WO2014206107A1 - 抗pd-1抗体及其应用 - Google Patents

抗pd-1抗体及其应用 Download PDF

Info

Publication number
WO2014206107A1
WO2014206107A1 PCT/CN2014/072574 CN2014072574W WO2014206107A1 WO 2014206107 A1 WO2014206107 A1 WO 2014206107A1 CN 2014072574 W CN2014072574 W CN 2014072574W WO 2014206107 A1 WO2014206107 A1 WO 2014206107A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
antibody
seq
variant
virus
Prior art date
Application number
PCT/CN2014/072574
Other languages
English (en)
French (fr)
Inventor
陈博
武海
Original Assignee
上海君实生物医药科技有限公司
苏州君盟生物医药科技有限公司
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
Priority to DK14818708.1T priority Critical patent/DK3026062T3/da
Priority to EP20189272.6A priority patent/EP3845562A1/en
Priority to ES14818708T priority patent/ES2822927T3/es
Priority to JP2016522196A priority patent/JP6681327B2/ja
Application filed by 上海君实生物医药科技有限公司, 苏州君盟生物医药科技有限公司 filed Critical 上海君实生物医药科技有限公司
Priority to RU2016102176A priority patent/RU2663795C2/ru
Priority to BR112015031883-5A priority patent/BR112015031883A2/pt
Priority to SI201431678T priority patent/SI3026062T1/sl
Priority to PL14818708T priority patent/PL3026062T3/pl
Priority to US14/392,360 priority patent/US10066013B2/en
Priority to EP14818708.1A priority patent/EP3026062B1/en
Publication of WO2014206107A1 publication Critical patent/WO2014206107A1/zh
Priority to PH12015502819A priority patent/PH12015502819A1/en
Priority to US16/045,363 priority patent/US10815302B2/en
Priority to US17/022,719 priority patent/US20210009688A1/en
Priority to HRP20201600TT priority patent/HRP20201600T1/hr

Links

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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/04—Amoebicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • A61P9/10—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
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • 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

Definitions

  • the present invention belongs to the field of biomedicine and relates to an antibody or a functional fragment thereof which specifically binds to PD-1 with high affinity. Also provided are nucleic acid molecules encoding the antibodies of the invention or functional fragments thereof, expression vectors and host cells for expressing the antibodies of the invention or functional fragments thereof, and methods of producing the antibodies or functional fragments thereof of the invention.
  • the invention also provides immunoconjugates and pharmaceutical compositions comprising the antibodies of the invention or functional fragments thereof, and the use of the antibodies or functional fragments thereof of the invention for the treatment of various diseases including cancer and infectious diseases, inflammatory diseases )Methods. Background technique
  • Programmed cell death 1, PD-1 is a member of the CD28 family and is an immunosuppressive receptor expressed on the surface of activated T cells and B cells (Yao, Zhu et al. Advances in Targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov, 2013, 12(2): 130-146).
  • the receptor binds to its ligands PD-L1 and PD-L2 to effectively reduce the immune response in which immune T cells are involved.
  • Tumor cells escape from the body by high expression of PD-L1 (Okazaki and Honjo, PD-1 and PD-1 ligands: from discovery to clinical application. 2007, 19(7): 813-824 2007). Blocking the interaction of PD1 with PD-L1 can significantly increase the activity of CD8+ cytotoxic T cells to kill tumor cells.
  • PD-1 is mainly expressed on CD4+ ⁇ cells, CD8+ ⁇ cells, ⁇ cells, ⁇ cells and activated monocytes, mainly by ⁇ cell receptor (TCR) or ⁇ cell receptor (BCR) signals.
  • TCR ⁇ cell receptor
  • BCR ⁇ cell receptor
  • TNF enhances the expression of PD-1 on the surface of these cells.
  • the gene Pdcdl is located at 2q37.3 and is 9.6 kb in length, consisting of 5 exons and 4 introns, and contains 663 bp promoter upstream.
  • the extracellular domain contains an immunoglobulin variable region IgV domain, and the intracellular region contains two tyrosine-based signal transduction motifs ITIM (immunoreceptor tyrosine inhibition motif) and ITSM (immunoreceptor) Tyrosine conversion phantom).
  • ITIM immunoglobulin variable region
  • ITSM immunoseceptoreceptor
  • PD-L1 and PD-L2 There are two PD-1 ligands: PD-L1 and PD-L2.
  • PD-L1 is also known as B7H1 or CD274, and PD-L2 is called B7DC or CD273.
  • the PD-L gene is located at the 9p24.2 site of human chromosomes and is 42 kb in size.
  • These ligands have 21 to 27% amino acid sequence homology and structural similarity to B7-1, B7-2, and ICOSL: both contain an immunoglobulin-like variable region domain, a constant region domain, and a
  • the cytoplasmic tail of PD-L1 is more conserved than PD-L2 in the transmodel region and a short cytoplasmic tail.
  • PD-L1 and PD-L2 are expressed in different cell populations (Shimauchi, Kabashima et al., Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma. Int J Cancer, 2007, 121(12): 2585-2590), these cells include non-hematopoietic tissue as well as various tumor types.
  • PD-L1 is mainly expressed in T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, and bone marrow-derived mast cells.
  • PD-L1 is also expressed in non-bone marrow-derived cells such as vascular endothelial cells, epithelial cells, skeletal muscle cells, hepatocytes, renal tubular epithelial cells, islet cells, brain stellate cells, and various non-lymphoid tumors such as melanoma.
  • liver cancer, gastric cancer, renal cell carcinoma cells also expressed in the immune sputum, such as the placenta, eyes.
  • PD-L1 has a broad range of regulation of autoreactive T, sputum cells and immune tolerance, and that ⁇ and ⁇ cell responses play a role in peripheral tissues.
  • the PD-L2 expression region is extremely limited, present only in macrophages and dendritic cells, and is thought to play a major role in immune presentation.
  • PD-L1 is expressed on the surface of a variety of tumor cells including: lung cancer, liver cancer, ovarian cancer, cervical cancer, skin cancer, bladder cancer, colon cancer, breast cancer, glioma, kidney cancer, gastric cancer, esophageal cancer , mouth Squamous cell carcinoma, head and neck cancer. And a lot of expressions have been found around these cancers.
  • CD8+ T cells of PD-L1 CD8+ T cells of PD-L1.
  • Clinical statistics show that the high expression level of PD-L1 on tumor cells is associated with poor prognosis in cancer patients (Okazaki and Honjo 2007, supra).
  • a variety of chronic and acute viruses also evade human immunity through PD-1 and PD-L1 signals.
  • the level of PD-1 expression in HIV-infected individuals is closely related to the degree of depletion of sputum cells and can be used as a marker of AIDS progression (Trabattoni, Saresella et al" B7-H1 is up-regulated in HIV infection and is Blood, 2003, 101(7): 2514-2520).
  • the present invention relates to an anti-PD-1 antibody capable of binding to programmed death factor 1 (PD-1) and a functional fragment thereof.
  • PD-1 programmed death factor 1
  • an antibody of the invention is comprised of SEQ ID NO: 1, 2, 3, 7, 8, 9, 13, 14, or the weight of any of the listed variants
  • the chain CDRs, and/or light chain CDRs selected from the group consisting of SEQ ID NO: 4, 5, 6, 10, 11, 12, 16, 17, 18 or any of the listed variants.
  • the antibody to the heavy chain CDR1, CDR2 and CDR3 of the antibody or a functional fragment thereof is selected from the group consisting of the following group of acid sequences or variants thereof:
  • SEQ ID NO: 13 SEQ ID NO: 14
  • the set of amino acid sequences of SEQ ID NO: 15 and/or its light chain CDR1, CDR2 and CDR3 is selected from the group consisting of the following acid sequences or variants thereof:
  • the heavy chain CDR1, CDR2 and CDR3 of the antibody of the invention or a functional fragment thereof, and the acid sequence of the light chain CDR1, CDR2 and CDR3 are selected from the group consisting of the following amino acid sequences or variants thereof A group that:
  • an antibody of the invention or a functional fragment thereof comprises a heavy chain variable region selected from the amino acid sequence of SEQ ID NO: 19, 21, 23 or a variant of any of the sequences, and/or selected From the amino acid sequence SEQ ID NO: 20, 22, 24 or a light chain variable region of a variant of any of said sequences.
  • the heavy chain variable region is SEQ ID NO: 19 or a variant thereof and the light chain variable region is SEQ ID NO: 20 or a variant thereof.
  • the heavy chain variable region is SEQ ID NO: 21 or a variant thereof and the light chain variable region is SEQ ID NO: 22 or a variant thereof.
  • the heavy chain variable region is SEQ ID NO: 23 or a variant thereof and the light chain variable region is SEQ ID NO: 24 or a variant thereof.
  • the antibody of the present invention or a functional fragment thereof may be a chimeric antibody, a humanized antibody or a fully human antibody.
  • An antibody of the invention or a functional fragment thereof can be humanized.
  • Methods of preparing humanized antibodies are well known to those skilled in the art.
  • a humanized anti-PD-1 antibody of the invention can be prepared by transferring a CDR sequence of the invention into a variable region of a human antibody.
  • the humanized antibody does not produce an anti-antibody reaction (AAR) and a human anti-mouse antibody response (HAMA), is not rapidly cleared by neutralization by anti-antibodies, and has immune effector functions such as ADCC and CDC.
  • AAR anti-antibody reaction
  • HAMA human anti-mouse antibody response
  • the humanized PD-1 antibody or functional fragment thereof of the invention comprises a SEQ ID NO: 33, 35, 36 or any of the sequences selected from the group consisting of SEQ ID NO: 33, 35, 36 A heavy chain variable region of a variant, and/or a light chain variable region selected from the amino acid sequence of SEQ ID NO: 34, 37 or a variant of any of said sequences.
  • the heavy chain variable region is SEQ ID NO: 33 or a variant thereof and the light chain variable region is SEQ ID NO: 34 or a variant thereof.
  • the heavy chain variable region is SEQ ID NO: 35 or a variant thereof and the light chain variable region is SEQ ID NO: 34 or a variant thereof.
  • the heavy chain variable region is SEQ ID NO: 36 or a variant thereof and the light chain variable region is SEQ ID NO: 34 or a variant thereof.
  • the heavy chain variable region is SEQ ID NO: 35 or a variant thereof and the light chain variable region is SEQ ID NO: 37 or a variant thereof.
  • the invention also provides an isolated nucleic acid molecule encoding an antibody or functional fragment of the invention.
  • the nucleic acid molecule comprises the nucleotide sequence set forth in SEQ ID NOs: 25-30, 38-42, or a combination thereof.
  • the invention also provides an expression vector comprising the nucleic acid molecule and a host cell comprising the vector.
  • the present invention provides a method of producing an anti-PD-1 antibody or a functional fragment thereof, comprising: cultivating the above-described host cell of the present invention under conditions permitting production of the antibody or a functional fragment thereof, and recovering such production Said antibody or functional fragment thereof.
  • the invention relates to an immunoconjugate comprising an antibody of the invention or a functional fragment thereof conjugated to a therapeutic agent.
  • the therapeutic agent is preferably a toxin, a radioisotope, a drug or a cytotoxic agent.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody of the invention or a functional fragment thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method for preventing or treating a disease or condition by eliminating, inhibiting or reducing PD-1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody of the invention Or a functional fragment thereof, a nucleic acid, an expression vector, a host cell, an immunoconjugate or a pharmaceutical composition.
  • the disease or condition is selected from the group consisting of a cancer, an infectious disease or an inflammatory disease;
  • the cancer is preferably selected from the group consisting of melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, Head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, pussy Cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute Leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocy
  • the inflammatory disease is preferably selected from acute disseminated encephalomyelitis, Addison's disease, and rigidity Spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, arthritis, Bechert's disease, bullous pemphigoid, abdominal disease, Chagas disease, Crohn's disease , dermatomyositis, type 1 diabetes, pulmonary hemorrhagic-nephritis syndrome,
  • the invention also provides the use of an antibody of the invention, or a functional fragment thereof, nucleic acid, expression vector, host cell, immunoconjugate or pharmaceutical composition, for the manufacture of a medicament for the treatment of a disease or condition.
  • Figure 1 shows the protein size of the PD-1 extracellular domain of human (hu) and cynomolar (cyno) as indicated by SDS-PAGE.
  • Figure 2 shows the binding of biotinylated rh-PD-Ll to human T cells as determined by flow cytometry.
  • Figure 3 shows PD-L1 control, clones 1, 10, 11, 55, and 64 P as determined by flow cytometry and binds PD-1 on the cell surface to ligand PD-L1.
  • Figure 4 shows the binding of control antibodies, clones 1, 10, 11, 55 and 64 to PD-1 and other CD28 family members (ICOS, CTLA-4 and CD28).
  • Figure 5 shows a tetanus stimulation test for detecting in vitro stimulation of T cells by chimeric antibodies.
  • Figure 6 shows the secretion levels of humanized antibodies clones 38, 39, 41, and 48 (control (conIgG4)) IL2 detected by the CD8+ cytokine assay kit.
  • FIG. 7 shows that dendritic cells were co-cultured with engineered MD-MAB-453 cells for 3 days, and the extracted T cells and the humanized anti-PD-1 antibody clones 38, 39, 41 and 48 of the invention were added ( Control (conIgG4)) GFP fluorescence values obtained after 3 days of co-culture.
  • Figure 8 shows the binding of the humanized antibody of the present invention to human, cynomolgus and murine PD-1 proteins.
  • Figure 9 shows the alignment of PD-1 sequences of human, cynomolgus (Cyno) and mouse (mouse), in which mouse PD-1 differs from human and cynomolgus PD-1 protein. The area is marked with a frame.
  • FIG. 10 shows the in vitro stimulation of humanized antibodies.
  • T cell proliferation assay The results of the cold-resistance memory response experiment.
  • FIG. 11 shows the results of in vitro stimulation of humanized antibody T cell proliferation assay-virus polypeptide antigen memory response experiments. detailed description
  • the present invention provides an anti-PD-1 antibody capable of binding to programmed death factor 1 (PD-1) and a functional fragment thereof.
  • the antibody of the present invention or a functional fragment thereof has at least one of the following properties: is capable of blocking the interaction of PD-1 and PD-L1 with high affinity; capable of binding with PD-1 with high specificity, and with other CD28 families Members (such as ICOS, CTLA-4, and CD28) do not bind; activate tumor-specific T cells, thereby killing tumor cells, promoting CD8+ entry into solid tumor tissues, and greatly increasing the levels of immune effectors such as IFNy.
  • the invention also provides humanized anti-PD-1 antibodies and functional fragments thereof.
  • the humanized antibody is obtained by computer simulation design and combined with phage display technology, and the binding epitope is also identified according to its binding property to different species of PD-1 protein. .
  • the humanized anti-PD-1 antibody and functional fragment thereof of the present invention in addition to the advantageous properties of the above-mentioned anti-PD-1 antibody and its functional fragment, also bind human or cynomolgus PD-1 protein with high affinity. , but does not interact with the murine PD-1 protein.
  • sequences of the present invention can replace, add, and/or delete one or more of the sequences of the present invention without substantial impact on antibody activity (eg, 1, 2, 3, 4, 5, 6, 7). , 8, 9 or 10 or more amino acids, to obtain variants of the sequence of the antibody or functional fragment thereof. They are all considered to be included within the scope of the present invention. Substituting acid with similar properties as in the variable region.
  • the sequences of the variants of the invention may be at least 95%, 96%, 97%, 98% or 99% identical to the sequence from which they are derived.
  • sequence identity described in the present invention can be measured using sequence analysis software. For example, the computer program BLAST using the default parameters, especially BLASTP or TBLASTN.
  • the antibody of the present invention may be full length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen binding portion (for example, a Fab, F(ab,) 2 or scFv fragment), or may be modified to affect function. .
  • the invention includes anti-PD-1 antibodies having a modified glycosylation pattern. In some applications, it may be useful to modify to remove undesired glycosylation sites, or to have no fucose moiety on the oligosaccharide chain to, for example, enhance antibody-dependent cellular cytotoxicity (ADCC) function. In other applications, galactosylation modifications can be made to alter complement dependent cytotoxicity (CDC).
  • ADCC enhance antibody-dependent cellular cytotoxicity
  • the term "functional fragment” as used herein especially refers to antibody fragments such as Fv, scFv (sc refers to single strand), Fab, F(ab,) 2, Fab ⁇ scFv-Fc fragment or diabody (diabody).
  • Either by chemical modification or by incorporation into liposomes should be able to increase any fragment of half-life, such as the addition of poly(alkylene) glycols such as polyethylene glycol ("PEGylated, PEG”(”called PEGylated fragment of Fv-PEG, scFv-PEG, Fab-PEG, F(ab')2-PEG or Fab'-PEG) ("PEG” is polyethylene glycol),
  • PEG polyethylene glycol
  • the functional fragment will consist of or comprise a partial sequence of a heavy or light variable chain from which the antibody is derived, the partial sequence being sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived, for PD-1, It is preferably at least equal to 1/100 of the affinity of the antibody from which it is derived, and in a more preferred manner at least equal to 1/10.
  • a functional fragment will comprise a minimum of 5 amino acids, preferably 10, 15, 25, 50 and 100 contiguous amino acids of the antibody sequence from which it is derived.
  • the present invention also provides a recombinant DNA vector comprising a DNA molecule encoding the anti-PD-1 antibody of the present invention.
  • the recombinant DNA vector is an expression vector, and a person skilled in the art clones the DNA molecule of the antibody into an expression vector, transforms the host cell, and obtains an antibody by inducing expression.
  • the expression vector of the present invention contains the DNA sequence of the heavy chain variable region, the light chain variable region and/or the constant region of the encoded anti-PD-1 antibody.
  • the expression vector further comprises a promoter and a DNA sequence encoding a secretion signal peptide, and at least one drug resistance gene for screening.
  • the host cell of the present invention may be a prokaryotic host cell, a eukaryotic host cell or a bacteriophage.
  • the prokaryotic host cell may be Escherichia coli, Bacillus subtilis, Streptomyces or Streptomyces.
  • the eukaryotic host cell may be a fungus such as Pichia pastoris, Saccharomyces cerevisiae, fission yeast, Trichoderma, or the like, such as a plant cell such as tobacco, such as BHK cells, CHO cells, Mammalian cells such as COS cells and myeloma cells.
  • the invention is The host cell is preferably a mammalian cell, more preferably a BHK cell, a CHO cell, an NSO cell or a COS cell.
  • composition denotes a combination of at least one drug, and optionally a pharmaceutically acceptable carrier or excipient, that are combined together to achieve a particular purpose.
  • the pharmaceutical compositions include combinations that are separated in time and/or space, as long as they are capable of acting together to achieve the objectives of the present invention.
  • the components contained in the pharmaceutical composition e.g., the antibody, nucleic acid molecule, nucleic acid molecule combination, and/or conjugate according to the present invention
  • the components contained in the pharmaceutical composition may be administered to the subject as a whole or separately to the subject.
  • the components contained in the pharmaceutical composition are separately administered to a subject, the components may be administered to the subject simultaneously or sequentially.
  • the pharmaceutically acceptable carrier is water, a buffered aqueous solution, an isotonic saline solution such as PBS (phosphate buffer), glucose, mannitol, dextrose, lactose, starch, magnesium stearate, fiber Or magnesium carbonate, 0.3% glycerol, hyaluronic acid, ethanol or polyalkylene glycol such as polypropylene glycol, triglyceride and the like.
  • PBS phosphate buffer
  • glucose mannitol
  • dextrose dextrose
  • lactose starch
  • magnesium stearate fiber Or magnesium carbonate
  • 0.3% glycerol, hyaluronic acid ethanol
  • polyalkylene glycol such as polypropylene glycol, triglyceride and the like.
  • the type of pharmaceutically acceptable carrier employed depends inter alia on whether the composition according to the invention is formulated for oral, nasal, intradermal, subcutaneous, intramuscular or intravenous administration.
  • composition according to the present invention can be administered by any suitable route, for example, orally, nasally, intradermally, subcutaneously, intramuscularly or intravenously.
  • the invention provides a pharmaceutical composition that is a combination of an anti-PD-1 antibody and a second therapeutic agent.
  • the second therapeutic agent is any agent that is advantageously combined with an anti-PD-1 antibody.
  • agents that may be advantageously combined with an anti-PD-1 antibody include, but are not limited to, other agents that inhibit PD-1 activity (including other antibodies or antigen-binding fragments thereof, peptide inhibitors, small molecule antagonists, etc.) and/or interference Reagents for signal transduction upstream or downstream of PD-1.
  • the term "preventing or treating a disease or condition by eliminating, inhibiting or reducing PD-1 activity" as used herein is intended to mean a disease or condition caused by PD-1 expression or characterized by PD-1 expression.
  • the disease or condition is selected from a cancer or an infectious disease.
  • the cancer includes, but is not limited to, lung cancer, liver cancer, ovarian cancer, cervical cancer, skin cancer, bladder cancer, colon cancer, breast cancer, glioma, renal cancer, gastric cancer, esophageal cancer, oral squamous cell carcinoma, head and neck cancer.
  • the infection sexual diseases include, but are not limited to, HIV infection and hepatitis B virus infection.
  • terapéuticaally effective amount refers to a dose sufficient to demonstrate its benefit to the subject to which it is administered.
  • the actual amount administered, as well as the rate and time course of administration, will depend on the condition and severity of the subject being treated.
  • the prescription of treatment eg, the determination of the dose, etc.
  • the prescription of treatment is ultimately the responsibility of the GP and other physicians and depends on their decision, usually considering the disease being treated, the condition of the individual patient, the site of delivery, the method of administration, and the Other factors known.
  • subject refers to a mammal, such as a human, but can also be other animals, such as wild animals (such as herons, donkeys, cranes, etc.), livestock (such as ducks, geese, etc.) or Experimental animals (such as raccoon, monkey, rat, mouse, rabbit, guinea pig, etc.).
  • wild animals such as herons, donkeys, cranes, etc.
  • livestock such as ducks, geese, etc.
  • Experimental animals such as raccoon, monkey, rat, mouse, rabbit, guinea pig, etc.
  • the downstream primer is 5, -
  • the cell fluid to be separated is diluted to a suitable concentration with a pre-warmed RPMI medium, approximately 5.00 x 10 7 cells/ml. Pour the cell fluid into the syringe so that it does not pass through the nylon column. Cover with a syringe and incubate for 1 hour. Open the lower mouth, slowly discharge (1 drop / min), and collect in the centrifuge tube. Centrifuge lOOOxg for 10 minutes to obtain the desired T lymphocytes.
  • the lymph nodes at the roots of the thighs of the mice were taken, and the B-cell-rich suspension was taken after grinding in physiological saline, and electrotransformed according to the conventional method (see BTX company's electro-transfer manual) and SP2/. 0 cell fusion.
  • the fused cells were cultured in RPMI-1640 whole medium (Sigma) containing HAT at 5% CO 2 at 37 °C.
  • the primer sequence used in the amplification reaction is complementary to the first framework region and constant region of the antibody variable region (Larrick, JW" et al., (1990) Scand. J. Immunol., 32, 121-128 and Coloma, JJet Al., (1991) BioTechniques.
  • V3V1V ⁇ nVDTOV33VV3 ⁇ 313VD3_L TO ⁇ V ⁇ :) V913VlllV:)V:)VI0333:)li:) 3
  • ⁇ ⁇ cells (Beijing Institute of Hematology) cloned the heavy chain constant region Fc fragment and the light chain 1 ⁇ /£ constant region, ligated into the CDNA3.1 plasmid (see Walls MA, Hsiao H and Harris LJ (1993), Nucleic Acids Research, Vol. 21, No. 12 2921 -2929 ).
  • the heavy and light chain sequence fragments described in Example 6 were synthesized by Genscript, the heavy chain was digested with Xho I and Age I, and the light chain fragment was digested with Sma I and Dra III, and ligated into the corresponding modified pCDNA3.1.
  • the cloned DNA sequence was determined in the plasmid and sequenced. Subsequent experimental materials were obtained by transfecting the cells with this series of plasmids and purifying them.
  • Example 8 Chimeric antibody stimulated T cell function in vitro - a tetanus toxin stimulation test
  • Freshly prepared PBMCs were plated into 96-well flat bottom plates, incubated, and various concentrations of antibody and 100 ng/ml tetanus toxin (TT) (List Biological Laboratories) were added. The supernatant was harvested three days later, and the IFNy content in the supernatant was measured by Elisa using R&D System's IFNy kit.
  • TT tetanus toxin
  • the cytokine secreted by the immune cells activated by TT stimulation was greatly increased after blocking the PD-1 signal.
  • the candidate antibody titer is higher than the application number: 200980147059.0 purchased from Biolegend Company ⁇ 12 ⁇ 2 ⁇ 7.
  • Humanization was carried out according to the variable region sequence of the antibody secreted by the hybridoma cells obtained above. Briefly, the humanization process involves the following steps: A. Aligning the gene sequence of the antibody secreted by each hybridoma cell with the human embryonic antibody gene sequence to find a sequence with high homology; B. Analysis and investigation HLA-DR affinity, selecting the human embryonic framework sequence with low affinity; c. Using the computational technique, using the molecular docking analysis of the variable region and its surrounding framework amino acid sequence, and examining its spatial stereoscopic binding mode.
  • VVViiVVVE E)iDVVV:OV:)E)E)E)V:):)E)E)lii:):)VE ⁇ :) E):OE) ⁇ E ⁇ V:OE)V:)E) E) E) V: iLL EXL
  • PBMC Beijing Institute of Hematology
  • 10 ug/ml of antibody and 100 ng/ml of tetanus toxin (TT) were added to the culture. After 3 days of culture, the supernatant was collected.
  • the secretion levels of humanized antibody clones 38, 39, 41 and 48 (control (conIgG4)) IL2 were detected using Life Technology's Luminex instrument and EMD's CD8+ cytokine detection kit. The results (see Figure 6) show that humanized antibodies can stimulate the function of T cells.
  • Example 12 Humanized antibodies can stimulate T cells to kill tumor cells in vitro
  • MD-MAB-453 cells were infected with Qiagen expressing the PD-L1 protein, and a MD-MAB-453 cell line stably expressing PD-L1 was obtained, and the GFP gene was further introduced into the IG gene. It stably expresses GFP protein. Extraction of dendritic cells (DC) from fresh peripheral blood cells, co-cultured with the above-described modified MD-MAB-453 cells (300 cells/well) at 300 cells/well in a 96-well plate for 3 days, and then the extracted T was added.
  • DC dendritic cells
  • T cell proliferation was quantified by dilution factor of CSFE using flow cytometry (FACS) after days 6, 8 and 10. The results can be seen from FIG. 11, as compared to control I g G, blocking the PD-1 polypeptide to stimulate the mixed signal CEF inducing activated immune cells are further proliferation.

Abstract

本发明提供了以高亲和力与PD-1特异性结合的抗体或其功能性片段。还提供了编码本发明抗体或其功能性片段的核酸分子，用于表达本发明抗体或其功能性片段的表达载体和宿主细胞，以及本发明抗体或其功能性片段的生产方法。本发明还提供了包含本发明抗体或其功能性片段的免疫缀合物以及药物组合物，以及使用本发明的抗体或其功能性片段治疗多种疾病（包括癌症和感染性疾病、炎性疾病）的方法。

Description

抗 PD-1抗体及其应用 技术领域
[01] 本发明属于生物医药领域， 涉及以高亲和力与 PD-1特异性 结合的抗体或其功能性片段。还提供了编码本发明抗体或其功能 性片段的核酸分子，用于表达本发明抗体或其功能性片段的表达 载体和宿主细胞， 以及本发明抗体或其功能性片段的生产方法。 本发明还提供了包含本发明抗体或其功能性片段的免疫缀合物 以及药物组合物，以及使用本发明的抗体或其功能性片段治疗多 种疾病 （包括癌症和感染性疾病、 炎性疾病）的方法。 背景技术
[02] 程序性死亡因子 l(programmed cell death 1， PD-1)是 CD28 家族成员， 并且是在活化 T细胞和 B细胞表面上表达的免疫抑 制性受体 (Yao， Zhu et al. Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov, 2013, 12(2): 130-146)。 该受体和其配体 PD-L1和 PD-L2 相结合可以有效降低免疫 T 细胞参与的免疫应答。 肿瘤细胞通 过高表达 PD-L1逃^ L体内免 督 (Okazaki和 Honjo, PD-1 and PD-1 ligands: from discovery to clinical application.
Figure imgf000002_0001
2007, 19(7): 813-824 2007)。 阻断 PD1 与 PD-L1的相互作用可以显著提高 CD8+细胞毒 T细胞的活性， 以杀伤肿瘤细胞。
[03] PD-1 主要表达于 CD4+ Τ 细胞、 CD8+ Τ 细胞、 ΝΚΤ 细 胞、 Β 细胞和活化的单核细胞表面， 主要受 Τ 细胞受体 (TCR) 或 Β 细胞受体 (BCR)信号的 i秀导表达， TNF可增强 PD-1 在这 些细胞表面的表达 (Francisco, Sage et al" The PD-1 pathway in tolerance and autoimmunity. Immunol Rev, 2010， 236: 219-242)。 人 PD-1由基因 Pdcdl编码， 位于 2q37.3， 全长 9.6 kb, 由 5 个 外显子和 4 个内含子组成，其上游包含 663 bp 的启动子。 PD-1 分子结构由胞外区、跨膜区和胞内区构成，胞外区的 基酸序列 和 CTLA-4有 24% 的同源性， 和 CD28具有 28% 的同源性， 其基因主要有 7个单核甘酸多态性位点。 胞外区含有一个免疫 球蛋白可变区 IgV结构域， 胞内区含有两个基于酪氨酸的信号 转导模体 ITIM (免疫受体酪氨酸抑制作用模体 )和 ITSM (免 疫受体酪氨酸转换作用模体）。在 T细胞被激活后， PD-1主要通 过 ITSM模体， 将酪氨酸磷脂酶 SHP2集合， 导致包括 CD3 、
PKC9和 ZAP70等效应分子的去磷酸化。
[04] PD-1 配体有两个： PD-L1 和 PD-L2。PD-L1 又称 B7H1 或 CD274, PD-L2称为 B7DC 或 CD273。 PD-L基因位于人的染 色体 9p24.2位点，大小为 42 kb。这些配体和 B7-l、B7-2、ICOSL 有 21~27% 的氨基酸序列同源性和结构相似性： 均包含一个免 疫球蛋白样可变区结构域、一个恒定区样结构域和一个跨模区和 一个短的胞质尾巴， PD-L1 的胞质尾巴比 PD-L2 更保守。 PD-L1 和 PD-L2表达于不同的细胞群体 (Shimauchi, Kabashima et al., Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma. Int J Cancer, 2007, 121(12): 2585-2590), 这 些细胞包括非造血组织以及各种肿瘤类型。 PD-Ll 主要表达于 T 细胞、 B细胞、 树突状细胞、 巨噬细胞、 间充质干细胞和骨髓来 源的肥大细胞。 PD-L1 也表达于非骨髓来源的细胞， 如血管内 皮细胞、 上皮细胞、 骨骼肌细胞、 肝细胞、 肾小管上皮细胞、 胰 岛细胞， 脑部星状细胞和各类非淋巴系肿瘤如黑色素瘤、 肝癌、 胃癌、 肾细胞癌， 亦表达于免疫特赦部位的细胞，如胎盘、眼睛。 这表明 PD-L1 在调节自身反应性 T、 Β 细胞和免疫耐受方面具 有一定广泛性， 并且在外周组织 Τ和 Β细胞应答起作用。 但是 PD-L2表达区域却极其有限， 仅在巨噬细胞和树突细胞中存在， 被认为主要在免疫呈递中起作用。
[05] PD-1和 PD-L1相互作用以调节控制 Τ细胞的活化在肿瘤和 病毒感染中得到了大量 ¾ϋ。 PD-Ll表达于多种肿瘤细胞表面， 这些肿瘤细胞包括： 肺癌， 肝癌， 卵巢癌， 宫颈癌， 皮肤癌， 膀 胱癌， 结肠癌， 乳腺癌， 神经胶质瘤， 肾癌， 胃癌， 食道癌， 口 腔鳞状细胞癌， 头颈癌。 而且在这些癌症周边也发现了大量表达
PD-L1的 CD8+T细胞。 临床统计显示， PD-L1在肿瘤细胞上的 高表达水平与癌症患者不良预后相关 (Okazaki和 Honjo 2007, 同上)。
[06] 多种慢性和急性病毒也通过 PD-1和 PD-L1信号逃避人体免 测。 例如： HIV感染者体内 PD-1 的表达水平与 Τ 细胞的 耗竭程度密切相关， 且可作为 AIDS 病情进展的标志之一 (Trabattoni, Saresella et al" B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood, 2003, 101(7): 2514-2520). 此现象也同样适用慢性乙肝患 者 (Evans, Riva et al" Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion., Hepatology, 2008， 48(3): 759-769)。 动 物实验显示， PD-1基因剔除小鼠比正常小鼠更好地控制病毒感 染； 而将 HBV特异型 T细胞转移到 HBV转基因动物中会引发 肝炎。 发明内容
[07] 本发明涉及能够结合程序性死亡因子 1 ( PD-1 )的抗 PD-1 抗体及其功能性片段。
[08] 一方面，本发明的抗体或其功能性片段包 ^^自 列 SEQ ID NO: 1， 2， 3, 7, 8， 9， 13, 14， 15或任何所 列之变体的 重链 CDR，和 /或选自 列 SEQ ID NO: 4， 5， 6， 10， 11， 12， 16， 17， 18或任何所 列之变体的轻链 CDR。
[09] 在一些优选的实施方案中，所述抗体或其功能性片段的重链 CDR1、 CDR2和 CDR3的暴基酸序列选自以下各 基酸序列或 其变体的组中的一组：
Figure imgf000004_0001
C SEQ ID NO:13 SEQ ID NO:14 SEQ ID NO:15 和 /或其轻链 CDR1、 CDR2和 CDR3的氨基酸序列选自以下各 ^^酸序列或其变体的组中的一组：
Figure imgf000005_0001
在一些优选的实施方案中，本发明抗体或其功能性片段的重 链 CDR1、 CDR2和 CDR3以及轻链 CDR1、 CDR2和 CDR3的 ^^酸序列选自以下各氨基酸序列或其变体的组中的一组：
Figure imgf000005_0002
[10] 在一些实施方案中，本发明抗体或其功能性片段包含选自氨 基酸序列 SEQ ID NO: 19， 21， 23或任何所述序列之变体的重链 可变区， 和 /或选自氨基酸序列 SEQ ID NO: 20， 22， 24或任何所 述序列之变体的轻链可变区。
[11] 在一个优选的实施方案中， 所述重链可变区为 SEQ ID NO: 19或其变体并且所述轻链可变区为 SEQ ID NO: 20或其变体。
[12] 在另一个优选的实施方案中， 所述重链可变区为 SEQ ID NO: 21或其变体并且所述轻链可变区为 SEQ ID NO: 22或其变 体。
[13] 在又一个优选的实施方案中， 所述重链可变区为 SEQ ID NO: 23或其变体并且所述轻链可变区为 SEQ ID NO: 24或其变 体。 [14] 本发明的抗体或其功能性片段可以是嵌合抗体、人源化抗体 或全人抗体。
[15] 本发明的抗体或其功能性片段可以是人源化的。制备人源化 抗体的方法是本领域技术人员公知的。例如，可以通过将本发明 的 CDR序列转移至人抗体可变区中来制备本发明的人源化抗 PD-1抗体。 所述人源化抗体不会产生抗抗体反应 ( AAR )和人 抗鼠抗体反应 ( HAMA ), 不会因被抗抗体中和而被快速清除， 并且具有免疫效应功能， 如 ADCC和 CDC作用。
[16】在一些优选的实施方案中， 本发明的人源化 PD-1抗体或其 功能性片段包含选自 ^J^^t列 SEQ ID NO: 33, 35, 36或任何 所述序列之变体的重链可变区， 和 /或选自氨基酸序列 SEQ ID NO: 34, 37或任何所述序列之变体的轻链可变区。
[17] 在本发明人源化抗体或其功能性片段的一个优选的实施方 案中， 所述重链可变区为 SEQ ID NO: 33或其变体并且所述轻 链可变区为 SEQ ID NO: 34或其变体。
[18] 在本发明人源化抗体或其功能性片段的另一个优选的实施 方案中， 所述重链可变区为 SEQ ID NO: 35或其变体并且所述 轻链可变区为 SEQ ID NO: 34或其变体。
[19] 在本发明人源化抗体或其功能性片段的另一个优选的实施 方案中， 所述重链可变区为 SEQ ID NO: 36或其变体并且所述 轻链可变区为 SEQ ID NO: 34或其变体。
[20] 在本发明人源化抗体或其功能性片段的又一个优选的实施 方案中， 所述重链可变区为 SEQ ID NO: 35或其变体并且所述 轻链可变区为 SEQ ID NO: 37或其变体。
[21] 本发明还提供了编码本发明抗体或功能性片段的分离的核 酸分子。 在一个优选的实施方案中， 所述核酸分子包含 SEQ ID NO: 25-30, 38-42所示的核苷酸序列或其组合。
[22] 本发明还提供了包含所述核酸分子的表达载体以及包含所 达载体的宿主细胞。 [23] 本发明提供了产生抗 PD-1抗体或其功能性片段的方法， 其 包括：在允许产生所述抗体或其功能性片段的条件下培养本发明 的上述宿主细胞， 以及回收这样产生的所述抗体或其功能性片 段。
[24] 在另一方面，本发明涉及包含与治疗剂缀合的本发明抗体或 其功能性片段的免疫缀合物。所述治疗剂优选地为毒素、放射性 同位素、 药物或细胞毒剂。
[25] 本发明还涉及包含本发明抗体或其功能性片段以及可药用 载体的药物组合物。
[26] 在另一方面，本发明提供了用于通过消除、抑制或降低 PD-1 活性来预防或治疗疾病或病症的方法，其包括向有此需要的对象 施用治疗有效量的本发明抗体或其功能性片段,核酸,表达载体, 宿主细胞，免疫缀合物或药物组合物。其中所述疾病或病症选自 癌症、感染性疾病或炎性疾病；所述癌症优选选自黑素瘤、肾癌、 前列腺癌、 乳癌、 结肠癌、 肺癌、 骨癌、 胰腺癌、 皮肤癌、 头或 颈癌、 皮肤或眼内恶性黑素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛区 癌、 胃癌、 睾丸癌、 子宫癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 阴户癌、 何杰金氏病、 非何杰金氏淋巴瘤、 食道癌、 小 肠癌、 内分泌系统的癌症、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、尿道癌、 阴茎癌、 慢性或急性白血病， 其包括急性 髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血 病、慢性淋巴细胞性白血病、儿童期实体瘤、淋巴细胞性淋巴瘤、 膀胱癌、 肾或输尿管癌、 肾盂癌、 中枢神经系统的赘生物、原发 性中枢神经系统淋巴瘤、 肿瘤血管发生、脊髓轴肿瘤、脑干胶质 瘤、 垂体腺瘤、 卡波西氏肉瘤、 表皮样癌、 鳞状细胞癌、 T细胞 淋巴瘤、环境诱发的癌症、其包括石棉所诱发的那些， 和所述癌 症的组合； 所述感染性疾病优选选自 HIV、 流行性感冒、 疱疹、 贾第虫病、 疟疾、 利什曼病、 以下病毒引起的致病感染： 肝炎病 毒（甲型、 乙型和丙型）、疱疹病毒（例如 VZV、 HSV-1、 HAV-6、 HSV-II和 CMV、 埃巴二氏病毒）、 腺病毒、 流感病毒、 黄病毒、 艾柯病毒、 鼻病毒、 柯萨奇病毒、 冠状病毒、 呼吸道合胞病毒、 腿腺炎病毒、 轮状病毒、 麻渗病毒、 风奢病毒、 细小病毒、 牛痘 病毒、 HTLV病毒、 登革热病毒、 乳头瘤病毒、 软疣病毒、 脊髓 ^^炎病毒、 狂犬病病毒、 JC病毒和虫媒病毒 >脑炎病毒， 以 下细菌引起的致病感染： 衣原体、 立克次氏体、 分枝杆菌、 葡萄 球菌、 链球菌、 肺炎球菌、 脑膜炎球菌和 conococci、 克雷伯氏 菌、 变形菌、 沙雷氏菌、 假单胞菌、 军团菌、 白喉、 沙门氏菌、 杆菌、 霍乱、 破伤风、 肉毒中毒、 炭疽、 鼠疫、 钩端螺旋体病和 莱姆氏病细菌， 以下真菌引起的致病感染： 假丝酵母 (白色假丝 酵母、 克鲁斯假丝酵母、 光滑假丝酵母、 热带假丝酵母等）、 新 型隐球酵母、 曲霉（烟曲霉、 黑曲霉等）、 毛霉目的属（毛霉属、 犁头霉属、 根霉属）、 申克氏孢子丝菌、 皮炎芽酵母、 巴西副球 孢子菌、粗球孢菌和加膜组织胞浆菌，及以下寄生虫引起的致病 感染： 痢疾内变形虫、 结肠肠袋虫、 福纳氏虫、 棘变形虫、 吸吮 贾第虫、 隐孢子虫、 卡氏肺嚢虫、 间日疟原虫、 田鼠巴贝虫、 布 鲁斯锥虫、 克鲁兹锥虫、 多氏利什曼虫、 鼠弓浆虫和 巴西日圆 线虫； 所述炎性疾病优选选自急性播散性脑脊髓炎、 阿狄森病、 强直性脊柱炎、 抗磷脂抗体综合征、 自身免疫性溶血性贫血、 自 身免疫性肝炎、关节炎、贝切特病、大疱性类天疱疮、腹部疾病、 恰加斯病、克罗恩病、皮肌炎、 1型糖尿病、肺出血-腎炎综合征、 移植物抗宿主病、 格雷夫斯病、 格-巴二氏综合征、 桥本病、 超 IgE综合征、 特发性血小板减少性紫癜、 红斑狼疮、 多发性硬化 症、 重症肌无力、 天疱疮、 恶性贫血、 多肌炎、 原发性胆汁性肝 硬变、 银屑病、 类风湿关节炎、 斯耶格伦综合征、 颞动脉炎、 血 管炎和韦格纳肉芽肿病。
[27] 本发明还提供了本发明的抗体或其功能性片段、 核酸、， 表 达载体、宿主细胞、免疫缀合物或药物组合物在制备用于治疗疾 病或病症的药物中的用途。 附图说明
[28] 图 1所示为 SDS-PAGE所显示的人源性（hu )和食蟹猴源 性（cyno )的 PD-1胞外结构区的蛋白质大小。 [29] 图 2所示为流式细胞术测定的生物素标记 rh-PD-Ll与人 T 细胞结合。
[30] 图 3所示为通过流式细胞术测定的 PD-L1对照、克隆 1， 10， 11、 55和 64 P且碍细胞表面的 PD-1与配体 PD-L1结合。
[31] 图 4所示为对照抗体、 克隆 1， 10， 11、 55和 64与 PD-1 以及其他 CD28家族成员（ ICOS、 CTLA-4以及 CD28 )的结合。
[32] 图 5所示为检测嵌合抗体对 T细胞的体外刺激的破伤风毒 素刺激实验。
[33] 图 6所示为 CD8+细胞因子检测试剂盒检测的人源化抗体克 隆 38、 39、 41以及 48 (对照 （conIgG4 ) ) IL2的分泌水平。
[34] 图 7所示为树突细胞与经改造 MD-MAB-453细胞共同培养 3天后，加入提取的 T细胞和本发明人源化抗 PD-1抗体克隆 38、 39、 41以及 48 (对照（ conIgG4 ) )共同培养 3天后得到的 GFP 荧光值。
[35] 图 8所示为本发明的人源化抗体与人、食蟹猴以及鼠源 PD-1 蛋白的结合。
[36] 图 9所示为人（ human )、 食蟹猴（ Cyno )和小鼠（ mouse ) PD-1序列的比对， 其中小鼠 PD-1与人和食蟹猴 PD-1蛋白的主 要不同区域用框架标注。
[37] 图 10显示人源化抗体体外刺激 T细胞增殖实验 伤风抗 原记忆应答实验的结果。
[38] 图 11显示人源化抗体体外刺激 T细胞增殖实验一病毒多肽 抗原记忆应答实验的结果。 具体实施方式
[39] 除非另有定义，本文使用的所有科技术语具有本领域普通技 术人员所理解的相同含义。关于本领域的定义及术语， 专业人员 具体可参考 Current Protocols in Molecular Biology ( Ausubel )。 氨基酸残基的缩写是本领域中所用的指代 20个常用 酸之 一的标准 3字母和 /或 1字母代码。
[40] 本发明提供了能够结合程序性死亡因子 1( PD-1 )的抗 PD-1 抗体及其功能性片段。本发明的抗体或其功能性片段具有以下特 性的至少一种：能够以高亲和力阻断 PD-1和 PD-L1的相互作用； 能够与 PD-1 以高特异性结合， 而与其它 CD28 家族成员 （如 ICOS、 CTLA-4和 CD28 )不发生结合； 激活肿瘤特异性 T细 胞， 从而杀伤肿瘤细胞， 促进 CD8+进入实体瘤组织， 使 IFNy 等免疫效应物的水平大大增加。
[41] 本发明还提供了人源化抗 PD-1抗体及其功能性片段。 所述 人源化抗体由免疫小鼠产生的鼠源抗体经由计算机模拟设计并 结合噬菌体展示技术而得到， 并且根据其与不同物种的 PD-1蛋 白的结合特性，其结合表位也相应被鉴定。本发明所述的人源化 抗 PD-1抗体及其功能性片段除具备上述抗 PD-1抗体及其功能 性片段的有利特性外，还以高亲和力结合人或食蟹猴 PD-1蛋白 , 但不与鼠源 PD-1蛋白相互作用。
[42] 在不实质性影响抗体活性的前提下，本领域技术人员可以对 本发明的序列替换、添加和 /或缺失一个或更多个（例如 1、 2、 3、 4、 5、 6、 7、 8、 9或 10个或更多个）氨基酸， 以获得所述抗体 或其功能性片段之序列的变体。它们都被视为包括在本发明保护 的范围内。如在可变区将具有类似性质的^^酸进行替换。本发 明所述变体的序列可以与其来源序列有至少有 95%、 96%、 97%、 98%或 99%的一致性。 本发明所述的序列一致性可以使 用序列分析软件测量。例如使用缺省参数的计算机程序 BLAST, 尤其是 BLASTP或 TBLASTN。
[43] 本发明的抗体可以是全长的 （例如， IgGl或 IgG4抗体） 或可仅包含抗原结合部分（例如， Fab、 F(ab，)2或 scFv片段）， 或可以被修饰以影响功能。本发明包括具有修饰的糖基化模式的 抗 PD-1抗体。 在一些应用中， 进行修饰以除去不期望的糖基化 位点可以是有用的，或在寡糖链上不存在岩藻糖部分以例如增强 抗体依赖性细胞毒性 ( ADCC )功能的抗体。 在另一些应用中， 可进行半乳糖基化修饰以改变补体依赖性细胞毒性（ CDC )。 [44] 本文所使用的术语 "功能性片段"尤其是指抗体片段如 Fv、 scFv ( sc指单链） 、 Fab, F(ab，） 2、 Fab\ scFv-Fc片段或者双 抗体 ( diabody ) 、 或者通过化学修饰或通过掺入脂质体中应能 够增加半寿期的任何片段， 所述化学修饰例如添加聚（亚烷基） 二醇如聚乙二醇（ "聚乙二醇化， PEG化" ） （被称为 Fv-PEG、 scFv-PEG、 Fab-PEG, F(ab')2-PEG或 Fab'-PEG的聚乙二醇 化片段） （ "PEG" 为聚乙二醇） ， 所述片段具有 EGFR结合 活性。优选地，所述功能片段将由其来源抗体的重或轻可变链的 部分序列构成或者包含它们，所述部分序列足以保留与其来源抗 体相同的结合特异性和充分的亲和力， 对于 PD-1 , 优选至少等 于其来源抗体亲和力的 1/100， 在更优选方式中至少等于 1/10。 这种功能片段将包含最少 5个氨基酸，优选其来源的抗体序列的 10、 15、 25、 50和 100个连续氨基酸。
[45] 本领域技术人员可以将编码本发明所述抗 PD-1 抗体的 DNA分子克隆到载体中， 进而转化宿主细胞。 因此， 本发明还 提供了一种重组 DNA载体， 其含有编码本发明所述抗 PD-1抗 体的 DNA分子。
[46] 优选地， 所述重组 DNA载体是一种表达载体， 本领域技术 人员将所述抗体的 DNA分子克隆到表达载体中，转化宿主细胞， 通过诱导表达获得抗体。 本发明的表达载体含有编码的抗 PD-1 抗体的重链可变区、轻链可变区和 /或恒定区的 DNA序列。然而， 也可有分别构建两种表达载体， 一种含有重链可变区和恒定区， 另一种含有轻链可变区和恒定区，一同转染哺乳动物。在一个优 选的实施方案中，所述表达载体进一步含有启动子和编码分泌信 号肽的 DNA序列， 以及至少一种用于筛选的抗药基因。
[47] 本发明所述宿主细胞可以为其为原核宿主细胞、真核宿主细 胞或噬菌体。， 所述原核宿主细胞可以为大肠杆菌、 枯草杆菌、 链尊菌或奇异变形菌等。所述真核宿主细胞，可以为如巴斯德毕 赤酵母、 酿酒酵母、 裂殖酵母、 木霉等真菌， 如草地粘虫等昆虫 细胞， 如烟草等植物细胞， 如 BHK细胞、 CHO细胞、 COS细 胞、 骨髓瘤细胞等哺乳动物细胞。在一些实施方案中， 本发明所 述宿主细胞优选为哺乳动物细胞， 更优选 BHK细胞、 CHO细 胞、 NSO细胞或 COS细胞。
[48] 本文使用的术语 "药物组合物 "表示组合在一起以实现某种 特定目的的至少一种药物以及任选地可药用载体或辅料的组合。 在某些实施方案中， 所述药物组合物包括在时间和 /或空间上分 开的组合， 只要其能够共同作用以实现本发明的目的。 例如， 所 述药物组合物中所含的成分（例如根据本发明的抗体、核酸分子、 核酸分子组合和 /或缀合物）可以以整体施用于对象， 或者分开 施用于对象。当所述药物组合物中所含的成分分开地施用于对象 时， 所述成分可以同时或依次施用于对象。优选地， 所述可药用 载体是水、緩冲水溶液、 、等渗盐溶液如 PBS (磷酸盐緩冲液）、 葡萄糖、甘露醇、右旋葡萄糖、乳糖、 淀粉、硬脂酸镁、 纤维素、 碳酸镁、 0.3%甘油、 透明质酸、 乙醇或聚亚烷基二醇如聚丙二 醇、甘油三酯等。所用可药用载体的类型尤其依赖于根据本发明 的组合物是否配制为用于口服、 鼻、 皮内、 皮下、 肌内或静脉施 用。根据本发明的组合物可包含润湿剂、乳化剂或緩冲液物质作 为添加剂。
[49] 才艮据本发明的药物组合物可通过任何适宜的途径施用，例如 可口服、 鼻、 皮内、 皮下、 肌内或静脉内施用。
[50] 在一个相关方面， 本发明提供了为抗 PD-1抗体与第二治疗 剂的组合的药物组合物。在一个实施方案中，所述第二治疗剂是 有利地与抗 PD-1抗体组合的任意试剂。 可有利地与抗 PD-1抗 体组合的示例性试剂包括但不限于抑制 PD-1 活性的其他试剂 (包括其他抗体或其抗原结合片段、肽抑制剂、小分子拮抗剂等） 和 /或干扰 PD-1上游或下游信号转导的试剂。
[51] 本文使用的术语"通过消除、 抑制或降低 PD-1 活性来预防 或治疗疾病或病症"旨在表示由 PD-1表达所导致或者以 PD-1表 达为症状 /特征的疾病或病症。 在一些实施方案中， 所述疾病或 病症选自癌症或感染性疾病。所述癌症包括但不限于肺癌，肝癌， 卵巢癌， 宫颈癌， 皮肤癌， 膀胱癌， 结肠癌， 乳腺癌， 神经胶质 瘤， 肾癌， 胃癌， 食道癌， 口腔鳞状细胞癌， 头颈癌。 所述感染 性疾病包括但不限于 HIV病毒感染和乙型肝炎病毒感染。
[52] 本文使用的"治疗有效量，，是指足以显示其对于所施用对象 益处的剂量。施用的实际量， 以及施用的速率和时间过程会取决 于所治疗者的自身情况和严重程度。治疗的处方（例如对剂量的 决定等）最终是全科医生及其它医生的责任并依赖其做决定，通 常考虑所治疗的疾病、 患者个体的情况、递送部位、施用方法以 及对于医生来说已知的其它因素。
[53] 本文所使用的术语"对象，，是指哺乳动物，如人类，但也可以 是其它动物， 如野生动物（如苍鹭、 鹳、 鹤等） ， 家畜 （如鸭、 鹅等）或实验动物（如狸猩、猴子、大鼠、小鼠、兔子、豚鼠等）。
[54] 提供了以下实施例以证明并进一步解释本发明的一些优选 的实施方式和方面， 不应被解释为限制其范围。
实施例
实施例 1.克隆人 PD1胞外结构区入真核表达质粒
[55] 以 Trizol RNA提取试剂盒（ Invitrogen ) ί 外周血细胞（北 京市红十字血液中心） 中提取总 RNA, 用 Invitrogen的逆转录 试剂盒得到 cDNA , 以该 cDNA 为模板， 上游引物为 5'-GTACGCTAGCCACCATGCAGATCCCACAGGC -'3 ( SEQ ID N0.31 ) 下 游 引 物 为 5， -
GATCCTCGAGCCACCAGGGTTTGGAACTG -'3 ( SEQ ID NO.32 )， PCR扩增 PD1胞外片段。 扩增产物在经 Nhe I和 Xho I双酶切后，克隆到 pCDNA3.1的真核表达质粒系统.以此质粒转 染 293T细胞（ATCC ) 3天后， 收集培养上清液， 纯化 h-PDl。 以此类似， 我们从食蟹猴的外周血细胞中也提取了总 RNA并将 其产生的 cDNA克隆至了真核表达系统。
[56] 如图 1 显示， 由于糖基化等修饰原因， 人源性（hu )和食 蟹猴源性 ( cyno )的 PD-1胞外结构区蛋白大小在 SDS-PAGE经 考马斯亮蓝染色后显示 50K道尔顿左右。 实施例 2.检测细胞上 PD-1与配体 PD-L1结合
1. 外周血细胞中分离 Τ细胞
[57] 外周血细胞（北京血液研究所）悬液在通过尼龙毛柱 (北京 海德生物技术公司）时， Β细胞、 浆细胞、 单核细胞和一些辅助 细胞被选择性粘附于尼龙毛上， 而多数 Τ细胞则通过尼龙毛柱， 由此获得富含 Τ细胞群。其操作简述如下：取 50ml玻璃注射器， 拔去注射芯，在注射器头上套一段带夹子的胶管。将尼龙毛梳理， 填入注射器内。 将注射器固定在支架上， 倒入 37 的 RPMI细 胞培养液以预处理尼龙毛。 关闭阀门半小时后， 打开阀门， 放 掉细胞培养液。 将要分离的细胞液用预先加温的 RPMI培养液 稀释成适当的浓度， 约 5.00 x 107个细胞 / ml。 将细胞液倒入注 射器内， 使之没过尼龙毛柱。 盖上注射器， 温育 1小时。 打 开下口， 緩慢放流（1 滴 / min ), 收集于离心管中。 lOOOxg 离 心 10分钟， 即获所需的 T淋巴细胞。
2. 生物素标记 rh-PD-Ll重组蛋白
[58] 将购自于义翘神州生物公司的 100 ug rh-PD-Ll重组蛋白与 溶解于 DMSO中的生物素-氨基己酸 -NHS ( ( Thermo ) 以 1: 4 的摩尔比混合， 室温放置 1小时， 将反应混合物通过 G25凝胶 柱（Thermo ) 以分离生物素标记的 rh-PD-Ll和游离生物素。
3. 生物素标记 rh-PD-Ll与人 T细胞结合
[59] 将不同浓度生物素标记的 rh-PD-Ll重组蛋白和 105分离的 T细胞混合， 在 4摄氏度孵育 15分钟。 以 PBS洗涤 3次后， 加 入链亲合素别藻蓝蛋白（ Thermo ) (SA-APC)至 0.2ug/ml, 并在 4摄氏度孵育 20分钟。 以 PBS洗涤 3次后上 Beckman Dickson Calibur细胞流式仪在 660nm检测。结果如图 2所示， 其结果表 明生物素标记的 PD-L1蛋白可以同 T细胞结合。
实施例 3.抗 rh-PD-1抗体的制备 1.免疫动物
[60] 将 10 ug 浓度为 lmg/ml的 rh-PD-1重组蛋白作为抗原与等 量免疫佐剂 （福氏佐剂 （Sigma-Aldrich ) )混合， 取 3只 6周大 雌性 FVB小鼠进行皮下免疫。 在初次免疫以后， 每一周进行一 次相同剂量的加强免疫。
2. 细胞融合
[61] 在最后一针加强免疫后，取小鼠大腿根处淋巴结，在生理盐 水中碾磨后取富含 B细胞的悬浮液，按常规方法电转（参见 BTX 公司电转仪手册）与 SP2/0细胞融合。 将融合细胞在含有 HAT 的 RPMI-1640全培养基 ( Sigma )中置于 5%C02， 37°C条件下 培养。
实施例 4. 配体和受体封闭实验
[62] 在 20000种单克隆杂交瘤细胞中， 通过酶标（Elisa )反应， 筛选出 1220种所分泌的抗体可结合 PD-1蛋白的克隆。在这 1220 种抗体中， 其中有五种可以不同程度抑制生物素标记的 PD-L1 与 T细胞上 PD-1受体结合。
[63] 将上述五种抗体 （ lug/ml ) 与 312ng/ml 生物素标记的 rh-PD-Ll (浓度）混合室温孵育 20分钟。 然后将混合物与分离 的 T细胞在 4摄氏度孵育 15分钟， 以生理盐水洗涤 3次后， 加 入 0.2 ug/ml的 SA-APC并在 4摄氏度孵育 15分钟。以生理盐水 洗涤 3次后，将样品上 BD公司流式细胞仪检测以验证其是否可 以抑制 rh-PD-Ll与 T细胞表面的 PD-1受体结合。
[64] 由图 3可见， 克隆 1 , 10， 11可阻碍细胞表面的 PD-1与配 体 PD-L1结合。 而克隆 55和 64则只可以微弱抑制。
实施例 5. 与其他 CD28家族蛋白的结合
[65] 为进一步检验克隆 1、 10、 11、 55和 64的候选抗体的结合 特异性，将 lug/ml的 rh-PD-1或其它 CD28家族成员蛋白 ICOS、 CTLA-4和 CD28 ( R&D System )置于 96孔酶标板中的 0.05M PH9碳酸盐包被緩冲液中， 4 过夜。 次日， 弃去孔内溶液， 用 洗涤緩冲液（ PBS+0.5% TWEEN )洗 3次。然后加入含有 3%BSA 的 PBS 溶液封闭 20 分钟。 用洗涤緩冲液洗 3 次后加入 100ullug/ml候选抗体， 室温孵育 1小时后用洗涤緩冲液冲洗 3 次， 用洗涤緩冲液以 1比 10000倍稀释 HRP交联羊抗小鼠抗体 ( Jsckson Immunoresearch ), 室温觯育 1小时， 经洗漆緩冲液 洗涤 3次后， 加入 50ul TMB (四甲基联苯胺 )底物溶液显色， 室温反应 10分钟后， 以 25ul 0.5M 的硫酸溶液终止反应并在 450nm处读出吸光度。
[66] 由图 4可见， 所有测试的候选抗体均识别结合 rh-PD-l， 但 是， 它们均不识别其它 CD28家族成员。
实施例 6.候选抗体可变区序列
[67] 将候选杂交瘤细胞总数量培养到 107个细胞， lOOOrpm离 心 10分钟收集细胞， 并以 Trizol试剂盒（Invitrogen )提取总 RNA。 以所述 RNA为模板， 合成第一链 cDNA ( Qiagen )后， 以第一链 cDNA 为后续模板扩增杂交瘤细胞所对应的可变区 DNA序列。 扩增反应中所使用的引物序列与抗体可变区第一框 架区和恒定区互补 （ Larrick，J.W" et al., (1990) Scand. J. Immunol., 32, 121-128和 Coloma，J.J.et al., (1991) BioTechniques. 11， 152-156等人）。在 50μ1反应体系中，分别加入 cDNA Ιμΐ，10 xPCR緩冲液 5μ1， 上游及下游引物各 Ιμΐ (25 pmol) ,dNTP Ιμΐ，25 mmolPL MgCl2 lul，H20 39μ1，95 预变性 10 min，加 Taq i ( Invitrogen ) Ιμΐ，^A温度循环， 进行 PCR扩增。 反应条 件为 94 变性 1 min，58 *€退火 1 min ,72 延伸 115 min，共 30 个循环， 然后 72 "C保温 10 min。
[68] 将扩增产物测序后， 得到杂交瘤克隆 1、 10和 11重链和轻 链可变区序列为：
VVVV1VVV9D119VVV3V99993139DD1193VD11V3D1191V3V31199VV311 103丄: )V11V1113TO 31D丄 丄 EV3VD3V:UV3VV3丄：) V3V:)111V3V:)V∞ V:)丄 nm ">nnm ")i ιππ^νην^ιπηηη ι ι ι ινηΊ νν ι ι i wywi")i i"nm mni
DV3D99VD VVVDV3DID3V1D91VVDV111V1DDV3VWD91VV1DV1V3V1D11VDDV9VD19V1D1V
I I I I η I
-νάΆ一一 > επαο
¾3
丄 V3V1V丄: nVDTOV33VV3丄∞313VD3_L TO丄 V丄：) V913VlllV:)V:)VI0333:)li:) 3
：—— YdA—— > - 'ϋΛ >
-ΖΙΛ >τπσο
tL ZL0/n0ZSD/lDd 0Ϊ衝 OZ OAV 克隆 10
茧链
QVQLQQSGAELVRPGASVTLSCKASGYTFTDYEMm-fVKQTPVHGLEWIGAIDPETGGAAYMQKFKG
Figure imgf000018_0001
Figure imgf000018_0002
克隆
重链
Figure imgf000019_0001
轻链
< FR1 > CDR1 < FR2 > CDR2
< FR3 > CDR3 <-- FR4一一 >
Figure imgf000019_0002
ACAGCAACCACTGGGTGTTCGGTGGAGGAACCAAACTGACTGTCCTA
实施例 7.构建嵌合抗体表达载体
[69] ^ όι细胞（北京血液研究所） 中克隆重链恒定区 Fc片段 和轻链 1^/£恒定区，连入 CDNA3.1质粒（见 Walls MA, Hsiao H 和 Harris LJ (1993), Nucleic Acids Research, Vol. 21， No. 12 2921 -2929 )加以^ 。实施例 6所述重链和轻链序列片段由 Genscript 公司合成， 重链经 Xho I和 Age I酶切， 轻链片段经 Sma I和 Dra III酶切后， 连入相对应改造的 pCDNA3.1质粒中， 并经测 序确定克隆 DNA序列。后续的实验材料均由此系列质粒转染细 胞后， 提纯获得。
实施例 8.嵌合抗体体外刺激 T细胞功能实验一破伤风毒素刺激 试验 [70] 将新鲜制备的 PBMC铺板至 96孔平底板中， 孵育过 ^， 加入不同浓度的抗体及 100ng/ml 的破伤风毒素 （ TT ) ( List Biological Laboratories )。三天后收获上清，并使用 R&D System 公司的 IFNy试剂盒通过 Elisa检测上清液中的 IFNy含量。由图 5结果可见， 在阻断 PD-1信号后， 受 TT刺激激活的免疫细胞 分泌的细胞因子大大增加。 并且候选抗体效价高于申请号： 200980147059.0中购于 Biolegend公司的 ΕΗ12·2Η7。
实施例 9. 不同抗体轻重链互换后与 PD-1相互作用
[71] 将抗体 1, 10的轻重 ^目互重新组合， 得到 H1L10 (重链 1 轻链 10 )和 H10L1 (重链 10轻链 1 )。 类似于实施例 7中所述， 我们得到重新组合的抗体， 并与原有抗体 1 (重链 1, 轻链 1 ) 和原有抗体 10(重链 10，轻链 10 )在 Elisa实验结果产生的 EC50 结果见下表：
Figure imgf000020_0001
结果表明，新组合产生的抗体仍然可以高效结合 PD-1蛋白。
实施例 10. 抗体的人源化改造
[72] 根据上述获得的杂交瘤细胞分泌的抗体的可变区序列，进行 人源化改造。 简言之， 人源化改造过程涉及以下步骤： A、 把各 杂交瘤细胞分泌的抗体的基因序列与人胚胎系抗体基因序列进 行比对， 找出同源性高的序列； B、 分析考察 HLA-DR亲和性， 选出亲和力低的人胚胎系框架序列； c、 利用计算才 ^拟技术， 应用分子对接分析可变区及其周边的框架氨基酸序列，考察其空 间立体结合方式。通过计算静电力，范德华力，亲疏水性和熵值， 分析各杂交瘤细胞分泌的抗体基因序列中可与 PD-1作用以及维 护空间构架的关键氨基酸个体，将其嫁接回已经选择的人胚胎系 基因框架， 并在此^！上标配出必须保留的框架区 酸位点， 合成随机引物， 自制噬菌体文库， 筛选人源化抗体文库（Pini，A. 等, et al. (1998). Design and Use of a Phage Display Library: HUMAN ANTIBODIES WITH SUBNANOMOLAR AFFINITY AGAINST A MARKER OF ANGIOGENESIS ELUTED FROM A TWO-DIMENSIONAL GEL., Journal of Biological Chemistry, 273(34): 21769-21776 )„ 在此 J^lll上我们得到了以下多个人源化 抗体。 其中包括以下克隆， 其中， 38， 39, 41的轻 列相同， 39和 48的重链序列相同。
Figure imgf000022_0001
Figure imgf000022_0002
VVViiVVVE)E)iDVVV:OV:)E)E)E)V:):)E)E)lii:):)VE丄：) E):OE)丄 E丄 V:OE)V:)E)E)E)V:iLL EXL
Figure imgf000022_0003
Figure imgf000022_0004
.SZ.0/M0ZN3/X3d ■Οΐ衝 OZ OAV VVVilVVVE)E)iDWV:DV:)E)3E)V:):)E)E)iii:OVE)丄:) SIDE)丄 3丄 V )E)V:)E)E)E)V:iLLlDE)丄
Figure imgf000023_0001
Mia^iiaDs^iLidAHSsOaoAAASAaa iaAasiMiiijaiiasasssjHadAS <—― —― > επαθ < £Έ >
Figure imgf000023_0002
Figure imgf000023_0003
聽 8fr
Figure imgf000023_0004
Mia^iisDs^JiidAHSsQaoAAASAaavaAasiMiiijaiissssssjHadAS <—― —― > ε¾αο < ε¾ω >
2¾αο < Ζ^Λ > τ¾αο < Ι^Λ >
Figure imgf000023_0005
saao < SHJ >τπαο < τπ^ > 難 τν
.SZ .0/M0ZN3/X3d ■0Ϊ衝 OZ OAV 实施例 11.人源化抗体在体外刺激 T细胞
[73] 将新鲜制备的 PBMC (北京血液研究所）铺板至 96孔平底 板中， 孵育过 加入 10ug/ml的抗体及 100ng/ml的破伤风 毒素（TT )，培养 3天后收集上清液， 用 Life Technology公司 的 Luminex仪与 EMD公司的 CD8+细胞因子检测试剂盒检测人 源化抗体克隆 38、 39、 41以及 48 (对照（conIgG4 ) ) IL2的分 泌水平。结果（见图 6 )显示人源化抗体均可刺激 T细胞的功能。
实施例 12.人源化抗体可在体外刺激 T细胞杀伤肿瘤细胞
[74] 以表达 PD-L1蛋白的†曼病毒 ( Qiagen )感染 MD-MAB-453 细胞，得到稳定表达 PD-L1的 MD-MAB-453细胞系，在此^ I 上再导入 GFP基因，使其稳定表达 GFP蛋白。 ^新鲜外周血 细胞中提取树突细胞 ( DC ), 在 96孔盘中， 以 300个细胞 /孔与 上述改造的 MD-MAB-453细胞（ 300个 /孔 )共同培养 3天后， 加入提取的 T细胞（ 1000个 /孔 )和 10ug/ml的人源化抗 PD-1 抗体隆 38、 39、 41 以及 48 (对照（conIgG4 ) )， 再共同培养 3 天， 读取 GFP荧光值。 结果（见图 7 )表明人源化抗体均刺激 T 细胞以杀伤肿瘤细胞。
实施例 13. 人源化抗体与不同物种 PD-1蛋白的结合
[75] 将 1 ug/ml的上€ 源 PD-1、 食蟹猴 PD-1以及鼠源 PD-1 ( Sinobiological购得）稀释在 0.05M PH9的碳酸盐包被緩冲液 中， 在 4"€下过夜。 次日， 弃去孔内溶液， 用洗涤緩冲液清洗 3 次。 然后加入含有 3%BSA的 PBS溶液封闭 20分钟。 用洗涤緩 冲液洗 3次后加入 lOOul稀释后不同浓度候选抗体， 室温孵育 1 小时后用洗涤緩冲液冲洗 3次，用洗涤緩冲液以 1:10000倍稀释 HRP缀合羊抗人抗体 ( Jackson Immunoresearch ) 室温觯育 1 小时，经洗涤緩冲液冲洗 3次后，加入 50ul TMB底物溶液显色， 室温反应 10分钟后， 以 25ul 0.5M 的硫酸溶液终止反应并在 450nm处读出吸光度。 结果（图 8A、 B、 C )表明， 各克隆以类 似的亲和力结合人或食蟹猴 PD-1蛋白，但它们均不与鼠源 PD-1 蛋白相互作用。
[76] 比对人、 食蟹猴和小鼠 PD-1序列（见图 9， 其中小鼠 PD-1 与人和食蟹猴 PD-1 蛋白的主要不同区域用框架标注）。 通过实 ϋ实， 候选抗体对 PD-1蛋白的表位存在于这几个区域中。
实施例 14.人源化抗体体外刺激 T细胞增殖实验一破伤风抗原 记忆应答实验
[77] 将新鲜制备的 PBMC (北京血液研究所）铺板至 96孔平底 板中，孵育过夜后用 CFSE标记，加入 10ug/ml的人源化抗体（38, 39, 41和 48 )及 100ng/ml的破伤风毒素 ( TT ) ( List Biological Laboratories )。在第 6, 8和 10天后用流式细胞计数仪 ( FACS ) 通过 CSFE的稀释倍数对 T细胞增值进行定量分析。 由图 10结 果可见， 与对照 IgG相比， 阻断 PD-1信号诱导 TT刺激激活的 免疫细胞进一步分裂增殖。
实施例 15.人源化抗体体外刺激 T细胞增殖实验一病毒多肽抗 原记忆应答实验
[78] 将新鲜制备的 PBMC (北京血液研究所）铺板至 96孔平底 板中， 孵育过夜后用 CFSE标记，加入浓度 10ug/ml的人源化抗 体（ 38， 39, 41和 48 )及 lug/ml的 CEF多肽混合物（ CMV,
EBV和 Influenza )。 在第 6, 8 和 10 天后用流式细胞计数仪 ( FACS )通过 CSFE的稀释倍数对 T细胞增值进行定量分析。 由图 11结果可见， 与对照 IgG相比， 阻断 PD-1信号诱导 CEF 混合多肽刺激激活的免疫细胞进一步分裂增殖。

Claims

权 利 要 求
1. 能够结合程序性死亡因子 1 ( PD-1 ) 的抗体或其功能性 片段， 其包含选自處基 字列 SEQ ID NO: 1， 2， 3， 7， 8， 9， 13， 14， 15或任何所述序列之变体的重链 CDR, 和 /或选自氨基酸序列 SEQ ID NO: 4， 5， 6， 10， 11， 12， 16， 17, 18或任何所述序列之变体 的轻链 CDR。
2.权利要求 1所述的抗体或其功能性片段， 其中所述重链 CDR的 CDR1、 CDR2和 CDR3的暴基酸序列选自以下各 碁 酸序列或其变体的组中的一组：
Figure imgf000026_0001
和 /或所述轻链 CDR的 CDR1、 CDR2和 CDR3的氨基酸序列选 自以下各氨基酸序列或其变体的组中的一组：
Figure imgf000026_0002
3.权利要求 1 或 2 所述的抗体或其功能性片段， 其重链 CDR1、 CDR2和 CDR3以及轻链 CDR1、 CDR2和 CDR3的氨 基酸序列选自以下各氨基酸序列或其变体的组中的一组：
Figure imgf000026_0003
SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID c
NO:13 NO:14 NO:15 NO:16 NO:17 NO:18
4.权利要求 1至 3中任一项所述的抗体或其功能性片段， 其包含选自 基酸序列 SEQ ID NO: 19， 21， 23或任何所述序列 之变体的重链可变区，和 /或选自氨基酸序列 SEQ ID NO: 20, 22, 24或任何所述序列之变体的轻链可变区。
5.权利要求 1至 4中任一项所述的抗体或其功能性片段， 其中所述重链可变区为 SEQ ID NO: 19或其变体并且所述轻链 可变区为 SEQ ID NO: 20或其变体，或者所述重链可变区为 SEQ ID NO: 21或其变体并且所述轻链可变区为 SEQ ID NO: 22或其 变体， 或者所述重链可变区为 SEQ ID NO: 23或其变体并且所 述轻链可变区为 SEQ ID NO: 24或其变体。
6.权利要求 1至 5中任一项所述的抗体或其功能性片段， 其为嵌合抗体、 人源化抗体或全人抗体。
7.权利要求 1至 6中任一项所述的抗体或其功能性片段， 其包含选自 基酸序列 SEQ ID NO: 33, 35, 36或任何所述序列 之变体的重链可变区， 和 /或选自 列 SEQ ID NO: 34， 37 或任何所述序列之变体的轻链可变区。
8.权利要求 1至 7中任一项所述的抗体或其功能性片段， 其中所述重链可变区为 SEQ ID NO: 33或其变体并且所述轻链 可变区为 SEQ ID NO: 34或其变体，或者所述重链可变区为 SEQ ID NO: 35或其变体并且所述轻链可变区为 SEQ ID NO: 34或其 变体， 或者所述重链可变区为 SEQ ID NO: 36或其变体并且所 述轻链可变区为 SEQ ID NO: 34或其变体， 或者所述重链可变 区为 SEQ ID NO: 35或其变体并且所述轻链可变区为 SEQ ID NO: 37或其变体。
9. 分离的核酸分子， 其编码权利要求 1至 8中任一项所述 的抗体或功能性片段。
10.表达载体， 其包含权利要求 9所述的核酸分子。
11. 宿主细胞， 其包含权利要求 10所述的表达载体。
12.产生抗 PD-1抗体或其功能性片段的方法， 其包括： 在 允许产生所述抗体或其功能性片段的条件下培养包含权利要求 11 所述的宿主细胞， 以及回收这样产生的所述抗体或其功能性 片段。
13.免疫缀合物， 其包含与治疗剂偶联的权利要求 1至 8中 任一项所述的抗体或其功能性片段， 优选地所述治疗剂为毒素、 放射性同位素、 药物或细胞毒剂。
14. 药物组合物， 其包含权利要求 1至 8中任一项所述的抗 体或其功能性片段， 以及可药用载体。
15. 用于通过消除、 抑制或降低 PD-1活性来预防或治疗疾 病或病症的方法，其包括向有此需要的对象施用治疗有效量的权 利要求 1至 8所述的抗体或其功能性片段,权利要求 9所述的核 酸分子、权利要求 10所述的表达载体、权利要求 11所述的宿主 细胞、权利要求 13所述的免疫缀合物或权利要求 14所述的药物 组合物，其中所述疾病或病症选自癌症、感染性疾病或炎性疾病； 所述癌症优选选自黑素瘤、 肾癌、 前列腺癌、 乳癌、 结肠癌、 肺 癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛区癌、 胃癌、 睾丸癌、 子宫癌、 输 卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 阴户癌、 何杰金氏病、 非何杰金氏淋巴瘤、 食道癌、 小肠癌、 内分泌系统的癌症、 甲状 腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、 尿道癌、 阴茎癌、 慢性或急性白血病，其包括急性髓细胞样白血病、慢性髓细胞样 白血病、 急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、 儿 童期实体瘤、淋巴细胞性淋巴瘤、 膀胱癌、 腎或输尿管癌、 肾盂 癌、 中枢神经系统的赘生物、原发性中枢神经系统淋巴瘤、肿瘤 血管发生、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏肉瘤、 表皮样癌、 鳞状细胞癌、 T细胞淋巴瘤、 环境诱发的癌症、 其包 括石棉所诱发的那些，和所述癌症的组合； 所述感染性疾病优选 选自 HIV、 流行性感冒、 疱疹、 贾第虫病、 疟疾、 利什曼病、 以下病毒引起的致病感染： 肝炎病毒（甲型、 乙型和丙型）、 疱 疹病毒（例如 VZV、 HSV-1、 HAV-6、 HSV-II和 CMV、 埃巴二 氏病毒）、 腺病毒、 ¾^感病毒、 黄病毒、 艾柯病毒、 鼻病毒、 柯 萨奇病毒、冠状病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、 麻疹病毒、 风疹病毒、 细小病毒、 牛痘病毒、 HTLV病毒、 登革 热病毒、 头瘤病毒、软疲病毒、脊髓灰质炎病毒、狂犬病病毒、 JC病毒和虫媒病毒性脑炎病毒， 以下细菌引起的致病感染： 衣 原体、 立克次氏体、 分枝杆菌、 葡萄球菌、 链球菌、 肺炎球菌、 脑膜炎球菌和 conococci、 克雷伯氏菌、 变形菌、 沙雷氏菌、 假 单胞菌、 军团菌、 白喉、 沙门氏菌、 杆菌、 霍乱、 破伤风、 肉毒 中毒、 炭疽、 鼠疫、 钩端螺旋体病和莱姆氏病细菌， 以下真菌引 起的致病感染： 假丝酵母 (白色假丝酵母、 克鲁斯假丝酵母、 光 滑假丝酵母、 热带假丝酵母等）、新型隐球酵母、 曲霉（烟曲霉、 黑曲霉等）、 毛霉目的属（毛霉属、 犁头霉属、 根霉属）、 申克氏 孢子丝菌、皮炎芽酵母、 巴西副球孢子菌、粗球孢菌和加膜组织 胞浆菌， 及以下寄生虫引起的致病感染： 痢疾内变形虫、 结肠肠 袋虫、 福纳氏虫、 棘变形虫、 吸吮贾第虫、 隐孢子虫、 卡氏肺嚢 虫、 间日疟原虫、 田鼠巴贝虫、 布鲁斯锥虫、 克鲁兹雉虫、 多氏 利什曼虫、 鼠弓浆虫和 巴西日圆线虫； 所述炎性疾病优选选自 急性播散性脑脊髓炎、 阿狄森病、 强直性脊柱炎、抗磷脂抗体综 合征、 自身免疫性溶血性贫血、 自身免疫性肝炎、 关节炎、 贝切 特病、 大疱性类天疱疮、 腹部疾病、 恰加斯病、 克罗恩病、 皮肌 炎、 1型糖尿病、肺出血-肾炎综合征、移植物抗宿主病、格雷夫 斯病、 格-巴二氏综合征、 桥本病、 超 IgE综合征、 特发性血小 板减少性紫癜、红斑狼疮、多发性硬化症、重症肌无力、天疱疮、 恶性贫血、 多肌炎、原发性胆汁性肝硬变、银屑病、 类风湿关节 炎、 斯耶格伦综合征、 颞动脉炎、 血管炎和韦格纳肉芽肿病。
PCT/CN2014/072574 2013-06-26 2014-02-26 抗pd-1抗体及其应用 WO2014206107A1 (zh)

Priority Applications (14)

Application Number Priority Date Filing Date Title
BR112015031883-5A BR112015031883A2 (pt) 2013-06-26 2014-02-26 anti-pd-1 anticorpo e o uso dele
ES14818708T ES2822927T3 (es) 2013-06-26 2014-02-26 Anticuerpo anti-PD-1 y su uso
JP2016522196A JP6681327B2 (ja) 2013-06-26 2014-02-26 抗ｐｄ−１抗体およびその応用
PL14818708T PL3026062T3 (pl) 2013-06-26 2014-02-26 Przeciwciała anty-pd-1 i ich zastosowanie
RU2016102176A RU2663795C2 (ru) 2013-06-26 2014-02-26 Антитело к pd-1 и его применение
EP20189272.6A EP3845562A1 (en) 2013-06-26 2014-02-26 Anti-pd-1 antibody and use thereof
SI201431678T SI3026062T1 (sl) 2013-06-26 2014-02-26 ANTI-PD-1 protitelo in njegova uporaba
DK14818708.1T DK3026062T3 (da) 2013-06-26 2014-02-26 Anti-pd-1-antistof og anvendelse deraf
US14/392,360 US10066013B2 (en) 2013-06-26 2014-02-26 Anti-PD-1 antibody and use thereof
EP14818708.1A EP3026062B1 (en) 2013-06-26 2014-02-26 Anti-pd-1 antibody and use thereof
PH12015502819A PH12015502819A1 (en) 2013-06-26 2015-12-18 Anti-pd-1 antibody and use thereof
US16/045,363 US10815302B2 (en) 2013-06-26 2018-07-25 Anti-PD-1 antibody and use thereof
US17/022,719 US20210009688A1 (en) 2013-06-26 2020-09-16 Anti-pd-1 antibody and use thereof
HRP20201600TT HRP20201600T1 (hr) 2013-06-26 2020-10-07 Anti-pd-1 antitijelo i njegova uporaba

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310258289.2A CN104250302B (zh) 2013-06-26 2013-06-26 抗pd‑1抗体及其应用
CN201310258289.2 2013-06-26

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/392,360 A-371-Of-International US10066013B2 (en) 2013-06-26 2014-02-26 Anti-PD-1 antibody and use thereof
US16/045,363 Continuation US10815302B2 (en) 2013-06-26 2018-07-25 Anti-PD-1 antibody and use thereof

Publications (1)

Publication Number Publication Date
WO2014206107A1 true WO2014206107A1 (zh) 2014-12-31

Family

ID=52140971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/072574 WO2014206107A1 (zh) 2013-06-26 2014-02-26 抗pd-1抗体及其应用

Country Status (16)

Country Link
US (3) US10066013B2 (zh)
EP (2) EP3026062B1 (zh)
JP (1) JP6681327B2 (zh)
CN (1) CN104250302B (zh)
BR (1) BR112015031883A2 (zh)
DK (1) DK3026062T3 (zh)
ES (1) ES2822927T3 (zh)
HR (1) HRP20201600T1 (zh)
HU (1) HUE052487T2 (zh)
MY (1) MY176822A (zh)
PH (1) PH12015502819A1 (zh)
PL (1) PL3026062T3 (zh)
PT (1) PT3026062T (zh)
RU (1) RU2663795C2 (zh)
SI (1) SI3026062T1 (zh)
WO (1) WO2014206107A1 (zh)

Cited By (153)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016106159A1 (en) * 2014-12-22 2016-06-30 Enumeral Biomedical Holding, Inc. Anti-pd-1 antibodies
US9394365B1 (en) 2014-03-12 2016-07-19 Yeda Research And Development Co., Ltd Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
US9512227B2 (en) 2014-03-12 2016-12-06 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
KR20170020933A (ko) * 2015-06-09 2017-02-24 베이징 동팡 바이오테크 컴퍼니 리미티드 항 pd-1 단일 클론 항체 및 이의 획득 방법
WO2017079116A2 (en) 2015-11-03 2017-05-11 Janssen Biotech, Inc. Antibodies specifically binding pd-1 and tim-3 and their uses
WO2017087599A1 (en) 2015-11-18 2017-05-26 Lyvgen Biopharma Holdings Limited Anti-pd-1 antibodies and therapeutic uses thereof
WO2017133540A1 (en) 2016-02-02 2017-08-10 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
WO2017125815A3 (en) * 2016-01-22 2017-09-08 MabQuest SA Pd1 specific antibodies
WO2017205721A1 (en) 2016-05-27 2017-11-30 Agenus Inc. Anti-tim-3 antibodies and methods of use thereof
WO2017220989A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 and il-2 cytokines
WO2018071500A1 (en) 2016-10-11 2018-04-19 Agenus Inc. Anti-lag-3 antibodies and methods of use thereof
WO2018081621A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
WO2018106862A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
WO2018106864A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Antibodies and methods of use thereof
WO2018132739A2 (en) 2017-01-13 2018-07-19 Agenus Inc. T cell receptors that bind to ny-eso-1 and methods of use thereof
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018191502A2 (en) 2017-04-13 2018-10-18 Agenus Inc. Anti-cd137 antibodies and methods of use thereof
WO2018204363A1 (en) 2017-05-01 2018-11-08 Agenus Inc. Anti-tigit antibodies and methods of use thereof
JP2018533973A (ja) * 2015-09-29 2018-11-22 セルジーン コーポレイション Ｐｄ−１結合タンパク質及びその使用方法
US10144779B2 (en) 2015-05-29 2018-12-04 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
WO2018222722A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising an anti-lag-3 antibody or an anti-lag-3 antibody and an anti-pd-1 or anti-pd-l1 antibody
WO2018222718A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
WO2018222711A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
WO2018223040A1 (en) 2017-06-01 2018-12-06 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
WO2019046856A1 (en) 2017-09-04 2019-03-07 Agenus Inc. T-CELL RECEPTORS THAT BIND TO SPECIFIC PHOSPHOPEPTIDES OF MIXED LINEAR LEUKEMIA (MLL) AND METHODS OF USE THEREOF
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2019090330A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Methods of treating a tumor
US10344090B2 (en) 2013-12-12 2019-07-09 Shanghai Hangrui Pharmaceutical Co., Ltd. PD-1 antibody, antigen-binding fragment thereof, and medical application thereof
WO2019137541A1 (en) * 2018-01-15 2019-07-18 Nanjing Legend Biotech Co., Ltd. Single-domain antibodies and variants thereof against pd-1
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019144098A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
WO2019144126A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019195452A1 (en) 2018-04-04 2019-10-10 Bristol-Myers Squibb Company Anti-cd27 antibodies and uses thereof
WO2019210055A2 (en) 2018-04-26 2019-10-31 Agenus Inc. Heat shock protein-binding peptide compositions and methods of use thereof
US10465007B2 (en) 2017-01-20 2019-11-05 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-PD-1 antibodies and uses thereof
JP2019532669A (ja) * 2016-09-14 2019-11-14 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッドＢｅｉｊｉｎｇ Ｈａｎｍｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Ｐｄ−１に特異的に結合する可能な抗体及びその機能的断片
WO2019219064A1 (en) * 2018-05-17 2019-11-21 Nanjing Leads Biolabs Co.Ltd Antibody binding pd-1 and use thereof
WO2019232319A1 (en) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions and methods for inhibiting cd73
US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020061376A2 (en) 2018-09-19 2020-03-26 Alpine Immune Sciences, Inc. Methods and uses of variant cd80 fusion proteins and related constructs
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
WO2020076799A1 (en) 2018-10-09 2020-04-16 Bristol-Myers Squibb Company Anti-mertk antibodies for treating cancer
WO2020081928A1 (en) 2018-10-19 2020-04-23 Bristol-Myers Squibb Company Combination therapy for melanoma
WO2020086724A1 (en) 2018-10-23 2020-04-30 Bristol-Myers Squibb Company Methods of treating tumor
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
EP3666905A1 (en) 2018-12-11 2020-06-17 Sanofi E. coli positive for pks island as marker of positive response to anti-pd1 therapy in colorectal cancer
WO2020123453A2 (en) 2018-12-11 2020-06-18 Theravance Biopharma R&D Ip, Llc Alk5 inhibitors
WO2020150152A1 (en) 2019-01-14 2020-07-23 Genentech, Inc. Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2020154189A1 (en) 2019-01-21 2020-07-30 Sanofi Therapeutic rna and anti-pd1 antibodies for advanced stage solid tumor cancers
WO2020198676A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020198672A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020214995A1 (en) 2019-04-19 2020-10-22 Genentech, Inc. Anti-mertk antibodies and their methods of use
WO2020211804A1 (zh) 2019-04-17 2020-10-22 上海君实生物医药科技股份有限公司 抗pd-1抗体在制备治疗实体瘤的药物中的用途
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2021006199A1 (ja) 2019-07-05 2021-01-14 小野薬品工業株式会社 Ｐｄ－１／ｃｄ３二重特異性タンパク質による血液がん治療
WO2021008523A1 (zh) 2019-07-15 2021-01-21 上海君实生物医药科技股份有限公司 抗tigit抗体及其应用
WO2021025140A1 (ja) 2019-08-08 2021-02-11 小野薬品工業株式会社 二重特異性タンパク質
WO2021042019A1 (en) 2019-08-30 2021-03-04 Agenus Inc. Anti-cd96 antibodies and methods of use thereof
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
WO2021062018A1 (en) 2019-09-25 2021-04-01 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
US10995141B2 (en) 2019-04-19 2021-05-04 ImmunoBrain Checkpoint, Inc. Modified anti-PD-L1 antibody and methods and uses for treating a neurodegenerative disease
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092380A1 (en) 2019-11-08 2021-05-14 Bristol-Myers Squibb Company Lag-3 antagonist therapy for melanoma
WO2021092044A1 (en) 2019-11-05 2021-05-14 Bristol-Myers Squibb Company M-protein assays and uses thereof
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021102468A1 (en) 2019-11-22 2021-05-27 Theravance Biopharma R&D Ip, Llc Substituted 1,5-naphthyridines or quinolines as alk5 inhibitors
WO2021127554A1 (en) 2019-12-19 2021-06-24 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
US11072651B2 (en) 2016-09-14 2021-07-27 Beijing Hanmi Pharm. Co., Ltd. Antibody specifically binding to IL-17A, encoding nucleic acid, and method of using the antibody
WO2021155149A1 (en) 2020-01-31 2021-08-05 Genentech, Inc. Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
WO2021152548A1 (en) 2020-01-30 2021-08-05 Benitah Salvador Aznar Combination therapy for treatment of cancer and cancer metastasis
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
WO2021155840A1 (zh) 2020-02-07 2021-08-12 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗恶性肿瘤中的用途
WO2021160152A1 (zh) 2020-02-13 2021-08-19 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗神经内分泌瘤中的用途
WO2021160151A1 (zh) 2020-02-13 2021-08-19 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗肿瘤中的用途
WO2021176424A1 (en) 2020-03-06 2021-09-10 Ona Therapeutics, S.L. Anti-cd36 antibodies and their use to treat cancer
WO2021194942A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anti-ccr8 antibodies for treating cancer
WO2021203131A1 (en) 2020-03-31 2021-10-07 Theravance Biopharma R&D Ip, Llc Substituted pyrimidines and methods of use
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
US11174316B2 (en) 2015-03-13 2021-11-16 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
WO2021253041A1 (en) 2020-06-10 2021-12-16 Theravance Biopharma R&D Ip, Llc Naphthyridine derivatives useful as alk5 inhibitors
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2022042626A1 (zh) 2020-08-27 2022-03-03 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗鼻咽癌中的用途
WO2022047189A1 (en) 2020-08-28 2022-03-03 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
WO2022042681A1 (en) * 2020-08-28 2022-03-03 Shanghai Junshi Biosciences Co., Ltd. Use of an anti-pd-1 antibody and a cytotoxic anticancer drug in treatment of non-small cell lung cancer
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022086957A1 (en) 2020-10-20 2022-04-28 Genentech, Inc. Peg-conjugated anti-mertk antibodies and methods of use
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022094567A1 (en) 2020-10-28 2022-05-05 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
WO2022098638A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
WO2022098628A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies
WO2022098648A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates
EP3368572B1 (en) 2015-10-02 2022-05-25 Symphogen A/S Anti-pd-1 antibodies and compositions
TWI765862B (zh) * 2015-09-03 2022-06-01 日商小野藥品工業股份有限公司 基於過敏反應素-１拮抗劑之癌免疫增強劑
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022119830A1 (en) 2020-12-02 2022-06-09 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022223006A1 (zh) 2021-04-22 2022-10-27 上海君实生物医药科技股份有限公司 抗pd-1抗体联合一线化疗治疗晚期非小细胞肺癌的用途
WO2022228705A1 (en) 2021-04-30 2022-11-03 F. Hoffmann-La Roche Ag Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate
WO2022232503A1 (en) 2021-04-30 2022-11-03 Genentech, Inc. Therapeutic and diagnostic methods and compositions for cancer
WO2022242738A1 (en) * 2021-05-20 2022-11-24 Shanghai Junshi Biosciences Co., Ltd. Use of anti-pd-1 antibody in combination with chemotherapy in treating esophageal cancer
WO2022242621A1 (zh) * 2021-05-17 2022-11-24 上海君实生物医药科技股份有限公司 治疗完全切除黏膜黑色素瘤的患者的药物及方法
WO2022251359A1 (en) 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Bicyclic inhibitors of alk5 and methods of use
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
WO2023279092A2 (en) 2021-07-02 2023-01-05 Genentech, Inc. Methods and compositions for treating cancer
WO2023010094A2 (en) 2021-07-28 2023-02-02 Genentech, Inc. Methods and compositions for treating cancer
WO2023007472A1 (en) 2021-07-30 2023-02-02 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
WO2023010095A1 (en) 2021-07-28 2023-02-02 F. Hoffmann-La Roche Ag Methods and compositions for treating cancer
WO2023056403A1 (en) 2021-09-30 2023-04-06 Genentech, Inc. Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
US11639385B2 (en) 2014-12-22 2023-05-02 Pd-1 Acquisition Group, Llc Anti-PD-1 antibodies
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
WO2023170606A1 (en) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023196964A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine learning identification, classification, and quantification of tertiary lymphoid structures
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
US11865159B2 (en) 2017-02-28 2024-01-09 Sanofi Therapeutic RNA
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
EP4310197A1 (en) 2022-07-21 2024-01-24 Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda Method for identifying lung cancer patients for a combination treatment of immuno- and chemotherapy
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
US11939380B2 (en) 2017-04-05 2024-03-26 Les Laboratoires Servier Combination therapies targeting PD-1, TIM-3, and LAG-3
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma

Families Citing this family (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104250302B (zh) 2013-06-26 2017-11-14 上海君实生物医药科技股份有限公司 抗pd‑1抗体及其应用
US9982052B2 (en) 2014-08-05 2018-05-29 MabQuest, SA Immunological reagents
ES2847311T3 (es) 2014-08-05 2021-08-02 MabQuest SA Reactivos inmunológicos que se unen a PD-1
CN116059219A (zh) 2015-07-16 2023-05-05 比奥克斯塞尔医疗股份有限公司 一种使用免疫调节治疗癌症的新颖方法
CN106699888B (zh) * 2015-07-28 2020-11-06 上海昀怡健康科技发展有限公司 一种pd-1抗体及其制备方法和应用
CN106390115A (zh) * 2015-07-29 2017-02-15 上海君实生物医药科技股份有限公司 一种人源化单克隆抗体的稳定制剂
WO2017024465A1 (en) * 2015-08-10 2017-02-16 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
CN106432494B9 (zh) * 2015-08-11 2022-02-15 广州誉衡生物科技有限公司 新型抗-pd-1抗体
SG10201914109VA (en) 2015-08-11 2020-02-27 Wuxi Biologics Cayman Inc Novel anti-pd-1 antibodies
MA48579A (fr) 2015-09-01 2020-03-18 Agenus Inc Anticorps anti-pd1 et méthodes d'utilisation de ceux-ci
CA3000638C (en) 2015-09-29 2024-02-27 Asia Biotech Pte. Ltd. Pd-1 antibodies and uses thereof
US11207393B2 (en) * 2015-10-16 2021-12-28 President And Fellows Of Harvard College Regulatory T cell PD-1 modulation for regulating T cell effector immune responses
CN105566496B (zh) * 2015-11-26 2019-04-02 大庆东竺明生物技术有限公司 阻断人程序性死亡因子1(pd-1)功能的单克隆抗体及其编码基因和应用
US11214617B2 (en) 2016-01-22 2022-01-04 MabQuest SA Immunological reagents
MX2017016851A (es) * 2016-03-04 2018-04-30 Sichuan Kelun Biotech Biopharmaceutical Co Ltd Anticuerpo para el ligando del factor 1 de muerte celular programada (pdl-1), composicion farmaceutica del mismo y uso de los mismos.
CN105950715B (zh) * 2016-04-27 2019-04-26 深圳市第三人民医院 检测δ42pd1的方法、引物及试剂盒
CN105968200B (zh) 2016-05-20 2019-03-15 瑞阳(苏州)生物科技有限公司 抗人pd-l1人源化单克隆抗体及其应用
CN106008714B (zh) 2016-05-24 2019-03-15 瑞阳(苏州)生物科技有限公司 抗人pd-1人源化单克隆抗体及其应用
CN106085955B (zh) * 2016-06-08 2019-09-10 中南大学 一种同时分离外周血t、b淋巴细胞的方法
CN106046162B (zh) * 2016-06-21 2019-04-02 大庆东竺明生物技术有限公司 抗人程序性死亡因子1（pd-1）单克隆抗体的制备及应用
WO2018035710A1 (en) 2016-08-23 2018-03-01 Akeso Biopharma, Inc. Anti-ctla4 antibodies
CN106967172B (zh) 2016-08-23 2019-01-08 康方药业有限公司 抗ctla4-抗pd-1 双功能抗体、其药物组合物及其用途
CN106977602B (zh) * 2016-08-23 2018-09-25 中山康方生物医药有限公司 一种抗pd1单克隆抗体、其药物组合物及其用途
MX2019002946A (es) * 2016-09-14 2019-09-26 Abbvie Biotherapeutics Inc Anticuerpos anti-pd-1 y sus usos.
WO2018053405A1 (en) 2016-09-19 2018-03-22 Celgene Corporation Methods of treating immune disorders using pd-1 binding proteins
US10766958B2 (en) 2016-09-19 2020-09-08 Celgene Corporation Methods of treating vitiligo using PD-1 binding antibodies
WO2018119474A2 (en) * 2016-12-23 2018-06-28 Remd Biotherapeutics, Inc. Immunotherapy using antibodies that bind programmed death 1 (pd-1)
CN108341871A (zh) * 2017-01-24 2018-07-31 三生国健药业（上海）股份有限公司 抗pd-1单克隆抗体及其制备方法和应用
CN106939049B (zh) 2017-04-20 2019-10-01 苏州思坦维生物技术股份有限公司 拮抗抑制人pd-1抗原与其配体结合的单克隆抗体及其制备方法与应用
WO2019036855A1 (en) 2017-08-21 2019-02-28 Adagene Inc. ANTI-CD137 MOLECULES AND THEIR USE
CN107446048B (zh) * 2017-09-13 2021-03-30 北京韩美药品有限公司 一种能够特异性地结合pd-1的抗体及其功能片段
TW201920282A (zh) * 2017-09-29 2019-06-01 中國大陸商上海藥明生物技術有限公司 抗egfr和pd-1的雙特異性抗體
WO2019096136A1 (zh) * 2017-11-14 2019-05-23 拜西欧斯（北京）生物技术有限公司 抗pd-1抗体及其制备方法和应用
WO2019109238A1 (en) 2017-12-05 2019-06-13 Lyvgen Biopharma Co., Ltd. Anti-cd137 antibodies and uses thereof
WO2019148445A1 (en) 2018-02-02 2019-08-08 Adagene Inc. Precision/context-dependent activatable antibodies, and methods of making and using the same
CN110269865A (zh) * 2018-03-16 2019-09-24 山东大学 黑根霉胞外多糖在制备治疗诱发性结肠癌药物中的应用
SG11202008802QA (en) * 2018-03-22 2020-10-29 Keires Ag Antagonistic pd-1, pd-l1 and lag-3 binding proteins
WO2019201169A1 (en) * 2018-04-15 2019-10-24 Salubris (Chengdu) Biotech Co., Ltd Antibodies binding pd-1 and uses thereof
CN108840932B (zh) * 2018-04-28 2022-03-29 中国科学院微生物研究所 一种pd-1特异性抗体及其抗肿瘤应用
IL307925A (en) 2018-05-07 2023-12-01 Genmab As Combination of an antibody against 1-PD and conjugation of a drug with an antibody against TF for use in the treatment of cancer
CN109160949B (zh) * 2018-07-23 2021-05-14 中国医学科学院血液病医院（血液学研究所） 一种鼠抗人pd-1单克隆抗体及应用
CA3107596A1 (en) 2018-08-23 2020-02-27 Seagen Inc. Anti-tigit antibodies
CN112972675A (zh) * 2018-09-07 2021-06-18 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗肿瘤中的用途
JP6988769B2 (ja) * 2018-11-08 2022-01-05 株式会社デンソー 開閉体制御装置及びモータ
CN111303283A (zh) * 2018-12-12 2020-06-19 上海君实生物医药科技股份有限公司 抗il-17a抗体及其应用
CN111423510B (zh) 2019-01-10 2024-02-06 迈威(上海)生物科技股份有限公司 重组抗人pd-1抗体及其应用
CN112969716B (zh) * 2019-02-03 2022-11-22 江苏恒瑞医药股份有限公司 抗pd-1抗体、其抗原结合片段及医药用途
EP3966252A4 (en) 2019-05-10 2023-01-25 Lyvgen Biopharma Holdings Limited HUMANIZED ANTI-CD137 ANTIBODIES AND THEIR USES
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
CN114206931A (zh) * 2019-09-30 2022-03-18 四川科伦博泰生物医药股份有限公司 抗pd-1抗体及其用途
TW202143969A (zh) * 2020-03-09 2021-12-01 大陸商和記黃埔醫藥（上海）有限公司 抗ｐｄ－１抗體和多受體酪胺酸激酶抑制劑的藥物組合及其使用方法
KR20230035576A (ko) 2020-07-07 2023-03-14 비온테크 에스이 Hpv 양성 암 치료용 rna
TW202204418A (zh) * 2020-07-16 2022-02-01 大陸商和鉑醫藥（上海）有限責任公司 Ｐｄ－１抗原結合蛋白及其應用
CN116348599A (zh) * 2020-08-31 2023-06-27 博奥信生物技术（南京）有限公司 Pd-1结合抗体及其用途
CN116323658A (zh) * 2020-09-28 2023-06-23 上海君实生物医药科技股份有限公司 靶向PD-1或PD-L1和TGF-β的双功能蛋白及其医药用途
CN112159476B (zh) * 2020-10-10 2022-08-02 中国药科大学 一种用于多发性骨髓瘤的双特异性抗体及其应用
JP2023549581A (ja) 2020-11-17 2023-11-27 シージェン インコーポレイテッド ツカチニブ及び抗ｐｄ－１／抗ｐｄ－ｌ１抗体の組み合わせによりがんを治療する方法
TW202245808A (zh) 2020-12-21 2022-12-01 德商拜恩迪克公司 用於治療癌症之治療性ｒｎａ
WO2022135667A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
TW202304506A (zh) 2021-03-25 2023-02-01 日商安斯泰來製藥公司 涉及抗claudin 18.2抗體的組合治療以治療癌症
CN113087796B (zh) * 2021-04-02 2022-03-18 河南省肿瘤医院 一种抗pd-l1抗体及其应用
KR20240046323A (ko) 2021-07-13 2024-04-08 비온테크 에스이 암에 대한 병용 요법에 있어서 cd40 및 cd137에 대한 다중특이 결합제
CN116019907A (zh) * 2021-07-29 2023-04-28 上海君实生物医药科技股份有限公司 抗pd-1抗体药物组合物及其用途
WO2023051926A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
CA3234647A1 (en) 2021-10-06 2023-04-13 Genmab A/S Multispecific binding agents against pd-l1 and cd137 in combination therapy
TW202333802A (zh) 2021-10-11 2023-09-01 德商拜恩迪克公司 用於肺癌之治療性rna(二)
WO2023083439A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
WO2023218046A1 (en) 2022-05-12 2023-11-16 Genmab A/S Binding agents capable of binding to cd27 in combination therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156712A1 (en) * 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
WO2011110621A1 (en) * 2010-03-11 2011-09-15 Ucb Pharma, S.A. Biological products: humanised agonistic anti-pd-1 antibodies
WO2011110604A1 (en) * 2010-03-11 2011-09-15 Ucb Pharma, S.A. Pd-1 antibody

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2166368T3 (es) * 1993-12-24 2002-04-16 Merck Patent Gmbh Inmunoconjugados.
CN1359937A (zh) * 2000-12-20 2002-07-24 上海博德基因开发有限公司 一种新的多肽——人细胞程序性死亡因子Mch11.11和编码这种多肽的多核苷酸
EP3287144A1 (en) 2002-07-03 2018-02-28 ONO Pharmaceutical Co., Ltd. Immunopotentiating compositions
CA2970873C (en) * 2005-05-09 2022-05-17 E. R. Squibb & Sons, L.L.C. Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
JP5406019B2 (ja) * 2006-05-17 2014-02-05 セルーメン、インコーポレイテッド 自動化組織分析のための方法
AU2007268591A1 (en) 2006-05-31 2007-12-06 Astellas Pharma Inc. Humanized anti-human osteopontin antibody
US9243052B2 (en) * 2007-08-17 2016-01-26 Daniel Olive Method for treating and diagnosing hematologic malignancies
EP2262837A4 (en) * 2008-03-12 2011-04-06 Merck Sharp & Dohme PD-1 BINDING PROTEINS
CA2736829C (en) * 2008-09-12 2018-02-27 Isis Innovation Limited Pd-1 specific antibodies and uses thereof
AU2009296392B2 (en) * 2008-09-26 2016-06-02 Dana-Farber Cancer Institute, Inc. Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor
KR101050829B1 (ko) * 2008-10-02 2011-07-20 서울대학교산학협력단 항 ｐｄ-1 항체 또는 항 ｐｄ-ｌ1 항체를 포함하는 항암제
CN102298053B (zh) * 2011-05-20 2014-01-29 中山大学肿瘤防治中心 原发性肝细胞肝癌术后复发风险评估的组合抗体试剂盒
CN104250302B (zh) 2013-06-26 2017-11-14 上海君实生物医药科技股份有限公司 抗pd‑1抗体及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156712A1 (en) * 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
WO2011110621A1 (en) * 2010-03-11 2011-09-15 Ucb Pharma, S.A. Biological products: humanised agonistic anti-pd-1 antibodies
WO2011110604A1 (en) * 2010-03-11 2011-09-15 Ucb Pharma, S.A. Pd-1 antibody

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
COLOMA, J. J. ET AL., BIOTECHNIQUES, vol. 11, 1991, pages 152 - 156
EVANS, RIVA ET AL.: "Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion.", HEPATOLOGY, vol. 48, no. 3, 2008, pages 759 - 769
FRANCISCO, SAGE ET AL.: "The PD-1 pathway in tolerance and autoimmunity", IMMUNOL REV, vol. 236, 2010, pages 219 - 242
JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 273, no. 34, 1998, pages 21769 - 21776
LARRICK, J.W. ET AL., SCAND. J. IMMUNOL., vol. 32, 1990, pages 121 - 128
OKAZAKI; HONJO: "PD-1 and PD-1 ligands: from discovery to clinical application", INTERNATIONAL IMMUNOLOGY, vol. 19, no. 7, 2007, pages 813 - 824
PINI, A: "Design and Use of a Phage Display Library", HUMAN ANTIBODIES WITH SUBNANOMOLAR AFFINITYAGAINST A MARKER OF ANGIOGENESIS ELUTED FROM A, 1998
See also references of EP3026062A4
SHIMAUCHI, KABASHIMA ET AL.: "Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T cells in adult T cell leukemia/lymphoma", INT J CANCER, vol. 121, no. 12, 2007, pages 2585 - 2590
TRABATTONI, SARESELLA ET AL.: "B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression", BLOOD, vol. 101, no. 7, 2003, pages 2514 - 2520
WALLS MA; HSIAO H; HARRIS LJ, NUCLEIC ACIDS RESEARCH, vol. 21, no. 12, 1993, pages 2921 - 2929
YAO, ZHU ET AL.: "Advances in targeting cell surface signaling molecules for immune modulation", NAT REV DRUG DISCOV, vol. 12, no. 2, 2013, pages 130 - 146

Cited By (215)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10344090B2 (en) 2013-12-12 2019-07-09 Shanghai Hangrui Pharmaceutical Co., Ltd. PD-1 antibody, antigen-binding fragment thereof, and medical application thereof
US11365255B2 (en) 2013-12-12 2022-06-21 Suzhou Suncadia Biopharmaceuticals Co., Ltd. PD-1 antibody, antigen-binding fragment thereof, and medical application thereof
US10981989B2 (en) 2014-03-12 2021-04-20 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US11884727B2 (en) 2014-03-12 2024-01-30 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of amyotrophic lateral sclerosis
US11643464B2 (en) 2014-03-12 2023-05-09 Yeda Research and Develpment & Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of a retinal degeneration disorder
US9982049B2 (en) 2014-03-12 2018-05-29 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
US9982051B2 (en) 2014-03-12 2018-05-29 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US11884728B2 (en) 2014-03-12 2024-01-30 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of amyotrophic lateral sclerosis
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US9512225B2 (en) 2014-03-12 2016-12-06 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US10961309B2 (en) 2014-03-12 2021-03-30 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US9982050B2 (en) 2014-03-12 2018-05-29 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
US9394365B1 (en) 2014-03-12 2016-07-19 Yeda Research And Development Co., Ltd Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
US9856318B2 (en) 2014-03-12 2018-01-02 Yeda Research And Development Co., Ltd. Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US9534052B2 (en) 2014-03-12 2017-01-03 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
US9982048B2 (en) 2014-03-12 2018-05-29 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
US11492405B2 (en) 2014-03-12 2022-11-08 Yeda Research And Development Co. Ltd Reducing systemic regulatory t cell levels or activity for treatment of disease and injury of the CNS
US9982047B2 (en) 2014-03-12 2018-05-29 Yeda Research And Development Co. Ltd. Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
US10214585B2 (en) 2014-03-12 2019-02-26 Yeda Research And Development Co., Ltd. Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US9512227B2 (en) 2014-03-12 2016-12-06 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of Alzheimer's disease
US10144778B2 (en) 2014-03-12 2018-12-04 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US10239942B2 (en) 2014-12-22 2019-03-26 Pd-1 Acquisition Group, Llc Anti-PD-1 antibodies
US10544217B2 (en) 2014-12-22 2020-01-28 Pd-1 Acquisition Group, Llc Anti-PD-1 antibodies
US11639385B2 (en) 2014-12-22 2023-05-02 Pd-1 Acquisition Group, Llc Anti-PD-1 antibodies
WO2016106159A1 (en) * 2014-12-22 2016-06-30 Enumeral Biomedical Holding, Inc. Anti-pd-1 antibodies
US11174316B2 (en) 2015-03-13 2021-11-16 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
US10144779B2 (en) 2015-05-29 2018-12-04 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US10479833B2 (en) 2015-05-29 2019-11-19 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US11267889B2 (en) 2015-05-29 2022-03-08 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
EP3736290A1 (en) 2015-05-29 2020-11-11 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
KR20170020933A (ko) * 2015-06-09 2017-02-24 베이징 동팡 바이오테크 컴퍼니 리미티드 항 pd-1 단일 클론 항체 및 이의 획득 방법
KR101876689B1 (ko) 2015-06-09 2018-08-02 베이징 동팡 바이오테크 컴퍼니 리미티드 항 pd-1 단일 클론 항체 및 이의 획득 방법
JP2017534247A (ja) * 2015-06-09 2017-11-24 北京東方百泰生物科技有限公司Ｂｅｉｊｉｎｇ Ｄｏｎｇｆａｎｇ Ｂｉｏｔｅｃｈ Ｃｏ．， Ｌｔｄ． 抗ｐｄ−１のモノクローナル抗体およびその獲得方法
EP3176182A4 (en) * 2015-06-09 2017-11-29 Beijing Dongfang Biotech Co., Ltd Anti-pd-1 monoclonal antibody and obtaining method therefor
EP3770177A1 (en) * 2015-06-09 2021-01-27 Beijing Dongfang Biotech Co., Ltd Anti-pd-1 monoclonal antibodies and obtaining method thereof
US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
TWI765862B (zh) * 2015-09-03 2022-06-01 日商小野藥品工業股份有限公司 基於過敏反應素-１拮抗劑之癌免疫增強劑
JP2018533973A (ja) * 2015-09-29 2018-11-22 セルジーン コーポレイション Ｐｄ−１結合タンパク質及びその使用方法
EP3368572B1 (en) 2015-10-02 2022-05-25 Symphogen A/S Anti-pd-1 antibodies and compositions
US10894830B2 (en) 2015-11-03 2021-01-19 Janssen Biotech, Inc. Antibodies specifically binding PD-1, TIM-3 or PD-1 and TIM-3 and their uses
EP4046655A1 (en) 2015-11-03 2022-08-24 Janssen Biotech, Inc. Antibodies specifically binding pd-1 and their uses
WO2017079116A2 (en) 2015-11-03 2017-05-11 Janssen Biotech, Inc. Antibodies specifically binding pd-1 and tim-3 and their uses
WO2017079112A1 (en) 2015-11-03 2017-05-11 Janssen Biotech, Inc. Antibodies specifically binding pd-1 and their uses
WO2017079115A1 (en) 2015-11-03 2017-05-11 Janssen Biotech, Inc. Antibodies specifically binding tim-3 and their uses
US10913797B2 (en) 2015-11-18 2021-02-09 Lyvgen Biopharma Holdings Limited Anti-PD-1 antibodies and therapeutic uses thereof
CN108601829B (zh) * 2015-11-18 2020-04-24 礼进生物医药科技（上海）有限公司 抗pd-1抗体及其治疗用途
CN108601829A (zh) * 2015-11-18 2018-09-28 礼进生物医药科技（上海）有限公司 抗pd-1抗体及其治疗用途
WO2017087599A1 (en) 2015-11-18 2017-05-26 Lyvgen Biopharma Holdings Limited Anti-pd-1 antibodies and therapeutic uses thereof
EP3377102A4 (en) * 2015-11-18 2019-07-10 Lyvgen Biopharma Holdings Limited ANTI-PD-1 ANTIBODIES AND THEIR THERAPEUTIC USES
WO2017125815A3 (en) * 2016-01-22 2017-09-08 MabQuest SA Pd1 specific antibodies
US10913801B2 (en) 2016-02-02 2021-02-09 Innovent Biologics (Suzhou) Co., Ltd. PD-1 antibodies
WO2017133540A1 (en) 2016-02-02 2017-08-10 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
EP3411410A4 (en) * 2016-02-02 2019-08-07 Innovent Biologics (Suzhou) Co., Ltd. PD-1 ANTIBODY
WO2017205721A1 (en) 2016-05-27 2017-11-30 Agenus Inc. Anti-tim-3 antibodies and methods of use thereof
WO2017220988A1 (en) 2016-06-20 2017-12-28 Kymab Limited Multispecific antibodies for immuno-oncology
WO2017220990A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 antibodies
WO2017220989A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 and il-2 cytokines
JP7164528B2 (ja) 2016-09-14 2022-11-01 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッド Ｐｄ－１に特異的に結合する可能な抗体及びその機能的断片
JP2019532669A (ja) * 2016-09-14 2019-11-14 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッドＢｅｉｊｉｎｇ Ｈａｎｍｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Ｐｄ−１に特異的に結合する可能な抗体及びその機能的断片
US11072651B2 (en) 2016-09-14 2021-07-27 Beijing Hanmi Pharm. Co., Ltd. Antibody specifically binding to IL-17A, encoding nucleic acid, and method of using the antibody
JP2021121216A (ja) * 2016-09-14 2021-08-26 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッドBeijing Hanmi Pharmaceutical Co., Ltd. Ｐｄ−１に特異的に結合する可能な抗体及びその機能的断片
WO2018071500A1 (en) 2016-10-11 2018-04-19 Agenus Inc. Anti-lag-3 antibodies and methods of use thereof
US10844119B2 (en) 2016-10-11 2020-11-24 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
US10882908B2 (en) 2016-10-11 2021-01-05 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
WO2018081621A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
US11117968B2 (en) 2016-11-03 2021-09-14 Bristol-Myers Squibb Company Activatable anti-CTLA-4 antibodies and uses thereof
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
WO2018106864A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Antibodies and methods of use thereof
WO2018106862A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
US11638755B2 (en) 2016-12-07 2023-05-02 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US10912831B1 (en) 2016-12-07 2021-02-09 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US11013802B2 (en) 2016-12-07 2021-05-25 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
EP4289484A2 (en) 2016-12-07 2023-12-13 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
WO2018132739A2 (en) 2017-01-13 2018-07-19 Agenus Inc. T cell receptors that bind to ny-eso-1 and methods of use thereof
US11560430B2 (en) 2017-01-20 2023-01-24 Tayu Huaxia Biotech Medical Group Co., LTD Anti-PD-1 antibodies and uses thereof
US10465007B2 (en) 2017-01-20 2019-11-05 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-PD-1 antibodies and uses thereof
US11865159B2 (en) 2017-02-28 2024-01-09 Sanofi Therapeutic RNA
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
US11939380B2 (en) 2017-04-05 2024-03-26 Les Laboratoires Servier Combination therapies targeting PD-1, TIM-3, and LAG-3
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018191502A2 (en) 2017-04-13 2018-10-18 Agenus Inc. Anti-cd137 antibodies and methods of use thereof
EP4275698A2 (en) 2017-05-01 2023-11-15 Agenus Inc. Anti-tigit antibodies and methods of use thereof
WO2018204363A1 (en) 2017-05-01 2018-11-08 Agenus Inc. Anti-tigit antibodies and methods of use thereof
WO2018222711A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
WO2018222722A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising an anti-lag-3 antibody or an anti-lag-3 antibody and an anti-pd-1 or anti-pd-l1 antibody
WO2018222718A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
EP4306542A2 (en) 2017-05-30 2024-01-17 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
EP4245375A2 (en) 2017-05-30 2023-09-20 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
WO2018223040A1 (en) 2017-06-01 2018-12-06 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
US11566073B2 (en) 2017-06-01 2023-01-31 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-PD-1 antibody
WO2019046856A1 (en) 2017-09-04 2019-03-07 Agenus Inc. T-CELL RECEPTORS THAT BIND TO SPECIFIC PHOSPHOPEPTIDES OF MIXED LINEAR LEUKEMIA (MLL) AND METHODS OF USE THEREOF
US11919957B2 (en) 2017-10-15 2024-03-05 Bristol-Myers Squibb Company Methods of treating tumor
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
WO2019090330A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Methods of treating a tumor
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2019137541A1 (en) * 2018-01-15 2019-07-18 Nanjing Legend Biotech Co., Ltd. Single-domain antibodies and variants thereof against pd-1
US11713353B2 (en) 2018-01-15 2023-08-01 Nanjing Legend Biotech Co., Ltd. Single-domain antibodies and variants thereof against PD-1
WO2019143607A1 (en) 2018-01-16 2019-07-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019144098A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
WO2019144126A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019195452A1 (en) 2018-04-04 2019-10-10 Bristol-Myers Squibb Company Anti-cd27 antibodies and uses thereof
WO2019210055A2 (en) 2018-04-26 2019-10-31 Agenus Inc. Heat shock protein-binding peptide compositions and methods of use thereof
US11136394B2 (en) 2018-05-17 2021-10-05 Nanjing Leads Biolabs Co., Ltd. Antibody binding PD-1 and use thereof
WO2019219064A1 (en) * 2018-05-17 2019-11-21 Nanjing Leads Biolabs Co.Ltd Antibody binding pd-1 and use thereof
WO2019232319A1 (en) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions and methods for inhibiting cd73
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020061376A2 (en) 2018-09-19 2020-03-26 Alpine Immune Sciences, Inc. Methods and uses of variant cd80 fusion proteins and related constructs
WO2020076799A1 (en) 2018-10-09 2020-04-16 Bristol-Myers Squibb Company Anti-mertk antibodies for treating cancer
WO2020081928A1 (en) 2018-10-19 2020-04-23 Bristol-Myers Squibb Company Combination therapy for melanoma
WO2020086724A1 (en) 2018-10-23 2020-04-30 Bristol-Myers Squibb Company Methods of treating tumor
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
EP3666905A1 (en) 2018-12-11 2020-06-17 Sanofi E. coli positive for pks island as marker of positive response to anti-pd1 therapy in colorectal cancer
WO2020123453A2 (en) 2018-12-11 2020-06-18 Theravance Biopharma R&D Ip, Llc Alk5 inhibitors
WO2020120501A1 (en) 2018-12-11 2020-06-18 Sanofi Pks-island positive e. coli as marker of negative response to anti-pd1 therapy in colorectal cancer
WO2020150152A1 (en) 2019-01-14 2020-07-23 Genentech, Inc. Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2020154189A1 (en) 2019-01-21 2020-07-30 Sanofi Therapeutic rna and anti-pd1 antibodies for advanced stage solid tumor cancers
WO2020198672A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020198676A1 (en) 2019-03-28 2020-10-01 Bristol-Myers Squibb Company Methods of treating tumor
WO2020211804A1 (zh) 2019-04-17 2020-10-22 上海君实生物医药科技股份有限公司 抗pd-1抗体在制备治疗实体瘤的药物中的用途
EP3957326A4 (en) * 2019-04-17 2023-03-29 Shanghai Junshi Biosciences Co., Ltd. USE OF ANTI-PD-1 ANTIBODIES IN THE PREPARATION OF A MEDICINE FOR THE TREATMENT OF SOLID TUMORS
US10995141B2 (en) 2019-04-19 2021-05-04 ImmunoBrain Checkpoint, Inc. Modified anti-PD-L1 antibody and methods and uses for treating a neurodegenerative disease
WO2020214995A1 (en) 2019-04-19 2020-10-22 Genentech, Inc. Anti-mertk antibodies and their methods of use
US11732046B2 (en) 2019-04-19 2023-08-22 ImmunoBrain Checkpoint, Inc. Modified anti-PD-L1 antibody and methods and uses for treating a neurodegenerative disease
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2021006199A1 (ja) 2019-07-05 2021-01-14 小野薬品工業株式会社 Ｐｄ－１／ｃｄ３二重特異性タンパク質による血液がん治療
WO2021008523A1 (zh) 2019-07-15 2021-01-21 上海君实生物医药科技股份有限公司 抗tigit抗体及其应用
WO2021025140A1 (ja) 2019-08-08 2021-02-11 小野薬品工業株式会社 二重特異性タンパク質
WO2021042019A1 (en) 2019-08-30 2021-03-04 Agenus Inc. Anti-cd96 antibodies and methods of use thereof
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
WO2021062018A1 (en) 2019-09-25 2021-04-01 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
WO2021092044A1 (en) 2019-11-05 2021-05-14 Bristol-Myers Squibb Company M-protein assays and uses thereof
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092380A1 (en) 2019-11-08 2021-05-14 Bristol-Myers Squibb Company Lag-3 antagonist therapy for melanoma
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021102468A1 (en) 2019-11-22 2021-05-27 Theravance Biopharma R&D Ip, Llc Substituted 1,5-naphthyridines or quinolines as alk5 inhibitors
WO2021127554A1 (en) 2019-12-19 2021-06-24 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
WO2021152548A1 (en) 2020-01-30 2021-08-05 Benitah Salvador Aznar Combination therapy for treatment of cancer and cancer metastasis
WO2021155149A1 (en) 2020-01-31 2021-08-05 Genentech, Inc. Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
WO2021155840A1 (zh) 2020-02-07 2021-08-12 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗恶性肿瘤中的用途
WO2021160152A1 (zh) 2020-02-13 2021-08-19 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗神经内分泌瘤中的用途
WO2021160151A1 (zh) 2020-02-13 2021-08-19 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗肿瘤中的用途
WO2021176424A1 (en) 2020-03-06 2021-09-10 Ona Therapeutics, S.L. Anti-cd36 antibodies and their use to treat cancer
WO2021194942A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anti-ccr8 antibodies for treating cancer
WO2021203131A1 (en) 2020-03-31 2021-10-07 Theravance Biopharma R&D Ip, Llc Substituted pyrimidines and methods of use
WO2021253041A1 (en) 2020-06-10 2021-12-16 Theravance Biopharma R&D Ip, Llc Naphthyridine derivatives useful as alk5 inhibitors
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
WO2022042626A1 (zh) 2020-08-27 2022-03-03 上海君实生物医药科技股份有限公司 抗pd-1抗体在治疗鼻咽癌中的用途
WO2022047189A1 (en) 2020-08-28 2022-03-03 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
WO2022042681A1 (en) * 2020-08-28 2022-03-03 Shanghai Junshi Biosciences Co., Ltd. Use of an anti-pd-1 antibody and a cytotoxic anticancer drug in treatment of non-small cell lung cancer
CN115518162A (zh) * 2020-08-28 2022-12-27 上海君实生物医药科技股份有限公司 抗pd-1抗体和细胞毒类抗癌药在治疗非小细胞肺癌中的用途
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
WO2022086957A1 (en) 2020-10-20 2022-04-28 Genentech, Inc. Peg-conjugated anti-mertk antibodies and methods of use
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022094567A1 (en) 2020-10-28 2022-05-05 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
WO2022098638A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
WO2022098628A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies
WO2022098648A2 (en) 2020-11-04 2022-05-12 Genentech, Inc. Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates
WO2022119830A1 (en) 2020-12-02 2022-06-09 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022223006A1 (zh) 2021-04-22 2022-10-27 上海君实生物医药科技股份有限公司 抗pd-1抗体联合一线化疗治疗晚期非小细胞肺癌的用途
WO2022228705A1 (en) 2021-04-30 2022-11-03 F. Hoffmann-La Roche Ag Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate
WO2022232503A1 (en) 2021-04-30 2022-11-03 Genentech, Inc. Therapeutic and diagnostic methods and compositions for cancer
WO2022242621A1 (zh) * 2021-05-17 2022-11-24 上海君实生物医药科技股份有限公司 治疗完全切除黏膜黑色素瘤的患者的药物及方法
WO2022242738A1 (en) * 2021-05-20 2022-11-24 Shanghai Junshi Biosciences Co., Ltd. Use of anti-pd-1 antibody in combination with chemotherapy in treating esophageal cancer
WO2022251359A1 (en) 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Bicyclic inhibitors of alk5 and methods of use
WO2022254227A1 (en) 2021-06-04 2022-12-08 Kymab Limited Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies
WO2023279092A2 (en) 2021-07-02 2023-01-05 Genentech, Inc. Methods and compositions for treating cancer
WO2023010095A1 (en) 2021-07-28 2023-02-02 F. Hoffmann-La Roche Ag Methods and compositions for treating cancer
WO2023010094A2 (en) 2021-07-28 2023-02-02 Genentech, Inc. Methods and compositions for treating cancer
WO2023007472A1 (en) 2021-07-30 2023-02-02 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
WO2023056403A1 (en) 2021-09-30 2023-04-06 Genentech, Inc. Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
WO2023170606A1 (en) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023196964A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine learning identification, classification, and quantification of tertiary lymphoid structures
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024017510A1 (en) 2022-07-21 2024-01-25 Fundación Para La Investigación Biomédica Del Hospital Universitario Puerta De Hierro Majadahonda Method for identifying lung cancer patients for a combination treatment of immuno- and chemotherapy
EP4310197A1 (en) 2022-07-21 2024-01-24 Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda Method for identifying lung cancer patients for a combination treatment of immuno- and chemotherapy
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma

Also Published As

Publication number Publication date
DK3026062T3 (da) 2020-10-12
EP3026062B1 (en) 2020-08-05
HUE052487T2 (hu) 2021-05-28
JP2016523265A (ja) 2016-08-08
MY176822A (en) 2020-08-24
ES2822927T3 (es) 2021-05-05
US20160272708A1 (en) 2016-09-22
HRP20201600T1 (hr) 2021-03-05
PH12015502819A1 (en) 2016-03-21
EP3026062A4 (en) 2017-08-16
JP6681327B2 (ja) 2020-04-15
EP3845562A1 (en) 2021-07-07
EP3026062A1 (en) 2016-06-01
PL3026062T3 (pl) 2021-01-11
PT3026062T (pt) 2020-10-13
SI3026062T1 (sl) 2020-12-31
US10815302B2 (en) 2020-10-27
US10066013B2 (en) 2018-09-04
US20210009688A1 (en) 2021-01-14
US20190023782A1 (en) 2019-01-24
RU2016102176A (ru) 2017-07-31
BR112015031883A2 (pt) 2018-02-14
CN104250302A (zh) 2014-12-31
RU2663795C2 (ru) 2018-08-09
CN104250302B (zh) 2017-11-14

Similar Documents

Publication Publication Date Title
US20210009688A1 (en) Anti-pd-1 antibody and use thereof
TWI772586B (zh) 三鏈抗體、其製備方法及其用途
WO2022042690A1 (zh) Ccr8抗体及其应用
CN111138546A (zh) 同源二聚体型双特异性抗体及其制备方法和用途
WO2016197497A1 (zh) 一种抗pd-1的单克隆抗体及其获得方法
WO2017201766A1 (zh) 抗人pd-1人源化单克隆抗体及其应用
JP2020504627A (ja) 抗ｐｄ−１抗体及びその使用
TW201946655A (zh) 新型抗體分子、其製備方法及其用途
WO2019184909A1 (zh) 新型抗体分子、其制备方法及其用途
TW201922784A (zh) ４﹘１ｂｂ抗體及其製備方法和應用
WO2019196309A1 (zh) 抗pd-l1抗体及其用途
CN111454358A (zh) 一种嵌合抗原受体及其应用
CN108473580A (zh) 抗人程序性死亡受体1抗体及其制备方法和用途
TW201934582A (zh) 抗pd-1/抗her2天然抗體結構樣異源二聚體形式雙特異抗體及其製備
KR20210027254A (ko) Tim-3에 대한 항체 및 그의 용도
WO2019096136A1 (zh) 抗pd-1抗体及其制备方法和应用
US10940212B2 (en) IL-21 agonist antibodies and methods of treatment using same
WO2017177217A2 (en) Chimeric receptors and uses thereof in immune therapy
CA2915882A1 (en) Il-21 binding proteins and uses thereof
CN113698492B (zh) 人间皮素嵌合抗原受体及其用途
WO2021143914A1 (zh) 一种激活型抗ox40抗体、生产方法及应用
TW202235104A (zh) 雙功能分子
TW202233680A (zh) 具有增加的選擇性之多靶向性雙特異性抗原結合分子
WO2021243028A1 (en) Bispecific molecules for selectively modulating t cells
TW202116812A (zh) 抗ｄｌｌ３嵌合抗原受體及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14818708

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: IDP00201508574

Country of ref document: ID

WWE Wipo information: entry into national phase

Ref document number: 12015502819

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 2016522196

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015031883

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 2014818708

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2016102176

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14392360

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112015031883

Country of ref document: BR

ENPW Started to enter national phase and was withdrawn or failed for other reasons

Ref document number: 112015031883

Country of ref document: BR

Free format text: PEDIDO RETIRADO EM RAZAO DO NAO CUMPRIMENTO DA EXIGENCIA PUBLICADA NA RPI NO 2433, DE 22/08/2017.

Ref document number: 112015031883

Country of ref document: BR

ENPZ Former announcement of the withdrawal of the entry into the national phase was wrong

Ref document number: 112015031883

Country of ref document: BR

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 112015031883

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20151218