thereof
US10093733B2 (en) 2014-12-11 2018-10-09 Abbvie Inc. LRP-8 binding dual variable domain immunoglobulin proteins
MX2017010919A (es) 2015-03-05 2017-12-07 Ab2 Bio Sa Proteina de union il-18 (il-18bp) y anticuerpos en enfermedades inflamatorias.
CN108513593A (zh) 2015-04-23 2018-09-07 南托米克斯有限责任公司 癌症新表位
TW201710286A (zh) 2015-06-15 2017-03-16 艾伯維有限公司 抗ｖｅｇｆ、ｐｄｇｆ及／或其受體之結合蛋白
MX2018003040A (es) 2015-09-11 2018-04-11 Abbvie Inc Metodos para el tratamiento de formas recurrentes de esclerosis multiple.
WO2017087768A1 (en) 2015-11-18 2017-05-26 Duke University Targeted delivery of interleukin-10 to tumor infiltrating lymphocytes
WO2017156298A1 (en) 2016-03-10 2017-09-14 Medimmune, Llc Ilt7 binding molecules and methods of using the same
CN109496218A (zh) 2016-06-01 2019-03-19 艾伯维公司 用于治疗脊髓损伤和疼痛的抗反义导向分子a（rgma）拮抗性抗体
US20170363620A1 (en) 2016-06-17 2017-12-21 Abbott Laboratories BIOMARKERS TO PREDICT NEW ONSET HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
EP3279667A1 (en) 2016-08-02 2018-02-07 Abbott Laboratories Cardiac troponin i and copeptin as biomarkers for short-term mortality in acute exacerbation of chronic obstructive pulmonary disease (aecopd)
US20180106818A1 (en) 2016-10-03 2018-04-19 Abbott Laboratories Methods of assessing gfap status in patient samples
US10324041B2 (en) 2016-12-21 2019-06-18 Abbott Japan Co., Ltd. Optical imaging system using lateral illumination for digital assays
US11047854B2 (en) 2017-02-06 2021-06-29 Abbott Japan Llc Methods for reducing noise in signal-generating digital assays
AU2018219247A1 (en) 2017-02-08 2019-07-25 Silbiotech, Inc. Methods for determining breast cancer risk
CA3055256A1 (en) 2017-03-09 2018-09-13 Mab Discovery Gmbh Antibodies specifically binding to human il-1r7
WO2018175942A1 (en) 2017-03-23 2018-09-27 Abbott Laboratories Methods for aiding in the diagnosis and determination of the extent of traumatic brain injury in a human subject using the early biomarker ubiquitin carboxy-terminal hydrolase l1
CA3053409A1 (en) 2017-04-15 2018-10-18 Abbott Laboratories Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury in a human subject using early biomarkers
US10877038B2 (en) 2017-04-28 2020-12-29 Abbott Laboratories Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury using early biomarkers on at least two samples from the same human subject
US10865238B1 (en) 2017-05-05 2020-12-15 Duke University Complement factor H antibodies
WO2018218169A1 (en) 2017-05-25 2018-11-29 Abbott Laboratories Methods for aiding in the determination of whether to perform imaging on a human subject who has sustained or may have sustained an injury to the head using early biomarkers
AU2018275236A1 (en) 2017-05-30 2019-10-31 Abbott Laboratories Methods for aiding in diagnosing and evaluating a mild traumatic brain injury in a human subject using cardiac troponin I
WO2019010131A1 (en) 2017-07-03 2019-01-10 Abbott Laboratories IMPROVED METHODS FOR MEASURING CARBOXY TERMINATION HYDROLASE LEVELS OF UBIQUITIN L1 IN BLOOD
WO2019023650A1 (en) 2017-07-28 2019-01-31 Duke University COMPOSITIONS AND METHODS FOR PROMOTING REGENERATION OF HEMATOPOIETIC STEM CELLS
AU2018378971A1 (en) 2017-12-09 2020-01-02 Abbott Laboratories Methods for aiding in the diagnosis and evaluation of a subject who has sustained an orthopedic injury and that has or may have sustained an injury to the head, such as mild traumatic brain injury (TBI), using glial fibrillary acidic protein (GFAP) and/or ubiquitin carboxy-terminal hydrolase l1 (UCH-L1)
CN110892266A (zh) 2017-12-09 2020-03-17 雅培实验室 使用gfap和uch-l1的组合辅助诊断和评价人类受试者中创伤性脑损伤的方法
US20190383832A1 (en) 2017-12-29 2019-12-19 Abbott Laboratories Novel biomarkers and methods for diagnosing and evaluating traumatic brain injury
JPWO2019194217A1 (ja) * 2018-04-04 2021-04-15 株式会社ｍＡｂＰｒｏｔｅｉｎ 検出感度の高いインターロイキン−１８タンパク質に対する抗体及びその応用
GB201809699D0 (en) * 2018-06-13 2018-08-01 Singapore Health Serv Pte Ltd IL-11 antibodies
EP3892300A4 (en) 2018-12-03 2022-12-14 Mabprotein Co.,Ltd. ANTIBODY RECOGNIZING A NEOEPITOPE OF ACTIVATED INTERLEUKIN-18 PROTEINS AND ITS USE
WO2020180695A1 (en) 2019-03-01 2020-09-10 Abbott Laboratories Methods for predicting major adverse cardiovascular events in subjects with coronary artery disease
KR102265432B1 (ko) * 2019-08-20 2021-06-15 주식회사 케어젠 피부 미백 활성을 갖는 펩타이드 및 이의 용도
EP4136459A1 (en) 2020-04-13 2023-02-22 Abbott Laboratories Methods, complexes and kits for detecting or determining an amount of a ss-coronavirus antibody in a sample
JP2023536737A (ja) 2020-08-04 2023-08-29 アボット・ラピッド・ダイアグノスティクス・インターナショナル・アンリミテッド・カンパニー Ｓａｒｓ－ｃｏｖ－２を検出するためのアッセイ
US20220043000A1 (en) 2020-08-04 2022-02-10 Abbott Laboratories Methods and kits for detecting sars-cov-2 protein in a sample
CN114773466B (zh) * 2020-11-26 2023-08-29 江苏荃信生物医药股份有限公司 一种抗人白介素23及包含其的试剂盒及其检测方法
WO2023102384A1 (en) 2021-11-30 2023-06-08 Abbott Laboratories Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi
CA3198161A1 (en) 2020-12-01 2022-06-09 Beth MCQUISTON Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi
WO2022147147A1 (en) 2020-12-30 2022-07-07 Abbott Laboratories Methods for determining sars-cov-2 antigen and anti-sars-cov-2 antibody in a sample
WO2022147178A1 (en) 2020-12-30 2022-07-07 Abbott Laboratories Improved methods, reagents and kits for detergent-based inactivation of betacoronavirus prior to and/or while assessing a biological sample for sars-cov-2 antigen or antibody
EP4067375A1 (en) * 2021-03-30 2022-10-05 Universität Ulm Fibril peptides
JP2024519858A (ja) 2021-05-18 2024-05-21 アボット・ラボラトリーズ 小児対象における脳損傷を査定する方法
CA3222291A1 (en) 2021-06-14 2022-12-22 Jaime MARINO Methods of diagnosing or aiding in diagnosis of brain injury caused by acoustic energy, electromagnetic energy, an over pressurization wave, and/or blast wind
WO2023286694A1 (ja) 2021-07-13 2023-01-19 国立大学法人東海国立大学機構 炎症性腸疾患を治療するための医薬組成物
EP4392783A1 (en) 2021-08-27 2024-07-03 Abbott Laboratories Methods for detecting immunoglobulin g, subclass 4 (igg4) in a biological sample
AU2022339759A1 (en) 2021-08-31 2024-03-07 Abbott Laboratories Methods and systems of diagnosing brain injury
WO2023056268A1 (en) 2021-09-30 2023-04-06 Abbott Laboratories Methods and systems of diagnosing brain injury
CA3240822A1 (en) 2021-12-17 2023-06-22 Tony Lee Systems and methods for determining uch-l1, gfap, and other biomarkers in blood samples
US20230213536A1 (en) 2021-12-28 2023-07-06 Abbott Laboratories Use of biomarkers to determine sub-acute traumatic brain injury (tbi) in a subject having received a head computerized tomography (ct) scan that is negative for a tbi or no head ct scan
WO2023150652A1 (en) 2022-02-04 2023-08-10 Abbott Laboratories Lateral flow methods, assays, and devices for detecting the presence or measuring the amount of ubiquitin carboxy-terminal hydrolase l1 and/or glial fibrillary acidic protein in a sample
WO2024006876A1 (en) 2022-06-29 2024-01-04 Abbott Laboratories Magnetic point-of-care systems and assays for determining gfap in biological samples
WO2024059708A1 (en) 2022-09-15 2024-03-21 Abbott Laboratories Biomarkers and methods for differentiating between mild and supermild traumatic brain injury
WO2024102383A1 (en) 2022-11-10 2024-05-16 Abbott Laboratories Methods of identifying macrotroponin in biological samples

Family Cites Families (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5019385A (en) * 1984-11-09 1991-05-28 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Novel lymphopine LK 2 and pharmaceutic compositions containing same
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
GB8823869D0 (en) * 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
US5530101A (en) * 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5060283A (en) * 1989-04-20 1991-10-22 Fuji Photo Film Co. , Ltd. Method and system for reading images with a movable light intercepting plate
US6075181A (en) * 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
DK0463151T3 (da) 1990-01-12 1996-07-01 Cell Genesys Inc Frembringelse af xenogene antistoffer
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
ATE185601T1 (de) 1990-07-10 1999-10-15 Cambridge Antibody Tech Verfahren zur herstellung von spezifischen bindungspaargliedern
EP0542810A1 (en) * 1990-08-02 1993-05-26 B.R. Centre Limited Methods for the production of proteins with a desired function
AU664976B2 (en) * 1990-08-29 1995-12-14 Gene Pharming Europe Bv Homologous recombination in mammalian cells
US5633425A (en) * 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5625126A (en) * 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5545806A (en) * 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5661016A (en) * 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5814318A (en) * 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5789650A (en) * 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5770429A (en) * 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1992009690A2 (en) 1990-12-03 1992-06-11 Genentech, Inc. Enrichment method for variant proteins with altered binding properties
ATE439435T1 (de) 1991-03-01 2009-08-15 Dyax Corp Chimäres protein mit mikroprotein mit zwei oder mehr disulfidbindungen und ausgestaltungen davon
WO1992018619A1 (en) 1991-04-10 1992-10-29 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
DE4122599C2 (de) * 1991-07-08 1993-11-11 Deutsches Krebsforsch Phagemid zum Screenen von Antikörpern
AU2515992A (en) * 1991-08-20 1993-03-16 Genpharm International, Inc. Gene targeting in animal cells using isogenic dna constructs
JPH07509137A (ja) 1992-07-24 1995-10-12 セル　ジェネシス，インク． 異種抗体の生産
US5625825A (en) * 1993-10-21 1997-04-29 Lsi Logic Corporation Random number generating apparatus for an interface unit of a carrier sense with multiple access and collision detect (CSMA/CD) ethernet data network
EP0692536B1 (en) * 1994-07-14 2000-11-22 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo IFN-Y production inducing protein and monoclonal antibody of the same
US6309636B1 (en) * 1995-09-14 2001-10-30 Cancer Research Institute Of Contra Costa Recombinant peptides derived from the Mc3 anti-BA46 antibody, methods of use thereof, and methods of humanizing antibody peptides
JPH08101497A (ja) * 1994-09-30 1996-04-16 Shin Etsu Chem Co Ltd ペリクル
US5643763A (en) * 1994-11-04 1997-07-01 Genpharm International, Inc. Method for making recombinant yeast artificial chromosomes by minimizing diploid doubling during mating
JP4004088B2 (ja) * 1995-09-26 2007-11-07 株式会社林原生物化学研究所 免疫担当細胞においてインターフェロン−γの産生を誘導する蛋白質
US6207641B1 (en) * 1995-03-10 2001-03-27 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Pharmaceutical composition containing IFN-γ inducing polypeptide or factor for treating and/or preventing IFN-γ susceptive diseases
US7135458B1 (en) * 1995-11-15 2006-11-14 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Interferon-γ inducing polypeptide, pharmaceutical composition thereof, monoclonal antibody thereto, and methods of use
TW581771B (en) 1994-11-15 2004-04-01 Hayashibara Biochem Lab Recombinant production of a polypeptide for inducing interferon-gamma production, and monoclonal antibody against the polypeptide
JP2724987B2 (ja) * 1994-11-15 1998-03-09 株式会社林原生物化学研究所 インターフェロン−γの産生を誘導するポリペプチド
JP2952750B2 (ja) * 1995-02-23 1999-09-27 株式会社林原生物化学研究所 モノクローナル抗体
US6130364A (en) * 1995-03-29 2000-10-10 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US6091001A (en) * 1995-03-29 2000-07-18 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
JPH11503914A (ja) * 1995-04-21 1999-04-06 セル ジェネシス，インコーポレイテッド 大ゲノムｄｎａ欠失の生成
EP0822830B1 (en) 1995-04-27 2008-04-02 Amgen Fremont Inc. Human anti-IL-8 antibodies, derived from immunized xenomice
AU2466895A (en) 1995-04-28 1996-11-18 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1997002479A2 (en) * 1995-06-30 1997-01-23 Yale University Human monoclonal anti-tumor antibodies
US6127977A (en) 1996-11-08 2000-10-03 Cohen; Nathan Microstrip patch antenna with fractal structure
ATE352613T1 (de) * 1995-08-29 2007-02-15 Kirin Brewery Chimäres tier und methode zu dessen herstellung
AU1341797A (en) 1995-12-29 1997-07-28 Incyte Pharmaceuticals, Inc. Nucleic acids encoding interferon gamma inducing factor-2
BRPI9707379B8 (pt) 1996-02-09 2015-07-07 Abbvie Biotechnology Ltd Composições farmacêuticas compreendendo anticorpo humano recombinante geneticamente engenheirado, e anticorpo humano recombinante geneticamente engenheirado.
US5714352A (en) * 1996-03-20 1998-02-03 Xenotech Incorporated Directed switch-mediated DNA recombination
US5994619A (en) * 1996-04-01 1999-11-30 University Of Massachusetts, A Public Institution Of Higher Education Of The Commonwealth Of Massachusetts, As Represented By Its Amherst Campus Production of chimeric bovine or porcine animals using cultured inner cell mass cells
US5834597A (en) 1996-05-20 1998-11-10 Protein Design Labs, Inc. Mutated nonactivating IgG2 domains and anti CD3 antibodies incorporating the same
WO1997044468A1 (en) 1996-05-20 1997-11-27 Schering Corporation HUMAN INTERLEUKIN-1j AND ANTAGONISTS THEREOF
EP0816499A3 (en) * 1996-06-27 1999-10-27 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Genomic DNA encoding a polypeptide capable of inducing the production of interferon-gamma
US6790442B1 (en) * 1996-06-27 2004-09-14 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Genomic DNA encoding a polypeptide capable of inducing the production of interferon-γ
TW515843B (en) * 1996-07-25 2003-01-01 Hayashibara Biochem Lab Process for producing an active polypeptide inducing interferon-γ production
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
JP4024366B2 (ja) * 1996-11-29 2007-12-19 株式会社林原生物化学研究所 ポリペプチド
EP1972194A1 (en) 1996-12-03 2008-09-24 Amgen Fremont Inc. Transgenic mammals having human ig loci including plural vh and vk regions and antibodies produced therefrom
US7141393B2 (en) * 1996-12-26 2006-11-28 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Interleukin-18-receptor proteins
US6087116A (en) * 1997-03-12 2000-07-11 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Interleukin-18 (IL-18) receptor polypeptides and their uses
EP0998300A1 (en) 1997-03-18 2000-05-10 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
IL121860A0 (en) * 1997-08-14 1998-02-22 Yeda Res & Dev Interleukin-18 binding proteins their preparation and use
US7220717B2 (en) * 1997-08-14 2007-05-22 Yeda Research And Development Company Ltd. Interleukin-18 binding proteins, their preparation and use
JP2001521906A (ja) 1997-11-03 2001-11-13 ザ・ウイスター・インステイテユート・オブ・アナトミー・アンド・バイオロジー 血管新生を阻害し、癌を処置するための方法及び組成物
US6541606B2 (en) * 1997-12-31 2003-04-01 Altus Biologics Inc. Stabilized protein crystals formulations containing them and methods of making them
JP4271850B2 (ja) 1998-01-23 2009-06-03 イミュネックス・コーポレーション Ｉｌ−１８受容体
IL137037A0 (en) * 1998-01-23 2001-06-14 Immunex Corp Acpl dna and polypeptides
EP1060193A2 (en) 1998-03-03 2000-12-20 Abgenix, Inc. Cd147 binding molecules as therapeutics
US20020029391A1 (en) 1998-04-15 2002-03-07 Claude Geoffrey Davis Epitope-driven human antibody production and gene expression profiling
ATE437947T1 (de) * 1998-06-01 2009-08-15 Agensys Inc Serpentintransmembranantigene exprimiert in menschlichem krebs und deren verwendungen
CA2276216A1 (en) * 1998-06-24 1999-12-24 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo An artificial peptide capable of neutralizing the biological activity of interleukin-18
US20020142374A1 (en) 1998-08-17 2002-10-03 Michael Gallo Generation of modified molecules with increased serum half-lives
KR100537558B1 (ko) 1998-09-01 2005-12-19 가부시끼가이샤 하야시바라 세이부쓰 가가꾸 겐꾸조 인터류킨-18 결합 단백질
US6270758B1 (en) * 1998-10-08 2001-08-07 Duke University Substantially non-toxic biologically active mucosal adjuvants in vertebrate subjects
GEP20053594B (en) 1998-12-23 2005-08-10 Pfizer Human Monoclonal Antibodies to CTLA-4
AR022952A1 (es) * 1999-03-19 2002-09-04 Smithkline Beecham Corp ANTICUERPO MONOCLONAL DE ROEDOR ESPECIFICAMENTE NEUTRALIZANTE PARA LA INTERLEUQUINA-18 HUMANA , UN FRAGMENTO FAB NEUTRALIZANTE o FRAGMENTO F(AB')2, UNA REGION DE COMPLEMENTARIEDAD DE CADENA LIGERA DE INMONOGLOBULINA(CDR), UNA MOLECULA DE ACIDO NUCLEICO, COMPOSICION FARMACEUTICA QUE LO COMPRENDE, EL
KR20140094647A (ko) 1999-03-25 2014-07-30 아비에 도이치란트 게엠베하 운트 콤파니 카게 사람 ｉｌ-12에 결합하는 사람 항체 및 이의 제조방법
US6946129B1 (en) 1999-06-08 2005-09-20 Seattle Genetics, Inc. Recombinant anti-CD40 antibody and uses thereof
IL131047A0 (en) 1999-07-22 2001-01-28 Yeda Res & Dev Use of il-18 inhibitors
WO2001058956A2 (en) 2000-02-10 2001-08-16 Abbott Laboratories Antibodies that bind human interleukin-18 and methods of making and using
DK1257292T3 (da) * 2000-02-21 2011-07-18 Merck Serono Sa Anvendelse af IL-18-inhibitorer
DE10019967A1 (de) * 2000-04-20 2001-10-25 Fenning Biomed Gmbh Dr Antikörper gegen natives gp96, deren Herstellung und Verwendung
MXPA02010787A (es) 2000-05-03 2003-07-14 Amgen Inc Peptidos modificados como agentes terapeuticos.
UA87658C2 (uk) * 2000-05-05 2009-08-10 Апплайд Резеч Системз Арс Холдинг Н.В. Застосування il-18 як діагностичного маркера серцевої недостатності
PE20011350A1 (es) * 2000-05-19 2002-01-15 Vertex Pharma PROFARMACO DE UN INHIBIDOR DE ENZIMA CONVERTIDORA DE INTERLEUCINA-1ß (ICE)
CZ20024085A3 (cs) * 2000-06-15 2003-05-14 Smithkline Beecham Corporation Způsob přípravy fyziologicky aktivního IL-18 polypeptidu
WO2002032374A2 (en) * 2000-10-18 2002-04-25 Immunex Corporation Methods for treating il-18 mediated disorders
EP2325205A3 (en) 2000-12-28 2011-10-12 Altus Pharmaceuticals Inc. Crystals of whole antibodies and fragments thereof and methods for making and using them
CA2435466C (en) 2001-01-29 2012-04-03 Applied Research Systems Ars Holding N.V. Use of il-18 inhibitors for the treatment and/or prevention of heart disease
ATE528987T1 (de) * 2001-07-12 2011-11-15 Taiho Pharmaceutical Co Ltd Il-18 transgenes tier
ME00548B (me) * 2002-03-22 2011-10-10 Serono Lab Korišćenje inhibitora il-18 za liječenje i/ili prevenciju perifernih vaskularnih bolesti
US7253260B2 (en) * 2002-04-17 2007-08-07 Smithkline Beecham Corporation Human IL-18 crystal structure
US20060177871A1 (en) * 2002-08-13 2006-08-10 Janson Cheryl A Murine IL-18 crystal structure
US7279155B2 (en) * 2002-10-08 2007-10-09 Ares Trading S.A. Method of treatment using a cytokine able to bind IL-18BP to inhibit the activity of a second cytokine
WO2004094020A2 (en) * 2003-04-17 2004-11-04 Fluidigm Corporation Crystal growth devices and systems, and methods for using same
KR100988129B1 (ko) * 2003-04-30 2010-10-18 쥬리디컬 파운데이션 더 케모-세로-쎄라퓨틱 리서치 인스티튜트 인간 항인간 인터루킨-18 항체와 그 단편, 및 이들의이용방법
SI1622939T1 (sl) * 2003-05-13 2012-06-29 Merck Serono Sa Akrivne variante il-18 vezavnega proteina in medicinske uporabe le-tega
CA2535859A1 (en) * 2003-08-14 2005-03-03 Dyax Corp. Endotheliase-2 ligands
GB0323965D0 (en) * 2003-10-13 2003-11-19 Glaxosmithkline Biolog Sa Immunogenic compositions
US7968684B2 (en) * 2003-11-12 2011-06-28 Abbott Laboratories IL-18 binding proteins
PL1720979T3 (pl) * 2004-03-01 2008-03-31 Ares Trading Sa Zastosowanie podłoża pozbawionego surowicy do hodowli komórkowej do wytwarzania IL-18BP w komórkach ssaków
US20080090766A1 (en) * 2004-03-11 2008-04-17 Tomoaki Hoshino Preventive or therapeutic agents for diseases including interleukin-18 inhibitor as an active ingredient
US7557084B2 (en) * 2004-03-31 2009-07-07 Regeneron Pharmaceuticals, Inc. IL-18 specific polypeptides and therapeutic uses thereof
FI116804B (fi) * 2004-05-18 2006-02-28 Ekspansio Engineering Ltd Oy Materiaalikappaleiden eri suuntiin osoittavien pintojen optinen tarkastus
CA2569795C (en) * 2004-06-29 2013-08-13 Ares Trading S.A. Process for the purification of il-18 binding protein
US7887802B2 (en) * 2004-07-16 2011-02-15 Atsuo Sekiyama IL-18 receptor antagonist and pharmaceutical composition containing the antagonist
ES2372728T3 (es) * 2004-08-20 2012-01-25 Glaxosmithkline Llc Cicatrización de heridas mediante la administración de il-18 humana.
AU2006254103B2 (en) * 2005-06-03 2012-09-06 Ares Trading S.A. Production of recombinant IL-18 binding protein
US7612181B2 (en) * 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
US7615220B2 (en) * 2006-04-07 2009-11-10 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-18 receptor
PE20090190A1 (es) * 2007-03-23 2009-03-22 Smithkline Beecham Corp Combinacion de anticuerpos anti-cd20 y polipeptidos de il-18

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Griffiths AD等.Human anti-self antibodies with high specificity from phagedisplay libraries.The EMBO Journal12 2.1993,12(2),725-734.
Griffiths AD等.Human anti-self antibodies with high specificity from phagedisplay libraries.The EMBO Journal12 2.1993,12(2),725-734. *

Also Published As

Publication number Publication date
NO20023788L (no) 2002-10-09
CL2012001063A1 (es) 2013-06-21
EP1257585A2 (en) 2002-11-20
EP2338515A2 (en) 2011-06-29
EP2338515A3 (en) 2011-11-16
EP2332579A2 (en) 2011-06-15
KR20030021153A (ko) 2003-03-12
AR027404A1 (es) 2003-03-26
TW201036638A (en) 2010-10-16
HUP0300423A2 (hu) 2003-06-28
TWI335336B (zh) 2011-01-01
BR0108188A (pt) 2003-02-25
EP2360184A3 (en) 2011-11-16
IL151044A0 (en) 2003-04-10
KR20110032012A (ko) 2011-03-29
EP2360184A2 (en) 2011-08-24
US7767207B2 (en) 2010-08-03
AU2011201536A1 (en) 2011-04-28
KR100951067B1 (ko) 2010-04-07
AU2006252098B9 (en) 2011-04-14
MY146017A (en) 2012-06-15
AR077568A2 (es) 2011-09-07
KR101111103B1 (ko) 2012-02-13
US20130101595A1 (en) 2013-04-25
KR20090078372A (ko) 2009-07-17
KR20120011898A (ko) 2012-02-08
TW201305214A (zh) 2013-02-01
WO2001058956A2 (en) 2001-08-16
CN102206277A (zh) 2011-10-05
AU2011201536B2 (en) 2013-07-04
US20110008357A1 (en) 2011-01-13
CN1461310A (zh) 2003-12-10
CA2800450A1 (en) 2001-08-16
IL206980A0 (en) 2010-12-30
HUP0300423A3 (en) 2008-07-28
NZ520392A (en) 2005-04-29
PL356836A1 (en) 2004-07-12
CN102504024A (zh) 2012-06-20
CA2399148A1 (en) 2001-08-16
AU2006252098B2 (en) 2011-02-24
AU2006252098A1 (en) 2007-01-11
BG107045A (bg) 2003-05-30
US20100104563A1 (en) 2010-04-29
MXPA02007756A (es) 2004-09-10
JP2012139224A (ja) 2012-07-26
WO2001058956A3 (en) 2002-03-07
NO20023788D0 (no) 2002-08-09
BG111004A (bg) 2011-11-30
JP2004500086A (ja) 2004-01-08
TWI373343B (en) 2012-10-01
EP2332579A3 (en) 2011-09-21
SK12942002A3 (sk) 2003-05-02
ZA200206266B (en) 2003-11-06
AU2001236807A1 (en) 2001-08-20

Similar Documents

Publication Publication Date Title
CN1461310B (zh) 结合人白介素-18的抗体及制备和使用方法
AU2019369498A1 (en) Multivalent regulatory T cell modulators
KR101920250B1 (ko) 인간 온코스타틴 m 항체 및 이용 방법
CN101977935A (zh) 用于治疗和监测il-13相关病症的方法和组合物
US7615220B2 (en) High affinity human antibodies to human IL-18 receptor
CN103154026B (zh) 抗il-17的抗体
CN102906113A (zh) 治疗性dll4结合蛋白
CN109517065A (zh) Il-18结合分子
CN110357963A (zh) 抗人st2抗体及其用途
US7935793B2 (en) Treatment of inflammatory bowel diseases with anti-IP-10 antibodies
KR20100014869A (ko) Ｃｘｃｒ3에 대한 인간화 항체
EP1708961B1 (en) Anti-ip-10 antibodies
CN101600456A (zh) 治疗il-13相关疾病和监测il-13相关疾病治疗的方法和组合物
KR20210141583A (ko) 항-il-12/il-23 항체를 사용한 소아 대상의 건선 치료 방법
TWI840399B (zh) 結合人il-4r的抗體、其抗原結合片段及其醫藥用途
JP7419544B2 (ja) 抗ＩＬ－１β抗体
WO2022037527A1 (zh) 结合bcma的单可变结构域及抗原结合分子
CN115427444A (zh) 用抗il12/il23抗体治疗溃疡性结肠炎的安全且有效的方法
CN114555120A (zh) 用抗il12/il23抗体治疗溃疡性结肠炎的安全且有效的方法
TW202023612A (zh) 結合人ｉｌ－４ｒ的抗體、其抗原結合片段及其醫藥用途

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: ABBVIE INC.

Free format text: FORMER OWNER: ABBOTT GMBH. + CO. KG

Effective date: 20130619

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20130619

Address after: Illinois State

Patentee after: Abbvie Inc.

Address before: Ludwigshafen, Germany

Patentee before: Abbott GmbH. & Co. Kg

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20130612

Termination date: 20150209

EXPY Termination of patent right or utility model