WO2015085847A1 - Pd-1抗体、其抗原结合片段及其医药用途 - Google Patents

Pd-1抗体、其抗原结合片段及其医药用途 Download PDF

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WO2015085847A1
WO2015085847A1 PCT/CN2014/091090 CN2014091090W WO2015085847A1 WO 2015085847 A1 WO2015085847 A1 WO 2015085847A1 CN 2014091090 W CN2014091090 W CN 2014091090W WO 2015085847 A1 WO2015085847 A1 WO 2015085847A1
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antibody
seq
antigen
binding fragment
variable region
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PCT/CN2014/091090
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English (en)
French (fr)
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袁纪军
屈向东
林菊芳
叶鑫
曹国庆
陶维康
张连山
张蕾
扬莉
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to EP14868918.5A priority Critical patent/EP3081576B1/en
Priority to US15/103,758 priority patent/US10344090B2/en
Priority to SG11201604738TA priority patent/SG11201604738TA/en
Priority to UAA201607505A priority patent/UA119659C2/uk
Priority to MYPI2016001084A priority patent/MY184154A/en
Priority to RS20191248A priority patent/RS59480B1/sr
Priority to JP2016558249A priority patent/JP6502959B2/ja
Priority to DK14868918.5T priority patent/DK3081576T3/da
Priority to MEP-2019-261A priority patent/ME03527B/me
Priority to NZ721624A priority patent/NZ721624B2/en
Priority to LT14868918T priority patent/LT3081576T/lt
Priority to ES14868918T priority patent/ES2746805T3/es
Priority to MX2016007620A priority patent/MX370449B/es
Priority to PL14868918T priority patent/PL3081576T3/pl
Priority to CR20160319A priority patent/CR20160319A/es
Priority to EA201691225A priority patent/EA035037B1/ru
Priority to CA2932966A priority patent/CA2932966C/en
Priority to SI201431354T priority patent/SI3081576T1/sl
Priority to AU2014361473A priority patent/AU2014361473B2/en
Priority to BR112016013338-2A priority patent/BR112016013338B1/pt
Priority to CN201480011008.6A priority patent/CN105026428B/zh
Priority to KR1020167018704A priority patent/KR102256152B1/ko
Application filed by 上海恒瑞医药有限公司, 江苏恒瑞医药股份有限公司 filed Critical 上海恒瑞医药有限公司
Publication of WO2015085847A1 publication Critical patent/WO2015085847A1/zh
Priority to HK16101701.0A priority patent/HK1213910A1/zh
Priority to IL246137A priority patent/IL246137B/en
Priority to PH12016501120A priority patent/PH12016501120B1/en
Priority to ZA2016/04660A priority patent/ZA201604660B/en
Priority to US16/426,001 priority patent/US11365255B2/en
Priority to HRP20191678 priority patent/HRP20191678T1/hr
Priority to CY20191100996T priority patent/CY1122245T1/el

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • 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
    • 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
    • C07K2317/50—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
    • C07K2317/567—Framework region [FR]
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present invention relates to a PD-1 antibody, an antigen-binding fragment of PD-1, a chimeric antibody comprising the CDR region of the PD-1 antibody, a humanized antibody, and a medicament comprising the PD-1 antibody and an antigen-binding fragment thereof A composition, and its use as an anticancer drug.
  • Tumor immunotherapy is a long-term hot spot in the field of cancer therapy, in which T cell tumor immunotherapy is at its core. Tumor immunotherapy is a way to fully utilize and mobilize killer T cells in tumor patients and kill tumors. It may be the most effective and safest way to treat tumors. At the same time, tumor escape is a huge obstacle to tumor immunotherapy. Tumor cells use their own inhibition of the immune system to promote rapid tumor growth.
  • tumor immunotherapy is to maximize the patient's own immune system response to the tumor. It not only activates the original immune system response in the body, but also maintains the duration of the immune system response and the intensity of the response. key.
  • T cells Activation of T cells in humans takes a system of two signaling pathways.
  • a series of costimulatory molecules are required to provide a second signal.
  • the T cells are given a normal immune response.
  • This dual-signal pathway system plays a vital role in the balance of the immune system in the body. It strictly regulates the body's immune response to both self and non-self antigens.
  • a second signal provided by a costimulatory molecule it will result in a non-responsive or sustained specific immune response of the T cell, resulting in tolerance. Therefore, the second signaling pathway plays a very important regulatory role in the whole process of the body's immune response.
  • PD-l Programmed death-l
  • CTL-4 cytotoxic T Iymphocyte antigen 4
  • PD-1 has two ligands, PD-L1 and PD-L2.
  • PD-L1 is mainly expressed on T cells, B cells, macrophages, and dendritic cells (DCs), and expression on cells after activation can be up-regulated.
  • the expression of PD-L2 is relatively limited, mainly expressed on antigen presenting cells, such as activated macrophages and dendritic cells.
  • the new study found that high PD-L1 protein expression was detected in human tumor tissues such as breast cancer, lung cancer, gastric cancer, colon cancer, kidney cancer, and melanoma, and the expression level of PD-L1 was closely related to the clinical and prognosis of patients. . Since PD-L1 plays a role in suppressing T cell proliferation by the second signaling pathway, blocking the binding between PD-L1/PD-1 has become a very potential emerging target in the field of tumor immunotherapy.
  • the present invention provides a PD-1 antibody having high affinity, high selectivity, and high biological activity.
  • the present invention provides a PD-1 antibody or antigen-binding fragment thereof, comprising:
  • An antibody light chain variable region wherein said antibody light chain variable region is at least one selected from the group consisting of LCDR: SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8;
  • An antibody heavy chain variable region comprising at least one HCDR selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody light chain variable region comprises an LCDR1 as set forth in SEQ ID NO: 6.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody light chain variable region comprises an LCDR2 as set forth in SEQ ID NO: 7.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody light chain variable region comprises the SEQ ID NO: 8 LCDR3 region.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody heavy chain variable region comprises HCDR1 as set forth in SEQ ID NO:3.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody heavy chain variable region comprises HCDR2 as set forth in SEQ ID NO:4.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody heavy chain variable region comprises HCDR3 as set forth in SEQ ID NO:5.
  • the present invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody light chain variable region package is SEQ ID NO: 6, SEQ ID NO: 7 and LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 8.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof, wherein said antibody heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, and HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 5.
  • the invention provides a PD-1 antibody or antigen-binding fragment thereof a segment, wherein the antibody light chain variable region comprises LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively; and wherein said antibody heavy chain is
  • the variable region comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively.
  • the PD-1 antibody or antigen-binding fragment thereof according to the invention, wherein the antibody is a murine antibody or a fragment thereof.
  • a murine antibody or fragment thereof according to the invention wherein the antibody light chain variable region further comprises a light chain FR region of a murine kappa, lambda chain or variant thereof.
  • a murine antibody or fragment thereof according to the invention further comprises a light chain constant region of a murine kappa, lambda chain or variant thereof.
  • the murine antibody or fragment thereof according to the invention wherein the antibody heavy chain variable region further comprises a heavy chain FR region of murine IgG1, IgG2, IgG3, IgG4 or variants thereof.
  • the murine antibody or fragment thereof according to the invention further comprises a heavy chain constant region of murine IgG1, IgG2, IgG3, IgG4 or variants thereof.
  • the PD-1 antibody or antigen-binding fragment thereof according to the invention, wherein the antibody is a chimeric antibody or a fragment thereof.
  • the PD-1 chimeric antibody or fragment thereof according to the invention wherein the chimeric antibody light chain variable region sequence is: SEQ ID NO: 10.
  • the PD-1 chimeric antibody or fragment thereof according to the invention wherein the chimeric antibody heavy chain variable region sequence is: SEQ ID NO:9.
  • a PD-1 chimeric antibody or fragment thereof according to the invention further comprises a light chain constant region of a human kappa, lambda chain or variant thereof.
  • the PD-1 chimeric antibody or fragment thereof according to the invention further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising a human Source IgG2 or IgG4 heavy chain constant region, or IgG1 with no ADCC (antibody-dependent cell-mediated cytotoxicity) toxicity after amino acid mutation.
  • a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof preferably comprising a human Source IgG2 or IgG4 heavy chain constant region, or IgG1 with no ADCC (antibody-dependent cell-mediated cytotoxicity) toxicity after amino acid mutation.
  • the PD-1 antibody or antigen-binding fragment thereof according to the invention, wherein the antibody is a humanized antibody or a fragment thereof.
  • the PD-1 humanized antibody or fragment thereof according to the present invention wherein the humanized antibody light chain variable region further comprises a human light ⁇ , a ⁇ chain or a variant thereof Chain FR zone.
  • the PD-1 humanized antibody or fragment thereof according to the invention wherein the light chain FR region sequence on the variable region of the humanized antibody light chain is derived from SEQ. ID NO:
  • the PD-1 humanized antibody or fragment thereof according to the invention wherein the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 12, or Variants.
  • a PD-1 humanized antibody or fragment thereof according to the invention wherein said humanized antibody light chain variable region variant preferably has 0- in the light chain variable region Amino acid change of 10; the amino acid change of the variable region sequence variant on the light chain variable region of the humanized antibody is preferably A43S.
  • the PD-1 humanized antibody or fragment thereof according to the invention further comprises a light chain constant region of a human kappa, lambda chain or variant thereof.
  • the PD-1 humanized antibody or fragment thereof according to the present invention wherein the humanized antibody heavy chain variable region further comprises human IgG1, IgG2, IgG3, IgG4 or a variant thereof The heavy chain FR region of the body.
  • the PD-1 humanized antibody or fragment thereof according to the present invention wherein the heavy chain FR region sequence on the heavy chain variable region of the humanized antibody is derived from a human species
  • the combined sequence of heavy chain IgHV3-7 and JH6 SEQ ID NO: 13; FR1, FR2, FR3 region and FR4 region of JH6 comprising human germline heavy chain IgHV3-7.
  • the PD-1 humanized antibody or fragment thereof according to the invention wherein the humanized antibody heavy chain sequence is the sequence set forth in SEQ ID NO: 11, or Variant; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably an amino acid change of G44R.
  • the PD-1 humanized antibody or fragment thereof according to the invention further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising Human IgG2 or IgG4 heavy chain constant region.
  • the variant is preferably a heavy chain constant region mutation with reduced or absent ADCC effector function, more preferably N297A, L234A, L235A of IgG1; IgG2/4 chimera, F235E of IgG4, or L234A/E235A mutation.
  • the PD-1 antibody or antigen-binding fragment thereof according to the present invention wherein the antigen-binding fragment is Fab, Fv, sFv, F(ab') 2 .
  • the invention further provides a DNA molecule encoding a PD-1 antibody or antigen-binding fragment thereof as described above.
  • the invention further provides an expression vector comprising a DNA molecule as described above.
  • the invention further provides a host cell transformed with an expression vector as described above.
  • the host cell according to the invention wherein the host cell is a bacterium, preferably E. coli.
  • the host cell provided by the invention is a yeast, preferably Pichia pastoris.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a PD-1 antibody or antigen-binding fragment thereof according to the invention and a pharmaceutically acceptable excipient, dilution or carrier.
  • the invention further provides a use of a PD-1 antibody or antigen-binding fragment thereof according to the invention, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of a PD-1 mediated disease or condition ;
  • the disease described therein is preferably a cancer; more preferably a cancer expressing PD-L1; the cancer is most preferably breast cancer, lung cancer, gastric cancer, intestinal cancer, kidney cancer, melanoma; most preferably non-small cell lung cancer , melanoma and kidney cancer.
  • the invention further provides a method of treating and preventing a PD-1 mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a PD-1 antibody or antigen-binding fragment thereof according to the invention, or comprising a pharmaceutical composition thereof; wherein the disease is preferably cancer; more preferably, a cancer expressing PD-L1; and the cancer is most preferably breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma, Non-small cell lung cancer; most preferably non-small cell lung cancer, melanoma and kidney cancer.
  • Figure 1 Human peripheral blood mononuclear cell proliferation assay. It was shown that the PD-1 antibody mAb005 to be tested can effectively stimulate the proliferation of human peripheral blood mononuclear cells with an EC50 of 83 ng/ml.
  • FIG. 2 Cytokine IFN- ⁇ secretion test in human peripheral blood mononuclear cells. It was shown that the PD-1 antibody mAb005 to be tested can effectively stimulate the secretion of cytokine IFN- ⁇ while stimulating the proliferation of PBMC with an EC50 of 13 ng/ml.
  • Figure 3 Inhibitory effect of the PD-1 antibody H005-1 of the present invention on the growth of glioma cells.
  • Figure 4 Graph of tumor volume change after treatment.
  • Figure 5 Figure of body weight changes after treatment.
  • the antibody of the present invention refers to an immunoglobulin, which is a tetrapeptide chain structure in which two identical heavy chains and two identical light chains are linked by interchain disulfide bonds.
  • the immunoglobulin heavy chain constant region has different amino acid composition and arrangement order, so its antigenicity is also different. Accordingly, immunoglobulins can be classified into five classes, or isoforms of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain ⁇ , ⁇ , respectively. Chain, ⁇ chain.
  • IgG can be classified into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified as either a kappa chain or a lambda chain by the constant region.
  • Each of the five types of Ig may have a kappa chain or a lambda chain.
  • the antibody light chain variable region of the present invention may further comprise a light chain constant region comprising a human or murine kappa, lambda chain or a variant thereof.
  • the antibody heavy chain variable region of the present invention may further comprise a heavy chain constant region,
  • the heavy chain constant region comprises human or murine IgGl, 2, 3, 4 or variants thereof.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly, being the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region (C region).
  • the variable region includes three hypervariable regions (HVR) and four relatively conserved framework regions (FR). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR).
  • Each of the light chain variable region (LCVR) and the heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, and the order from the amino terminus to the carboxy terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the CDR amino acid residues of the LCVR region and the HCVR region of the antibody or antigen-binding fragment of the invention conform to the known Kabat numbering rules (LCDR1-3, HCDE2-3) in number and position, or to the kabat and chothia numbering rules ( HCDR1).
  • murine antibody is in the present invention a monoclonal antibody to human PD-1 prepared according to the knowledge and skill in the art.
  • the test subject is injected with the PD-1 antigen at the time of preparation, and then the hybridoma expressing the antibody having the desired sequence or functional properties is isolated.
  • the murine PD-1 antibody or antigen-binding fragment thereof may further comprise a light chain constant region of a murine kappa, a lambda chain or a variant thereof, or further comprising a murine IgG1 , heavy chain constant region of IgG2, IgG3 or IgG4 or a variant thereof.
  • chimeric antibody is an antibody obtained by fusing a variable region of a murine antibody with a constant region of a human antibody, and can alleviate an immune response induced by a murine antibody.
  • a hybridoma that secretes a murine-specific monoclonal antibody is selected, and then the variable region gene is cloned from the mouse hybridoma cell, and the constant region gene of the human antibody is cloned as needed to change the mouse.
  • the region gene and the human constant region gene are ligated into a chimeric gene and inserted into a human vector, and finally the chimeric antibody molecule is expressed in a eukaryotic industrial system or a prokaryotic industrial system.
  • the antibody light chain variable region of the PD-1 chimeric antibody further comprises a light chain FR region of a murine kappa, a lambda chain or a variant thereof, and an antibody light chain variable region
  • the sequence is shown in SEQ ID NO: 10.
  • the antibody heavy chain variable region of the PD-1 chimeric antibody further comprises a heavy chain FR region of murine IgG1, IgG2, IgG3, IgG4 or a variant thereof, and the antibody heavy chain variable region sequence is SEQ ID NO: 10 Shown.
  • the constant region of a human antibody may be selected from the heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising a human IgG2 or IgG4 heavy chain constant region, or without ADCC (antibody-dependent) after amino acid mutation Cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity) toxic IgG1.
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into human antibody variable region frameworks, ie different types of human germline An antibody produced in an antibody framework sequence. It is possible to overcome the strong antibody variable antibody response induced by chimeric antibodies by carrying a large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references.
  • the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase ), as well as in Kabat, EA, etc.
  • the CDR sequence of the PD-1 humanized antibody mouse is selected from the group consisting of SEQ ID NOs: 3, 4, 5, 6, 7, 8.
  • the human antibody variable region framework is designed to be selected, wherein the light chain FR region sequence on the antibody light chain variable region is derived from the combined sequence of the human germline light chain IGKV1-39 and JK4: SEQ ID NO: 14.
  • FR1 region comprising FR1, FR2, FR3 region and JK4 of human germline light chain IGKV1-39; wherein the heavy chain FR region sequence on the heavy chain variable region of the antibody is derived from human germline heavy chain IgHV3-7 and The combined sequence of JH6: SEQ ID NO: 13; FR1, FR2, FR3 region of human germline heavy chain IgHV3-7 and FR4 region of JH6.
  • the human antibody variable region can be subjected to minimal reverse mutation to maintain activity.
  • the "antigen-binding fragment” as used in the present invention refers to a Fab fragment having antigen-binding activity, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment sFv fragment which binds to human PD-1;
  • the antibody is selected from one or more of the CDR regions of SEQ ID NO: 3 to SEQ ID NO: 8.
  • the Fv fragment contains the antibody heavy chain variable region and the light chain variable region, but has no constant region and has the smallest antibody fragment of the entire antigen binding site.
  • Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding.
  • the two antibody variable regions can also be joined by a different linker into a single polypeptide chain, referred to as a single chain antibody or a single chain Fv (sFv).
  • binding to PD-1 refers to the ability to interact with human PD-1.
  • antigen binding site refers to a three-dimensional spatial site that is discrete on an antigen and is recognized by an antibody or antigen-binding fragment of the present invention.
  • the "ADCC” described in the present invention is an antibody-dependent cell-mediated cytotoxicity, which means that a cell expressing an Fc receptor directly kills an antibody by Fc segment of the recognition antibody.
  • Target cells The ADCC effector function of the antibody can be reduced or eliminated by modification of the Fc segment on IgG.
  • the modification refers to mutations in the heavy chain constant region of the antibody, such as N297A, L234A, L235A selected from IgG1; IgG2/4 chimera, F235E of IgG4, or L234A/E235A mutation.
  • the fusion protein described in the present invention is a protein product co-expressed by two genes obtained by DNA recombination.
  • Recombinant PD-1 extracellular domain Fc fusion protein A fusion protein co-expressed by the PD-1 extracellular domain and the human antibody Fc fragment by DNA recombination.
  • the PD-1 extracellular region refers to a portion of the PD-1 protein expressed outside the cell membrane, and the sequence is shown in the SEQ ID NO: 1 scribe region below.
  • a mouse can be immunized with human PD-1 or a fragment thereof, and the obtained antibody can be renatured, purified, and subjected to amino acid sequencing by a conventional method.
  • the antigen-binding fragment can also be prepared by a conventional method.
  • the antibodies or antigen-binding fragments of the invention are genetically engineered to add one or more human FR regions in a non-human CDR region.
  • the light chain FR germline used in the antibody or antigen-binding fragment of the present invention includes A3 and O2.
  • Specific germline heavy chain FRs for use in the antibodies or antigen-binding fragments of the invention include VH3-21 and VH3-23.
  • the engineered antibodies or antigen-binding fragments of the invention can be prepared and purified by conventional methods. For example, coding The cDNA sequences of the heavy chain (SEQ ID NO: 11) and the light chain (SEQ ID NO: 12) can be cloned and recombined into a GS expression vector. The recombinant immunoglobulin expression vector can stably transfect CHO cells. As a more preferred prior art, mammalian expression systems result in glycosylation of antibodies, particularly at the highly conserved N-terminus of the FC region. Stable clones were obtained by expressing antibodies that specifically bind to human PCSK9. Positive clones were expanded in serum-free medium in a bioreactor to produce antibodies.
  • the culture medium from which the antibody is secreted can be purified by a conventional technique.
  • the column is passed through an A or G Sepharose FF column with an adjusted buffer.
  • the non-specifically bound components are washed away.
  • the bound antibody was eluted by a pH gradient method, and the antibody fragment was detected by SDS-PAGE and collected.
  • the antibody can be concentrated by filtration in a conventional manner. Soluble mixtures and multimers can also be removed by conventional methods such as molecular sieves, ion exchange.
  • the resulting product needs to be frozen immediately, such as -70 ° C, or lyophilized.
  • the antibody of the present invention refers to a monoclonal antibody.
  • the monoclonal antibody or mAb according to the present invention refers to an antibody obtained from a single clonal cell strain, and the cell strain is not limited to a eukaryotic, prokaryotic or phage clonal cell strain.
  • Monoclonal antibodies or antigen-binding fragments can be obtained recombinantly using, for example, hybridoma technology, recombinant techniques, phage display technology, synthetic techniques (e.g., CDR-grafting), or other prior art techniques.
  • administering when applied to an animal, human, experimental subject, cell, tissue, organ or biological fluid, refers to an exogenous drug, therapeutic agent, diagnostic agent or composition and animal, human, subject Contact of the test subject, cell, tissue, organ or biological fluid.
  • administering can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
  • Treatment of the cells includes contact of the reagents with the cells, and contact of the reagents with the fluid, wherein the fluids are in contact with the cells.
  • administeristering and “treating” also means treating, for example, cells in vitro and ex vivo by reagents, diagnostics, binding compositions, or by another cell.
  • Treatment when applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventive measures, research and diagnostic applications.
  • Treatment means administering to a patient a therapeutic agent for internal or external use, such as a composition comprising any of the binding compounds of the present invention, the patient having one or more symptoms of the disease, and the therapeutic agent is known to have Therapeutic effect.
  • a therapeutic agent is administered in a subject or population to be treated to effectively alleviate the symptoms of one or more diseases, whether by inducing such symptoms to degenerate or inhibiting the progression of such symptoms to any degree of clinical right measurement.
  • the amount of therapeutic agent also referred to as "therapeutically effective amount” effective to alleviate the symptoms of any particular disease can vary depending on a variety of factors, such as the patient's disease state, age and weight, and the ability of the drug to produce a desired effect in the patient.
  • Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other professional health care provider to assess the severity or progression of the condition.
  • Embodiments of the invention e.g., methods of treatment or preparations
  • Constantly modified refers to an amino acid in another amino acid substitution protein having similar characteristics (eg, charge, side chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.) DEK changes frequently without changing the biological activity of the protein. It will be appreciated by those skilled in the art that, in general, a single amino acid substitution in a non-essential region of a polypeptide does not substantially alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., Page 224, (4th edition)). In addition, substitution of structurally or functionally similar amino acids is unlikely to disrupt biological activity.
  • a binding compound consisting essentially of the amino acid sequence recited may also include one or more amino acids that do not significantly affect the properties of the binding compound.
  • an "effective amount” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate the diagnosis.
  • An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Exogenous refers to a substance that is produced outside of a living organism, cell, or human body depending on the background.
  • Endogenous refers to a substance produced in a cell, organism or human body depending on the background.
  • “Homology” refers to sequence similarity between two polynucleotide sequences or between two polypeptides. When positions in both comparison sequences are occupied by the same base or amino acid monomer subunit, for example if each position of two DNA molecules is occupied by adenine, then the molecule is homologous at that position .
  • the percent homology between the two sequences is a function of the number of matches or homology positions shared by the two sequences divided by the number of positions compared ⁇ 100. For example, in the optimal alignment of sequences, if there are 6 matches or homologs in 10 positions in the two sequences, then the two sequences are 60% homologous. In general, comparisons are made when the maximum sequence of homology is obtained by aligning the two sequences.
  • the expression "cell”, “cell line” and “cell culture” are used interchangeably and all such names include progeny.
  • the words “transformants” and “transformed cells” include primary test cells and cultures derived therefrom, regardless of the number of transfers. It should also be understood that all offspring may not be exactly identical in terms of DNA content due to intentional or unintentional mutations. Mutant progeny having the same function or biological activity as screened for in the originally transformed cell are included. In the case of a different name, it is clearly visible from the context.
  • PCR polymerase chain reaction
  • oligonucleotide primers can be designed; these primers are identical or similar in sequence to the corresponding strand of the template to be amplified.
  • the 5' terminal nucleotides of the two primers may coincide with the ends of the material to be amplified.
  • PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA, phage or plasmid sequences transcribed from total cellular RNA, and the like. See, in general, Mullis et al. (1987) Cold Spring Harbor Symp. Ouant. Biol. 51:263; Editing by Erlich, (1989) PCR TECHNOLOGY (Stockton Press, N.Y.).
  • PCR used herein is considered as an example, but not the only example, of a nucleic acid polymerase reaction method for amplifying a nucleic acid test sample, which comprises using a known nucleic acid and a nucleic acid polymerase as a primer to amplify or Produce a specific portion of the nucleic acid.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the invention is further described in the following examples, which are not intended to limit the scope of the invention.
  • the experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, such as the cold spring harbor antibody technology experiment manual, molecular cloning manual; or according to the conditions recommended by the raw material or commodity manufacturer.
  • Reagents without specific source are routine reagents purchased from the market.
  • a murine monoclonal antibody directed against human PD-1 was generated and transfected with purified recombinant PD-1 extracellular domain Fc fusion protein (PD-1Fc) (SEQ ID NO: 1); or PD-1 (SEQ ID NO: 2)
  • PD-1Fc extracellular domain Fc fusion protein
  • the CHO cells were used as antigens to immunize Balb/C mice and SJL mice.
  • Human PD-1 antigen was purchased from ORIGENE, catalog number SC117011, NCBI Reference Sequence: NM_005018.1.
  • PD-1Fc recombinant PD-1 extracellular domain Fc fusion protein
  • PD-1, PD-1 antigen of transfected cells SEQ ID NO: 2
  • the purified antigens used were high dose (50 ug) and low dose (10 ug), respectively, and PD-1 transfected CHO cells were immunized to 0.5-1 ⁇ 10 7 cells. .
  • Immunization was performed 3 times on days 0, 14, and 35 with complete Freund's adjuvant, and the immune response was monitored by post-orbital bleeding.
  • Plasma was screened by ELISA to obtain mice with anti-PD-1 human immunoglobulin titers. On day 56, mice with the highest anti-PD-1 human immunoglobulin titers were boosted. After 3 days, the mice were sacrificed and the spleens were removed for fusion.
  • the hybridoma cells after fusion were subjected to antibody screening to obtain murine mAb mAb005.
  • the heavy and light chain variable region sequences of murine mAb mAb005 are as follows:
  • the PD-1 antibody blocks the signaling pathway of PD-1 and its ligand by binding to the extracellular domain of PD-1.
  • An in vitro ELISA assay was used to detect the binding properties of the PD-1 antibody.
  • the biotin-labeled PD-1 extracellular domain FC fusion protein (PD-1FC) was coated into a 96-well plate by binding to neutralizing avidin, and the signal strength after antibody addition was used to judge the antibody and PD- The binding characteristics of 1.
  • the neutralizing avidin for binding to biotin was diluted to 1 ⁇ g/ml with PBS buffer, added to a 96-well plate in a volume of 100 ⁇ l/well, and left at 4 ° C for 16 h to 20 h.
  • the PBS buffer in a 96-well plate was aspirated, and the plate was washed once with PBST (pH 7.4 PBS containing 0.05% tweeen 20) buffer, and then added to 120 ⁇ l/well of PBST/1% milk, and incubated for 1 hour at room temperature to block.
  • PBST pH 7.4 PBS containing 0.05% tweeen 20
  • the blocking solution was removed, and the plate was washed once with PBST buffer, and then 1 ⁇ g/ml of biotin-labeled PD1-FC diluted with PBST/1% milk was added, and incubated at room temperature for 1 hour.
  • the blocking solution was removed, and the plate was washed 3 times with PBST buffer, and then the PD-1 antibody to be tested was diluted with PBST/1% milk to a suitable concentration, and incubated at room temperature for 1.5 hours.
  • the reaction system was removed, and the plate was washed three times with PBST, and then HRP-labeled anti-mouse antibody secondary antibody (The Jackson Laboratory) diluted with PBST/1% milk was added at 100 ⁇ l/well, and incubated at room temperature for 1 h. After washing the plate 3 times with PBST, 100 ⁇ l/well of TMB was added and incubated at room temperature for 5-10 min. The reaction was stopped by the addition of 100 ⁇ l/well of 1 M H 2 SO 4 . Microplate absorbance was read at 450nm with NOVOStar, calculated values ELISA binding 50 EC.
  • the binding results showed that the antibody mAb005 had a very high binding activity to both human PD-1Fc (human PD-1) and cynomolgus PD-1Fc (cyno PD-1).
  • PD-L1 on the surface of tumor cells binds to PD-1 on the surface of T cells, thereby inhibiting the proliferation of T cells.
  • the antibody of PD-1 can block the signaling pathway of PD-L1/PD-1 by binding to PD-1, thereby stimulating the proliferation of T cells.
  • the binding blocking assay of PD-1/PD-L1 was used to detect the blocking activity of the PD-1 antibody on the signaling pathway.
  • PD-1-FC was diluted to 1 ⁇ g/ml with PH 9.6 CB buffer (1.59 g Na 2 CO 3 and 2.93 g NaHCO 3 dissolved in 1 L distilled water), and added to a 96-well plate in a volume of 100 ⁇ l/well. Place at °C for 16h-20h.
  • the PBS buffer in a 96-well plate was aspirated, and the plate was washed once with PBST (pH 7.4 PBS containing 0.05% tweeen 20) buffer, and then added to 120 ⁇ l/well of PBST/1% milk, and incubated for 1 hour at room temperature to block. Remove the blocking solution and wash the plate once with PBST buffer.
  • the reaction system was removed, and the plate was washed 6 times with PBST, and then 100 ul/well of Streptavidin-Peroxidase Polymer diluted 1:400 in PBST buffer was added, and the mixture was incubated at room temperature for 50 minutes with shaking. After washing the plate 6 times with PBST, 100 ⁇ l/well TMB was added and incubated for 5-10 min at room temperature. The reaction was stopped by the addition of 100 ⁇ l/well of 1 M H 2 SO 4 . NOVOStar microplate reader with absorbance read at 450nm, values 50 calculated IC PD-1 antibody binding ligand PD-L1 blockade.
  • the experimental results show that the antibody mAb005 can very effectively block the binding between PD-L1 and PD-1.
  • the selective binding protein human PD-1, human ICOS, human CTLA4, human CD28, mouse PD-1, (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was diluted to 1 ⁇ g/ml with 100 ⁇ l/well in PBS buffer. The volume was added to a 96-well plate and placed at 4 ° C for 16 h - 20 h. The PBS buffer in a 96-well plate was aspirated, and the plate was washed once with PBST (pH 7.4 PBS containing 0.05% tweeen 20) buffer, and then added to 120 ⁇ l/well of PBST/1% milk, and incubated for 1 hour at room temperature to block.
  • PBST pH 7.4 PBS containing 0.05% tweeen 20
  • the PD-1 antibody to be tested was added and incubated at room temperature for 1.5 h.
  • the reaction system was removed, and the plate was washed three times with PBST, and then HRP-labeled anti-mouse antibody secondary antibody (The Jackson Laboratory) diluted with PBST/1% milk was added at 100 ⁇ l/well, and incubated at room temperature for 1 hour.
  • HRP-labeled anti-mouse antibody secondary antibody The Jackson Laboratory
  • 100 ⁇ l/well of TMB was added and incubated at room temperature for 5-10 min.
  • the reaction was stopped by the addition of 100 ⁇ l/well of 1 M H 2 SO 4 .
  • Absorbance values were read at 450 nm using a NOVOStar plate reader.
  • Example 4 In vitro cell binding assay of PD-1 antibody
  • FACS fluorescence-activated cell sorter
  • the PD-1 highly expressed CHO cells were centrifuged at 1000 rpm for 5 minutes, the pellet was collected and suspended in 10-15 ml of pre-cooled flow buffer, and the cells were counted. The cells were collected by centrifugation at 1000 rpm for 5 minutes in a 50 ml centrifuge tube, the supernatant was discarded, and the pellet was resuspended in a pre-cooled blocking buffer at a density of 0.5-1.0 x 10 7 cells/ml. After incubating at 4 ° C for 30 minutes, it was resuspended to 100 ⁇ l per well and added to a 96-well plate. After centrifugation of the 96-well plate at 1500 rpm for 5 minutes, the supernatant was discarded.
  • the results show that the antibody mAb005 can also bind to PD-1 on the cell surface.
  • the Biacore method is a well-established method for the objective detection of the affinity and kinetics of proteins.
  • GE Biacore
  • the PD-1 antibody of the present invention to be tested was covalently linked to a CM5 (GE) chip by a standard amino coupling method using a kit supplied by Biacore. Then, a series of concentration gradients of PD-1His protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) diluted in the same buffer were injected in each cycle before and after the injection, and the regeneration reagent was regenerated in the kit. Antigen-antibody binding kinetics were followed for 3 minutes and dissociation kinetics were followed for 10 minutes. The data obtained were analyzed using the 1:1 (Langmuir) binding model using GE's BIAevaluation software. The ka(kon), kd(koff) and KD values determined by this method are shown in the table below.
  • PBMC peripheral blood mononuclear cells
  • the fresh human PBMC was adjusted to a cell density of 2 ⁇ 10 6 /ml, and 2 ml per well was inoculated into a 6-well plate, placed in a 37 ° C, 5% CO 2 incubator for 6 hours, and the suspended cells were aspirated, and 2 ml was added to the adherent cells.
  • RPMI1640 medium containing 100 ng/ml GM-CSF (granulocyte colony-stimulating biological factor) and 100 ng/ml IL-4, and after adding for 1 day, 1 ml of each well containing 100 ng/ml GM-CSF and 100 ng/ml IL-4 was added.
  • TNF- ⁇ tumor necrosis factor-a
  • Luminescent Cell Viability Assay kit detects cell proliferation.
  • Figure 1 It shows that the PD-1 antibody mAb005 to be tested can effectively stimulate the proliferation of human peripheral blood mononuclear cells with an EC50 of 83 ng/ml. The remaining samples were tested for the secretion of cytokine IFN- ⁇ . The results are shown in Figure 2. It is shown that the PD-1 antibody mAb005 can effectively stimulate the secretion of cytokine IFN- ⁇ while stimulating the proliferation of PBMC with an EC50 of 13 ng/ml.
  • mAb005LCVR mAb005LCVR
  • mAb005HCVR mAb005HCVR
  • the template of the antibody heavy chain is IgHV3-7/JH6, and the FR4 region of FR1, FR2, FR3, and JK4 of human germline light chain IGKV1-39 is selected, the sequence is SEQ ID NO: 13; the template of light chain is IGKV1- 39/JK4, FR1, FR2, FR3, and FR4 of JK4 of human germline light chain IGKV1-39 were selected, and the sequence is SEQ ID NO: 14.
  • the murine antibody CDR region was transplanted onto the selected humanized template, the CDR region of the human template was replaced, and then recombined with the IgG4 constant region to obtain a humanized antibody H005-1. Then, based on the three-dimensional structure of the murine antibody, the residues that have an important interaction with the CDRs and the residues of the CDRs, and the residues that have an important influence on the conformation of VL and VH are subjected to back mutation to obtain humanization. Subsequent antibodies H005-2, H005-3, H005-4, the sequences are shown in the table below.
  • the HC sequence of the humanized antibody H005-1 grafted into the murine CDR region was (SEQ ID NO: 11), and the humanized antibody LC sequence was (SEQ ID NO: 12). Point mutations at sites that may affect antibody activity, the sequence of which is:
  • the cDNA was synthesized based on the amino acid sequences of the humanized antibody light and heavy chains (SEQ NO 11, SEQ NO 12 and its variants), digested with BamHI and XhoI, and the cDNA fragment was inserted into the BamHI/XhoI cleavage site.
  • pcDNA3.1 expression vector (Life Technologies Cat. No. V790-20).
  • the expression vector and the transfection reagent PEI (Polysciences, Inc. Cat. No. 23966) were transfected into HEK293 cells (Life Technologies Cat. No. 11625019) at a ratio of 1:2 and placed in a CO 2 incubator for incubation 4- 5 days. After the expressed antibody is recovered by centrifugation, the antibody is purified by a conventional method to obtain a humanized antibody of the present invention.
  • the humanized antibody was subjected to ELISA binding assay in vitro (method step is the same as in Example 2), ligand binding blocking assay (method step is the same as in Example 2), affinity kinetics experiment (method step is the same as in Example 5), The results are shown in the table below:
  • Example 9 Inhibition of tumor cell growth by PD-1 antibody
  • U87MG cells (glioma cells): purchased from the Chinese Academy of Sciences cell bank, article number TCHu138;
  • PBMC cells peripheral blood mononuclear cells
  • Shanghai Blood Center PBMC cells
  • CD3 purchased from Miltenyi Biotec article number 130-093-387;
  • CD28 purchased from Miltenyi Biotec article number 130-093-375;
  • Cell Counting Kit-8 purchased from Tongren Chemical, article number CK04;
  • mIgG (negative control): purchased from SANTA CRUZ article number: sc-2025; used at a concentration of 1660 ng/ml.
  • U87MG cell culture was carried out in EMEM medium containing 10% FBS and 1% P/S, and 1 ⁇ 10 4 cells were added to each well in a 96-well plate.
  • Antibody H005-1 was diluted with PBS to a different concentration gradient (as shown in the horizontal axis of Figure 3), 10 ul per well in a 96-well plate, and cultured for 4 hours at 37 ° C in a 5% CO 2 incubator.
  • Example 10 Proliferative activity of H005-1 against tuberculin-stimulated PBMC
  • the humanized antibody H005-1 was tested for the proliferative activity of tuberculin-stimulated PBMC in vitro.
  • the cell culture plates were incubated at 37 ° C for 72 hours in a 5% CO 2 incubator to detect PBMC cell proliferation (Promega, cat #G7571) and IFN- ⁇ secretion (Neo Bioscience, cat # EHC 102g). The results are as follows:
  • the experimental results show that the humanized antibody H005-1 can activate the proliferation of PBMC stimulated by exogenous tuberculin and the secretion of IFN- ⁇ .
  • Example 11 Inhibition experiment of U-87MG subcutaneous xenograft tumor by H005-1

Abstract

本发明提供了人PD-1抗体、其抗原结合片段及其医药用途，还提供了包含所述抗体CDR区的嵌合抗体、人源化抗体、包含人PD-1抗体及其抗原结合片段的药物组合物，以及所述抗体在制备用于治疗疾病或病症的药物中的用途。

Description

PD-1抗体、其抗原结合片段及其医药用途 技术领域
本发明涉及一种PD-1抗体，PD-1的抗原结合片段，包含所述PD-1抗体CDR区的嵌合抗体、人源化抗体，以及包含PD-1抗体及其抗原结合片段的药物组合物，以及其作为抗癌药物的用途。
背景技术
肿瘤免疫治疗是肿瘤治疗领域一个长时间的热点，其中T细胞的肿瘤免疫治疗又处于其核心位置。肿瘤免疫治疗是充分利用、调动肿瘤患者体内的杀伤性T细胞，对肿瘤进行杀伤作用，它可能是最有效的也是最安全的治疗肿瘤的途径。与此同时，肿瘤逃逸是肿瘤免疫治疗面临的一个巨大障碍，肿瘤细胞利用其自身对免疫系统的抑制作用促进了肿瘤的快速生长。
肿瘤的免疫逃逸机制与机体对肿瘤的免疫应答之间存在着极为复杂的关系。肿瘤免疫治疗早期肿瘤特异性的杀伤性T细胞是有其生物活性的，但随着肿瘤生长后期失去了杀伤的功能。所以肿瘤免疫治疗是为了最大限度的提高患者自身对肿瘤的免疫系统反应，它不但要在体内激活原有的免疫系统反应，更要维持免疫系统反应的持续时间和反应强度，才是免疫治疗肿瘤的关键。
人体内T细胞的活化采取了两条信号通路的系统，除了需要通过抗原呈递细胞递呈MHC-抗原肽给T细胞提供第一信号外，还需要一系列协同刺激分子提供第二信号，进而才能使T细胞产生正常的免疫应答。这个双信号通路系统对体内免疫系统的平衡起到着至关重要的作用，它严格调控着机体对自身和非自身抗原产生不同的免疫应答。如果缺少协同刺激分子提供的第二信号，将会导致T细胞的无应答或持续特异性免疫应答，从而产生耐受。因此，第二信号通路在机体免疫应答的整个过程中起着非常关键的调节作用。
程序性死亡分子1(programmed death-l,PD-l)是1992年发现的表达在T细胞表面的一个蛋白受体，参与到细胞的凋亡过程之中。PD-l属于CD28家族，与细胞毒性T淋巴细胞抗原4(cytotoxic T Iymphocyte antigen 4,CTLA-4)具有23％的氨基酸同源性，但其表达却与CTLA不同，主要表达在活化的T细胞、B细胞和髓系细胞上。PD-1有两个配体，分别为PD-L1和PD-L2。PD-L1的主要表达于T细胞、B细胞、巨噬细胞和树突状细胞(dendritic cell,DC)上，在活化后细胞上的表达能够进行上调。而PD-L2的表达相对较局限，主要表达在抗原呈递细胞上.，如活化的巨噬细胞和树突状细胞。
新的研究发现乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤等人类肿瘤组织中检测到高PD-L1蛋白的表达，且PD-L1的表达水平和患者的临床及预后紧密相关。 由于PD-L1起到着第二信号通路抑制T细胞增殖的作用，所以阻断PD-L1/PD-1之间结合成为了肿瘤免疫治疗领域一个非常有潜力的新兴靶点。
目前有多家跨国制药公司在研发针对PD-1的单克隆抗体，它通过阻断PD-L1/PD-1之间结合，最大限度的提高患者自身对肿瘤的免疫系统反应，从而达到对肿瘤细胞进行杀伤的目的。如WO2009114335。BMS公司和Merck公司的PD-1单克隆抗体在临床结果中，在非小细胞肺癌、黑素瘤和肾癌中都看到了一定的响应率，而且响应率和肿瘤PD-L1的表达有很高的关联性。这表明PD-1抗体对肿瘤有着积极疗效。
本发明提供有着高亲和力，高选择性，高生物活性的PD-1抗体。
发明内容
本发明提供一种PD-1抗体或其抗原结合片段，其包含：
抗体轻链可变区，所述的抗体轻链可变区至少1个选自如以下序列所示的LCDR：SEQ ID NO:6，SEQ ID NO:7或SEQ ID NO:8；和
抗体重链可变区，所述的抗体重链可变区至少1个选自如以下序列所示的HCDR：SEQ ID NO:3，SEQ ID NO:4或SEQ ID NO:5。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:6所示的LCDR1。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:7所示的LCDR2。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:8LCDR3区。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:3所示的HCDR1。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:4所示的HCDR2。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:5所示的HCDR3。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其所述的抗体轻链可变区包分别如SEQ ID NO:6、SEQ ID NO:7和SEQ ID NO:8所示的LCDR1、LCDR2和LCDR3。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片段，其所述的抗体重链可变区包含分别如SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5所示的HCDR1、HCDR2和HCDR3。
在本发明一个优选的实施方案中，本发明提供一种PD-1抗体或其抗原结合片 段，其中所述的抗体轻链可变区包含分别如SEQ ID NO:6、SEQ ID NO:7和SEQ ID NO:8所示的LCDR1、LCDR2和LCDR3；且其中所述的抗体重链可变区包含分别如SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5所示的HCDR1、HCDR2和HCDR3。
在本发明一个优选的实施方案中，根据本发明提供的PD-1抗体或其抗原结合片段，其中所述的抗体为鼠源抗体或其片段。
在本发明一个优选的实施方案中，根据本发明提供的鼠源抗体或其片段，其抗体轻链可变区进一步包含鼠源κ、λ链或其变体的轻链FR区。
在本发明一个优选的实施方案中，根据本发明提供的鼠源抗体或其片段，其进一步包含鼠源κ、λ链或其变体的轻链恒定区。
在本发明一个优选的实施方案中，根据本发明提供的鼠源抗体或其片段，其抗体重链可变区进一步包含鼠源IgG1,IgG2,IgG3,IgG4或其变体的重链FR区。
在本发明一个优选的实施方案中，根据本发明提供的鼠源抗体或其片段，其进一步包含鼠源IgG1,IgG2,IgG3,IgG4或其变体的重链恒定区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1抗体或其抗原结合片段，其中所述的抗体为嵌合抗体或其片段。
在本发明一个优选的实施方案中，根据本发明提供的PD-1嵌合抗体或其片段，其中所述的嵌合抗体轻链可变区序列为：SEQ ID NO:10。
在本发明一个优选的实施方案中，根据本发明提供的PD-1嵌合抗体或其片段，其中所述的嵌合抗体重链可变区序列为：SEQ ID NO:9。
在本发明一个优选的实施方案中，根据本发明提供的PD-1嵌合抗体或其片段，其进一步包含人源κ、λ链或其变体的轻链恒定区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1嵌合抗体或其片段，其进一步包含人源IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区，优选包含人源IgG2或IgG4重链恒定区，或者使用氨基酸突变后无ADCC(antibody-dependent cell-mediated cytotoxicity，抗体依赖的细胞介导的细胞毒作用)毒性的IgG1。
在本发明一个优选的实施方案中，根据本发明提供的PD-1抗体或其抗原结合片段，其中所述的抗体为人源化抗体或其片段。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其人源化抗体轻链可变区进一步包含人源κ、λ链或其变体的轻链FR区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其中所述人源化抗体轻链可变区上的轻链FR区序列，来源于如SEQ ID NO:14所示的人种系轻链IGKV1-39和JK4的组合序列；其包含人种系轻链IGKV1-39的FR1，FR2，FR3区和JK4的FR4区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其中所述人源化抗体轻链序列为如SEQ ID NO:12所示的序列，或其变体。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其中所述人源化抗体轻链可变区变体优选在轻链可变区有0-10的氨基酸变化；所述人源化抗体轻链可变区上的可变区序列变体的氨基酸变化优选为A43S。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其进一步包含人源κ、λ链或其变体的轻链恒定区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其人源化抗体重链可变区进一步包含人源IgG1,IgG2,IgG3,IgG4或其变体的重链FR区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其中所述人源化抗体重链可变区上的重链FR区序列，来源于人种系重链IgHV3-7和JH6的组合序列：SEQ ID NO:13；包含人种系重链IgHV3-7的FR1，FR2，FR3区和JH6的FR4区。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其中所述人源化抗体重链序列为如SEQ ID NO:11所示的序列，或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
在本发明一个优选的实施方案中，根据本发明提供的PD-1人源化抗体或其片段，其进一步包含人源IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区，优选包含人源IgG2或IgG4重链恒定区。因为IgG2或IgG4没有ADCC毒性，或者使用氨基酸突变后无ADCC(antibody-dependent cell-mediated cytotoxicity，抗体依赖的细胞介导的细胞毒作用)毒性的IgG1。所述的变体优选ADCC效应功能降低或缺失的重链恒定区突变，更优选IgG1的N297A，L234A，L235A；IgG2/4chimera，IgG4的F235E,或L234A/E235A突变。
在本发明一个优选的实施方案中，根据本发明提供的PD-1抗体或其抗原结合片段，其中所述的抗原结合片段为Fab、Fv、sFv、F(ab’)2。
本发明进一步提供一种编码如上所述的PD-1抗体或其抗原结合片段的DNA分子。
本发明进一步提供一种含有如上所述的DNA分子的表达载体。
本发明进一步提供一种用如上所述的表达载体转化的宿主细胞。
在本发明一个优选的实施方案中，根据本发明提供的宿主细胞，其中所述的宿主细胞为细菌，优选为大肠杆菌。
在本发明一个优选的实施方案中，本发明提供的宿主细胞为酵母菌，优选为毕赤酵母。
本发明进一步提供一种药物组合物，其含有根据本发明所述的PD-1抗体或其抗原结合片段和可药用的赋形剂、稀释或载体。
本发明进一步提供一种根据本发明所述的PD-1抗体或其抗原结合片段、或包含其的的药物组合物，在制备用于治疗PD-1介导的疾病或病症的药物中的用途； 其中所述的疾病优选为癌症；更优选为表达PD-L1的癌症；所述的癌症最优选为乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤；最优选为非小细胞肺癌、黑素瘤和肾癌。
本发明进一步提供一种治疗和预防PD-1介导的疾病或病症的方法，该方法包括给予所需患者治疗有效量的根据本发明所述的PD-1抗体或其抗原结合片段、或包含其的的药物组合物；其中所述的疾病优选为癌症；更优选为表达PD-L1的癌症；所述的癌症最优选为乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤、非小细胞肺癌；最优选为非小细胞肺癌、黑素瘤和肾癌。
附图说明：
图1：人外周血单个核细胞增殖试验。显示待测PD-1抗体mAb005可以有效的刺激人外周血单个核细胞的增殖，EC50为83ng/ml。
图2：人外周血单个核细胞细胞因子IFN-γ分泌试验。显示待测PD-1抗体mAb005可以在刺激PBMC增殖的同时，有效的刺激其细胞因子IFN-γ的分泌，EC50为13ng/ml。
图3：本发明PD-1抗体H005-1对胶质瘤细胞生长的抑制效果。
图4：治疗后的肿瘤体积变化图。
图5：治疗后的小鼠体重变化图。
发明详述
一、术语
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
本发明所述的抗体指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM，IgD，IgG，IgA和IgE，其相应的重链分别为μ链，δ链γ，α链，ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1，IgG2，IgG3，IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中第每类Ig都可以有κ链或λ链。
在本发明中，本发明所述的抗体轻链可变区可进一步包含轻链恒定区，所述的轻链恒定区包含人源或鼠源的κ、λ链或其变体。
在本发明中，本发明所述的抗体重链可变区可进一步包含重链恒定区，所述 的重链恒定区包含人源或鼠源的IgG1,2,3,4或其变体。
抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大，为可变区(V区)；靠近C端的其余氨基酸序列相对稳定，为恒定区(C区)。可变区包括3个高变区(HVR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性，又称为互补性决定区(CDR)。每条轻链可变区(LCVR)和重链可变区(HCVR)由3个CDR区4个FR区组成，从氨基端到羧基端依次排列的顺序为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。轻链的3个CDR区指LCDR1，LCDR2，和LCDR3；重链的3个CDR区指HCDR1，HCDR2和HCDR3。发明所述的抗体或抗原结合片段的LCVR区和HCVR区的CDR氨基酸残基在数量和位置符合已知的Kabat编号规则(LCDR1-3，HCDE2-3)，或者符合kabat和chothia的编号规则(HCDR1)。
术语“鼠源抗体”在本发明中为根据本领域知识和技能制备的对人PD-1的单克隆抗体。制备时用PD-1抗原注射试验对象，然后分离表达具有所需序列或功能特性的抗体的杂交瘤。在本发明一个优选的实施方案中，所述的鼠源PD-1抗体或其抗原结合片段，可进一步包含鼠源κ、λ链或其变体的轻链恒定区，或进一步包含鼠源IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区。
术语“嵌合抗体(chimeric antibody)”，是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体，可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体，要选建立分泌鼠源性特异性单抗的杂交瘤，然后从小鼠杂交瘤细胞中克隆可变区基因，再要据需要克隆人抗体的恒定区基因，将小鼠可变区基因与人恒定区基因连接成嵌合基因后插入人载体中，最后在真核工业系统或原核工业系统中表达嵌合抗体分子。在本发明一个优选的实施方案中，所述的PD-1嵌合抗体的抗体轻链可变区进一步包含鼠源κ、λ链或其变体的轻链FR区，抗体轻链可变区序列如SEQ ID NO:10所示。所述的PD-1嵌合抗体的抗体重链可变区进一步包含鼠源IgG1,IgG2,IgG3,IgG4或其变体的重链FR区，抗体重链可变区序列如SEQ ID NO:10所示。人抗体的恒定区可选自人源IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区，优选包含人源IgG2或IgG4重链恒定区，或者使用氨基酸突变后无ADCC(antibody-dependent cell-mediated cytotoxicity，抗体依赖的细胞介导的细胞毒作用)毒性的IgG1。
术语“人源化抗体(humanized antibody)”，也称为CDR移植抗体(CDR-grafted antibody)，是指将小鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量小鼠蛋白成分，从而诱导的强烈的抗体可变抗体反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com.ac.uk/vbase可获得)，以及在Kabat，E.A.等人，1991Sequences of Proteins of Immunological Interest，第5版中找到。在本发明一个优选的实施方 案中，所述的PD-1人源化抗体小鼠的CDR序列选自SEQ ID NO:3，4，5，6，7，8。人的抗体可变区框架经过设计选择，其中所述抗体轻链可变区上的轻链FR区序列，来源于人种系轻链IGKV1-39和JK4的组合序列：SEQ ID NO:14，包含人种系轻链IGKV1-39的FR1，FR2，FR3区和JK4的FR4区；其中所述抗体重链可变区上的重链FR区序列，来源于人种系重链IgHV3-7和JH6的组合序列：SEQ ID NO:13；包含人种系重链IgHV3-7的FR1，FR2，FR3区和JH6的FR4区。为避免免疫原性下降的同时，引起的活性下降，可对所述的人抗体可变区可进行最少反向突变，以保持活性。
本发明中所述的“抗原结合片段”，指具有抗原结合活性的Fab片段，Fab‘片段，F(ab’)2片段，以及与人PD-1结合的Fv片段sFv片段；包含本发明所述抗体的选自SEQ ID NO:3至SEQ ID NO:8中的一个或多个CDR区。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv(sFv)。本发明的术语“与PD-1结合”，指能与人PD-1相互作用。本发明的术语“抗原结合位点”指抗原上不连续的，由本发明抗体或抗原结合片段识别的三维空间位点。
本发明中所述的“ADCC”，即antibody-dependent cell-mediated cytotoxicity，抗体依赖的细胞介导的细胞毒作用，是指表达Fc受体的细胞通过识别抗体的Fc段直接杀伤被抗体包被的靶细胞。可通过对IgG上Fc段的修饰，降低或消除抗体的ADCC效应功能。所述的修饰指在抗体的重链恒定区进行突变，如选自IgG1的N297A，L234A，L235A；IgG2/4chimera，IgG4的F235E,或L234A/E235A突变。
本发明中所述的融合蛋白是一种通过DNA重组，得到的两个基因共表达的蛋白产物。重组PD-1胞外区Fc融合蛋白通过DNA重组，把PD-1胞外区和人抗体Fc片段共表达的融合蛋白。所述的PD-1胞外区，是指PD-1蛋白表达在细胞膜以外的部分，序列见下面SEQID NO:1划线区。
生产和纯化抗体和抗原结合片段的方法在现有技术中熟知和能找到，如冷泉港的抗体实验技术指南，5-8章和15章。如，小鼠可以用人PD-1或其片段免疫，所得到的抗体能被复性，纯化，并且可以用常规的方法进行氨基酸测序。抗原结合片段同样可以用常规方法制备。发明所述的抗体或抗原结合片段用基因工程方法在非人源的CDR区加上一个或多个人FR区。人FR种系序列可以从ImMunoGeneTics(IMGT)的网站http://imgt.cines.fr得到，或者从免疫球蛋白杂志，2001ISBN012441351上获得。具体的，本发明所述的抗体或抗原结合片段所用的轻链FR种系包括A3和O2。本发明所述的抗体或抗原结合片段所用的具体的种系重链FR包括VH3-21和VH3-23。
本发明工程化的抗体或抗原结合片段可用常规方法制备和纯化。比如，编码 重链(SEQID NO：11)和轻链(SEQID NO：12)的CDNA序列，可以克隆并重组至GS表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术，哺乳动物类表达系统会导致抗体的糖基化，特别是在FC区的高度保守N端。通过表达与人PCSK9特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化。比如，用含调整过的缓冲液的A或G Sepharose FF柱进行过柱。洗去非特异性结合的组分。再用PH梯度法洗脱结合的抗体，用SDS-PAGE检测抗体片段，收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体，也可以用常规方法去除，比如分子筛，离子交换。得到的产物需立即冷冻，如-70℃，或者冻干。
本发明的抗体指单克隆抗体。本发明所述的单克隆抗体或mAb，指由单一的克隆细胞株得到的抗体，所述的细胞株不限于真核的，原核的或噬菌体的克隆细胞株。单克隆抗体或抗原结合片段可以用如杂交瘤技术、重组技术、噬菌体展示技术，合成技术(如CDR-grafting)，或其它现有技术进行重组得到。
“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
“治疗”意指给予患者内用或外用治疗剂，诸如包含本发明的任一种结合化合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，无论是通过诱导这类症状退化还是抑制这类症状发展到任何临床右测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽本发明的实施方案(例如治疗方法或制品)在缓解每个患都有的目标疾病症状方面可能无效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者中应当减轻目标疾病症状。
“保守修饰”或“保守置换或取代”是指具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其它氨基酸置换蛋白中的氨基酸，使 得可频繁进行改变而不改变蛋白的生物学活性。本领域技术人员知晓，一般而言，多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性(参见例如Watson等(1987)Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224页，(第4版))。另外，结构或功能类似的氨基酸的置换不大可能破环生物学活性。
整个说明书和权利要求书中使用的术语“基本上由……组成”或其变形表示包括所有所述元件或元件组，并且任选包括与所述元件类似或不同性质的其它元件，所述其它元件非显著改变指定给药方案、方法或组合物的基本性质或新性质。作为非限制性例子，基本上由所提及的氨基酸序列组成的结合化合物还可以包括一种或多种氨基酸，其不显著影响结合化合物的性质。
“有效量”包含足以改善或预防医字病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“外源性”指要据背景在生物、细胞或人体外产生的物质。“内源性”指根据背景在细胞、生物或人体内产生的物质。
“同源性”是指两个多核苷酸序列之间或两个多肽之间的序列相似性。当两个比较序列中的位置均被相同碱基或氨基酸单体亚基占据时，例如如果两个DNA分子的每一个位置都被腺嘌呤占据时，那么所述分子在该位置是同源的。两个序列之间的同源怀百分率是两个序列共有的匹配或同源位置数除以比较的位置数×100的函数。例如，在序列最佳比对时，如果两个序列中的10个位置有6个匹配或同源，那么两个序列为60％同源。一般而言，当比对两个序列而得到最大的同源性百分率时进行比较。
本文使用的表述“细胞”、“细胞系”和“细胞培养物”可互换使用，并且所有这类名称都包括后代。因此，单词“转化体”和“转化细胞”包括原代受试细胞和由其衍生的培养物，而不考虑转移数目。还应当理解的是，由于故意或非有意的突变，所有后代在DNA含量方面不可能精确相同。包括具有与最初转化细胞中筛选的相同的功能或生物学活性的突变后代。在意指不同名称的情况下，其由上下文清楚可见。
本文使用的“聚合酶链式反应”或“PCR”是指其中微量的特定部分的核酸、RNA和/或DNA如在例如美国专利号4,683,195中所述扩增的程序或技术。一般来说，需要获得来自目标区域末端或之外的序列信息，使得可以设计寡核苷酸引物；这些引物在序列方面与待扩增模板的对应链相同或相似。2个引物的5’末端核苷酸可以与待扩增材料的末端一致。PCR可用于扩增特定的RNA序列、来自总基因组DNA的特定DNA序列和由总细胞RNA转录的cDNA、噬菌体或质粒序列等。一般参见Mullis等(1987)Cold Spring Harbor Symp.Ouant.Biol.51:263；Erlich编辑， (1989)PCR TECHNOLOGY(Stockton Press,N.Y.)。本文使用的PCR被视为用于扩增核酸测试样品的核酸聚合酶反应法的一个实例，但不是唯一的实例，所述方法包括使用作为引物的已知核酸和核酸聚合酶，以扩增或产生核酸的特定部分。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选包含1-3个抗体重链可变区”意味着特定序列的抗体重链可变区可以但不必须存在。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。本发明实施例中未注明具体条件的实验方法，通常按照常规条件，如冷泉港的抗体技术实验手册，分子克隆手册；或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1：抗体的制备
生成针对人PD-1的鼠源单克隆抗体，用纯化的重组PD-1胞外区Fc融合蛋白(PD-1Fc)(SEQID NO:1)；或PD-1(SEQID NO:2)转染的CHO细胞作为抗原，免疫Balb/C小鼠和SJL小鼠。人PD-1抗原购自ORIGENE,货号SC117011，NCBI Reference Sequence:NM_005018.1。
PD-1Fc，重组PD-1胞外区Fc融合蛋白(SEQ ID NO：1)：
MDMRVPAQLLGLLLLWFPGSRCPGWFLDSPDRPWNPPTFSPALLVVTEGDNATF
TCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDF
HMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPR
PAGQFQTLVDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE
YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK。
PD-1，转染细胞的PD-1抗原(SEQ ID NO：2)：
MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFT
CSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFH
MSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRP
AGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAV
PVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGP
RSAQPLRPEDGHCSWPL。
对于使用PD-1胞外区Fc融合蛋白的免疫，使用的纯化抗原分别为高剂量(50ug)和低剂量(10ug)，PD-1转染的CHO细胞免疫为0.5-1×107个细胞。用完全弗氏佐剂分别于第0,14,35天进行3次免疫，通过眼窝后放血监测免疫应答。通过ELISA筛选血浆，获取有抗PD-1人免疫球蛋白滴度的小鼠。于第56天，对有最高的抗PD-1人免疫球蛋白滴度的小鼠进行加强免疫。3天后，处死小鼠并取出脾来进行融合。融合后的杂交瘤细胞进行抗体筛选，得到鼠单抗mAb005。鼠单抗mAb005的重链和轻链可变区序列如下：
mAb005HCVR
EVMLVESGGGLVKPGGSLKLSCAASGFTFSSYMMSWVRQTPEKRLEWVATISG
GGANTYYPDSVKGRFTISRDNAKNTLYLQMSSLRSEDTALYYCARQLYYFDYW
GQGTTLTVSS                     SEQID NO：9
mAb005LCVR
DIQMTQSPASQSASLGEGVTITCLASQTIGTWLTWYQQKPGKSPQLLIYTATSLA
DGVPSRFSGSGSGTKFSFKISSLQAEDFVTYYCQQVYSIPWTFGGGTKLEIK
                                                      SEQID NO：10
其含有下列CDR序列：
名称 序列 编号
HCDR1 SYMMS SEQID NO：3
HCDR2 TISGGGANTYYPDSVKG SEQID NO：4
HCDR3 QLYYFDY SEQID NO：5
LCDR1 LASQTIGTWLT SEQID NO：6
LCDR2 TATSLAD SEQID NO：7
LCDR3 QQVYSIPWT SEQID NO：8
实施例2：抗体的筛选
PD-1抗体体外ELISA结合实验：
PD-1抗体是通过和PD-1胞外区的结合，从而阻断PD-1和其配体的信号通路。体外的ELISA实验被用来检测PD-1抗体的结合特性。生物素标记的PD-1胞外区FC融合蛋白(PD-1FC)通过和中和亲和素的结合，包被到96孔板中，抗体加入后信号的强弱被用于判断抗体和PD-1的结合特性。
用PBS缓冲液将用于和生物素结合的中和亲和素稀释至1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置16h-20h。将96孔板中PBS缓冲液吸掉，用PBST(PH7.4PBS含0.05％tweeen20)缓冲液洗板1次后，加入120μl/孔PBST/1％milk，室温孵育1h进行封闭。移去封闭液，用PBST缓冲液洗板1次后，加入用PBST/1％milk稀释的1μg/ml的生物素标记PD1-FC，置室温孵育1h。移去封闭液，用PBST缓冲液洗板3次后，加入用PBST/1％milk稀释至合适浓度的待测PD-1抗体，置室 温孵育1.5h。移去反应体系，用PBST洗板3次后，以100μl/孔加入用PBST/1％milk稀释HRP标记的抗鼠抗体二抗(The Jackson Laboratory)，室温孵育1h。用PBST洗板3次后，加入100μl/孔TMB，于室温孵育5-10min。加入100μl/孔1M H2SO4终止反应。用NOVOStar酶标仪在450nm处读取吸收值，计算ELISA结合EC50值。
Figure PCTCN2014091090-appb-000001
结合结果显示抗体mAb005对人源PD-1Fc(human PD-1)和食蟹猴PD-1Fc(cyno PD-1)都有着非常高的结合活性。
PD-1抗体体外PD-1配体结合阻断实验：
肿瘤细胞表面的PD-L1通过和T细胞表面的PD-1的结合，从而对T细胞的增殖起到抑制的效果。PD-1的抗体能通过和PD-1的结合，而阻断PD-L1/PD-1的信号通路，进而刺激T细胞的增殖。PD-1/PD-L1的结合阻断实验用于检测PD-1抗体对于信号通路的阻断活性。
本实验中，将胞外区与FC融合的PD-1蛋白(PD-1-FC)包被96孔板后，加入待测的PD-1抗体，进行孵育反应；稍后再加入生物素标记的PD-L1，孵育反应。洗板后，检测生物素标记的PD-L1结合量，计算得到PD-1抗体对配体PD-L1结合阻断的IC50值。
用PH 9.6CB缓冲液(1.59g Na2CO3和2.93g NaHCO3溶于1L蒸馏水)将PD-1-FC稀释至1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置16h-20h。将96孔板中PBS缓冲液吸掉，用PBST(PH7.4PBS含0.05％tweeen20)缓冲液洗板1次后，加入120μl/孔PBST/1％milk，室温孵育1h进行封闭。移去封闭液，用PBST缓冲液洗板1次后，加入90μl用样品稀释液(PH7.4PBS含5％BSA，0.05％Tween20)稀释至合适浓度的待测PD-1抗体，置4℃预孵育1h。以10μl/孔的体积加入10×浓度的生物素标记PD-L1(北京义翘神州生物技术有限公司)(10μg/ml)，在振荡器上振荡、混匀后，置37℃孵育1h。移去反应体系，用PBST洗板6次后，加入100ul/孔用PBST缓冲液1:400稀释的Streptavidin–Peroxidase Polymer，室温振荡孵育50分钟。用PBST洗板6次后，加入100μl/孔TMB，于室温孵育5-10min。加入100μl/孔1M H2SO4终止反应。用NOVOStar酶标仪在450nm处读取吸收值，计算PD-1抗体对配体PD-L1结合阻断的IC50值。
Figure PCTCN2014091090-appb-000002
实验结果显示抗体mAb005能非常有效的阻断PD-L1与PD-1之间的结合。
实施例3：PD-1抗体体外结合选择性实验
为检测PD-1抗体对于PD-1同一家族其他蛋白的特异结合活性，human CTLA4,human CD28被用于进行结合检测。同时，为了检测PD-1抗体对于人/猴以外的不同种属的差异性，小鼠的PD-1也进行了结合检测。
用PBS缓冲液将选择性结合蛋白：human PD-1,human ICOS，human CTLA4,human CD28,mouse PD-1，(北京义翘神州生物技术有限公司)，稀释至1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置16h-20h。将96孔板中PBS缓冲液吸掉，用PBST(PH7.4PBS含0.05％tweeen20)缓冲液洗板1次后，加入120μl/孔PBST/1％milk，室温孵育1h进行封闭。移去封闭液，用PBST缓冲液洗板3次后，加入待测PD-1抗体，置室温孵育1.5h。移去反应体系，用PBST洗板3次后，以100μl/孔加入用PBST/1％milk稀释HRP标记的抗鼠抗体二抗(The Jackson Laboratory)，室温孵育1小时。用PBST洗板3次后，加入100μl/孔TMB，于室温孵育5-10min。加入100μl/孔1M H2SO4终止反应。用NOVOStar酶标仪在450nm处读取吸收值。
Figure PCTCN2014091090-appb-000003
结果显示，抗体mAb005对PD-1家族的其他蛋白没有特异的结合活性。同时，mAb对鼠源的PD-1也没有种属交叉活性。
实施例4：PD-1抗体体外细胞结合实验
FACS(fluorescence-activated cell sorter荧光活性细胞分选)是一个用于检测蛋白和细胞结合的试验方法。本测试用于检测本发明的PD-1抗体和细胞表面表达的天然PD-1结合活性。本测试所用的细胞为PD-1高表达的CHO细胞(见实施例1中，PD-1(SEQID NO:2)转染的CHO细胞)。
将PD-1高表达的CHO细胞以1000rpm的转速离心5分钟，收集沉淀并用10-15ml的预冷的流式缓冲液悬浮，细胞计数。用50ml的离心管中以1000rpm的转速离心5分钟收集细胞，丢掉上清，沉淀用预冷封闭缓冲液重悬，密度为0.5-1.0×107细胞/毫升。于4℃孵育30分钟后，重悬以每孔100μl加入到96孔板。96孔板在1500rpm的转速下离心5分钟后，弃上清。向每个孔加入100μl一抗，将细胞重悬，4℃避光孵育60分钟。离心弃上清，加入100μl的l:400稀释的FITC标记二抗(BD Biosciences)。将细胞重悬，4℃避光孵育60分钟。用流式缓冲液洗两次细胞，并用1％的多聚甲醛重悬细胞进行固定，进行流式检测。
Figure PCTCN2014091090-appb-000004
结果显示抗体mAb005同样可以结合细胞表面的PD-1。
实施例5：体外结合亲和力和动力学实验
Biacore方法是一个公认的客观检测蛋白相互间亲和力和动力学的检测方法。我们通过Biacore(GE)分析本发明待测PD-1抗体表征亲和力及结合动力学。
利用由Biacore提供的试剂盒，采用标准氨基偶联法将本发明待测PD-1抗体共价连接至CM5(GE)芯片上。然后将将稀释于同样缓冲液中的一系列浓度梯度的PD-1His蛋白(北京义翘神州生物技术有限公司)于前后各个循环进样，进样后均以试剂盒内配再生试剂再生。追踪抗原-抗体结合动力学3分钟并追踪解离动力学10分钟。使用GE的BIAevaluation软件以1:1(Langmuir)结合模型分析所得数据，以此法测定的ka(kon)、kd(koff)和KD值显示于下表。
待测抗体 ka(1/Ms) kd(1/s) KD(M)
mAb005 1.057E+5 3.769E-4 3.566E-9
结果显示抗体mAb005对PD-1的结合达到了Kd 3.57nM。
实施例6：体外细胞学实验
新鲜人外周血单个核细胞(PBMC)在抗体作用下的增殖试验，用来对抗体mAb005进行细胞活性的检测。
新鲜人PBMC调整细胞密度为2×106/ml，每孔2ml接种于6孔板，37℃,5％CO2培养箱中放置6小时，将悬浮细胞吸走，向贴壁细胞中加入2ml含有100ng/ml GM-CSF(粒细胞集落刺激生物因子)和100ng/ml IL-4的RPMI1640培养基，培养2天后每孔再加入1ml含有100ng/ml GM-CSF和100ng/ml IL-4的RPMI1640培养基，继续培养2天后，每孔加入100ng/ml TNF-α(肿瘤坏死因子-a)，继续培养2天得到成熟树突细胞。将上述树突细胞及同种异体的T细胞分别离心重悬成浓度为1×106/ml和1×105/ml，于96孔板中每孔各加入100μl，抗体用PBS按一定倍数稀释成不同浓度梯度96孔板中每孔加入20μl，37℃，5％CO2培养箱中培养5天，取100μl用CellTiter-
Figure PCTCN2014091090-appb-000005
Luminescent Cell Viability Assay试剂盒检测细胞增殖，结果见图1，显示待测PD-1抗体mAb005可以有效的刺激人外周血单个核细胞的增殖，EC50为83ng/ml。剩余样品检测细胞因子IFN-γ的分泌，结果见图2，显示待测PD-1抗体mAb005可以在刺激PBMC增殖的同时，有效的刺激其细胞因子IFN-γ的分泌，EC50为13ng/ml。
实施例7：小鼠抗体人源化实验
参照mAb005的抗体轻链可变区序列(mAb005LCVR，SEQID NO：10)和重链可变区序列(mAb005HCVR，SEQID NO：9)，在Germline数据库中选取与其非CDR区匹配最好的人源化模板。其中抗体重链的模版为IgHV3-7/JH6，选择人种系轻链IGKV1-39的FR1，FR2，FR3，和JK4的FR4区，序列为SEQ ID NO：13；轻链的模版为IGKV1-39/JK4，选择人种系轻链IGKV1-39的FR1，FR2，FR3，和JK4的FR4，序列为SEQ ID NO：14。
人种系重链模版(SEQ ID NO：13):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQ
DGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARWGQGTTV
TVSS；
人种系轻链模板(SEQ ID NO：14)：
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS
SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFGGGTKVEIK。
将鼠源抗体CDR区移植到选择的人源化模板上，替换人源模板的CDR区，再与IgG4恒定区重组，得到人源化的抗体H005-1。然后，以鼠源抗体的三维结构为基础，对包埋残基、与CDR区有直接相互作用的残基，以及对VL和VH的构象有重要影响的残基进行回复突变，得到人源化之后的抗体H005-2，H005-3，H005-4，序列见下表。
抗体表达
H005-1HC
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG
GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY
WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS
GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR
VESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE
VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKV
SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL
HNHYTQKSLSLSLGK
                                                SEQID NO：11
H005-1LC
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA
DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA
APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE
QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
                                                SEQID NO：12
鼠源CDR区移植的人源化抗体H005-1的HC序列为(SEQID NO：11)，人源化抗体LC序列为(SEQID NO：12)。对可能影响抗体活性的位点进行点突变，其序列为：
  HC LC
H005-1 SEQID NO：11 SEQID NO：12
H005-2 SEQID NO：11,G44R SEQID NO：12
H005-3 SEQID NO：11 SEQID NO：12,A43S
H005-4 SEQID NO：11,G44R SEQID NO：12,A43S
根据各人源化抗体轻链和重链的氨基酸序列(SEQ NO 11,SEQ NO 12及其变体)合成cDNA，用BamHI和XhoI消化后，将cDNA片段通过BamHI/XhoI酶切位点插入到pcDNA3.1表达载体(Life Technologies Cat.No.V790-20)中。将表达载体和转染试剂PEI(Polysciences,Inc.Cat.No.23966)以1:2的比例转染HEK293细胞(Life Technologies Cat.No.11625019)，并置于CO2孵育箱中孵育4-5天。表达的抗体通过离心回收后，按常规方法进行抗体纯化，得到本发明的人源化抗体。
实施例8：人源化抗体活性数据
对人源化的抗体在体外进行了ELISA结合实验(方法步骤同实施例2)，配体结合阻断实验(方法步骤同实施例2)，亲和力动力学实验(方法步骤同实施例5)，结果显示于下表：
待测抗体 ELISA,EC50,nM LBB assay,IC50,nM KD(M)
H005-1 0.11 1.27 2.79E-09
H005-2 0.14 1.27 2.98E-09
H005-3 0.15 1.33 2.45E-09
H005-4 0.14 1.36 3.89E-09
试验结果显示人源化的抗体H005-1,H005-2,H005-3,H005-4都保持了和PD-1的结合活性，它们的亲和力动力学KD分别为2.79，2.98,2.45,3.89nM。同时所有人源化抗体也能有效的对PD-L1/PD-1通路产生阻断活性。
实施例9：PD-1抗体对肿瘤细胞生长的抑制
一、实验材料：
U87MG细胞(胶质瘤细胞)：购自中科院细胞库，货号TCHu138；
PBMC细胞(外周血单个核细胞)来自上海血液中心；
CD3:购自Miltenyi Biotec货号130-093-387；
CD28:购自Miltenyi Biotec货号130-093-375；
Cell Counting Kit-8：购自同仁化学，货号CK04；
mIgG(阴性对照)：购自SANTA CRUZ货号：sc-2025；使用浓度为1660ng/ml。
二、实验方法：
1.U87MG细胞培养在含有10％FBS、1％P/S的EMEM培养基中，96孔板中每孔加入1×104个细胞。
2.抗体H005-1用PBS按一定倍数稀释成不同浓度梯度(如图3横坐标所示)，96孔板中每孔加入10ul，37℃、5％CO2培养箱中培养4小时。
3.细胞贴壁后每孔加入80ul PBMC细胞悬液，细胞密度为2×104个/孔，每孔分别加入10ul CD3和CD28抗体，CD3和CD28抗体终浓度均为500ng/ml。
4.37℃，5％CO2培养箱中培养72小时，每孔加入10ul CCK8显色，2小时后检测OD450。
三、实验结果：
结果如图3所示，与mIgG(阴性对照)相比，不同浓度PD-1抗体(H005-1)对U87MG细胞生长有明显的抑制效果，最高浓度抑制率约为30％。
实施例10：H005-1对结核菌素刺激的PBMC增殖活性
对人源化的抗体H005-1在体外对结核菌素刺激的PBMC的增殖活性进行检测。
取15ml新鲜PBMC细胞，约3×107个，加入20μl结核菌素(上海碧优生物科技，cat#97-8800)，37℃、5％CO2培养箱培养5天。第6天，取上述培养的细胞离心，重悬至新鲜的培养基中，调整密度为5×105个/ml。在96孔细胞培养板中加入190μl重悬后的细胞，将人源化抗体H005-1加入上述96孔细胞培养板的对应孔中，每孔10μl，对照组和空白组分别加入10μl PBS。细胞培养板置于37℃，5％CO2培养箱孵育72小时后检测PBMC细胞增殖(Promega，cat#G7571)和IFN-γ的分泌(Neo Bioscience，cat#EHC102g)。结果如下：
受试样品对结核菌素刺激的PBMC增殖和IFN-γ分泌的激活作用
Sample T cell proliferation EC50(ng/ml) IFN-λ EC50(ng/ml)
H005-1 15.95±17.15 56.87±48.53
注：n＝4
实验结果显示人源化的抗体H005-1可以很好的激活外源结核菌素刺激下的PBMC的增殖以及IFN-γ的分泌。
实施例11：H005-1对U-87MG皮下移植瘤抑制实验
将U87细胞(5×106个)100ul接种于SCID-Beige小鼠右肋部皮下，待7-10d肿瘤长至80-100mm3后，去除体重、肿瘤过大和过小的，按肿瘤体积将小鼠随机分为H005-110mg/kg组和Human IgG 10mg/kg组，每组7只(D0)。将经CD3抗体刺激3天的两种PBMC以1:1比例混合，以5×105cells/60ul量注射到肿瘤组织中，并开始皮下注射抗体，7天一次，共给药3次。每周测2次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：V＝1/2×a×b2；其中a、b分别表示长、宽。
结果见图4：治疗后的肿瘤体积变化图，和图5：治疗后的鼠重变化图，显示抗体H005-1可以很好的抑制肿瘤U87MG的生长，而且对小鼠的体重没有任何的影响。

Claims (27)

  1. 一种PD-1抗体或其抗原结合片段，其包含：
    抗体轻链可变区，所述的抗体轻链可变区包含至少1个选自如以下序列所示的LCDR：SEQ ID NO:6，SEQ ID NO:7或SEQ ID NO:8；和
    抗体重链可变区，所述的抗体重链可变区包含至少1个选自如以下序列所述的HCDR：SEQ ID NO:3，SEQ ID NO:4或SEQ ID NO:5。
  2. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:6所示的LCDR1。
  3. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:7所示的LCDR2。
  4. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含如SEQ ID NO:8所示的LCDR3。
  5. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:3所示的HCDR1。
  6. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:4所示的HCDR2。
  7. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含如SEQ ID NO:5所示的HCDR3。
  8. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含分别如SEQ ID NO:6、SEQ ID NO:7和SEQ ID NO:8所示的LCDR1、LCDR2和LCDR3。
  9. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体重链可变区包含分别如SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5所示的HCDR1、HCDR2和HCDR3。
  10. 如权利要求1所述的PD-1抗体或其抗原结合片段，其中所述的抗体轻链可变区包含分别如SEQ ID NO:6、SEQ ID NO:7和SEQ ID NO:8所示的LCDR1、LCDR2和LCDR3；且其中所述的抗体重链可变区包含分别如SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5所示的HCDR1、HCDR2和HCDR3。
  11. 如权利要求1-10任一项所述的PD-1抗体或其抗原结合片段，其中所述的抗体或其抗原结合片段为鼠源抗体或其片段。
  12. 如权利要求1-10任一项所述的PD-1抗体或其抗原结合片段，其中所述的抗体或其抗原结合片段为嵌合抗体或其片段。
  13. 如权利要求12所述的PD-1抗体或其抗原结合片段，其中所述的嵌合抗体轻链可变区序列为：SEQ ID NO:10。
  14. 如权利要求12所述的PD-1抗体或其抗原结合片段，其中所述的嵌合抗体重链可变区序列为：SEQ ID NO:9。
  15. 如权利要求1-10任一项所述的PD-1抗体或其抗原结合片段，其中所述的抗体或其抗原结合片段为人源化抗体或其片段。
  16. 如权利要求15所述的PD-1抗体或其抗原结合片段，其中所述人源化抗体轻链可变区上的轻链FR区序列，来源于如SEQ ID NO:14所示的人种系轻链IGKV1-39和JK4的组合序列；其包含人种系轻链IGKV 1-39的FR1，FR2，FR3区和JK4的FR4区。
  17. 如权利要求15所述的PD-1抗体或其抗原结合片段，其中所述人源化抗体轻链序列为如SEQ ID NO:12所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化。
  18. 如权利要求15所述的PD-1抗体或其抗原结合片段，其中所述人源化抗体重链可变区进一步包含人源IgG1,IgG2,IgG3或IgG4或其变体的重链FR区，优选包含人源IgG2或IgG4重链FR区。
  19. 如权利要求15所述的PD-1抗体或其抗原结合片段，其中所述人源化抗体重链可变区上的重链FR区序列，来源于如SEQ ID NO:13所示的人种系重链IgHV3-7和JH6的组合序列；其包含人种系重链IgHV3-7的FR1，FR2，FR3区和JH6的FR4区。
  20. 如权利要求15所述的PD-1抗体或其抗原结合片段，其中所述人源化抗体重链序列为如SEQ ID NO:11所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
  21. 一种编码如权利要求1-20任一项所述的抗体的DNA分子。
  22. 一种含有如权利要求21所述的DNA分子的表达载体。
  23. 一种用如权利要求22所述的表达载体转化的宿主细胞。
  24. 如权利要求23所述的宿主细胞，其中所述的宿主细胞为细菌，优选为大肠杆菌。
  25. 如权利要求23所述的宿主细胞，其中所述的宿主细胞为酵母菌，优选为毕赤酵母。
  26. 一种药物组合物，其含有如权利要求1至20任一项所述的PD-1抗体或其抗原结合片段和可药用的赋形剂、稀释剂或载体。
  27. 如权利要求1至20任一项所述的PD-1抗体或其抗原结合片段、如权利要求26所述的药物组合物，在制备用于治疗PD-1介导的疾病或病症的药物中的用途，其中所述的疾病或病症优选为癌症；更优选为表达PD-L1的癌症；最优选为乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤、非小细胞肺癌；最优选为非小细胞肺癌、黑素瘤和肾癌。
PCT/CN2014/091090 2013-12-12 2014-11-14 Pd-1抗体、其抗原结合片段及其医药用途 WO2015085847A1 (zh)

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MYPI2016001084A MY184154A (en) 2013-12-12 2014-11-14 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
RS20191248A RS59480B1 (sr) 2013-12-12 2014-11-14 Pd-1 antitelo, njegov fragment koji se vezuje na antigen, i njegova medicinska primena
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MEP-2019-261A ME03527B (me) 2013-12-12 2014-11-14 Pd-1 antitijelo, njegov fragment koji se vezuje na antigen, i njegova medicinska primjena
NZ721624A NZ721624B2 (en) 2013-12-12 2014-11-14 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
LT14868918T LT3081576T (lt) 2013-12-12 2014-11-14 Pd-1 antikūnas, antigeną surišantis jo fragmentas ir jų medicininis pritaikomumas
ES14868918T ES2746805T3 (es) 2013-12-12 2014-11-14 Anticuerpo de PD-1, fragmento de unión a antígeno del mismo y aplicación médica del mismo
MX2016007620A MX370449B (es) 2013-12-12 2014-11-14 Anticuerpo pd-1, fragmento de unión al antígeno de este y uso médico de este.
PL14868918T PL3081576T3 (pl) 2013-12-12 2014-11-14 Przeciwciało anty pd-1, jego fragment wiążący antygen i ich zastosowanie medyczne
SG11201604738TA SG11201604738TA (en) 2013-12-12 2014-11-14 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
EP14868918.5A EP3081576B1 (en) 2013-12-12 2014-11-14 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
EA201691225A EA035037B1 (ru) 2013-12-12 2014-11-14 Антитело к pd-1, его антигенсвязывающий фрагмент и их медицинское применение
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AU2014361473A AU2014361473B2 (en) 2013-12-12 2014-11-14 PD-1 antibody, antigen-binding fragment thereof, and medical application thereof
BR112016013338-2A BR112016013338B1 (pt) 2013-12-12 2014-11-14 Anticorpo pd-1 ou fragmento de ligação a antígeno do mesmo, seus usos e composição farmacêutica
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KR1020167018704A KR102256152B1 (ko) 2013-12-12 2014-11-14 Ｐｄ-1 항체, 이의 항원 결합 단편, 및 이의 의약 용도
HK16101701.0A HK1213910A1 (zh) 2013-12-12 2016-02-17 抗體、其抗原結合片段及其醫藥用途
IL246137A IL246137B (en) 2013-12-12 2016-06-09 Antibody pd-1, its antigenic binding part, and its medical use
PH12016501120A PH12016501120B1 (en) 2013-12-12 2016-06-10 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
ZA2016/04660A ZA201604660B (en) 2013-12-12 2016-07-07 Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof
US16/426,001 US11365255B2 (en) 2013-12-12 2019-05-30 PD-1 antibody, antigen-binding fragment thereof, and medical application thereof
HRP20191678 HRP20191678T1 (hr) 2013-12-12 2019-09-17 Pd-1 protutijelo, njegov fragment koji se veže na antigen, i njegova medicinska primjena
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