WO2022242737A1 - 药物组合及其用途 - Google Patents

药物组合及其用途 Download PDF

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Publication number
WO2022242737A1
WO2022242737A1 PCT/CN2022/094047 CN2022094047W WO2022242737A1 WO 2022242737 A1 WO2022242737 A1 WO 2022242737A1 CN 2022094047 W CN2022094047 W CN 2022094047W WO 2022242737 A1 WO2022242737 A1 WO 2022242737A1
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amino acid
acid sequence
seq
sequence shown
terminal
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PCT/CN2022/094047
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English (en)
French (fr)
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王晨光
张晓娇
党晓萌
张晋
付雨婷
王一涵
王超
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天津立博美华基因科技有限责任公司
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Priority to AU2022277263A priority Critical patent/AU2022277263A1/en
Priority to CN202280036836.XA priority patent/CN117396222A/zh
Priority to EP22804057.2A priority patent/EP4342492A1/en
Publication of WO2022242737A1 publication Critical patent/WO2022242737A1/zh

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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
    • 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
    • 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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • This application relates to the field of biomedicine, in particular to the development and application of a drug combination.
  • the PD-L1/PD-1 signaling pathway is a very important co-inhibitory signaling pathway in the immune response.
  • ITAM immunoreceptor tyrosine activation motif
  • Stimulator of interferon genes is an immunostimulatory small molecule target, mainly distributed in immune-related tissue cells, such as highly expressed in thymus, spleen and peripheral blood leukocytes.
  • cGAMP can bind and activate STING in the endoplasmic reticulum.
  • STING activation leads to nuclear translocation of transcription factors, induces the expression of interferon (INF) and cytokines, promotes the aggregation and activation of T cells, and then kills tumor cells.
  • the STING pathway can also be activated by synthetic cyclic dinucleotides (CDNs), triggering an innate immune response.
  • CDNs synthetic cyclic dinucleotides
  • Combination of PD-L1/PD-1 inhibitors and STING pathway agonists relieves inhibitory signals, enhances T cell activation, and promotes adaptive immune system response; on the other hand, induces the expression of INF and cytokines, and promotes T cell Aggregation of cells, activation of the innate immune system response, and a two-pronged approach to enhance the response of cytotoxic cells to tumors, etc., have high clinical prospects and application value.
  • PD-1 is found to be highly expressed on the surface of CD8+ T cells that specifically recognize HIV, and the virus activates the PD-L1/PD-1 signaling pathway to make CD8+ T cells that specifically recognize HIV
  • the activity is inhibited, the secretion ability of cytokines and the proliferation ability of T cells are greatly weakened, and the adaptive immune function defect is caused. It can be seen that this therapy may also have considerable application value in the treatment of this type of disease.
  • the application provides a drug combination and its application in antitumor drugs.
  • the drug combination consists mainly of two parts:
  • Immune checkpoint inhibitors such as PD-1/PD-L1
  • STING pathway agonists such as cyclic dinucleotide cGAMP and its derivatives.
  • the drug combination of the application can prepare high-efficiency, low-toxicity antitumor drugs.
  • the present application provides a pharmaceutical combination comprising a programmed cell death protein 1 (PD-1) inhibitor and/or a programmed death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist.
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death ligand 1
  • the STING pathway agonist comprises a cyclic dinucleotide.
  • cyclic dinucleotide is selected from c-di-AMP, c-di-GMP, c-di-GMP-F, 3',3'-cGAMP, 3',3 '-cGAMP-F, 2',3'-cGAMP, Rp/Sp(CL656), ADU-S100, ADU-S100 disodium, derivatives thereof, and combinations thereof.
  • the STING pathway agonist comprises 2',3'-cGAMP or a derivative thereof.
  • the STING pathway agonist comprises a flavonoid.
  • the flavonoids include CMA, DMXAA, methoxyketone, 6,4'-dimethoxyflavone, 4'-methoxyflavone, 3',6'-dihydroxyflavone, 7,2'-dihydroxyflavone, daidzein, Formononetin, retinoid 7-methyl ether, xanthone and/or any combination thereof.
  • the STING pathway agonist comprises DNA
  • the STING pathway agonist comprises type I interferon (IFN).
  • IFN type I interferon
  • the type I interferon comprises IFN- ⁇ or IFN- ⁇ .
  • the PD-1 inhibitor has one or more of the following characteristics:
  • PD-1 Inhibit or reduce the expression of PD-1, such as the transcription or translation of PD-1;
  • Inhibiting or reducing PD-1 activity such as inhibiting or reducing the binding of PD-1 to its cognate ligand, such as PD-L1 or PD-L2;
  • the PD-1 inhibitor comprises an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the anti-PD-1 antibody is selected from Pembrolizumab, Nivolumab, Pidilizumab, SHR-1210, MEDI0680, BGB-A317, TSR-042, REGN2810, PF-06801591, RB0004, Tislelizumab, Camrelizumab, Toripalimab , Sintilimab, biosimilars thereof, bioenhancers thereof, bioequivalents thereof, and combinations thereof.
  • the anti-PD-1 antibody comprises at least one CDR in the antibody heavy chain variable region (VH)
  • the VH comprises the amino acid sequence shown in SEQ ID NO:8.
  • the anti-PD-1 antibody comprises VH
  • the VH comprises HCDR3
  • the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:3.
  • VH further comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence shown in SEQ ID NO:2.
  • VH further comprises HCDR1, wherein said HCDR1 comprises the amino acid sequence shown in SEQ ID NO:1.
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:3, and the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:2, the Said HCDR1 comprises the amino acid sequence shown in SEQ ID NO:1.
  • the C-terminal of the HFR1 is directly or indirectly linked to the N-terminal of the HCDR1, and the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 4 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:4.
  • the VH includes a framework region HFR2
  • the N-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2 Indirectly connected
  • the HFR2 comprises the amino acid sequence shown in SEQ ID NO: 5 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 5.
  • the VH includes a framework region HFR3
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR3 is directly or indirectly connected to the N-terminal of the HCDR3 Indirectly linked
  • the HFR3 comprises the amino acid sequence shown in SEQ ID NO: 6 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 6.
  • the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO: 7 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:7.
  • the C-terminus of HFR1 is directly or indirectly connected to the N-terminus of the HCDR1, and the N-terminus of the HFR2 is connected to the N-terminus of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the HFR3 The C-terminal is directly or indirectly connected to the N-terminal of the HCDR3, and the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3;
  • the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 4 or with The amino acid sequence shown in SEQ ID NO: 4 has an amino acid sequence
  • said anti-PD-1 antibody comprises VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO:8.
  • the anti-PD-1 antibody comprises an antibody heavy chain (HC)
  • the HC comprises an amino acid sequence shown in SEQ ID NO:9.
  • the anti-PD-1 antibody comprises at least one CDR in the antibody light chain variable region (VL)
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17.
  • said anti-PD-1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 8
  • said anti-PD-1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17.
  • the anti-PD-1 antibody comprises a VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:10.
  • said VL further comprises LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 11.
  • said VL further comprises LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:12.
  • the VL comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 10, and the LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 11, the Said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:12.
  • the anti-PD-1 antibody comprises VH and antibody VL
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3, and the HCDR2 comprises SEQ ID NO: 3
  • the HCDR1 comprises the amino acid sequence shown in SEQ ID NO:1
  • the VL comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid shown in SEQ ID NO:10 Sequence
  • the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:11
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:12.
  • the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 13 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13.
  • the N-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR1, and the C-terminal of the LFR2 is directly or indirectly connected to the N-terminal of the LCDR2.
  • the LFR2 comprises the amino acid sequence shown in SEQ ID NO: 14 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 14.
  • the VL includes a framework region LFR3
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the N-terminal of the LCDR3 Indirectly connected
  • the LFR3 comprises the amino acid sequence shown in SEQ ID NO: 15 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 15.
  • the N-terminal of the LFR4 is directly or indirectly connected to the C-terminal of the LCDR3, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO: 16 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO: 16.
  • the VL includes framework regions LFR1, LFR2, LFR3 and LFR4, the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the N-terminus of the LFR2 is connected to the LCDR1
  • the C-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR2
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminus is directly or indirectly connected to the N-terminus of the LCDR3, and the N-terminus of the LFR4 is directly or indirectly connected to the C-terminus of the LCDR3
  • the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 13 or with The amino acid sequence shown in SEQ ID NO: 13 has an amino acid sequence with at least about 70% sequence identity
  • the LFR2 comprises the amino acid sequence
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17.
  • the anti-PD-1 antibody comprises VH and VL
  • the VH comprises the amino acid sequence shown in SEQ ID NO:8
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17 .
  • said anti-PD-1 antibody comprises an antibody light chain (LC)
  • said LC comprises an amino acid sequence shown in SEQ ID NO:18.
  • the anti-PD-1 antibody comprises HC and LC
  • the HC comprises the amino acid sequence shown in SEQ ID NO:9
  • the LC comprises the amino acid sequence shown in SEQ ID NO:18.
  • the PD-L1 inhibitor has one or more of the following characteristics:
  • PD-L1 Inhibit or reduce the expression of PD-L1, such as the transcription or translation of PD-L1;
  • Inhibiting or reducing PD-L1 activity such as inhibiting or reducing the binding of PD-L1 to its cognate receptor, such as PD-1;
  • the PD-L1 inhibitor comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the anti-PD-L1 antibody is selected from Durvalumab, Atezolizumab, Avelumab, Envafolimab, MDX-1105, YW243.55.S70, MDPL3280A, AMP-224, LY3300054, RB0005, biological analogs thereof, Bioenhancers thereof, bioequivalents thereof and combinations thereof.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO:25.
  • the anti-PD-L1 antibody comprises VH
  • the VH comprises HCDR3
  • the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:21.
  • VH further comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence shown in SEQ ID NO:20.
  • VH further comprises HCDR1, wherein said HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19.
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, and the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, the Said HCDR1 comprises the amino acid sequence shown in SEQ ID NO:19.
  • the C-terminal of the HFR1 is directly or indirectly connected to the N-terminal of the HCDR1, and the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 22 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO: 22.
  • the N-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2 Indirectly linked
  • the HFR2 comprises the amino acid sequence shown in SEQ ID NO: 23 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 23.
  • the VH includes a framework region HFR3
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR3 is directly or indirectly connected to the N-terminal of the HCDR3 Indirectly connected
  • the HFR3 comprises the amino acid sequence shown in SEQ ID NO: 24 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 24.
  • the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO: 7 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:7.
  • the C-terminus of HFR1 is directly or indirectly connected to the N-terminus of the HCDR1, and the N-terminus of the HFR2 is connected to the N-terminus of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the HFR3 The C-terminal is directly or indirectly connected to the N-terminal of the HCDR3, and the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3;
  • the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 22 or with The amino acid sequence shown in SEQ ID NO:22 has an amino acid sequence
  • said anti-PD-L1 antibody comprises VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO:25.
  • said anti-PD-L1 antibody comprises HC
  • said HC comprises the amino acid sequence shown in SEQ ID NO:26.
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 25
  • said anti-PD-L1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 25
  • said anti-PD-L1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.
  • the anti-PD-L1 antibody comprises a VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:27.
  • the anti-PD-L1 antibody comprises VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:28, SEQ ID NO:29 or SEQ ID NO:30 .
  • said VL further comprises LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO:31.
  • said VL further comprises LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32.
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, and said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 31, said Said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32.
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 28, and said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 31, said Said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32;
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:29
  • the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32;
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:30
  • the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32.
  • the anti-PD-L1 antibody comprises VH and antibody VL
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, and the HCDR2 Comprising the amino acid sequence shown in SEQ ID NO:20
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO:19
  • the VL includes LCDR1, LCDR2 and LCDR3, wherein the LCDR1 includes the amino acid sequence shown in SEQ ID NO:27
  • the amino acid sequence of the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32.
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, and the HCDR2 Comprising the amino acid sequence shown in SEQ ID NO: 20, the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 19; and the VL includes LCDR1, LCDR2 and LCDR3, wherein the LCDR1 includes SEQ ID NO: 28, SEQ ID NO: The amino acid sequence shown in ID NO: 29 or SEQ ID NO: 30, the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 31, and the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 32.
  • the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 33 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:33.
  • the N-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR1, and the C-terminal of the LFR2 is directly or indirectly connected to the N-terminal of the LCDR2.
  • the LFR2 comprises the amino acid sequence shown in SEQ ID NO: 34 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 34.
  • the VL includes a framework region LFR3
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the N-terminal of the LCDR3 Indirectly linked
  • the LFR3 comprises the amino acid sequence shown in SEQ ID NO: 35 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 35.
  • the N-terminal of the LFR4 is directly or indirectly connected to the C-terminal of the LCDR3, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO: 36 or An amino acid sequence having at least about 70% sequence identity to the amino acid sequence set forth in SEQ ID NO:36.
  • the VL includes framework regions LFR1, LFR2, LFR3 and LFR4, the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the N-terminus of the LFR2 is connected to the LCDR1
  • the C-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR2
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminus is directly or indirectly connected to the N-terminus of the LCDR3, and the N-terminus of the LFR4 is directly or indirectly connected to the C-terminus of the LCDR3
  • the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 33 or with The amino acid sequence shown in SEQ ID NO:33 has an amino acid sequence with at least about 70% sequence identity
  • the LFR2 comprises the amino acid sequence shown
  • the anti-PD-L1 antibody comprises a VL
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37.
  • the anti-PD-L1 antibody comprises a VL
  • the VL comprises the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.
  • the anti-PD-L1 antibody comprises VH and VL
  • the VH comprises the amino acid sequence shown in SEQ ID NO:25
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37 .
  • the anti-PD-L1 antibody comprises VH and VL
  • the VH comprises the amino acid sequence shown in SEQ ID NO: 25
  • the VL comprises SEQ ID NO: 38, SEQ ID NO: 39 or the amino acid sequence shown in SEQ ID NO:40.
  • said anti-PD-L1 antibody comprises LC
  • said LC comprises the amino acid sequence shown in SEQ ID NO:41.
  • the LC comprises the amino acid sequence shown in SEQ ID NO:42, SEQ ID NO:43 or SEQ ID NO:44.
  • the anti-PD-L1 antibody comprises HC and LC
  • the HC comprises the amino acid sequence shown in SEQ ID NO:26
  • the LC comprises the amino acid sequence shown in SEQ ID NO:41.
  • the anti-PD-L1 antibody comprises HC and LC
  • the HC comprises the amino acid sequence shown in SEQ ID NO:26
  • the LC comprises SEQ ID NO:42, SEQ ID NO:43 Or the amino acid sequence shown in SEQ ID NO:44.
  • the PD-1 inhibitor and/or PD-L1 inhibitor, and ii) the STING pathway agonist in the drug combination are not mixed with each other in the drug combination.
  • the PD-1 inhibitor and/or PD-L1 inhibitor, and ii) the STING pathway agonist in the pharmaceutical combination are in a single dosage form.
  • the pharmaceutical combination is formulated as a pharmaceutical composition.
  • the pharmaceutical composition includes a PD-1 inhibitor or PD-L1 inhibitor, and a STING pathway agonist.
  • the STING pathway agonist is present in an amount of about 0.0001 mg/kg to about 200 mg/kg.
  • the PD-1 inhibitor or PD-L1 inhibitor is present in an amount of 0.0001 mg/kg to about 200 mg/kg.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the present application also provides the use of the aforementioned drug combination in the preparation of medicines for treating neoplastic diseases.
  • the neoplastic disease comprises tumor and/or wart disease.
  • the present application also provides the aforementioned drug combination for treating neoplastic diseases.
  • the present application also provides a drug for treating neoplastic diseases, which comprises the aforementioned drug combination.
  • the present application also provides a method for treating neoplastic diseases, which comprises administering an effective amount of the aforementioned drug combination to a subject in need.
  • the neoplasm comprises tumors and/or warts.
  • administering comprises topical, intraneoplastic (eg, intratumor or intrawart) or systemic administration.
  • intraneoplastic eg, intratumor or intrawart
  • systemic administration e.g, topical, intraneoplastic (eg, intratumor or intrawart) or systemic administration.
  • administering comprises intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection and/or intraneoplastic injection.
  • a PD-1 inhibitor or a PD-L1 inhibitor i) an agonist of the STING pathway in the drug combination are administered by the same or different routes of administration.
  • it comprises injecting said STING pathway agonist into the neoplasm.
  • it also includes injecting or systemically infusing the PD-1 inhibitor or PD-L1 inhibitor into the neoplasm.
  • injection of the STING pathway agonist and systemic infusion of the PD-1 inhibitor or PD-L1 inhibitor into the neoplasm are included.
  • it comprises injecting i) the PD-1 inhibitor or PD-L1 inhibitor STING pathway agonist, and ii) the STING pathway agonist in the drug combination into the neoplasm.
  • i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the pharmaceutical combination are administered simultaneously or at different times.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered before and/or after administration of the STING pathway agonist.
  • the method comprises: i) injecting the STING pathway agonist into the neoplasm; ii) injecting or systemically infusing the PD- 1 inhibitor or PD-L1 inhibitor.
  • the PD-1 inhibitor or PD-L1 inhibitor in the drug combination is administered simultaneously with ii) the STING pathway agonist.
  • the PD-1 inhibitor or PD-L1 inhibitor in the drug combination is administered simultaneously with ii) the STING pathway agonist by intraneoplastic injection, and the PD -1 inhibitor or PD-L1 inhibitor is located in the same dosage form as the STING pathway agonist.
  • the present application provides a kit comprising the aforementioned drug combination.
  • Figure 1 shows the in vivo drug efficacy study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP drug combination described in this application-the body weight changes of mice in each group during the administration period.
  • Figure 2 shows the in vivo pharmacodynamic study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP drug combination described in this application - the change in the survival rate of mice in each group during the administration period.
  • Figure 3A shows the in vivo drug efficacy study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP drug combination described in this application-the changes of tumor proliferation in mice in each group during administration.
  • Figure 3B shows the in vivo efficacy study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP drug combination described in this application-the changes of tumor proliferation in mice in each group on day 17 after treatment.
  • Figure 4 shows the in vivo efficacy study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP drug combination described in this application - the inhibition rate of tumor weight in mice dissected after the observation of administration.
  • Figure 5 shows the in vivo drug efficacy study of the PD-1 inhibitor RB0004 and 2',3'-cGAMP drug combination described in this application-the changes of tumor proliferation in mice in each group during administration.
  • Figure 6 shows the in vivo efficacy study of the PD-1 inhibitor RB0004 and 2',3'-cGAMP drug combination described in this application - the inhibition rate of tumor weight in mice dissected after the observation of administration.
  • Figure 7 shows the in vivo efficacy study of the PD-L1 inhibitor RB0005 described in this application and different doses of 2',3'-cGAMP drug combination - the inhibition rate of tumor weight in mice dissected after the observation of administration.
  • Figure 8 shows the in vivo pharmacodynamic study of the PD-1 inhibitor RB0004 described in this application and different doses of 2',3'-cGAMP drug combination - changes in tumor proliferation in mice in each group during administration.
  • Figure 9 shows the in vivo efficacy study of the PD-1 inhibitor RB0004 described in this application and different doses of 2',3'-cGAMP drug combination - the change of survival rate of mice in each group during the administration period.
  • Figure 10 shows the trend of tumor proliferation in each group of mice during the administration period in Example 5 of the present application.
  • Figure 11 shows the survival curves of mice in each group during the administration period in Example 5 of the present application.
  • Figure 12 shows the average tumor mass of mice in each group during the administration period in Example 5 of the present application.
  • Figure 13 shows the trend of tumor proliferation in each group of mice during the administration period in Example 6 of the present application.
  • Figure 14 shows the survival curves of mice in each group during the administration period in Example 6 of the present application.
  • Figure 15 shows the average tumor mass of mice in each group during the administration period in Example 6 of the present application.
  • Figure 16 shows the trend of tumor proliferation in each group of mice during the administration period in Example 7.2.1 of the present application.
  • Figure 17 shows the survival curves of mice in each group during the administration period in Example 7.2.1 of the present application.
  • Figure 18 shows the average tumor mass of mice in each group during the administration period in Example 7.2.1 of the present application.
  • Figure 19 shows the trend of tumor proliferation in each group of mice during the administration period in Example 7.2.2 of the present application.
  • Figure 20 shows the survival curves of mice in each group during the administration period in Example 7.2.2 of the present application.
  • Figure 21 shows the average tumor mass of mice in each group during the administration period in Example 7.2.2 of the present application.
  • Figure 22 shows the trend of tumor proliferation in each group of mice during the administration period in Example 7.2.3 of the present application.
  • Figure 23 shows the survival curves of mice in each group during the administration period in Example 7.2.3 of the present application.
  • Figure 24 shows the change trend of the tumor volume of a single mouse in the compound preparation group during the administration period in Example 7.2.3 of the present application.
  • Figure 25 shows the average tumor mass of mice in each group during the administration period in Example 7.2.3 of the present application.
  • Figure 26 shows the relative tumor volume inhibition rate of mice in each group during the administration period in Example 8 of the present application.
  • Figure 27 shows the trend of tumor proliferation in each group of mice during the administration period in Example 9 of the present application.
  • Figure 28 shows the survival curves of mice in each group during the administration period in Example 9 of the present application.
  • Figure 29 shows the average tumor mass of mice in each group during the administration period in Example 9 of the present application.
  • Figure 30 shows the trend of tumor proliferation in each group of mice during the administration period in Example 10 of the present application.
  • Figure 31 shows the average tumor volume of mice in each group at the end point of the experiment in Example 10 of the present application.
  • Figure 32 shows the survival curves of mice in each group during the administration period in Example 10 of the present application.
  • Figure 33 shows the trend of the tumor volume change of a single mouse in the G5 group during the administration period in Example 10 of the present application.
  • Figure 34 shows the trend of tumor proliferation in each group of mice during the administration period in Example 11 of the present application.
  • Figure 35 shows the survival curves of mice in each group during the administration period in Example 11 of the present application.
  • Figure 36 shows the average tumor mass of mice in each group during the administration period in Example 11 of the present application.
  • Figure 37 shows the trend of tumor proliferation in each group of mice during the administration period in Example 12 of the present application.
  • Figure 38 shows the survival curves of mice in each group during the administration period in Example 12 of the present application.
  • Figure 39 shows the average tumor volume of mice in each group on day 7 in Example 12 of the present application.
  • Figure 40 shows the average tumor mass of mice in each group during the administration period in Example 12 of the present application.
  • Figure 41 shows the trend of tumor proliferation in each group of mice during the administration period in Example 13 of the present application.
  • Figure 42 shows the survival curves of mice in each group during the administration period in Example 13 of the present application.
  • Figure 43 shows the average tumor mass of mice in each group during the administration period in Example 13 of the present application.
  • PD-1 generally refers to programmed cell death protein 1, a 288 amino acid type I membrane protein first described in 1992 (Ishida et al., EMBO J., 11 (1992), 3887-3895).
  • PD-1 is a member of the expanded CD28/CTLA-4 family of T cell regulators and has two ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273).
  • the protein's structure includes an extracellular IgV domain, followed by a transmembrane region and an intracellular tail.
  • the intracellular tail contains two phosphorylation sites located in the immunoreceptor tyrosine-based inhibitory motif and the immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates TCR signaling. This is consistent with the binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 after ligand binding.
  • PD-1 is not expressed on naive T cells, it is upregulated following T cell receptor (TCR)-mediated activation and is observed on both activated and exhausted T cells (Agata et al., Int. Immunology 8 (1996), 765-772). These exhausted T cells have a dysfunctional phenotype and are unable to respond appropriately.
  • the PD-1 may include human PD-1 (hPD-1) or its variants, isotypes and species homologues, and analogs having at least one common epitope with hPD-1.
  • the amino acid sequence of an exemplary hPD-1 can be found under GenBank Accession No. U64863.
  • the term "PD-L1" generally refers to programmed cell death 1 ligand 1, also known as B7 homolog 1, B7-H1, cluster of differentiation 274, (3)274 or CD274, which is related to PD-1 binding downregulates T cell activation and cytokine secretion.
  • P-L1 includes any native PD-L1 of any vertebrate origin, including mammals, such as primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats) ).
  • the term encompasses "full length", unprocessed PD-L1 as well as any form of PD-L1 produced by cellular processing.
  • PD-L1 can exist as a transmembrane protein or as a soluble protein.
  • "PD-L1" includes intact PD-L1 and its fragments, and also includes functional variants, isoforms, species homologues, derivatives, analogs of PD-L1, and PD-L1 with at least one Epitope analogs.
  • the basic structure of PD-L1 includes four domains: extracellular Ig-like V-type domain and Ig-like C2-type domain, transmembrane domain and cytoplasmic domain.
  • Exemplary human PD-L1 amino acid sequences can be found under NCBI Accession No. NP_001254653 or UniProt Accession No. Q9NZQ7.
  • the term "inhibitor” generally refers to the ability to completely or partially prevent or reduce one or more specific biomolecules (for example, proteins (such as PD-1 or PD-L1), polypeptides, lipopolysaccharides, glycoproteins , ribonucleoprotein complexes, etc.) physiologically functional compounds/substances or compositions.
  • the reduction of the physiological function of one or more specific proteins may include the reduction of the activity of the protein itself (such as the ability to bind to other molecules, etc.) or the reduction of the existing amount of the protein itself.
  • Suitable inhibitor molecules may include antagonist antibodies or antibody fragments, fragments or derivatives of small molecules, peptides, antisense oligonucleotides, small organic molecules, and the like.
  • the inhibitor is capable of blocking activation of a cell signaling pathway.
  • the PD-1/PD-L1 inhibitor is an anti-PD-1/PD-L1 antibody or antigen-binding fragment thereof.
  • STING Stimulator of Interferon Genes
  • MITA human monocytes
  • MPYS MPYS
  • STING Stimulator of Interferon Genes
  • ER human monocytes
  • Human STING is encoded by the gene TMEM173.
  • the STING pathway can result from exogenous cyclic dinucleotides (CDNs) produced by bacterial infection or structurally distinct endogenous CDNs, such as those produced by cyclic GMP-AMP synthase (cGAS) in response to sensing cytoplasmic dinucleotides.
  • CDNs exogenous cyclic dinucleotides
  • cGAS cyclic GMP-AMP synthase
  • Circular GMP-AMP (cGAMP)) produced by stranded DNA (dsDNA) is activated (Ablasser et al., 2013; Diner et al., 2013).
  • the cytoplasmic domain of STING forms dimers, and the CDN binds at the dimer interface (Burdette, D.L. et al., 2011).
  • the cytoplasmic tail of STING acts as an adapter for TBK-1 and IRF-3, causing their phosphorylation.
  • Phosphorylated IRF-3 enters the nucleus to induce transcription of genes encoding type I IFNs and cytokines for promoting intercellular host immune defense (Keating et al., 2011).
  • Activation of STING can lead to the production of type I interferons (such as IFN- ⁇ and IFN- ⁇ ) through the IRF3 (interferon regulatory factor 3) pathway and through the oncogenic transcription factor NF- ⁇ B (activated B-cell nuclear factor ⁇ -light chain enhancer) pathway leads to the production of proinflammatory cytokines (IL-1 ⁇ , IL-1 ⁇ , IL-2, IL-6, TNF- ⁇ , etc.).
  • the STING pathway can regulate the innate immune recognition of immunogenic tumors and promote the antitumor effects of interferons.
  • IFN- ⁇ plays an anti-tumor effect through TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in vivo and promotes tumor cell apoptosis.
  • TRAIL tumor necrosis factor-related apoptosis-inducing ligand
  • STING pathway agonist generally refers to binding to STING (stimulator of interferon genes, or TMEM173), activating STING, and triggering activation of the IRF3-TBK1 pathway, resulting in type I interferon and other gene Molecules with increased transcription.
  • cyclic dinucleotide generally refers to a class of dinucleotides having two phosphodiester bonds or two phosphorothioate diester bonds or one phosphodiester bond between two nucleosides.
  • Exemplary cyclic dinucleotides include, but are not limited to, 3'-5'c-di-AMP (c-di-AMP), 3'-5'c-di-GMP (c-di-GMP), c -di-GMP-F, 3',3'cGAMP (also known as 3'-5',3'-5'cGAMP, a product of the Vibrio cholerae DncV protein), 3',3'-cGAMP-F , 2',3'-cGAMP (also known as 2'-5',3'-5'cGAMP, which is the product of human cGAS protein), Rp/Sp(CL656), ADU-S100, ADU-S100 disodium and combinations thereof.
  • c-di-AMP 3'-5'c-di-GMP
  • c-di-GMP 3'-5'c-di-GMP
  • c -di-GMP-F 3',3'cGAMP
  • nucleoside generally refers to a glycosylamine comprising a nitrogenous base and a five-carbon sugar, wherein the nitrogenous base is bound to the five-carbon sugar by a ⁇ -glycosidic bond.
  • nucleotide generally refers to any nucleoside attached to a phosphate group at position 5', 3' or 2' of the sugar moiety.
  • antibody is generally used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments as long as they show the desired biological activity (Miller et al (2003) Jour. of Immunology 170:4854-4861).
  • Antibodies can be murine, human, humanized, chimeric, or derived from other species.
  • a full-length antibody typically refers to an antibody consisting of two “full-length antibody heavy chains” and two “full-length antibody light chains”.
  • a “full-length antibody heavy chain” is generally a polypeptide consisting, in the N-terminal to C-terminal direction, of an antibody heavy chain variable domain (VH), an antibody constant heavy chain domain 1 (CH1), an antibody hinge region (HR) , antibody heavy chain constant domain 2 (CH2), and antibody heavy chain constant domain 3 (CH3), abbreviated as VH-CH1-HR-CH2-CH3; and in the case of antibodies of the IgE subclass, optionally It also includes the antibody heavy chain constant domain 4 (CH4).
  • VH antibody heavy chain variable domain
  • CH1 antibody constant heavy chain domain 1
  • HR antibody hinge region
  • CH2 antibody heavy chain constant domain 2
  • CH3 antibody heavy chain constant domain 3
  • a "full-length antibody heavy chain” is a polypeptide consisting of VH, CH1, HR, CH2 and CH3 in an N-terminal to C-terminal direction.
  • a “full-length antibody light chain” is generally a polypeptide consisting of an antibody light chain variable domain (VL) and an antibody light chain constant domain (CL) in the N-terminal to C-terminal direction, abbreviated as VL-CL.
  • the antibody light chain constant domain (CL) may be kappa (kappa) or lambda (lambda).
  • the two full-length antibody chains are linked together by an inter-polypeptide disulfide bond between the CL domain and the CH1 domain and between the hinge region of the full-length antibody heavy chain.
  • Typical examples of full-length antibodies are natural antibodies such as IgG (eg, IgGl and IgG2), IgM, IgA, IgD, and IgE).
  • an antigen binding domain generally refers to a portion of an antibody molecule comprising the amino acids responsible for the specific binding between the antibody and the antigen.
  • the portion of an antigen that is specifically recognized and bound by an antibody is referred to as an "epitope" as described above.
  • An antigen binding domain can typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it need not comprise both.
  • Fd fragments for example, have two VH regions and typically retain some antigen-binding function of the full antigen-binding domain.
  • antigen-binding fragments of antibodies include (1) Fab fragments, monovalent fragments having VL, VH, constant light chain (CL) and CH1 domains; (2) F(ab') 2 fragments, having two Bivalent fragment of two Fab fragments connected by sulfur bridge; (3) Fd fragment with two VH and CH1 domains; (4) Fv fragment with VL and VH domains of antibody single arm, (5) dAb fragment (Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli," Nature 341:544-546 (1989), which is hereby incorporated by reference in its entirety), which has a VH domain; (6) Isolated Complementarity Determining Regions (CDRs); (7) Single-chain Fv (scFv), for example derived from a scFv-library.
  • Fab fragments monovalent fragments having VL, VH, constant light chain (CL) and CH1 domains
  • the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows it to be produced as a single protein in which the VL and VH regions pair to form a monovalent molecule chain (termed single-chain Fv (scFv)) (see, e.g., Huston et al., "Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli," Proc.
  • scFv single-chain Fv
  • VHH relates to variable antigens from heavy chain antibodies of the family Camelidae (camel, dromedary, llama, alpaca, etc.) Binding domain (see Nguyen VK et al., 2000, The EMBO Journal, 19, 921-930; Muyldermans S., 2001, J Biotechnol., 74, 277-302 and review Vanlandschoot P. et al., 2011, Antiviral Research 92 , 389-407). VHHs may also be referred to as Nanobodies (Nb) and/or Single Domain Antibodies. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the function of the fragments is evaluated in the same manner as intact antibodies.
  • variable region or “variable domain” generally refers to a region in which some segments of the variable domain may have large differences in sequence between antibodies.
  • a “variable region” in a light chain may comprise the light chain variable region VL; a “variable region” in a heavy chain may comprise the heavy chain variable region VH.
  • the variable domains mediate antigen binding and determine the specificity of a particular antibody for its particular antigen.
  • the variability is not evenly distributed throughout the variable domains. It is usually concentrated in three segments called hypervariable regions (CDRs or HVRs) in the light and heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR).
  • variable domains of native heavy and light chains each comprise four FR regions, most adopting a ⁇ -sheet configuration, connected by three CDRs, which form a circular connection and in some cases form part of the ⁇ -sheet structure .
  • the CDRs in each chain are held in close proximity by the FR regions, and the CDRs from the other chain together contribute to the formation of the antibody's antigen-binding site (see Kabat et al, Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)).
  • the terms "VH" and "VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody or antigen-binding molecule thereof.
  • CDR generally refers to the complementarity determining regions within the variable sequences of antibodies.
  • CDR1, CDR2 and CDR3 are 3 CDRs in each variable region of the heavy and light chains, which are called CDR1, CDR2 and CDR3 for each variable region.
  • the precise boundaries of these CDRs have been defined differently according to different systems.
  • the system described by Kabat Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody , but also provides the precise residue limits that define these three CDRs.
  • These CDRs can be referred to as Kabat CDRs.
  • Padlan FASEB J.9:133 -139 (1995)
  • MacCallum JMoI Biol 262 (5): 732-45 (1996)
  • CDR bounds may not strictly follow one of the above-mentioned systems, but Still overlapping with the Kabat CDRs, although they could be shortened or lengthened according to the following predictions or experimental findings, specific residues or groups of residues or even the entire CDR did not significantly affect antigen binding.
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • percent (%) sequence identity generally refers to the amino acids with which two or more aligned amino acid sequences are identical compared to the number of amino acid residues that make up the total length of these amino acid sequences The number of matches ("hits") for .
  • alignment is used, for two or more sequences, when the sequences are compared and aligned for maximum correspondence (as measured using sequence comparison algorithms known in the art), or when manually aligned and visually Upon inspection, the percentage of amino acid residues that are identical (eg, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity) can be determined.
  • sequences compared to determine sequence identity can be distinguished by one or more amino acid substitutions, additions or deletions.
  • Suitable programs for aligning protein sequences are known to those skilled in the art.
  • the percent sequence identity of protein sequences can be determined, for example, with programs such as CLUSTALW, Clustal Omega, FASTA or BLAST, for example using the NCBI BLAST algorithm (AltschulSF et al. (1997), Nucleic Acids Res. 25:3389-3402) .
  • the term “combination”, “therapeutic combination”, “combination therapy” or “drug combination” generally refers to a combination comprising at least two active ingredients/therapeutic agents, wherein STING pathway agonist and PD-1/
  • the PD-L1 inhibitors can be administered independently at the same time or separately within a time interval such that the combination partner exhibits a synergistic (eg, synergistic) effect.
  • each active ingredient/therapeutic agent can be prepared as a separate formulation (solid, liquid, gel, etc.), and in some embodiments, each active ingredient/therapeutic agent can be present in a different container, It can also be formulated into a desired preparation with a suitable carrier simultaneously or separately when needed; in some embodiments, each active ingredient/therapeutic agent can be from different sources (such as prepared, produced or sold by different merchants); in some In an embodiment, each active ingredient/therapeutic agent may be mixed to form a pharmaceutical composition.
  • compositions generally refers to a preparation that is in a form that permits the biological activity of the active ingredient to be effective and that does not contain additional substances that are unacceptably toxic to the subject to which the composition is to be administered.
  • Such compositions may be sterile, and may contain a pharmaceutically acceptable carrier, such as physiological saline.
  • Suitable pharmaceutical compositions may comprise one or more buffers (e.g. acetate, phosphate or citrate buffers), surfactants (e.g. polysorbates), stabilizers (e.g. human albumin), preservatives, agents (such as benzyl alcohol), absorption enhancers for enhanced bioavailability, and/or other conventional solubilizing or dispersing agents.
  • buffers e.g. acetate, phosphate or citrate buffers
  • surfactants e.g. polysorbates
  • stabilizers e.g. human albumin
  • preservatives agents (such as benzyl alcohol), absorption enhancers for enhanced bioavailability,
  • the term "pharmaceutically acceptable carrier” generally refers to one or more non-toxic materials that do not interfere with the effectiveness of the biological activity of the active ingredient.
  • Such formulations may conventionally contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents.
  • Such pharmaceutically acceptable formulations may also contain compatible solid or liquid fillers, diluents or encapsulating substances suitable for human administration.
  • Other contemplated carriers, excipients, and/or additives that may be used in the formulations described herein may include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids , protein excipients (such as serum albumin, gelatin, casein), salt-forming counterions (such as sodium), etc.
  • Neoplastic generally refers to cells undergoing new and abnormal proliferation, especially a disease in which proliferation is uncontrolled and progresses, resulting in a neoplasm.
  • Neoplastic cells can be malignant, ie invasive and metastatic, or benign.
  • neoplastic generally refers to an abnormal mass of tissue in which the growth of the mass exceeds that of normal tissue and is not coordinated with the growth of normal tissue.
  • a “neoplastic” can be defined as “benign” or “malignant”, depending on the following characteristics: degree of cellular differentiation, including morphology and function, rate of growth, local invasion and metastasis.
  • benign neoplasms are generally well differentiated, have characteristically slower growth than malignant neoplasms, and remain localized to the site of origin. Furthermore, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites.
  • Malignant neoplasms are usually poorly differentiated (regressive), with characteristic rapid growth with progressive infiltration, invasion, and destruction of surrounding tissue. In addition, malignant neoplasms have the ability to metastasize to distant sites.
  • tumor or cancer
  • cancer generally refers to any medical condition characterized by the growth, proliferation or metastasis of neoplastic or malignant cells, and the tumor may be a solid tumor or a non-solid tumor.
  • wart generally refers to a type of superficial benign skin neoplasms caused by human papilloma virus (HPV), mainly caused by cell proliferation.
  • HPV belongs to the A genus of Papovaviridae in the DNA virus.
  • the term "administer" and similar terms are generally not limited to bodily administration, suitable methods include in vitro, ex vivo or in vivo methods.
  • suitable methods include in vitro, ex vivo or in vivo methods.
  • any method of administration known to those skilled in the art for contacting cells, organs or tissues with the composition may be employed.
  • the compounds may be introduced into the body of a subject in need of treatment by any route of introduction or delivery.
  • the compositions of the present application may be administered orally, topically, intranasally, intramuscularly, subcutaneously, intradermally, intrathecally, intraperitoneally, transdermally, or intratumorally.
  • the term “effective amount” or “effective dose” generally refers to an amount sufficient to achieve, or at least partially achieve, the desired effect.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is typically one that, when used alone or in combination with another therapeutic agent, promotes regression of disease (by reducing the severity of disease symptoms, frequency of asymptomatic periods of disease), any amount of drug that is evidenced by an increase in the degree and duration of the disease, or by the prevention of impairment or disability due to the presence of a disease.
  • the term “treating” generally refers to slowing or ameliorating the progression, severity, and and/or duration, or amelioration of one or more symptoms (eg, one or more identifiable symptoms) of a proliferative disorder.
  • the term “treating” may also refer to the improvement of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, not necessarily discernible by the patient.
  • the term “treating” in this application may also refer to inhibiting the progression of a proliferative disorder physically, eg, by stabilizing discernible symptoms, physiologically, eg, by stabilizing physical parameters, or both. In certain instances, the term “treating” may refer to reducing or stabilizing tumor size or cancer cell count.
  • the term “synergy” generally means that the combined effect of two or more active drugs is greater than the sum of each active drug alone.
  • the combination of two or more drugs results in “synergistic inhibition” of an activity or process, such as tumor growth, it means that the inhibition of that activity or process is greater than the sum of the inhibitory effects of the individual active drugs.
  • the calculation of the synergistic effect of the drug combination can be evaluated using the coefficient of drug interaction CDI/CI.
  • CDI the nature of the action of the two drugs is synergistic
  • CDI>1 the nature of the action of the two drugs is antagonistic.
  • subject generally refers to human or non-human animals, including but not limited to cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats or monkeys.
  • the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as about 0.5%, about 1%, about 1.5%, about 2% above or below the specified value , about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10%.
  • This application provides an agonist that induces the expression of INF and cytokines, activates the innate immune system response, and is used as a drug combination with an immune checkpoint inhibitor, including STING agonists (such as cyclic dinucleotides 2'3' -cGAMP and its derivatives) and immune checkpoint inhibitors (PD-1/PD-L1), among others.
  • STING agonists such as cyclic dinucleotides 2'3' -cGAMP and its derivatives
  • PD-1/PD-L1 immune checkpoint inhibitors
  • the present application provides a pharmaceutical combination, which may comprise a programmed cell death protein 1 (PD-1) inhibitor and/or a programmed death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist.
  • a pharmaceutical combination which may comprise a programmed cell death protein 1 (PD-1) inhibitor and/or a programmed death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist.
  • the STING pathway agonist comprises a cyclic dinucleotide.
  • cyclic dinucleotide is selected from c-di-AMP, c-di-GMP, c-di-GMP-F, 3', 3' cGAMP, 3', 3' - cGAMP-F, 2',3'-cGAMP, Rp/Sp (CL656), ADU-S100, ADU-S100 disodium, derivatives thereof and combinations thereof.
  • the STING pathway agonist comprises 2'3'-cGAMP or a derivative thereof.
  • the STING pathway agonist comprises a flavonoid.
  • the flavonoids include CMA, DMXAA, methoxyketone, 6,4'-dimethoxyflavone, 4'-methoxyflavone, 3',6'-dihydroxyflavone, 7,2'-dihydroxyflavone, daidzein, Formononetin, retinoid 7-methyl ether, xanthone and/or any combination thereof.
  • the STING pathway agonist comprises DNA
  • the STING pathway agonist comprises type I interferon (IFN).
  • IFN type I interferon
  • the type I interferon comprises IFN- ⁇ or IFN- ⁇ .
  • the PD-1 inhibitor has one or more of the following characteristics:
  • PD-1 Inhibit or reduce the expression of PD-1, such as the transcription or translation of PD-1;
  • Inhibiting or reducing PD-1 activity such as inhibiting or reducing the binding of PD-1 to its cognate ligand, such as PD-L1 or PD-L2;
  • the PD-1 inhibitor comprises an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the pharmaceutical combination may comprise: 1) an anti-PD-1 antibody or antigen-binding fragment thereof; and 2) a cyclic dinucleotide.
  • the anti-PD-1 antibody is selected from Pembrolizumab (Pembrolizumab), Nivolumab (Navolumab), Pidilizumab, SHR-1210 (Incyte/Jiangsu Hengrui Medicine Co., Ltd.), MEDI0680 (also known as AMP-514; Amplimmune Inc./Medimmune), BGB-A317 (BeiGene Ltd.), TSR-042 (also known as ANB011; AnaptysBio/Tesaro, Inc.), REGN2810 (Regeneron Pharmaceuticals, Inc./Sanofi - Aventis), PF-06801591 (Pfizer), RB0004, Tislelizumab, Camrelizumab, Toripalimab, Sintilimab, biosimilars thereof, bioenhancers thereof, bioequivalents thereof, and combinations thereof.
  • the drug combination may include: 1) Anti-PD-1 antibody, the anti-PD-1 antibody may be selected from Pembrolizumab (Pembrolizumab), Nivolumab (Nivolumab), Pidilizumab, SHR-1210 (Incyte /Jiangsu Hengrui Pharmaceutical Co., Ltd.), MEDI0680 (also known as AMP-514; Amplimmune Inc./Medimmune), BGB-A317 (BeiGene Ltd.), TSR-042 (also known as ANB011; AnaptysBio/Tesaro, Inc.) , REGN2810 (Regeneron Pharmaceuticals, Inc./Sanofi-Aventis), PF-06801591 (Pfizer), RB0004, biosimilars thereof, bioenhancers thereof, bioequivalents thereof, and combinations thereof; and 2) cyclic dinuclear Nucleotide, the cyclic dinucleotide can be selected from c-d
  • the anti-PD-1 antibody is RB0004.
  • RB0004 and other humanized anti-PD-1 monoclonal antibodies are disclosed in CN201610345750.1, WO2017201766A1.
  • the pharmaceutical combination comprises: 1) the anti-PD-1 antibody is RB0004 or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) STING pathway agonists include 2',3'- cGAMP or its derivatives.
  • the antibody is PD-1 and Pembrolizumab (trade name Keytruda, formerly known as Lambrolizumab (Lambrolizumab), also known as Merck 3745, MK-3475 or SCH-900475) is a combination with PD -1 binding humanized IgG4 monoclonal antibody.
  • Pembrolizumab is disclosed, for example, in Hamid, et al. (2013) New England Journal of Medicine 369(2):134-44, WO2009/114335 and US 8,354,509.
  • the pharmaceutical combination comprises: 1) the anti-PD-1 antibody is pembrolizumab or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) the STING pathway agonist includes 2',3'- cGAMP or its derivatives.
  • the anti-PD-1 antibody is Nivolumab (CAS registry number: 946414-94-4, alternative names include MDX-1106, MDX-1106-04, ONO-4538 or BMS-936558).
  • Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1.
  • Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind PD-1 are disclosed in US8,008,449 and WO2006/121168.
  • the pharmaceutical combination comprises: 1) the anti-PD-1 antibody is Nivolumab or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) STING pathway agonists include 2',3'- cGAMP or its derivatives.
  • the anti-PD-1 antibody is Pidilizumab.
  • Pidilizumab CT-011; Cure Tech
  • CT-011 Cure Tech
  • Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611.
  • Other anti-Rpd-1 antibodies are disclosed in US 8,609,089, US2010028330 and/or US20120114649.
  • Other anti-PD-1 antibodies include AMP514 (Amplimmune).
  • the pharmaceutical combination comprises: 1) the anti-PD-1 antibody is Pidilizumab or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) STING pathway agonists include 2',3'- cGAMP or its derivatives.
  • the anti-PD-1 antibody comprises at least one CDR in the antibody heavy chain variable region (VH)
  • the VH comprises the amino acid sequence shown in SEQ ID NO:8.
  • the anti-PD-1 antibody comprises VH
  • the VH comprises HCDR3
  • the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3 or the amino acid sequence shown in SEQ ID NO: 3 having at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, Amino acid sequences having about 98%, or about 99% sequence identity.
  • said VH further comprises HCDR2
  • said HCDR2 comprises or has at least about 70%, about 75% of the amino acid sequence set forth in SEQ ID NO:2 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • the VH further comprises HCDR1, wherein the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 1 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VH comprises HCDR1, HCDR2 and HCDR3, wherein said HCDR3 comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:3 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2 or has at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity
  • the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences having 91%, about 92%,
  • the C-terminal of the HFR1 is directly or indirectly linked to the N-terminal of the HCDR1, and the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 4 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2 Indirectly linked
  • the HFR2 comprises the amino acid sequence shown in SEQ ID NO:5 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:5 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VH includes a framework region HFR3
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR3 is directly or indirectly connected to the N-terminal of the HCDR3 Indirectly linked
  • the HFR3 comprises the amino acid sequence shown in SEQ ID NO:6 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:6 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO: 7 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the C-terminus of HFR1 is directly or indirectly connected to the N-terminus of the HCDR1, and the N-terminus of the HFR2 is connected to the N-terminus of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the HFR3 The C-terminal is directly or indirectly connected to the N-terminal of the HCDR3, and the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3;
  • the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 4 or with The amino acid sequence shown in SEQ ID NO: 4 has at least about 70%
  • said anti-PD-1 antibody comprises VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO:8 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about Amino acid sequences with 99% sequence identity.
  • said anti-PD-1 antibody comprises an antibody heavy chain (HC)
  • said HC comprises an amino acid sequence shown in SEQ ID NO: 9 or has at least the same amino acid sequence as shown in SEQ ID NO: 9 About 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98 %, or about 99% sequence identity of amino acid sequences.
  • the anti-PD-1 antibody comprises at least one CDR in the antibody light chain variable region (VL)
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17.
  • said anti-PD-1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 8
  • said anti-PD-1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:17.
  • the anti-PD-1 antibody comprises VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 10 or the amino acid sequence shown in SEQ ID NO: 10 having at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, Amino acid sequences having about 98%, or about 99% sequence identity.
  • said VL further comprises LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 11 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 11 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VL further comprises LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO: 12 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 12 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:10 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • said LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 11 or having at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO: 12 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 80% of the amino acid sequence shown in SEQ ID NO: 12 Amino acid
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3 or the same as SEQ ID
  • the amino acid sequence shown in NO:3 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, An amino acid sequence of about 96%, about 97%, about 98%, or about 99% sequence identity
  • the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2 or has the amino acid sequence shown in SEQ ID NO: 2
  • the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1 or has
  • the anti-PD-1 antibody can comprise VH and antibody VL
  • the VH can comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR3 can comprise the amino acid sequence shown in SEQ ID NO: 3, and the HCDR2 can comprise SEQ ID NO: 3
  • the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:1
  • the VL may comprise LCDR1, LCDR2 and LCDR3, wherein the LCDR1 may comprise SEQ ID NO:10
  • the amino acid sequence shown, the LCDR2 can include the amino acid sequence shown in SEQ ID NO: 11, and the LCDR3 can include the amino acid sequence shown in SEQ ID NO: 12.
  • the drug combination may include: 1) anti-PD-1 antibody, the anti-PD-1 antibody may include VH and antibody VL, the VH may include HCDR1, HCDR2 and HCDR3, wherein the HCDR3 may include SEQ
  • the HCDR2 can comprise the amino acid sequence shown in SEQ ID NO:2
  • the HCDR1 can comprise the amino acid sequence shown in SEQ ID NO:1
  • the VL can comprise LCDR1, LCDR2 and LCDR3, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:10
  • the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:11
  • the LCDR3 can comprise the amino acid sequence shown in SEQ ID NO:12 Amino acid sequence
  • 2) STING pathway agonist, the STING pathway agonist can be 2', 3'-cGAMP or its derivatives.
  • the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 13 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR1, and the C-terminal of the LFR2 is directly or indirectly connected to the N-terminal of the LCDR2.
  • the LFR2 comprises the amino acid sequence shown in SEQ ID NO: 14 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO: 14 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VL includes a framework region LFR3
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the N-terminal of the LCDR3 Indirectly linked
  • the LFR3 comprises the amino acid sequence shown in SEQ ID NO: 15 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO: 15
  • Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the LFR4 is directly or indirectly connected to the C-terminal of the LCDR3, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO: 16 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VL includes framework regions LFR1, LFR2, LFR3 and LFR4, the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the N-terminus of the LFR2 is connected to the LCDR1
  • the C-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR2
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminus is directly or indirectly connected to the N-terminus of the LCDR3, and the N-terminus of the LFR4 is directly or indirectly connected to the C-terminus of the LCDR3
  • the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 13 or with The amino acid sequence shown in SEQ ID NO: 13 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 9
  • the VL comprises the amino acid sequence shown in SEQ ID NO: 17 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about Amino acid sequences with 99% sequence identity.
  • said anti-PD-1 antibody comprises VH and VL
  • said VH comprises the amino acid sequence shown in SEQ ID NO:8 or has at least about 70 %, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, Or an amino acid sequence with about 99% sequence identity
  • the VL comprises the amino acid sequence shown in SEQ ID NO: 17 or has at least about 70%, about 75%, about 80% of the amino acid sequence shown in SEQ ID NO: 17 %, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity amino acid sequence.
  • the anti-PD-1 antibody may comprise VH and VL
  • the VH may comprise the amino acid sequence shown in SEQ ID NO:8
  • the VL may comprise the amino acid sequence shown in SEQ ID NO:17.
  • the drug combination may include: 1) anti-PD-1 antibody, wherein the anti-PD-1 antibody may include VH and VL, and the VH may include the amino acid sequence shown in SEQ ID NO: 8, and the Said VL may comprise the amino acid sequence shown in SEQ ID NO: 17; 2) STING pathway agonist, said STING pathway agonist may be 2', 3'-cGAMP or derivatives thereof.
  • the anti-PD-1 antibody comprises an antibody light chain (LC)
  • the LC comprises an amino acid sequence shown in SEQ ID NO: 18 or has at least the same amino acid sequence as shown in SEQ ID NO: 18 About 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98 %, or about 99% sequence identity of amino acid sequences.
  • the anti-PD-1 antibody comprises HC and LC
  • the HC comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:9 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • the LC comprises the amino acid sequence shown in SEQ ID NO: 18 or has at least about 70%, about 75%, about 80% with the amino acid sequence shown in SEQ ID NO: 18 Amino acids with about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity sequence.
  • the anti-PD-1 antibody may comprise HC and LC
  • the HC may comprise the amino acid sequence shown in SEQ ID NO:9
  • the LC may comprise the amino acid sequence shown in SEQ ID NO:18.
  • the drug combination may comprise: 1) anti-PD-1 antibody, wherein the anti-PD-1 antibody may comprise HC and LC, the HC may comprise the amino acid sequence shown in SEQ ID NO: 9, and the LC may comprise an amino acid sequence as shown in SEQ ID NO: 18; 2) STING pathway agonist, said STING pathway agonist may be 2', 3'-cGAMP or a derivative thereof.
  • the PD-L1 inhibitor has one or more of the following characteristics:
  • PD-L1 Inhibit or reduce the expression of PD-L1, such as the transcription or translation of PD-L1;
  • Inhibiting or reducing PD-L1 activity such as inhibiting or reducing the binding of PD-L1 to its cognate receptor, such as PD-1;
  • the PD-L1 inhibitor comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the pharmaceutical combination can comprise: 1) an anti-PD-L1 antibody or antigen-binding fragment thereof; and 2) a cyclic dinucleotide.
  • the anti-PD-L1 antibody is selected from Durvalumab (MEDI4736, disclosed in US2013/0034559A1), Atezolizumab (MPDL3280A, disclosed in US8,217,149), Avelumab (MSB0010718C, disclosed in US2014/0341917A1), MDX-1105, YW243.55.S70, MDPL3280A, AMP-224 (Amplimmune, GlaxoSmithKline), LY3300054 (Eli Lilly and Co.), RB0005, their biological analogs, their biological enhancers, their biological equivalents and their combination.
  • the pharmaceutical combination may comprise: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is selected from Durvalumab (MEDI4736, disclosed in US2013/0034559A1), Atezolizumab (MPDL3280A, disclosed in US8,217,149), Avelumab (MSB0010718C, disclosed in US2014/0341917A1), MDX-1105, YW243.55.S70, MDPL3280A, AMP-224, LY3300054, RB0005, their biological analogs, their biological enhancers, their biological equivalents and their combinations; and 2) a cyclic dinucleotide selected from c-di-AMP, c-di-GMP, c-di-GMP-F, 3',3'-cGAMP, 3' , 3'-cGAMP-F, 2',3'-cGAMP, Rp/Sp(CL656), ADU-S100, ADU-S100 disodium
  • the anti-PD-L1 antibody is RB0005.
  • RB0005 and other humanized anti-PD-L1 monoclonal antibodies are disclosed in CN201610340678.3, WO2017197667A1.
  • the pharmaceutical combination comprises: 1) the anti-PD-L1 antibody is RB0005 or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) the STING pathway agonist includes 2',3'- cGAMP or its derivatives.
  • the PD-L1 inhibitor is MDX-1105.
  • MDX-1105 also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.
  • the pharmaceutical combination comprises: 1) the anti-PD-L1 antibody is MDX-1105 or its biological enhancer, and its biological equivalent, and combinations thereof; and 2) STING pathway agonists include 2',3 '-cGAMP or a derivative thereof.
  • the PD-L1 inhibitor is YW243.55.S70.
  • the YW243.55.S70 antibody is an anti-PD-L1 antibody described in WO2010/077634.
  • the PD-L1 inhibitor is MDPL3280A (Genentech/Roche).
  • MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1.
  • Other human monoclonal antibodies to MDPL3280A and PD-L1 are disclosed in US Patent No. 7,943,743 and US Patent Publication No. 20120039906.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO:25.
  • the VH comprises HCDR3
  • the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21 or the amino acid sequence shown in SEQ ID NO: 21 having at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, Amino acid sequences having about 98%, or about 99% sequence identity.
  • said VH further comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 20 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • the VH further comprises HCDR1, wherein the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 19 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VH comprises HCDR1, HCDR2 and HCDR3, wherein said HCDR3 comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:21 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20 or has at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity
  • the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences having 91%, about 92%,
  • said VH can comprise HCDR1, HCDR2 and HCDR3, wherein said HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, said HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, and said HCDR1 comprises SEQ ID NO: Amino acid sequence shown in ID NO:19.
  • the C-terminal of the HFR1 is directly or indirectly connected to the N-terminal of the HCDR1, and the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 22 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2 Indirectly connected
  • the HFR2 comprises the amino acid sequence shown in SEQ ID NO:23 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:23 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VH includes a framework region HFR3
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR3 is directly or indirectly connected to the N-terminal of the HCDR3 Indirectly connected
  • the HFR3 comprises the amino acid sequence shown in SEQ ID NO:24 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:24 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO: 7 or
  • the amino acid sequence shown in SEQ ID NO: 7 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95% %, about 96%, about 97%, about 98%, or about 99% sequence identity of amino acid sequences.
  • the C-terminus of HFR1 is directly or indirectly connected to the N-terminus of the HCDR1, and the N-terminus of the HFR2 is connected to the N-terminus of the HCDR1
  • the C-terminal of the HFR2 is directly or indirectly connected to the C-terminal of the HCDR2
  • the C-terminal of the HFR2 is directly or indirectly connected to the N-terminal of the HCDR2
  • the N-terminal of the HFR3 is directly or indirectly connected to the C-terminal of the HCDR2
  • the HFR3 The C-terminal is directly or indirectly connected to the N-terminal of the HCDR3, and the N-terminal of the HFR4 is directly or indirectly connected to the C-terminal of the HCDR3;
  • the HFR1 comprises the amino acid sequence shown in SEQ ID NO: 22 or with The amino acid sequence shown in SEQ ID NO: 22 has at least about 70%
  • the VH comprises the amino acid sequence shown in SEQ ID NO: 25 or has at least about 70% of the amino acid sequence shown in SEQ ID NO: 25, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about Amino acid sequences with 99% sequence identity.
  • said anti-PD-L1 antibody comprises HC
  • said HC comprises the amino acid sequence shown in SEQ ID NO:26 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences for % sequence identity.
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 25
  • said anti-PD-L1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:37.
  • said anti-PD-L1 antibody comprises at least one CDR in VH
  • said VH comprises the amino acid sequence shown in SEQ ID NO: 25
  • said anti-PD-L1 antibody comprises at least one CDR in VL At least one CDR
  • the VL comprises the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40.
  • the anti-PD-L1 antibody comprises VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:27 or the amino acid sequence shown in SEQ ID NO:27 having at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, Amino acid sequences having about 98%, or about 99% sequence identity.
  • the anti-PD-L1 antibody comprises VL
  • the VL comprises LCDR1
  • the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:28, SEQ ID NO:29 or SEQ ID NO:30 or at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, Amino acid sequences having about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • said VL further comprises LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 31 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO: 31 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VL further comprises LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32 or has at least about 70%, about 75% of the amino acid sequence shown in SEQ ID NO:32 %, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences with sequence identity.
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:27 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • said LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31 or having at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences having 91%, about 92%, about 93%, about
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO:28 or has at least about 70% of the amino acid sequence shown in SEQ ID NO:28 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity, said LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31 or having at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity , the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences having 9
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:29 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • said LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31 or having at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity
  • the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences with 91%, about 92%, about 93%, about
  • said VL comprises LCDR1, LCDR2 and LCDR3, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO:30 or has at least about 70% of the amino acid sequence shown in SEQ ID NO:30 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity, said LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31 or having at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity , the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:32 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about Amino acid sequences having 9
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21 or the same as SEQ ID
  • the amino acid sequence shown in NO:21 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, An amino acid sequence of about 96%, about 97%, about 98%, or about 99% sequence identity
  • the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:20 or has the amino acid sequence shown in SEQ ID NO:20 At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about An amino acid sequence of 98%, or about 99% sequence identity
  • said HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19
  • the anti-PD-L1 antibody may comprise VH and antibody VL
  • the VH may comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 21, and the HCDR2 may comprise The amino acid sequence shown in SEQ ID NO:20
  • the HCDR1 can comprise the amino acid sequence shown in SEQ ID NO:19
  • the VL can comprise LCDR1, LCDR2 and LCDR3, wherein the LCDR1 can comprise SEQ ID NO:27
  • the LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:32.
  • the drug combination may include: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody may include VH and antibody VL, and the VH may include HCDR1, HCDR2 and HCDR3, wherein the HCDR3 may include
  • the amino acid sequence shown in SEQ ID NO:21 the HCDR2 can include the amino acid sequence shown in SEQ ID NO:20
  • the HCDR1 can include the amino acid sequence shown in SEQ ID NO:19
  • the VL can include LCDR1 , LCDR2 and LCDR3, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:27
  • the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 can comprise the amino acid sequence shown in SEQ ID NO:32
  • STING pathway agonists the STING pathway agonists can be 2', 3'-cGAMP or derivatives thereof.
  • the VH comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21 or the same as SEQ ID
  • the amino acid sequence shown in NO:21 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, An amino acid sequence of about 96%, about 97%, about 98%, or about 99% sequence identity
  • the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:20 or has the amino acid sequence shown in SEQ ID NO:20 At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about An amino acid sequence of 98%, or about 99% sequence identity
  • said HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19
  • the anti-PD-L1 antibody may comprise VH and antibody VL
  • the VH may comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 21, and the HCDR2 may comprise The amino acid sequence shown in SEQ ID NO:20
  • the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:19
  • the VL comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 may comprise SEQ ID NO:28
  • the LCDR2 can include the amino acid sequence shown in SEQ ID NO:31
  • the LCDR3 can include the amino acid sequence shown in SEQ ID NO:32.
  • the drug combination may comprise: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises VH and antibody VL, the VH may comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR3 may comprise SEQ
  • the HCDR2 can comprise the amino acid sequence shown in SEQ ID NO:20
  • the HCDR1 can comprise the amino acid sequence shown in SEQ ID NO:19
  • the VL can comprise LCDR1, LCDR2 and LCDR3, wherein said LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:28, SEQ ID NO:29 or SEQ ID NO:30
  • said LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:31
  • Said LCDR3 can comprise the amino acid sequence shown in SEQ ID NO:32
  • STING pathway agonist said STING pathway agonist can be 2', 3'-cGAMP or derivatives thereof.
  • the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 33 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR1, and the C-terminal of the LFR2 is directly or indirectly connected to the N-terminal of the LCDR2.
  • the LFR2 comprises the amino acid sequence shown in SEQ ID NO:34 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:34 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VL includes a framework region LFR3
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the N-terminal of the LCDR3 Indirectly linked
  • the LFR3 comprises the amino acid sequence shown in SEQ ID NO:35 or has at least about 70%, about 75%, about 80%, about 85%, about 90% of the amino acid sequence shown in SEQ ID NO:35 Amino acid sequences having %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the N-terminal of the LFR4 is directly or indirectly connected to the C-terminal of the LCDR3, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO: 36 or At least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about Amino acid sequences having 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the VL includes framework regions LFR1, LFR2, LFR3 and LFR4, the C-terminus of the LFR1 is directly or indirectly connected to the N-terminus of the LCDR1, and the N-terminus of the LFR2 is connected to the LCDR1
  • the C-terminal of the LFR2 is directly or indirectly connected to the C-terminal of the LCDR2
  • the N-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminal of the LFR3 is directly or indirectly connected to the C-terminal of the LCDR2
  • the C-terminus is directly or indirectly connected to the N-terminus of the LCDR3, and the N-terminus of the LFR4 is directly or indirectly connected to the C-terminus of the LCDR3
  • the LFR1 comprises the amino acid sequence shown in SEQ ID NO: 33 or with The amino acid sequence shown in SEQ ID NO: 33 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 9
  • the VL comprises the amino acid sequence shown in SEQ ID NO: 37 or has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about Amino acid sequences with 99% sequence identity.
  • the VL comprises the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40 or with SEQ ID NO: 38.
  • the amino acid sequence shown in SEQ ID NO:39 or SEQ ID NO:40 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93% Amino acid sequences having %, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • said VH comprises the amino acid sequence shown in SEQ ID NO:25 or has at least about 70% of the amino acid sequence shown in SEQ ID NO:25 %, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, Or an amino acid sequence with about 99% sequence identity
  • the VL comprises the amino acid sequence shown in SEQ ID NO: 37 or has at least about 70%, about 75%, about 80% of the amino acid sequence shown in SEQ ID NO: 37 %, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity amino acid sequence.
  • the anti-PD-L1 antibody may comprise VH and VL
  • the VH may comprise the amino acid sequence shown in SEQ ID NO:25
  • the VL may comprise the amino acid sequence shown in SEQ ID NO:37.
  • the drug combination may include: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody may include VH and VL, and the VH may include the amino acid sequence shown in SEQ ID NO: 25, and the Said VL may comprise the amino acid sequence shown in SEQ ID NO: 37; 2) STING pathway agonist, said STING pathway agonist may be 2', 3'-cGAMP or derivatives thereof.
  • said VH comprises the amino acid sequence shown in SEQ ID NO:25 or has at least about 70% of the amino acid sequence shown in SEQ ID NO:25 %, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, Or an amino acid sequence with about 99% sequence identity
  • the VL comprises the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40 or with SEQ ID NO:38, SEQ ID NO: 39 or the amino acid sequence shown in SEQ ID NO: 40 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, Amino acid sequences having about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity.
  • the anti-PD-L1 antibody may comprise VH and VL
  • the VH may comprise the amino acid sequence shown in SEQ ID NO:25
  • the VL may comprise SEQ ID NO:38, SEQ ID NO:39 or Amino acid sequence shown in SEQ ID NO:40.
  • the drug combination may include: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody may include VH and VL, and the VH may include the amino acid sequence shown in SEQ ID NO: 25, and the Said VL can comprise the amino acid sequence shown in SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40; 2) STING pathway agonist, said STING pathway agonist can be 2', 3'-cGAMP or its derivatives.
  • the LC comprises the amino acid sequence shown in SEQ ID NO:41 or has at least about 70%, about 70% of the amino acid sequence shown in SEQ ID NO:41 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Amino acid sequences for % sequence identity.
  • said LC comprises the amino acid sequence shown in SEQ ID NO:42, SEQ ID NO:43 or SEQ ID NO:44 or with SEQ ID NO:42 , SEQ ID NO:43 or the amino acid sequence shown in SEQ ID NO:44 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93% , about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity of amino acid sequences.
  • the anti-PD-L1 antibody comprises HC and LC
  • the HC comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:26 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • the LC comprises the amino acid sequence shown in SEQ ID NO: 41 or has at least about 70%, about 75%, about 80%, Amino acid sequences having about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity .
  • the anti-PD-L1 antibody may comprise HC and LC
  • the HC may comprise the amino acid sequence shown in SEQ ID NO:26
  • the LC may comprise the amino acid sequence shown in SEQ ID NO:41.
  • the drug combination may comprise: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody may comprise HC and LC, the HC may comprise the amino acid sequence shown in SEQ ID NO: 26, and the LC may comprise the amino acid sequence shown in SEQ ID NO: 41; 2) STING pathway agonist, said STING pathway agonist may be 2', 3'-cGAMP or derivatives thereof.
  • the anti-PD-L1 antibody comprises HC and LC
  • the HC comprises or has at least about 70% of the amino acid sequence set forth in SEQ ID NO:26 , about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or An amino acid sequence with about 99% sequence identity
  • the LC comprises the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43 or SEQ ID NO: 44 or is the same as SEQ ID NO: 42, SEQ ID NO: 43 or
  • the amino acid sequence shown in SEQ ID NO: 44 has at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95% %, about 96%, about 97%, about 98%, or about 99% sequence identity of amino acid sequences.
  • the anti-PD-L1 antibody can comprise HC and LC
  • the HC can comprise the amino acid sequence shown in SEQ ID NO:26
  • the LC can comprise SEQ ID NO:42, SEQ ID NO:43 or SEQ ID NO:43 Amino acid sequence shown in ID NO:44.
  • the drug combination may comprise: 1) anti-PD-L1 antibody, wherein the anti-PD-L1 antibody may comprise HC and LC, the HC may comprise the amino acid sequence shown in SEQ ID NO: 26, and the LC can comprise the amino acid sequence shown in SEQ ID NO:42, SEQ ID NO:43 or SEQ ID NO:44; 2) STING pathway agonist, the STING pathway agonist can be 2', 3'-cGAMP or its derivative thing.
  • the PD-1 inhibitor and/or PD-L1 inhibitor, and ii) the STING pathway agonist in the drug combination are not mixed with each other in the drug combination, That is, i) the PD-1 inhibitor and/or ii) the PD-L1 inhibitor and the STING pathway agonist are in separate dosage forms.
  • the PD-1 inhibitor and/or PD-L1 inhibitor, and ii) the STING pathway agonist in the pharmaceutical combination are in a single dosage form.
  • the pharmaceutical combination is formulated into a pharmaceutical composition (such as a compound preparation or a compound preparation).
  • the pharmaceutical composition can be injected directly into a large tumor without affecting normal (surrounding) tissue, enabling the killing of cancer cells, enabling the arrest or delay of the growth of a malignant mass (e.g., making the mass smaller or shrinking the tumor), And enabling terminal cancer patients to live with tumors (in a similar way to human patients living with parasites).
  • the drug combination When the drug combination is injected into the tumor, the drug can travel along blood vessels or lymphatic vessels to the metastases, and it will kill the metastatic cells. Injection of the drug combination into the tumor results in little trauma to the patient and can be repeated several times, eg monthly. Direct injections can also be given to both the primary tumor and secondary tumors to which the cancer has metastasized.
  • the pharmaceutical composition includes a PD-1 inhibitor or PD-L1 inhibitor, and a STING pathway agonist.
  • the pharmaceutical composition can include a PD-1 inhibitor and a STING pathway agonist.
  • the pharmaceutical composition may include an anti-PD-1 antibody or an antigen-binding fragment thereof and a cyclic dinucleotide.
  • the pharmaceutical composition can include a PD-L1 inhibitor and a STING pathway agonist.
  • the pharmaceutical composition may include an anti-PD-L1 antibody or an antigen-binding fragment thereof and a cyclic dinucleotide.
  • the STING pathway agonist is present in an amount of about 0.0001 mg/kg to about 200 mg/kg.
  • the STING pathway agonist can be present in the combinations described herein relative to the subject's body weight (ie, mg/kg).
  • the STING pathway agonist is present in an amount equal to about 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25mg/kg, 0.05mg/kg to about 10mg/kg, or 0.05mg/kg to about 5mg/kg, 0.5mg/kg to about 200mg/kg, 0.5mg/kg to about 150mg/kg, 0.5mg/kg to about 0.5m
  • the STING pathway agonist is present in an amount equal to about 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg.
  • the STING pathway agonist can be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg , 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg are present in combination.
  • the STING pathway agonist can be from about 1 mg to about 10 mg, 10 mg to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg, 200 mg to about 500 mg , 500 mg to about 1000 mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to about 1500 mg, or 1500 mg to about 2000 mg is present in the combination.
  • the STING pathway agonist can be about 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/ml, 6 mg/mL, 7 mg/mL, 8 mg/mL , 9mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, 100mg Amounts of 1/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 400 mg/mL or 500 mg/mL are present in combination.
  • the STING pathway agonist is administered at about 1 mg/mL to about 10 mg/mL, 5 mg/mL to about 10 mg/mL, 5 mg/mL to about 15 mg/mL, 10 mg/mL to about 25 mg/mL, 20 mg/mL An amount of mL to about 30 mg/mL, 25 mg/mL to about 50 mg/mL, or 50 mg/mL to about 100 mg/mL is present in combination.
  • the PD-1 inhibitor or PD-L1 inhibitor eg, anti-PD-1/PD-L1 antibody
  • the PD-1 inhibitor or PD-L1 inhibitor can be present in the combinations described herein relative to the subject's body weight (ie, mg/kg).
  • the PD-1 inhibitor or PD-L1 inhibitor is present in an amount equal to about 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg , 0.01 mg/kg to about 150 mg/kg, 0 01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg , 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg , 0.5 mg/kg to about 100 mg/kg
  • the PD-1 inhibitor or PD-L1 inhibitor is present in an amount equal to about 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg.
  • the anti-PD-1/PD-L1 antibody can be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, Amounts of 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg are present in combination.
  • the anti-PD-1/PD-L1 antibody can be about 1 mg to about 10 mg, 10 mg to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg , 200 mg to about 500 mg, 500 mg to about 1000 mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to about 1500 mg, or 1500 mg to about 2000 mg are present in combination.
  • the anti-PD-1/PD-L1 antibody can be about 0.1mg/mL, 0.5mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/ml, 6mg/mL, 7mg/mL mL, 8mg/mL, 9mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, Amounts of 90 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 400 mg/mL or 500 mg/mL are present in combination.
  • the anti-PD-1/PD-L1 antibody is administered at about 1 mg/mL to about 10 mg/mL, 5 mg/mL to about 10 mg/mL, 5 mg/mL to about 15 mg/mL, 10 mg/mL to about 25 mg /mL, 20 mg/mL to about 30 mg/mL, 25 mg/mL to about 50 mg/mL, or 50 mg/mL to about 100 mg/mL is present in combination.
  • the STING pathway agonist may be provided in an amount synergistic with the amount of the PD-1/PD-L1 inhibitor.
  • the dosage administered will of course vary with known factors such as the pharmacokinetic properties of the particular agent, and its mode and route of administration; the age, health, and weight of the recipient; the nature and extent of symptoms , the type of concurrent treatment, the frequency of treatment, and the expected effect.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the present application also provides the use of the aforementioned drug combination in the preparation of medicines for treating neoplastic diseases.
  • the neoplastic disease comprises tumor and/or wart disease.
  • the tumor includes, but is not limited to: hepatocellular carcinoma, liver metastatic cancer, advanced hepatocellular carcinoma, pancreatic cancer, adenocarcinoma, mast cell tumor or mast cell tumor, ovarian cancer, Non-small cell lung cancer, small cell lung cancer, melanoma, retinoblastoma, breast tumor, colorectal cancer, histiocytic sarcoma, brain tumor, astrocytoma, glioblastoma, neuroma, neuroblastoma , colon cancer, cervical cancer, sarcoma, prostate tumor, bladder tumor, reticuloendothelial tumor, Wilms tumor, ovarian cancer, bone cancer, osteosarcoma, kidney cancer, or cancer of the head and neck, oral cavity, larynx, or Oropharyngeal cancer, breast cancer, genitourinary tract cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma.
  • the present application also provides the aforementioned drug combination for treating neoplastic diseases.
  • the present application also provides a drug for treating neoplastic diseases, which comprises the aforementioned drug combination.
  • the present application also provides a method for treating neoplastic diseases, which comprises administering an effective amount of the aforementioned drug combination to a subject in need.
  • neoplasm located in a mammal in a location selected from:
  • Brain Brain, head, eyes, nasopharynx, mouth, tongue, neck, thyroid, gastrointestinal system, liver, pancreas, gallbladder, lungs, respiratory system, genitourinary system, kidneys, bladder, breast, lymphatic system, cardiovascular system , nervous system, skin, thoracic cavity, pleura, musculoskeletal system, abdomen, of a primary or secondary nature.
  • the neoplasm comprises tumors and/or warts.
  • administering comprises topical, intraneoplastic (eg, intratumor or intrawart) or systemic administration.
  • intraneoplastic eg, intratumor or intrawart
  • systemic administration e.g, topical, intraneoplastic (eg, intratumor or intrawart) or systemic administration.
  • intratumoral or intrawart injections the approach both allows for less trauma to the patient and allows the killing of cancer cells, but not normal cells. Injecting the drug combination directly into the malignancy also greatly reduces or eliminates many common side effects.
  • administering comprises intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection and/or intraneoplastic injection.
  • the tumor comprises:
  • Carcinoma or sarcoma of the esophagus, stomach, duodenum, small intestine, and the drug combination is injected into the tumor with a needle through the enteroscope, or through a hole made in the patient's abdominal wall during laparoscopic surgery. Injection into the tumor with a long syringe, or through a hole made in the patient's chest wall during thoracoscopic surgery;
  • cancer of the lung and the drug combination is injected with a syringe under the use of ultrasound, x-ray, CT scan or MR scan, or through a hole made in the patient's chest wall during thoracoscopic surgery; or
  • the neoplasm comprises a wart
  • the drug combination is injected through the patient's skin into the wart using a needle.
  • i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered by the same or different administration routes.
  • it comprises injecting said STING pathway agonist into the neoplasm.
  • it also includes injection or systemic infusion (eg, intravenous injection, intravenous infusion) of the PD-1 inhibitor or PD-L1 inhibitor into the neoplasm.
  • injection or systemic infusion eg, intravenous injection, intravenous infusion
  • it comprises injecting i) the PD-1 inhibitor or PD-L1 inhibitor, and ii) the STING pathway agonist of the drug combination into the neoplasm.
  • i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the pharmaceutical combination are administered simultaneously or at different times.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered before and/or after administration of the STING pathway agonist.
  • the PD-1 inhibitor or PD-L1 inhibitor in the drug combination and ii) the STING pathway agonist are administered simultaneously by intraneoplastic injection.
  • the PD-1 inhibitor or PD-L1 inhibitor in the drug combination is administered simultaneously with ii) the STING pathway agonist by intraneoplastic injection, and i) the The PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist are located in the same dosage form.
  • the PD-1 inhibitor or PD-L1 inhibitor in the drug combination is injected intravenously, and the STING pathway agonist is administered simultaneously by intratumoral injection, and the PD -1 inhibitor or PD-L1 inhibitor and the STING pathway agonist are in separate dosage forms.
  • the present application provides a kit comprising the aforementioned drug combination.
  • each component of the pharmaceutical combination in the kit may be provided in a separate individual container.
  • the components of the pharmaceutical combinations described herein may be provided in a single container.
  • the container may be a container ready to be administered to a patient in need thereof, such as an IV bag, ampoule, or syringe.
  • the STING pathway agonist in the kit is formulated for intratumoral or intrawart injection administration.
  • the PD-1/PD-L1 inhibitor can be provided, for example, in the form of a powder (eg, a lyophilized powder) or a solution for parenteral administration.
  • the PD-1/PD-L1 inhibitor can be an anti-PD-1/PD-L1 antibody as described herein formulated for administration by, for example, intravenous administration or intratumoral or intrawart injection.
  • the STING pathway agonist and PD-1/PD-L1 inhibitor are formulated as a compound preparation for intratumoral or intrawart injection.
  • kits described herein can be provided in sterile form.
  • the kit and its contents can be provided ready to be administered to a subject in need thereof.
  • the components of the kit are provided as formulations, and optionally in administration devices, such that administration requires little further action by the user.
  • administration devices such devices include those known and understood by those skilled in the art for the routes of administration described herein, such as, but not limited to, syringes, pumps, bags, cups, inhalers, drops, tube, patch, cream, or injector.
  • Kits described herein may also include instructions containing information on, for example, usage, dosage, administration, contraindications, and/or warnings regarding the use of such drugs.
  • mice C57/BL6JNifdc mice, female, weighing 17-22 g, 6-8 weeks old, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. [Experimental animal quality certificate number: SCXK (Beijing) 2016-0006] .
  • mice All mice were free to forage and drink, and were raised at room temperature (25 ⁇ 2)°C. Feed and water were all processed by autoclaving, and all experimental feeding processes were SPF grade.
  • Mouse colorectal cancer cell line MC38 mouse lung cancer Lewis tumor line LLC1, mouse melanoma cell line B16, mouse prostate cancer cell line RM-1, TRAMP-C1, mouse breast cancer cell line 4T1, NAFA, etc.
  • Tumor cell lines are selected from: mouse colorectal cancer cell lines CT26, MC38, mouse lung cancer Lewis tumor line LLC1, mouse melanoma cell line B16, mouse prostate cancer cell lines RM-1, TRAMP-C1, mouse mammary gland Cancer cell line 4T1, NAFA, etc.
  • Tumor cells were cultured and passaged, and the cells were collected in the logarithmic phase of the cells to make a cell suspension with a concentration of (1.0 ⁇ 107) per milliliter, and 0.1ml of the cell suspension was injected under the right flank of the mouse (the number of cells was 1.0 ⁇ 106 per mouse), the tumor grew to a diameter of about 5 mm in about 10 days, and the model was successfully established, and they were randomly divided into 8 groups, with 8 mice in each group.
  • Tumor weight inhibition rate [1-experimental group (G2/G3/G4) average tumor weight/negative control group G1 average tumor weight)] ⁇ 100%.
  • CDI(CI) AB/A*B.
  • AB is the ratio of the two-drug combination group to the control group.
  • the data are represented by x ⁇ s, processed by using SPSS10.0 software, and adopt one-way ANOVA (one-way ANOVA). After statistical processing, the P value of the data difference among the groups was determined, and P ⁇ 0.05 was judged as having a significant difference between the groups.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice.
  • mice After successfully establishing the subcutaneous colorectal cancer MC38 xenograft tumor model in mice, they were randomly divided into 6-8 mice in each group. Administer once every two days, and observe up to 15 days after a total of 3 administrations.
  • Figures 1-4 show that the new drug combination and each single drug can significantly inhibit tumor growth, and the anatomical tumor weight is significantly lower than that of the negative control group (P ⁇ 0.01, P ⁇ 0.001), and the efficacy of the new drug combination is better than 2', 3'-cGAMP or the PD-L1 antibody RB0005 were administered alone, indicating that the novel drug combination has greater advantages.
  • mice in the solvent control group began to appear "death" on the 9th day (when the tumor volume of a single mouse exceeded 2000mm 3 , the mouse could be considered dead in the statistical analysis of the survival rate of the mice. (It was not excluded in the analysis of the curve of tumor volume change))", during the 11th to 13th day, the survival rate of mice in the solvent control group decreased most obviously; the mice in each single drug group all appeared "death” on the 15th day , the difference between the two was not significant; in the G4 experimental group, one mouse's tumor disappeared, and one mouse almost disappeared (tumor volume ⁇ 100mm 3 ). At the end of the experiment, the survival rates of mice in each group were 0%, 37.5%, 75%, and 87.5%, respectively.
  • the tumor volume of the mice in the G1 solvent control group gradually increased over time; the tumor volume growth of the mice in the G4 test group (RB0005+2',3'-cGAMP) was significantly slowed down and the overall volume decreased.
  • the tumor weight of the mice in the G4 test group was significantly reduced, and the tumor weight inhibition rate was 73%, which was statistically significant (P ⁇ 0.001).
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of the subcutaneous xenograft tumor in mice.
  • mice After the humanized PD-1 mouse colorectal cancer MC38 subcutaneous xenograft tumor model was successfully established, they were randomly divided into 8 mice in each group and administered once every two days.
  • Figures 5 and 6 show that the new drug combination (separate dosage forms) and each single drug can inhibit tumor growth, and the anatomical tumor weight is significantly lower than that of the negative control group (P ⁇ 0.05, P ⁇ 0.001), and the new drug combination has excellent efficacy
  • Single administration of 2',3'-cGAMP or PD-1 antibody RB0004 shows that the new drug combination has greater advantages.
  • the tumor volume of the mice in the solvent control group (G1) gradually increased over time; after the mice in the single drug group (G2/G3) were treated, the tumor volume growth of the mice was slower than that of the solvent control group, and the tumor The volume is small; the tumor volume growth of the mice in the test group (G4) was significantly slowed down, and the overall volume appeared to decrease.
  • the anti-tumor effect of the drug combination composed of PD-L1 inhibitor RB0005 and different doses of STING agonist 2',3'-cGAMP was tested using the mouse colorectal cancer MC38 xenograft tumor model, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice .
  • mice After the successful establishment of the subcutaneous xenograft tumor model in mice, they were randomly divided into groups of 8 mice and administered once every two days.
  • Figure 7 shows that the three drug combinations and single drugs can inhibit tumor growth, and the inhibitory effect of the drug combination is more obvious, and the tumor weight inhibition rate is above 90% (P ⁇ 0.001).
  • the efficacy of the new drug combination is better than that of PD-L1 antibody RB0005 and 2',3'-cGAMP are used alone, indicating that the new drug combination has greater advantages.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination composed of PD-1 inhibitor RB0004 and different doses of STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumor in mice.
  • mice After the successful establishment of the subcutaneous xenograft tumor model in mice, they were randomly divided into groups of 8 mice and administered once every two days.
  • Figures 8-9 show that the three drug combinations can all inhibit tumor growth, and the tumor weight inhibition rate is above 70%. Especially in the compound 2',3'-cGAMP 0.1mpk dose group, the tumor inhibition effect is obvious and the survival rate is high (P ⁇ 0.05), the efficacy of the new drug combination is better than that of PD-1 antibody RB0004 alone, indicating that the new drug combination has greater advantages.
  • the anti-tumor effect of the combination of PD-1/PD-L1 inhibitor and STING agonist 2', 3'-cGAMP was tested by using the xenograft tumor model, that is, the inhibitory effect on the growth of subcutaneous xenograft tumor in mice.
  • mice After successful establishment of mouse colorectal cancer MC38 humanized CD274 cell subcutaneous xenograft tumor model, the mice were randomly divided into 6-8 groups, administered once every two days, and administered 3 times in total.
  • the tumor weight inhibition rates of RB0005 single-drug intraperitoneal and intratumoral (G2 ⁇ G3) administration methods were 26.8% and 19.9%; Well, the tumor weight inhibition rate was 58.5%, and the tumor inhibition effect of intraperitoneal administration was not obvious. Compared with the control group, the intratumoral difference was statistically significant (P ⁇ 0.001);
  • the single dosage form (G6 ⁇ G7) of the new compound preparation was administered intraperitoneally and intratumorally.
  • the tumor reinhibition rate of intratumoral administration was 81.7%.
  • the separate dosage form (G8) of the new compound preparation also exhibited tumor inhibition, the tumor weight inhibition rate was 78.1%, and the survival rate of mice at the end point of the experiment was 100%.
  • the novel drug combination of the present application has shown good drug synergistic effects, and the intratumoral administration of a single dosage form of the compound preparation has shown significant synergy Drug effect, CDI interaction value is 0.55.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice.
  • mice After the humanized PD-1 mouse colorectal cancer MC38 subcutaneous xenograft model was successfully established, they were randomly divided into groups of 6-8 mice, administered once every two days, and administered for a total of 3 times.
  • Table 2 The average tumor mass and tumor inhibition rate of each group
  • RB0004 single drug tumor reinhibition rate was 60.8%; cGAMP single drug tumor reinhibition rate was 61.9%;
  • the single dosage form of 2',3'-cGAMP and PD-1 monoclonal antibody has obvious tumor inhibitory effect and high survival rate (P ⁇ 0.05), and the synergistic drug effect is significant, and the efficacy of the new drug combination is better than that of PD-1 Antibody RB0004 was used alone, showing that the new drug combination has greater advantages.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination composed of the marketed PD-1 ⁇ PD-L1 inhibitor and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of the subcutaneous xenograft tumor in mice.
  • mice After successful establishment of the mouse colorectal cancer MC38 subcutaneous xenograft tumor model, the mice were randomly divided into groups of 6 to 8 mice, administered once every two days, for a total of 3 times.
  • cGAMP and the already-marketed PD1 inhibitor compound preparation G4 ⁇ 6 ⁇ 8 ⁇ 10 had statistically significant differences (P ⁇ 0.001), and the tumor weight inhibition rates were 88.2%, 79.1%, 93.5%, and 77.1%, respectively .
  • the four compound preparations all showed synergistic drug effects, among which the drug synergistic effect of the compound preparations of G8 group (Sindiri) was the most significant.
  • the survival rate of G2(LPG1501) ⁇ G3(Tira) ⁇ G9(Terui) in the single drug group was above 60%; the survival rate of the compound preparation G4 ⁇ G6 ⁇ G8 ⁇ G10S was 100%, which significantly improved the survival rate .
  • the compound preparation (single dosage form) of 2',3'-cGAMP and 4 kinds of PD-1 monoclonal antibodies already on the market has obvious tumor inhibitory effect, high survival rate (P ⁇ 0.05), and shows synergistic drug effect .
  • cGAMP and the marketed PD-L1 inhibitor Durvalumab have the effect of inhibiting tumor proliferation, and the drug effect is better than that of cGAMP or PD-L1 antibody alone, and there is a statistically significant difference (P ⁇ 0.001).
  • the rate is 63.6%.
  • the survival rate of mice in the compound preparation group was above 80%, which significantly improved the survival rate.
  • the combination preparation (single dosage form) of 2',3'-cGAMP and the marketed PD-L1 monoclonal antibody has obvious tumor inhibitory effect, high survival rate (P ⁇ 0.05), and shows synergistic drug effect.
  • the tumor weight inhibition rate of cGAMP and RB0005 compound preparation was 73.1%, compared with the control group, the difference was statistically significant (p ⁇ 0.05); and the tumor weight inhibition rate of the marketed PD-L1 inhibitor Tecentriq compound preparation (G4) The rate was 62.4%, and the efficacy of the compound preparation was better than that of cGAMP or PD-L1 antibody alone.
  • the combination preparation (single dosage form) of 2',3'-cGAMP, RB0005 and the marketed PD-L1 monoclonal antibody has a significant tumor inhibitory effect and a high survival rate (P ⁇ 0.05).
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination composed of PD-L1 inhibitor RB0005 and STING agonist 2',3'-cGAMP in different tumor proliferation stages, that is, the inhibitory effect on the growth of subcutaneous xenograft tumor in mice.
  • mice After successfully establishing the MC38 subcutaneous xenograft tumor model of colorectal cancer humanized CD274 in mice, they were randomly divided into groups of 6 to 8 mice, administered once every two days, and administered for a total of 3 times.
  • the tumor volume inhibition rate of the compound preparation was 49.9%, which was significantly statistically different from that of the control group (P ⁇ 0.01);
  • the tumor volume inhibition rate of the compound preparation was 55.5%, which was statistically different from that of the control group (P ⁇ 0.05);
  • the tumor volume inhibition rate of the compound preparation was 26.4%, which was not statistically different from that of the control group (P>0.05);
  • the new compound preparation (single dosage form) has tumor inhibitory effect on both the initial stage of tumor proliferation and the stage of rapid tumor proliferation, especially in the early stage of tumor proliferation, the inhibitory effect is more significant.
  • the xenograft tumor model was used to test the growth inhibitory effect of the small molecule STING agonist 2',3'-cGAMP and the PD-L1 inhibitor RB0005 after 48 hours on the growth of the MC38 xenograft tumor model.
  • mice After the humanized PD-1 mouse colorectal cancer MC38 subcutaneous xenograft model was successfully established, they were randomly divided into groups of 6-8 mice, administered once every two days, and administered for a total of 3 times.
  • the sequential administration group (G4) had a significant inhibitory effect on tumor proliferation, and during the observation period after administration, the tumor volume continued to decrease or even disappear. Compared with the control group and the RB0005 single-drug group, the sequential administration group (G4) had a statistically significant difference (ANOVA, P ⁇ 0.001), and the tumor weight inhibition rate was 95.5%.
  • the survival rate of the mice in the sequential combined administration group was 100%, which significantly increased the survival rate of the mice compared with the control group and the RB0005 single drug group.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination composed of PD-L1 inhibitor and STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumor in mice.
  • mice After the BALBc mouse breast cancer CT26 humanized CD274 cell subcutaneous xenograft model was successfully established, they were randomly divided into groups of 6 to 8 mice, administered once every two days, and administered for a total of 3 times.
  • Table 7 The average tumor volume and tumor inhibition rate of each group
  • the tumor growth rate was slow, and the tumors in the LPG1501-1mpk composite preparation group (G4) were reduced or even disappeared.
  • the tumor volume at the end of the test had statistically significant differences ( p ⁇ 0.05);
  • the survival rate of mice on Day 11 was 0, and the survival rate of the mice in the compound preparation G3 and G4 groups was above 50%.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice.
  • mice were randomly divided into 6-8 groups, administered once every two days, and administered 3 times in total.
  • the 4T1 model has poor response to RB0005 single drug, and RB0005 single drug has no obvious tumor inhibitory effect;
  • cGAMP monotherapy can inhibit tumor proliferation to a certain extent in this model, and the tumor weight of transplanted tumors was 34%, but there was a large difference within the group, and the survival rate at the end point of the experiment was 66.7%;
  • the tumor weight inhibition rate of the compound preparation was 37.5%. Compared with the control group and the RB0005 single-drug group, the difference was statistically significant (P ⁇ 0.05), and it showed a synergistic drug effect.
  • the CDI value was less than 1, and the survival rate at the experimental end point 83.3%;
  • the compound preparation (single dosage form) of 2', 3'-cGAMP and PD-L1 monoclonal antibody has a certain tumor inhibitory effect and improves the survival rate of mice, and 2', 3'-cGAMP improves the effect of RB0005 on 4T1 Model reactivity.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice.
  • mice After the humanized PD-1 mouse melanoma B16 subcutaneous xenograft model was successfully established, they were randomly divided into groups of 6 to 8 mice, administered once every two days, and administered for a total of 3 times.
  • Table 9 The average tumor volume and tumor inhibition rate of each group
  • the compound preparation (single dosage form) (G4) had a significant inhibitory effect on tumor proliferation, and the tumor proliferation was slow after administration.
  • the tumor inhibition rate was 84.9% on the 7th day.
  • the difference was statistically significant (P ⁇ 0.001).
  • the single dosage form of 2',3'-cGAMP and PD-1 monoclonal antibody has obvious tumor inhibitory effect, high survival rate (P ⁇ 0.05), and significant synergistic drug effect, and the efficacy of the new drug combination is better than that of PD-1 Antibody RB0004 was used alone, showing that the new drug combination has greater advantages.
  • the xenograft tumor model was used to test the anti-tumor effect of the drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, that is, the inhibitory effect on the growth of subcutaneous xenograft tumors in mice.
  • mice After successfully establishing the humanized PD-1 mouse lung cancer LLC-1 subcutaneous xenograft model, they were randomly divided into groups of 6 to 8 mice, administered once every two days, and administered for a total of 3 times.
  • RB0004 single drug has no obvious tumor inhibitory effect on this model;
  • cGAMP single drug has inhibitory effect on tumor, and the tumor weight inhibition rate is 47%;
  • the single dosage form of 2',3'-cGAMP and PD-1 monoclonal antibody has obvious tumor inhibitory effect, high survival rate (P ⁇ 0.05), and has synergistic drug effect, and the efficacy of the new drug combination is better than that of PD-1 Antibody RB0004 was used alone, showing that the new drug combination has greater advantages.

Abstract

一种药物组合及其应用。该药物组合包含PD-1抑制剂和/或PD-L1免疫检查点抑制剂；以及STING通路激动剂。该药物组合抗肿瘤药效比单独使用免疫检查点抑制剂或单独使用STING通路激动剂具有更好的抗肿瘤药效，实现了机体固有免疫通路激活和防止免疫逃逸双管齐下进行治疗，具有高效、低毒的临床应用前景。

Description

药物组合及其用途 技术领域
本申请涉及生物医药领域，具体的涉及一种药物组合的开发及其应用。
背景技术
过去十年来，靶向PD-1和PD-L1为癌症临床治疗开辟了新时代。然而，对于许多肿瘤类型，免疫检查点抑制剂单药效果不佳。即便对于免疫应答型肿瘤，大部分患者也没有持久的临床获益。绝大多数患者发生了原发性或后天性治疗耐药性。在多数情况下，免疫治疗耐药性可归因于免疫抑制性TME的存在和体内免疫细胞数量下降不足以激活T细胞抗肿瘤效应。因此，与单药治疗相比，积极寻求能够减少肿瘤环境中的免疫抑制或增强细胞毒性细胞对肿瘤反应的新的治疗策略尤为重要。
PD-L1/PD-1信号通路是免疫反应中非常重要的共抑制信号途径。研究表明，当PD-L1与PD-1结合后，将会通过补充具有SH2结构域的蛋白酪氨酸磷酸酶SHP-1和SHP-2。这两种磷酸酶能够使CD3ζ链的免疫受体酪氨酸活化基序(ITAM)磷酸化程度降低，削弱ZAP-70活化，并抑制TCR下游信号传递，从而起到共抑制T细胞活化的作用，通过这种负向调节效应来防止效应T细胞过度激活而导致自身免疫损伤。
干扰素基因刺激蛋白(stimulator of interferon genes,STING)是一种免疫刺激性小分子靶标，主要分布在免疫相关的组织细胞中，如在胸腺、脾及外周血白细胞中高表达。当肿瘤细胞发生坏死时，cGAMP可结合并激活内质网中的STING。STING活化导致转录因子的核转位，诱导干扰素(interferon,INF)和细胞因子的表达，促进T细胞的聚集和活化，进而杀伤肿瘤细胞。STING通路也可以被合成的环二核苷酸(CDN)所激活，从而触发固有免疫应答。
PD-L1/PD-1抑制剂与STING通路激动剂联用，一方面解除抑制性信号，增强T细胞活化，促进适应性免疫系统反应；另一方面诱导INF和细胞因子的表达，促进T细胞的聚集，激活固有免疫系统反应，双管齐下增强细胞毒性细胞对肿瘤等的反应，具有很高的临床前景及应用价值。
不仅如此，研究表明一些病毒感染也与PD-L1/PD-1信号通路息息相关。例如，在慢性HIV感染中，PD-1被发现在特异性识别HIV的CD8+T细胞表面高表达，病毒通过激活PD-L1/PD-1信号途径，使得特异性识别HIV的CD8+T细胞活性受到抑制，细胞因子的分泌能力及T细胞自身的增殖能力大大削弱，引发适应性免疫功能缺陷。由此可见，该疗法可能在这一类疾病的治疗中，同样具备相当的应用价值。
发明内容
本申请提供了一种药物组合及其在抗肿瘤药物中的应用。该药物组合主要由两部分组成：
(1)免疫检查点抑制剂(如PD-1/PD-L1)；(2)STING通路激动剂(如环状二核苷酸类cGAMP及其衍生物)。本申请的药物组合可以制备高效、低毒的抗肿瘤药物。
一方面，本申请提供一种药物组合，其包含程序性细胞死亡蛋白1(PD-1)抑制剂和/或程序性死亡配体1(PD-L1)抑制剂，以及STING通路激动剂。
在某些实施方式中，其中所述STING通路激动剂包括环状二核苷酸。
在某些实施方式中，其中所述环状二核苷酸选自c-di-AMP、c-di-GMP、c-di-GMP-F、3’,3’-cGAMP、3’,3’-cGAMP-F、2’,3’-cGAMP、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠、其衍生物及其组合。
在某些实施方式中，其中所述STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述STING通路激动剂包括类黄酮。
在某些实施方式中，其中所述类黄酮包括CMA、DMXAA、甲氧酮、6,4’-二甲氧基黄酮、4’-甲氧基黄酮、3’,6’-二羟基黄酮、7,2’-二羟基黄酮、黄豆苷元、Formononetin，视黄素7-甲基醚、吨酮和/或其任意组合。
在某些实施方式中，其中所述STING通路激动剂包括DNA。
在某些实施方式中，其中所述STING通路激动剂包括I型干扰素(IFN)。
在某些实施方式中，其中所述I型干扰素包括IFN-α或IFN-β。
在某些实施方式中，其中所述PD-1抑制剂具有以下一个或多个特征：
a.抑制或减少PD-1表达，例如PD-1的转录或翻译；
b.抑制或降低PD-1活性，例如抑制或降低PD-1与其同源配体，例如PD-L1或PD-L2的结合；和
c.结合PD-1或其一个或多个配体，例如PD-L1或PD-L2。
在某些实施方式中，其中所述PD-1抑制剂包括抗PD-1抗体或其抗原结合片段。
在某些实施方式中，其中所述抗PD-1抗体选自Pembrolizumab、Nivolumab、Pidilizumab、SHR-1210、MEDI0680、BGB-A317、TSR-042、REGN2810、PF-06801591、RB0004、Tislelizumab、Camrelizumab、Toripalimab、Sintilimab、其生物类似物、其生物增强物、其生物等效物及它们的组合。
在某些实施方式中，其中所述抗PD-1抗体包含抗体重链可变区(VH)中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH，所述VH包含HCDR3，所述HCDR3包含SEQ ID NO:3所示的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:2所示的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:1所示的氨基酸序列。
在某些实施方式中，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:4所示的氨基酸序列或与SEQ ID NO:4所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连；且所述HFR2包含SEQ ID NO:5所示的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连；且所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO:4所示的氨基酸序列或与SEQ ID NO:4所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:5所示 的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH，所述VH包含SEQ ID NO:8所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含抗体重链(HC)，所述HC包含SEQ ID NO:9所示氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含抗体轻链可变区(VL)中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列，且所述抗PD-1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:10所示的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:11所示的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中，其中抗PD-1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID  NO:13所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID NO:13所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VL，所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH以及VL，所述VH包含SEQ ID NO:8所示的氨基酸序列，且所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含抗体轻链(LC)，所述LC包含SEQ ID NO:18所示氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含HC和LC，所述HC包含SEQ ID NO:9 所示氨基酸序列，且所述LC包含如SEQ ID NO:18所示氨基酸序列。
在某些实施方式中，其中所述PD-L1抑制剂具有以下一个或多个特征：
a.抑制或减少PD-L1表达，例如PD-L1的转录或翻译；
b.抑制或降低PD-L1活性，例如抑制或降低PD-L1与其关联受体，例如PD-1的结合；和
c.结合PD-L1或其受体，例如PD-1。
在某些实施方式中，其中所述PD-L1抑制剂包括抗PD-L1抗体或其抗原结合片段。
在某些实施方式中，其中所述抗PD-L1抗体选自Durvalumab、Atezolizumab、Avelumab，Envafolimab、MDX-1105、YW243.55.S70、MDPL3280A、AMP-224、LY3300054、RB0005、其生物类似物、其生物增强物、其生物等效物及它们的组合。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH，所述VH包含HCDR3，所述HCDR3包含SEQ ID NO:21所示的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:20所示的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:19所示的氨基酸序列。
在某些实施方式中，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连；且所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相 连；且所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH，所述VH包含SEQ ID NO:25所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含HC，所述HC包含SEQ ID NO:26所示氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:27所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:31所示的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列；
所述LCDR1包含SEQ ID NO:29所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列；或
所述LCDR1包含SEQ ID NO:30所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID  NO:33所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID NO:33所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO: 25所示的氨基酸序列，且所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:41所示氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列，且所述LC包含SEQ ID NO:41所示氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列，且所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列。
在某些实施方式中，所述药物组合中的i)所述PD-1抑制剂和/或PD-L1抑制剂，与ii)所述STING通路激动剂在所述药物组合中彼此不混合。
在某些实施方式中，所述药物组合中的i)所述PD-1抑制剂和/或PD-L1抑制剂，与ii)所述STING通路激动剂位于单一的剂型中。
在某些实施方式中，其中所述药物组合被配制成药物组合物。
在某些实施方式中，其中所述药物组合物包括PD-1抑制剂或PD-L1抑制剂，以及STING通路激动剂。
在某些实施方式中，其中所述STING通路激动剂的存在量为约0.0001mg/kg至约200mg/kg。
在某些实施方式中，其中所述PD-1抑制剂或PD-L1抑制剂的存在量为0.0001mg/kg至约200mg/kg。
在某些实施方式中，其中所述药物组合物还包含一种或多种药学上可接受的载体。
另一方面，本申请还提供了前述药物组合在制备药物中的用途，所述药物用于治疗赘生性疾病。
在某些实施方式中，其中所述赘生性疾病包括肿瘤和/或疣类疾病。
另一方面，本申请还提供了前述药物组合用于治疗赘生性疾病。
另一方面，本申请还提供了一种治疗赘生性疾病的药物，其包含前述药物组合。
另一方面，本申请还提供了一种治疗赘生性疾病的方法，其包括向有需要的受试者施用有效量的前述药物组合。
在某些实施方式中，其中所述受试者患有赘生物。
在某些实施方式中，其中所述赘生物包括肿瘤和/或疣。
在某些实施方式中，其中所述施用包括局部、赘生物内(例如，肿瘤内或疣体内)或全身性施用。
在某些实施方式中，其中所述施用包括静脉注射、静脉滴注、肌肉注射、皮下注射和/或赘生物内注射。
在某些实施方式中，其中采取相同或不同的给药途径所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)STING通路激动剂。
在某些实施方式中，其包括向赘生物中注射所述STING通路激动剂。
在某些实施方式中，其还包括向赘生物中注射或全身输注所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，包括向赘生物中注射所述STING通路激动剂和全身输注所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，其包括向赘生物中注射药物组合中的i)所述PD-1抑制剂或PD-L1抑制剂STING通路激动剂，与ii)所述STING通路激动剂。
在某些实施方式中，其中同时或不同时施用所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂。
在某些实施方式中，其中在所述STING通路激动剂施用之前和/或施用之后施用所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，其中在所述STING通路激动剂施用之后施用所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，所述方法包括：i)向赘生物中注射所述STING通路激动剂；ii)在施用所述STING通路激动剂之后向赘生物中注射或全身输注所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，其中所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂同时施用。
在某些实施方式中，其中所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂通过赘生物内注射方式同时施用，且所述PD-1抑制剂或PD-L1抑制剂与所述STING通路激动剂位于同一剂型内。
另一方面，本申请提供了一种药盒，其包含前述药物组合。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示的是本申请所述PD-L1抑制剂RB0005与2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠体重变化。
图2显示的是本申请所述PD-L1抑制剂RB0005与2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠生存率变化。
图3A显示的是本申请所述PD-L1抑制剂RB0005与2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠肿瘤增殖变化。
图3B显示的是本申请所述PD-L1抑制剂RB0005与2’,3’-cGAMP药物组合体内药效研究-治疗后第17天各组小鼠肿瘤增殖变化。
图4显示的是本申请所述PD-L1抑制剂RB0005与2’,3’-cGAMP药物组合体内药效研究-给药观察结束后解剖所得小鼠瘤重抑制率。
图5显示的是本申请所述PD-1抑制剂RB0004与2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠肿瘤增殖变化。
图6显示的是本申请所述PD-1抑制剂RB0004与2’,3’-cGAMP药物组合体内药效研究-给药观察结束后解剖所得小鼠瘤重抑制率。
图7显示的是本申请所述PD-L1抑制剂RB0005与不同剂量的2’,3’-cGAMP药物组合体内药效研究-给药观察结束后解剖所得小鼠瘤重抑制率。
图8显示的是本申请所述PD-1抑制剂RB0004与不同剂量的2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠肿瘤增殖变化。
图9显示的是本申请所述PD-1抑制剂RB0004与不同剂量的2’,3’-cGAMP药物组合体内药效研究-给药期间各组小鼠生存率变化。
图10显示的是本申请实施例5中给药期间各组小鼠肿瘤增殖趋势。
图11显示的是本申请实施例5中给药期间各组小鼠生存曲线。
图12显示的是本申请实施例5中给药期间各组小鼠平均肿瘤质量。
图13显示的是本申请实施例6中给药期间各组小鼠肿瘤增殖趋势。
图14显示的是本申请实施例6中给药期间各组小鼠生存曲线。
图15显示的是本申请实施例6中给药期间各组小鼠平均肿瘤质量。
图16显示的是本申请实施例7.2.1中给药期间各组小鼠肿瘤增殖趋势。
图17显示的是本申请实施例7.2.1中给药期间各组小鼠生存曲线。
图18显示的是本申请实施例7.2.1中给药期间各组小鼠平均肿瘤质量。
图19显示的是本申请实施例7.2.2中给药期间各组小鼠肿瘤增殖趋势。
图20显示的是本申请实施例7.2.2中给药期间各组小鼠生存曲线。
图21显示的是本申请实施例7.2.2中给药期间各组小鼠平均肿瘤质量。
图22显示的是本申请实施例7.2.3中给药期间各组小鼠肿瘤增殖趋势。
图23显示的是本申请实施例7.2.3中给药期间各组小鼠生存曲线。
图24显示的是本申请实施例7.2.3中给药期间复合制剂组单只小鼠肿瘤体积变化趋势。
图25显示的是本申请实施例7.2.3中给药期间各组小鼠平均肿瘤质量。
图26显示的是本申请实施例8中给药期间各组小鼠相对肿瘤体积抑制率。
图27显示的是本申请实施例9中给药期间各组小鼠肿瘤增殖趋势。
图28显示的是本申请实施例9中给药期间各组小鼠生存曲线。
图29显示的是本申请实施例9中给药期间各组小鼠平均肿瘤质量。
图30显示的是本申请实施例10中给药期间各组小鼠肿瘤增殖趋势。
图31显示的是本申请实施例10中试验终点各组小鼠平均肿瘤体积。
图32显示的是本申请实施例10中给药期间各组小鼠生存曲线。
图33显示的是本申请实施例10中给药期间G5组单只小鼠肿瘤体积变化趋势。
图34显示的是本申请实施例11中给药期间各组小鼠肿瘤增殖趋势。
图35显示的是本申请实施例11中给药期间各组小鼠生存曲线。
图36显示的是本申请实施例11中给药期间各组小鼠平均肿瘤质量。
图37显示的是本申请实施例12中给药期间各组小鼠肿瘤增殖趋势。
图38显示的是本申请实施例12中给药期间各组小鼠生存曲线。
图39显示的是本申请实施例12中第7天各组小鼠平均肿瘤体积。
图40显示的是本申请实施例12中给药期间各组小鼠平均肿瘤质量。
图41显示的是本申请实施例13中给药期间各组小鼠肿瘤增殖趋势。
图42显示的是本申请实施例13中给药期间各组小鼠生存曲线。
图43显示的是本申请实施例13中给药期间各组小鼠平均肿瘤质量。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“PD-1”通常是指编程性细胞死亡蛋白1，是一种288个氨基酸的I型膜蛋白，首次在1992年有描述(Ishida et al.,EMBO J.,11(1992)，3887-3895)。PD-1是扩大的CD28/CTLA-4T细胞调节物家族的一个成员且具有两种配体，PD-L1(B7-H1，CD274)和PD-L2(B7-DC，CD273)。该蛋白质的结构包括一个胞外IgV域，接着是一个跨膜区和一个胞内尾。胞内尾含有位于免疫受体基于酪氨酸的抑制性基序和免疫受体基于酪氨酸的转换基序中的两个磷酸化位点，提示PD-1阴性负调节TCR信号。这与配体结合后SHP-1和SHP-2磷酸酶对PD-1的胞质尾的结合一致。虽然PD-1不在幼稚T细胞上表达，但是它在T细胞受体(TCR)介导的活化后上调且在活化的和耗尽的T细胞二者上观察到(Agata et al.,Int.Immunology8(1996),765-772)。这些耗尽的T细胞具有功能障碍性表型且不能够恰当地响应。虽然PD-1具有相对广泛的表达样式，但是它最重要的作用很可能是作为T细胞上的共抑制性受体(Chinai et al.,Trends in Pharmacological Sciences 36(2015),587-595)。当前的治疗办法因而聚焦于阻断PD-1与它的配体的相互作用以增强T细胞应答。在本申请中，所述PD-1可以包括人PD-1(hPD-1)或其变体、同种型以及物种同源物，以及与hPD-1具有至少一个共同表位的类似物。示例性的hPD-1的氨基酸序列可以在GenBank登录号U64863下找到。
在本申请中，术语“PD-L1”通常是指程序性细胞死亡1配体1，也可称为B7同源物1、B7-H1、分化簇274、(3)274或CD274，其与PD-1结合后下调T细胞活化和细胞因子分泌。“PD-L1”包括任何脊椎动物来源的任何天然PD-L1，所述任何脊椎动物来源包括哺乳动物，诸如灵长类(例如，人和食蟹猴)和啮齿类(例如，小鼠和大鼠)。所述术语涵盖“全长”、未加工的PD-L1以及由细胞加工所产生的任何形式的PD-L1。PD-L1可作为跨膜蛋白或作为可溶性蛋白存在。“PD-L1”包括完整的PD-L1及其片段，还包括PD-L1的功能性变体、同工型、物种同源物、衍生物、类似物，以及具有至少一个与PD-L1共同表位的类似物。PD-L1的基本结构包括4个结构域：胞外Ig样V型结构域和Ig样C2型结构域、跨膜结构域以及细胞 质结构域。示例性的人PD-L1氨基酸序列可在NCBI登录号NP_001254653或UniProt登录号Q9NZQ7下找到。
在本申请中，术语“抑制剂”通常指能够完全或部分地预防或降低一种或多种特定生物分子(例如，蛋白质(例如PD-1或PD-L1)、多肽、脂多糖、糖蛋白、核糖核蛋白复合体等)的生理功能的化合物/物质或组合物。所述降低一种或多种特定蛋白质的生理功能可以包含蛋白质本身活性(例如与其他分子结合的能力等)的降低或者本身存在量的降低。合适的抑制剂分子可以包括拮抗剂抗体或抗体片段、小分子的片段或衍生物、肽、反义寡核苷酸、小的有机分子等。在某些实施方式中，所述抑制剂能够阻碍细胞信号通路的激活。在某些实施方式中，所述PD-1/PD-L1抑制剂是抗PD-1/PD-L1抗体或其抗原结合片段。
在本申请中，术语“Pembrolizumab”，“Nivolumab”，“Pidilizumab”，“SHR-1210”，“MEDI0680”，“BGB-A317”，“TSR-042”，“REGN2810”、“PF-06801591”、“Durvalumab”，“Atezolizumab”，“Avelumab”，“Envafolimab”，“MDX-1105”，“YW243.55.S70”，“MDPL3280A”，“AMP-224”、“LY3300054”，“RB0004”，“RB0005”，“Tislelizumab”，“Camrelizumab”，“Toripalimab”，“Sintilimab”根据其在本领域中理解的一般和普通含义使用。
在本申请中，术语“STING(干扰素基因的刺激剂；亦称为THEM173、MITA、ERIS及MPYS)”通常是指在胸腺、脾脏、胎盘以及THP1人类单核细胞中表现的内质网(ER)跨膜蛋白。人STING由基因TMEM173编码。STING路径可以由细菌感染产生的外源性环状二核苷酸(CDN)或结构上不同的内源性CDN(诸如由环状GMP-AMP合酶(cGAS)响应于感测到胞质双股DNA(dsDNA)所产生的环状GMP-AMP(cGAMP))活化(Ablasser等人,2013；Diner等人,2013)。STING的胞质域形成二聚体，且CDN结合在二聚体界面处(Burdette,D.L.等人,2011)。在配位体结合后，STING的胞质尾部充当TBK-1及IRF-3的衔接子，从而引起其磷酸化。磷酸化的IRF-3进入核中以诱导编码I型IFN及用于促进细胞间宿主免疫防御的细胞因子的基因的转录(Keating等人,2011)。STING的激活可以通过IRF3(干扰素调节因子3)途径导致I型干扰素(例如IFN-α和IFN-β)产生并且通过致瘤性转录因子NF-κB(活化型B细胞核因子κ-轻链增强子)途径导致促炎细胞因子(IL-1α、IL-1β、IL-2、IL-6、TNF-α等)产生。STING通路可以调节免疫原性肿瘤的先天免疫识别，促进干扰素的抗肿瘤作用。IFN-γ在体内通过TRAIL(tumor necrosis factor-related apoptosis-inducing ligand)发挥抗肿瘤作用，促进肿瘤细胞凋亡。
在本申请中，术语“STING通路激动剂”通常是指与STING(干扰素基因的刺激物，或TMEM173)结合，活化STING，并且触发IRF3-TBK1途径的活化，导致I型干扰素和其他基因的转录增加的分子。
在本申请中，术语“环状二核苷酸(CDN)”通常是指一类在两个核苷之间具有两个磷酸二酯键或两个硫代磷酸酯二酯键或一个磷酸二酯键和一个硫代磷酸酯二酯键的环状分子。示例性的环状二核苷酸包括但不限于3’-5’c-di-AMP(c-di-AMP)、3’-5’c-di-GMP(c-di-GMP)、c-di-GMP-F、3’,3’cGAMP(也被称为3’-5’,3’-5’cGAMP，是霍乱弧菌DncV蛋白的产物)、3’,3’-cGAMP-F、2’,3’-cGAMP(也被称为2’-5’,3’-5’cGAMP，是人类cGAS蛋白的产物)、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠及其组合。
在本申请中，术语“核苷”通常是指包含氮碱基和五碳糖的糖基胺，其中含氮碱基通过β-糖苷键与五碳糖结合。术语“核苷酸”通常是指在糖部分的位置5’、3’或2’连接到磷酸酯基团的任何核苷。
在本申请中，术语“抗体”通常是指在最广泛的意义上加以使用并且具体地涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如，双特异性抗体)、和抗体片段，只要它们显示所期望的生物活性(Milleretal(2003)Jour.ofImmunology170:4854-4861)。抗体可以是鼠、人、人源化、嵌合抗体，或源于其它物种。
全长抗体典型地是指由两条“全长抗体重链”和两条“全长抗体轻链”组成的抗体。“全长抗体重链”通常是这样的多肽，其在N端到C端方向由抗体重链可变结构域(VH)、抗体恒定重链结构域1(CH1)，抗体铰链区(HR)，抗体重链恒定结构域2(CH2)，和抗体重链恒定结构域3(CH3)组成，缩写为VH-CH1-HR-CH2-CH3；并且在IgE亚类的抗体的情形中，任选地还包括抗体重链恒定结构域4(CH4)。在一些实施方式中，“全长抗体重链”是在N端到C端方向由VH，CH1，HR，CH2和CH3组成的多肽。“全长抗体轻链”通常是在N端到C端方向由抗体轻链可变结构域(VL)，和抗体轻链恒定结构域(CL)组成的多肽，缩写为VL-CL。所述抗体轻链恒定结构域(CL)可以是κ(kappa)或λ(lambda)。两条全长抗体链通过在CL结构域和CH1结构域之间的多肽间二硫键和全长抗体重链的铰链区之间的多肽间二硫键连接在一起。典型的全长抗体的实例是天然抗体如IgG(例如，IgG1和IgG2)，IgM，IgA，IgD，和IgE)。
在本申请中，术语“抗原结合片段”通常是指抗体分子的一部分，其包含负责抗体与抗原之间的特异性结合的氨基酸。抗原中由抗体特异性地识别和结合的部分是称作如上文所述的“表位”。抗原结合结构域可典型地包含抗体轻链可变区(VL)和抗体重链可变区(VH)；然而，其并非必须包含两者。Fd片段例如具有两个VH区并且通常保留完整抗原结合结构域的一些抗原结合功能。抗体的抗原结合片段的实例包括(1)Fab片段，具有VL、VH、恒定轻链(CL)和CH1结构域的单价片段；(2)F(ab’) 2片段，具有由铰链区的二硫桥连接的两个Fab片段的二 价片段；(3)具有两个VH和CH1结构域的Fd片段；(4)具有抗体单臂的VL和VH结构域的Fv片段，(5)dAb片段(Ward等人,“Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli,”Nature 341:544-546(1989)，其以引用的方式整体并入本申请)，其具有VH结构域；(6)分离的互补决定区(CDR)；(7)单链Fv(scFv)，例如源于scFV-文库。尽管Fv片段的两个结构域VL和VH是由独立基因编码，但其可通过合成连接子使用重组方法接合，合成连接子使得其被制备为其中VL和VH区配对以形成单价分子的单一蛋白链(称为单链Fv(scFv))(可参见例如Huston等人,“Protein Engineering of Antibody Binding Sites:Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli,”Proc.Natl.Acad.Sci.USA 85:5879-5883(1988))；和(8)VHH，“VHH”涉及来自骆驼科(骆驼、单峰骆驼、美洲驼、羊驼等)重链抗体的可变抗原结合结构域(参见Nguyen V.K.等人，2000，The EMBO Journal，19，921-930；Muyldermans S.，2001，J Biotechnol.，74，277-302以及综述Vanlandschoot P.等人，2011，Antiviral Research 92，389-407)。VHH也可称为纳米抗体(Nanobody)(Nb)和/或单域抗体。这些抗体片段使用所属领域的技术人员已知的常规技术获得，且以与完整抗体相同的方式评估所述片段的功能。
在本申请中，术语“可变区”或“可变结构域”通常指在抗体之间可变结构域的某些区段在序列上可能存在较大差异的区域。轻链中的“可变区”可以包含轻链可变区VL；重链中的“可变区”可以包含重链可变区VH。可变结构域介导抗原结合并决定特定抗体对其特定抗原的特异性。然而，可变性并非在整个可变结构域范围内均匀分布。它通常集中在轻链和重链可变结构域中称为高变区(CDR或HVR)的三个区段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区，大多数采用β-折叠构型，通过三个CDR连接，其形成环形连接，并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起，并且来自另一条链的CDR一同促进抗体的抗原结合位点的形成(参见Kabat et al,Sequences of Immunological Interest,Fifth Edition,National Institute of Health,Bethesda,Md.(1991))。术语“VH”和“VH结构域”可互换使用以指抗体或其抗原结合分子的重链可变区。
在本申请中，术语“CDR”通常是指抗体可变序列内的互补性决定区。在重链和轻链的每个可变区中存在3个CDR，对于每个可变区，其称为CDR1、CDR2和CDR3。这些CDR的精确界限已经根据不同系统进行了不同定义。Kabat描述的系统(Kabat等人，Sequences of Proteins of Immunological Interest(National Institutes ofHealth，Bethesda，Md.(1987)和(1991))不仅提供了适用于抗体的任何可变区的明确的残基编号系统，而且还提供了定义这三个CDR的 精确残基界限。这些CDR可称为Kabat CDR。Chothia及其同事(Chothia&Lesk，J.MoI.Biol.196:901-917(1987)和Chothia等人，Nature 342:877-883(1989))发现，Kabat CDR内的一些亚部分几乎采取了相同的肽骨架构象，尽管在氨基酸序列水平上具有很大差异。这些亚部分指定为L1、L2和L3，或者H1、H2和H3，其中“L”和“H”分别是指轻链和重链区域。这些区域可以称为Chothia CDR，其具有与Kabat CDR重叠的界限。Padlan(FASEB J.9:133-139(1995))和MacCallum(JMoI Biol 262(5):732-45(1996))中已经描述了定义与Kabat CDR重叠的CDR的其他界限。其他CDR界限可能没有严格遵照一个上述系统，但是仍然与Kabat CDR重叠，尽管根据以下预测或实验发现，他们可以被缩短或延长，特定残基或残基组或甚至整个CDR没有显著影响抗原结合。除非在说明书中另有明确说明，如本申请所用，术语“CDR”、“HCDR1”、“HCDR2”、“HCDR3”、“LCDR1”、“LCDR2”和“LCDR3”包括上文所述的任何方法(Kabat、Chothia或IMGT)所定义的CDR。
在本申请中，术语“百分比(％)序列同一性”通常是指两个或更多个经比对的氨基酸序列与组成这些氨基酸序列的总长度的氨基酸残基数相比而言一致的氨基酸的匹配(“命中”)数。换言之，使用比对，对于两个或更多个序列，当将这些序列针对最大对应(如使用本领域已知的序列比较算法测量的)进行比较和比对时，或者当手动比对和视觉检查时，可以确定相同的氨基酸残基的百分比(例如70％、75％、80％、85％、90％、95％、96％、97％、98％或99％序列同一性)。因此，进行比较以确定序列一致性的序列可以通过一个或多个氨基酸取代、添加或缺失来区分。用于比对蛋白序列的适合程序是本领域技术人员已知的。蛋白序列的百分比序列一致性可以例如用程序如CLUSTALW、Clustal Omega、FASTA或BLAST来确定，例如使用NCBI BLAST算法(AltschulSF等人(1997),Nucleic Acids Res.[核酸研究]25:3389-3402)。
在本申请中，术语“组合”、“治疗性组合”、“组合疗法”或“药物组合”通常是指至少包含两种活性成分/治疗剂的组合，其中STING通路激动剂和PD-1/PD-L1抑制剂可同时独立地施用或在使组合搭配物显示协作(例如协同)作用的时间间隔内单独施用。在一些实施方式中，各个活性成分/治疗剂可以各自制备成独立的制剂(固体、液体、凝胶体等)，在一些实施方式中，各个活性成分/治疗剂可以存在于不同的容器中，还可以在需要的时候同时或分别与合适的载体配制成期望的制剂；在一些实施方式中，各个活性成分/治疗剂可以是不同来源的(例如不同的商家制备生产或销售的)；在一些实施方式中，各个活性成分/治疗剂可以以混合的形式形成药物组合物。
在本申请中，术语“药物组合物”通常是指一种制剂，该制剂处于允许活性成分的生物活性有效的形式并且不含有对该组合物将要给予的受试者具有不可接受的毒性的另外的组分。 这种组合物可以是无菌的，并且可以包含药学上可接受的载体，例如生理盐水。合适的药物组合物可以包含一种或多种缓冲液(例如乙酸盐、磷酸盐或柠檬酸盐缓冲液)、表面活性剂(例如聚山梨酯)、稳定剂(例如人类白蛋白)、防腐剂(例如苯甲醇)、用于增强生物利用度的吸收促进剂、和/或其他常规的增溶剂或分散剂。本申请的药物组合物包括但不限于液体、冷冻和冻干组合物。
在本申请中，术语“药学上可接受的载体”通常是指不干扰活性成分的生物活性的有效性的一种或多种非毒性材料。这类制剂常规地可以含有盐、缓冲剂、防腐剂、相容的载体、以及任选地其他治疗剂。这类药学上可接受的制剂还可以含有适合于给予人的相容的固体或液体填料、稀释剂或包封物质。可以用于在此所描述的配制品中的其他设想的载体、赋形剂、和/或添加剂可以包括：例如，调味剂、抗微生物剂、增甜剂、抗氧化剂、抗静电剂、脂质、蛋白质赋形剂(如血清白蛋白、明胶、酪蛋白)、成盐平衡离子(如钠)等等。适合用于在此所描述的配制品中的这些和另外已知的药物载体、赋形剂和/或添加剂是本领域中已知的。
在本申请中，术语“赘生性”通常表示进行新的和非正常增殖的细胞，特别是其中增殖不受控制和进展，导致赘生物的疾病。赘生性细胞可以是恶性的，即侵袭性的和转移性的，或良性的。
在本申请中，术语“赘生物”通常是指组织的异常肿块，其中肿块的生长超过正常组织的生长，且不与正常组织的生长协调。“赘生物”可被定义为“良性”或“恶性”，其取决于以下特征：细胞分化的程度，包括形态和功能，生长的速率，局部侵袭和转移。“良性赘生物”通常是分化良好的，具有比恶性赘生物特征性更慢的生长，并且保持定位至来源部位。此外，良性肿瘤不具有渗透、侵袭或转移至远端部位的能力。“恶性赘生物”通常是低分化的(退行发育)，具有特征性快速生长，伴随周围组织的进行性渗透、侵袭和破坏。此外，恶性赘生物具有转移至远端部位的能力。
在本申请中，术语“肿瘤”或“癌症”通常是指以赘生性或恶性细胞生长、增殖或转移为特征的任何医学疾患，肿瘤可以是实体瘤或非实体瘤。
在本申请中，术语“疣”通常是指人类头瘤病毒(human papilloma Virus，HPV)引起的以细胞增生反应为主的一类皮肤浅表性良性赘生物。HPV属DNA病毒中乳多空病毒科A属，HPV分80余种亚型，与不同类型的疣有关。术语“疣(wart)”，除非另有说明，通常是指所有类型的疣，包括但不限于足底疣、普通疣、和生殖器疣。
在本申请中，术语“施用(administer)”和类似术语通常不限于身体施用，合适的方法包括体外、先体外后体内或体内方法。例如，可以采用本领域技术人员已知的用于使细胞、器官或 组织与组合物接触的任何施用方法。例如，可以通过任意引入或递送途径将所述化合物引入需要治疗的受试者的身体中。在一些实施方案中，本申请的组合物可以口服、局部、鼻内、肌内、皮下、皮内、鞘内、腹膜内、经皮或瘤内施用。
在本申请中，术语“有效量”或“有效剂量”通常是指足以实现或至少部分实现所需效果的量。药物或治疗剂的“治疗有效量”或“治疗有效剂量”通常是当单独使用或与另一种治疗剂组合使用时促进疾病消退(这通过疾病症状严重程度的降低、疾病无症状期的频度和持续时间的增加、或者由于罹患疾病而引起的损害或残疾的预防来证明)的任何药物量。
在本申请中，术语“治疗”通常是指由于施用一种或多种疗法(例如一种或多种治疗剂比如本申请的药物组合物)减慢或改善增生性病症的进展、严重程度和/或持续时间，或改善增生性病症的一种或多种症状(例如，一种或多种可辨别的症状)。在本申请中，术语“治疗”还可指改善增生性病症的至少一种可测量的物理参数比如肿瘤生长，不必是患者可辨别的。本申请中的术语“治疗”还可指通过例如稳定可辨别的症状以物理方式、通过例如稳定物理参数以生理学方式或两者抑制增生性病症的进展。在某些情形中，术语“治疗”可以指减小或稳定肿瘤尺寸或癌细胞计数。
在本申请中，术语“协同”通常是指两种或多种活性药物的联用的效力大于各活性药物单用之和。因此，当两种或多种药物的联用导致某活性或过程如肿瘤生长的“协同抑制”时，则指对该活性或过程的抑制作用大于各活性药物的抑制作用之和。在本申请中，药物组合的协同效果计算可以采用两药相互作用系数(coefficient of drugininteractionCDI/CI)评价。CDI(CI)按下列公式计算:CDI(CI)＝AB/A*B。根据解剖瘤重进行计算，AB是两药联合组与对照组的比值。A或B是各药单独使用组与对照组的比值。如CDI＜1，证明两药作用性质为协同；如CDI＝1，则两药作用性质为相加；如CDI>1，则两药作用性质为拮抗。(Pikman,Y.et al,Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia,(2017)Clin Cancer Res 23,1012-1024.PMID:28151717 PMCID:PMC5432118 DOI:10.1158/1078-0432.CCR-15-2869.)
在本申请中，术语“受试者”通常是指人类或非人类动物，包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴等。
在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下约0.5％、约1％、约1.5％、约2％、约2.5％、约3％、约3.5％、约4％、约4.5％、约5％、约5.5％、约6％、约6.5％、约7％、约7.5％、约8％、约8.5％、约9％、约9.5％、或约10％的范围内变动。
在本申请中，术语“包含”和其变形形式，包括“含有”、“包括”等其它形式，通常是指包含其它组分、元素、数值、步骤等。
发明详述
本申请提供一种诱导INF和细胞因子的表达，激活固有免疫系统反应的激动剂与免疫检查点抑制剂作为药物组合使用，包含STING类激动剂(如环状二核苷酸类2’3’-cGAMP及其衍生物)和免疫检查点抑制剂(PD-1/PD-L1)，等等。
一方面，本申请提供一种药物组合，其可以包含程序性细胞死亡蛋白1(PD-1)抑制剂和/或程序性死亡配体1(PD-L1)抑制剂，以及STING通路激动剂。
在某些实施方式中，其中所述STING通路激动剂包括环状二核苷酸。
在某些实施方式中，其中所述环状二核苷酸选自c-di-AMP、c-di-GMP、c-di-GMP-F、3’,3’cGAMP、3’,3’-cGAMP-F、2’,3’-cGAMP、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠、其衍生物及其组合。
在某些实施方式中，其中所述STING通路激动剂包括2’3’-cGAMP或其衍生物。
在某些实施方式中，其中所述STING通路激动剂包括类黄酮。
在某些实施方式中，其中所述类黄酮包括CMA、DMXAA、甲氧酮、6,4’-二甲氧基黄酮、4’-甲氧基黄酮、3’,6’-二羟基黄酮、7,2’-二羟基黄酮、黄豆苷元、Formononetin，视黄素7-甲基醚、吨酮和/或其任意组合。
在某些实施方式中，其中所述STING通路激动剂包括DNA。
在某些实施方式中，其中所述STING通路激动剂包括I型干扰素(IFN)。
在某些实施方式中，其中所述I型干扰素包括IFN-α或IFN-β。
在某些实施方式中，其中所述PD-1抑制剂具有以下一个或多个特征：
a.抑制或减少PD-1表达，例如PD-1的转录或翻译；
b.抑制或降低PD-1活性，例如抑制或降低PD-1与其同源配体，例如PD-L1或PD-L2的结合；和
c.结合PD-1或其一个或多个配体，例如PD-L1或PD-L2。
在某些实施方式中，其中所述PD-1抑制剂包括抗PD-1抗体或其抗原结合片段。
例如，所述药物组合可以包含：1)抗PD-1抗体或其抗原结合片段；和2)环状二核苷酸。
在某些实施方式中，其中所述抗PD-1抗体选自Pembrolizumab(派姆单抗)，Nivolumab(纳武单抗)，Pidilizumab，SHR-1210(Incyte/江苏恒瑞医药有限公司)，MEDI0680(也称为 AMP-514；Amplimmune Inc./Medimmune)，BGB-A317(BeiGene Ltd.)，TSR-042(也称为ANB011；AnaptysBio/Tesaro，Inc.)，REGN2810(Regeneron Pharmaceuticals，Inc./Sanofi-Aventis)、PF-06801591(Pfizer)、RB0004、Tislelizumab、Camrelizumab、Toripalimab、Sintilimab、其生物类似物、其生物增强物、其生物等效物及它们的组合。
例如，所述药物组合可以包含：1)抗PD-1抗体，所述抗PD-1抗体可以选自Pembrolizumab(派姆单抗)，Nivolumab(纳武单抗)，Pidilizumab，SHR-1210(Incyte/江苏恒瑞医药有限公司)，MEDI0680(也称为AMP-514；Amplimmune Inc./Medimmune)，BGB-A317(BeiGene Ltd.)，TSR-042(也称为ANB011；AnaptysBio/Tesaro，Inc.)，REGN2810(Regeneron Pharmaceuticals，Inc./Sanofi-Aventis)、PF-06801591(Pfizer)、RB0004、其生物类似物、其生物增强物、其生物等效物及它们的组合；和2)环状二核苷酸，所述环状二核苷酸可以选自c-di-AMP、c-di-GMP、c-di-GMP-F、3’,3’-cGAMP、3’,3’-cGAMP-F、2’,3’-cGAMP、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠及其组合。
在一些实施方案中，抗PD-1抗体是RB0004。RB0004和其它人源化抗PD-1单克隆抗体公开于CN201610345750.1，WO2017201766A1。例如，所述药物组合其包含：1)抗PD-1抗体是RB0004或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在另一些实施方式中，所述抗体是PD-1是Pembrolizumab(商品名Keytruda，以前的兰布罗珠单抗(Lambrolizumab)，也称为Merck 3745、MK-3475或SCH-900475)是与PD-1结合的人源化IgG4单克隆抗体。Pembrolizumab公开于例如Hamid，等人(2013)New England Journal of Medicine 369(2):134-44，W02009/114335和US 8,354,509。例如，所述药物组合其包含：1)抗PD-1抗体是Pembrolizumab或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在另一些实施方案中，所述抗PD-1抗体是Nivolumab(CAS登记号：946414-94-4，替代名称包括MDX-1106、MDX-1106-04、ONO-4538或BMS-936558)。Nivolumab是完全人IgG4单克隆抗体，其特异性阻断PD-1。US8,008,449和W02006/121168中公开了Nivolumab(克隆5C4)和其它特异性结合PD-1的人单克隆抗体。例如，所述药物组合其包含：1)抗PD-1抗体是Nivolumab或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在另一些实施方案中，抗PD-1抗体是Pidilizumab。Pidilizumab(CT-011；Cure Tech)是与PD-1结合的人源化IgGl单克隆抗体。Pidilizumab和其它人源化抗PD-1单克隆抗体公开于 W02009/101611中。US 8,609,089、US2010028330和/或US20120114649中公开了其它抗Rpd-1抗体。其它抗PD-1抗体包括AMP514(Amplimmune)。例如，所述药物组合其包含：1)抗PD-1抗体是Pidilizumab或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-1抗体包含抗体重链可变区(VH)中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH，所述VH包含HCDR3，所述HCDR3包含SEQ ID NO:3所示的氨基酸序列或与SEQ ID NO:3所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:2所示的氨基酸序列或与SEQ ID NO:2所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:1所示的氨基酸序列或与SEQ ID NO:1所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列或与SEQ ID NO:3所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列或与SEQ ID NO:2所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列或与SEQ ID NO:1所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:4所示的氨基酸序列或与SEQ ID  NO:4所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连；且所述HFR2包含SEQ ID NO:5所示的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连；且所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO:4所示的氨基酸序列或与SEQ ID NO:4所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:5所示的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％、约75％、约80％、 约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH，所述VH包含SEQ ID NO:8所示的氨基酸序列或与SEQ ID NO:8所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含抗体重链(HC)，所述HC包含SEQ ID NO:9所示氨基酸序列或与SEQ ID NO:9所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含抗体轻链可变区(VL)中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列，且所述抗PD-1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:10所示的氨基酸序列或与SEQ ID NO:10所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:11所示的氨基酸序列或与SEQ ID NO:11所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:12所示的氨基酸序列或与SEQ ID NO:12所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列或与SEQ ID NO:10所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列或与SEQ ID NO:11所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列或与SEQ ID NO:12所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列或与SEQ ID NO:3所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列或与SEQ ID NO:2所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列或与SEQ ID NO:1所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列或与SEQ ID NO:10所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列或与SEQ ID NO:11所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列或与SEQ ID NO:12所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，所述抗PD-1抗体可以包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2 和HCDR3，其中所述HCDR3可以包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:1所示的氨基酸序列；且所述VL可以包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:12所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-1抗体，所述抗PD-1抗体可以包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3可以包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:1所示的氨基酸序列；且所述VL可以包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:12所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID NO:13所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约 92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID NO:13所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VL，所述VL包含SEQ ID NO:17所示的氨基酸序列或与SEQ ID NO:17所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含VH以及VL，所述VH包含SEQ ID NO:8所示的氨基酸序列或与SEQ ID NO:8所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述VL包含SEQ ID NO:17所示的氨基酸序列或与SEQ ID NO:17所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-1抗体可以包含VH以及VL，所述VH可以包含SEQ ID NO:8所示的氨基酸序列，且所述VL可以包含SEQ ID NO:17所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-1抗体，其中所述抗PD-1抗体可以包含VH以及VL，所述VH可以包含SEQ ID NO:8所示的氨基酸序列，且所述VL可以包含SEQ ID NO:17所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-1抗体包含抗体轻链(LC)，所述LC包含SEQ ID NO:18所示氨基酸序列或与SEQ ID NO:18所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-1抗体包含HC和LC，所述HC包含SEQ ID NO:9所示氨基酸序列或与SEQ ID NO:9所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述LC包含如SEQ ID NO:18所示氨基酸序列或与SEQ ID NO:18所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:9所示氨基酸序列，且所述LC可以包含如SEQ ID NO:18所示氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-1抗体，其中所述抗PD-1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:9所示氨基酸序列，且所述LC可以包含如SEQ ID NO:18所示氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述PD-L1抑制剂具有以下一个或多个特征：
a.抑制或减少PD-L1表达，例如PD-L1的转录或翻译；
b.抑制或降低PD-L1活性，例如抑制或降低PD-L1与其关联受体，例如PD-1的结合；和
c.结合PD-L1或其受体，例如PD-1。
在某些实施方式中，其中所述PD-L1抑制剂包括抗PD-L1抗体或其抗原结合片段。
例如，所述药物组合可以包含：1)抗PD-L1抗体或其抗原结合片段；和2)环状二核苷 酸。
在某些实施方式中，其中所述抗PD-L1抗体选自Durvalumab(MEDI4736，公开于US2013/0034559A1)，Atezolizumab(MPDL3280A，公开于US8,217,149)，Avelumab(MSB0010718C，公开于US2014/0341917A1)，MDX-1105，YW243.55.S70，MDPL3280A，AMP-224(Amplimmune,GlaxoSmithKline)、LY3300054(Eli Lilly and Co.)、RB0005、其生物类似物、其生物增强物、其生物等效物及它们的组合。
例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体选自Durvalumab(MEDI4736，公开于US2013/0034559A1)，Atezolizumab(MPDL3280A，公开于US8,217,149)，Avelumab(MSB0010718C，公开于US2014/0341917A1)，MDX-1105，YW243.55.S70，MDPL3280A，AMP-224、LY3300054、RB0005、其生物类似物、其生物增强物、其生物等效物及它们的组合；和2)环状二核苷酸，所述环状二核苷酸选自c-di-AMP、c-di-GMP、c-di-GMP-F、3’,3’-cGAMP、3’,3’-cGAMP-F、2’,3’-cGAMP、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠及其组合。
在一些实施方案中，抗PD-L1抗体是RB0005。RB0005和其它人源化抗PD-L1单克隆抗体公开于CN201610340678.3，WO2017197667A1。例如，所述药物组合其包含：1)抗PD-L1抗体是RB0005或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在另一些实施方案中，PD-Ll抑制剂是MDX-1105。MDX-1105也称为BMS-936559，是W02007/005874中描述的抗PD-Ll抗体。例如，所述药物组合其包含：1)抗PD-L1抗体是MDX-1105或其其生物增强物，和其生物等效物、及其组合；和2)STING通路激动剂包括2’,3’-cGAMP或其衍生物。
在另一些实施方案中，PD-Ll抑制剂是YW243.55.S70。YW243.55.S70抗体是W02010/077634中描述的抗PD-L1抗体。
在另一些实施方案中，PD-Ll抑制剂是MDPL3280A(Genentech/Roche)。MDPL3280A是与PD-Ll结合的人Fc优化IgGl单克隆抗体。美国专利号7,943,743和美国专利公开号20120039906中公开了MDPL3280A和PD-L1的其它人单克隆抗体。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH，所述VH包含HCDR3，所述HCDR3包含SEQ ID NO:21所示的氨基酸序列或与SEQ ID NO:21所示的氨基酸序列具有至少约 70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:20所示的氨基酸序列或与SEQ ID NO:20所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:19所示的氨基酸序列或与SEQ ID NO:19所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列或与SEQ ID NO:21所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列或与SEQ ID NO:20所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列或与SEQ ID NO:19所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相 连；且所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连；且所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或SEQ ID NO:7所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH，所述VH包含SEQ ID NO:25所 示的氨基酸序列或与SEQ ID NO:25所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含HC，所述HC包含SEQ ID NO:26所示氨基酸序列或与SEQ ID NO:26所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:27所示的氨基酸序列或与SEQ ID NO:27所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列或与SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、 约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列或与SEQ ID NO:27所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28所示的氨基酸序列或与SEQ ID NO:28所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列；
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:29所示的氨基酸序列或与SEQ ID NO:29所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、 约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列；或
在某些实施方式中，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:30所示的氨基酸序列或与SEQ ID NO:30所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列或与SEQ ID NO:21所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列或与SEQ ID NO:20所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列或与SEQ ID NO:19所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列或与SEQ ID NO:27所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、 约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3可以包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:19所示的氨基酸序列；且所述VL可以包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:32所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体可以包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3可以包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:19所示的氨基酸序列；且所述VL可以包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:32所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列或与SEQ ID NO:21所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列或与SEQ ID NO:20所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列或与SEQ ID NO:19所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列或与SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列或与SEQ ID NO:31所示的氨基酸序列具有至少约70％、约75％、 约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列或与SEQ ID NO:32所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3可以包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:19所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:32所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH可以包含HCDR1，HCDR2和HCDR3，其中所述HCDR3可以包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2可以包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1可以包含SEQ ID NO:19所示的氨基酸序列；且所述VL可以包含LCDR1，LCDR2和LCDR3，其中所述LCDR1可以包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列，所述LCDR2可以包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3可以包含SEQ ID NO:32所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID NO:33所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID NO:33所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:37所示的氨基酸序列或与SEQ ID NO:37所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或 约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列或与SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO:25所示的氨基酸序列或与SEQ ID NO:25所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述VL包含SEQ ID NO:37所示的氨基酸序列或与SEQ ID NO:37所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含VH以及VL，所述VH可以包含SEQ ID NO:25所示的氨基酸序列，且所述VL可以包含SEQ ID NO:37所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体可以包含VH以及VL，所述VH可以包含SEQ ID NO:25所示的氨基酸序列，且所述VL可以包含SEQ ID NO:37所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO:25所示的氨基酸序列或与SEQ ID NO:25所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列或与SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含VH以及VL，所述VH可以包含SEQ ID NO:25所示的氨基酸序列，且所述VL可以包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体可以包含 VH以及VL，所述VH可以包含SEQ ID NO:25所示的氨基酸序列，且所述VL可以包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:41所示氨基酸序列或与SEQ ID NO:41所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列或与SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
在某些实施方式中，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列或与SEQ ID NO:26所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述LC包含SEQ ID NO:41所示氨基酸序列或与SEQ ID NO:41所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:26所示氨基酸序列，且所述LC可以包含SEQ ID NO:41所示氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:26所示氨基酸序列，且所述LC可以包含SEQ ID NO:41所示氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列或与SEQ ID NO:26所示的氨基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列，且所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列或与SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示的氨 基酸序列具有至少约70％、约75％、约80％、约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、或约99％序列同一性的氨基酸序列。
例如，其中所述抗PD-L1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:26所示氨基酸序列，且所述LC可以包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列。
又例如，所述药物组合可以包含：1)抗PD-L1抗体，其中所述抗PD-L1抗体可以包含HC和LC，所述HC可以包含SEQ ID NO:26所示氨基酸序列，且所述LC可以包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列；2)STING通路激动剂，所述STING通路激动剂可以是2’,3’-cGAMP或其衍生物。
在某些实施方式中，所述药物组合中的i)所述PD-1抑制剂和/或PD-L1抑制剂，与ii)所述STING通路激动剂在所述药物组合中彼此不混合，即i)所述PD-1抑制剂和/或ii)PD-L1抑制剂与STING通路激动剂位于分开的剂型中。
在某些实施方式中，所述药物组合中的i)所述PD-1抑制剂和/或PD-L1抑制剂，与ii)所述STING通路激动剂位于单一的剂型中。
在某些实施方式中，其中所述药物组合被配制成药物组合物(例如复合制剂或复方制剂)。该药物组合物可以直接注射到大肿瘤内，而不影响正常(周围)组织，使得能够杀死癌细胞，使得能够阻止或延迟恶性肿块的生长(例如，使肿块变小或使肿瘤缩小)，并且使晚期癌症患者能够与肿瘤一起生活(以与寄生虫一起生活的人患者类似的方式)。当将药物组合注射到肿瘤内时，该药物可以沿着血管或淋巴管流动至转移灶，并且它将杀死转移细胞。药物组合注射到肿瘤内导致对患者的很少创伤，并且可以例如每月重复多次。直接注射也可以同时施用于原发性肿瘤和癌症已转移到的继发性肿瘤。
在某些实施方式中，其中所述药物组合物包括PD-1抑制剂或PD-L1抑制剂，以及STING通路激动剂。
例如，所述药物组合物可以包括PD-1抑制剂和STING通路激动剂。又例如，所述药物组合物可以包括抗PD-1抗体或其抗原结合片段和环状二核苷酸。
例如，所述药物组合物可以包括PD-L1抑制剂和STING通路激动剂。又例如，所述药物组合物可以包括抗PD-L1抗体或其抗原结合片段和环状二核苷酸。
在某些实施方式中，其中所述STING通路激动剂的存在量为约0.0001mg/kg至约200mg/kg。例如，所述STING通路激动剂可以相对于受试者的体重存在于本文所述的组合中(即mg/kg)。在一些情况下，STING通路激动剂的存在量等于约0.0001mg/kg至约200mg/kg、 0.001mg/kg至约200mg/kg、0.01mg/kg至约200mg/kg、0.01mg/kg至约150mg/kg、0 01mg/kg至约100mg/kg、0.01mg/kg至约50mg/kg、0.01mg/kg至约25mg/kg、0.01mg/kg至约10mg/kg或0.01mg/kg至约5mg/kg、0.05mg/kg至约200mg/kg、0.05mg/kg至约150mg/kg、0.05mg/kg至约100mg/kg、0.05mg/kg至约50mg/kg、0.05mg/kg至约25mg/kg、0.05mg/kg至约10mg/kg或0.05mg/kg至约5mg/kg、0.5mg/kg至约200mg/kg、0.5mg/kg至约150mg/kg、0.5mg/kg至约100mg/kg、0.5mg/kg至约50mg/kg、0.5mg/kg至约25mg/kg、0.5mg/kg至约10mg/kg或0.5mg/kg至约5mg/kg。在其它情况下，STING通路激动剂的存在量等于约1mg/kg至约200mg/kg、1mg/kg至约150mg/kg、1mg/kg至约100mg/kg、1mg/kg至约50mg/kg、1mg/kg至约25mg/kg、1mg/kg至约10mg/kg或1mg/kg至约5mg/kg。
又例如，STING通路激动剂可以约1mg、5mg、10mg、15mg、20mg、25mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg的量存在于组合中。STING通路激动剂可以约1mg至约10mg、10mg至约20mg、25mg至约50mg、30mg至约60mg、40mg至约50mg、50mg至约100mg、75mg至约150mg、100mg至约200mg、200mg至约500mg、500mg至约1000mg、1000mg至约1200mg、1000mg至约1500mg、1200mg至约1500mg或1500mg至约2000mg的量存在于组合中。
又例如，STING通路激动剂可以约0.1mg/mL、0.5mg/mL、1mg/mL、2mg/mL、3mg/mL、4mg/mL、5mg/ml、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL、15mg/mL、20mg/mL、25mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、150mg/mL、200mg/mL、250mg/mL、300mg/mL、400mg/mL或500mg/mL的量存在于组合中。在一些实施例中，STING通路激动剂以约1mg/mL至约10mg/mL、5mg/mL至约10mg/mL、5mg/mL至约15mg/mL、10mg/mL至约25mg/mL、20mg/mL至约30mg/mL、25mg/mL至约50mg/mL或50mg/mL至约100mg/mL的量存在于组合中。
在某些实施方式中，其中所述PD-1抑制剂或PD-L1抑制剂(例如抗PD-1/PD-L1抗体)的存在量为约0.0001mg/kg至约200mg/kg。例如，所述PD-1抑制剂或PD-L1抑制剂可以相对于受试者的体重存在于本文所述的组合中(即mg/kg)。在一些情况下，PD-1抑制剂或PD-L1抑制剂的存在量等于约0.0001mg/kg至约200mg/kg、0.001mg/kg至约200mg/kg、0.01mg/kg至约200mg/kg、0.01mg/kg至约150mg/kg、0 01mg/kg至约100mg/kg、0.01mg/kg至约50mg/kg、0.01mg/kg至约25mg/kg、0.01mg/kg至约10mg/kg或0.01mg/kg至约5mg/kg、0.05mg/kg至 约200mg/kg、0.05mg/kg至约150mg/kg、0.05mg/kg至约100mg/kg、0.05mg/kg至约50mg/kg、0.05mg/kg至约25mg/kg、0.05mg/kg至约10mg/kg或0.05mg/kg至约5mg/kg、0.5mg/kg至约200mg/kg、0.5mg/kg至约150mg/kg、0.5mg/kg至约100mg/kg、0.5mg/kg至约50mg/kg、0.5mg/kg至约25mg/kg、0.5mg/kg至约10mg/kg或0.5mg/kg至约5mg/kg。在其它情况下，PD-1抑制剂或PD-L1抑制剂的存在量等于约1mg/kg至约200mg/kg、1mg/kg至约150mg/kg、1mg/kg至约100mg/kg、1mg/kg至约50mg/kg、1mg/kg至约25mg/kg、1mg/kg至约10mg/kg或1mg/kg至约5mg/kg。
又例如，抗PD-1/PD-L1抗体可以约1mg、5mg、10mg、15mg、20mg、25mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg的量存在于组合中。抗PD-1/PD-L1抗体可以约1mg至约10mg、10mg至约20mg、25mg至约50mg、30mg至约60mg、40mg至约50mg、50mg至约100mg、75mg至约150mg、100mg至约200mg、200mg至约500mg、500mg至约1000mg、1000mg至约1200mg、1000mg至约1500mg、1200mg至约1500mg或1500mg至约2000mg的量存在于组合中。
又例如，抗PD-1/PD-L1抗体可以约0.1mg/mL、0.5mg/mL、1mg/mL、2mg/mL、3mg/mL、4mg/mL、5mg/ml、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL、15mg/mL、20mg/mL、25mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、150mg/mL、200mg/mL、250mg/mL、300mg/mL、400mg/mL或500mg/mL的量存在于组合中。在一些实施例中，抗PD-1/PD-L1抗体以约1mg/mL至约10mg/mL、5mg/mL至约10mg/mL、5mg/mL至约15mg/mL、10mg/mL至约25mg/mL、20mg/mL至约30mg/mL、25mg/mL至约50mg/mL或50mg/mL至约100mg/mL的量存在于组合中。
在某些实施方式中，所述的STING通路激动剂可以与所述PD-1/PD-L1抑制剂的量协同的量提供。给药的剂量毫无疑问随已知的因素而变，该因素比如是特定试剂的药物动力学特性、和其给药模式和途径；受体的年龄、健康状况、和体重；症状性质和程度、并发治疗的种类、治疗频率、和预期效果。
在某些实施方式中，其中所述药物组合物还包含一种或多种药学上可接受的载体。
另一方面，本申请还提供了前述药物组合在制备药物中的用途，所述药物用于治疗赘生性疾病。
在某些实施方式中，其中所述赘生性疾病包括肿瘤和/或疣类疾病。
在某些实施方案中，所述肿瘤(或癌症)包括但不限于：肝细胞癌、肝转移性癌症、晚期肝细胞癌、胰腺癌、腺癌、肥大细胞瘤或肥大细胞肿瘤、卵巢癌、非小细胞肺癌、小细胞肺癌、黑素瘤、视网膜母细胞瘤、乳腺肿瘤、结肠直肠癌、组织细胞肉瘤、脑肿瘤、星形细胞瘤、胶质母细胞瘤、神经瘤、神经母细胞瘤、结肠癌、子宫颈癌、肉瘤、前列腺肿瘤、膀胱肿瘤、网状内皮组织肿瘤、肾母细胞瘤、卵巢癌、骨癌、骨肉瘤、肾癌、或头颈癌、口腔癌、喉癌、或口咽癌、乳腺癌、泌尿生殖道癌、肺癌、胃肠癌、表皮样癌、黑素瘤。
另一方面，本申请还提供了前述药物组合用于治疗赘生性疾病。
另一方面，本申请还提供了一种治疗赘生性疾病的药物，其包含前述药物组合。
另一方面，本申请还提供了一种治疗赘生性疾病的方法，其包括向有需要的受试者施用有效量的前述药物组合。
在某些实施方式中，其中所述受试者患有赘生物。
在某些实施方式中，其中所述赘生物位于哺乳动物中选自以下的位置中：
脑、头部、眼、鼻咽、口、舌、颈部、甲状腺、胃肠系统、肝脏、胰腺、胆囊、肺、呼吸系统、泌尿生殖系统、肾脏、膀胱、乳房、淋巴系统、心血管系统、神经系统、皮肤、胸腔、胸膜、肌肉骨骼系统、腹部，具有原发性或继发性性质。
在某些实施方式中，其中所述赘生物包括肿瘤和/或疣。
在某些实施方式中，其中所述施用包括局部、赘生物内(例如，肿瘤内或疣体内)或全身性施用。例如，采用瘤内或疣内注射，该方法既允许对患者的更少创伤，又允许杀死癌细胞，而不是正常细胞。药物组合直接注射入恶性肿瘤内也极大地降低或消除了许多常见的副作用。
在某些实施方式中，其中所述施用包括静脉注射、静脉滴注、肌肉注射、皮下注射和/或赘生物内注射。
在某些实施方式中，所述肿瘤包括：
(i)皮肤、眼、舌、口、甲状腺、乳房、子宫颈、子宫、肛门、前列腺、阴道、骨肉瘤、尿道癌、阴茎、睾丸和附睾的浅表恶性疾病，并且所述药物组合无需稀释用注射器直接注射到瘤体内；或
(ii)鼻咽的癌症，并且所述药物组合通过鼻咽镜用注射器或针注射到瘤体内；或
(iii)肝脏、肾脏和胆囊的癌症，并且所述药物组合使用注射器在超声的辅助下通过皮肤注射到瘤体内，或通过在腹腔镜手术过程中在患者的腹壁中形成的孔注射到瘤体内；或
(iv)卵巢、输卵管、胰腺、淋巴结转移或腹腔的直接腹膜侵入、腹部淋巴瘤的癌症，并 且所述药物组合通过在腹腔镜手术过程中在患者的腹壁中形成的孔，用注射器注射到瘤体内；或
(v)食道、胃、十二指肠、小肠的癌或肉瘤，并且所述药物组合通过肠镜用针注射到瘤体内，或通过在腹腔镜手术过程中在患者的腹壁中形成的孔经由长注射器注射到瘤体内，或通过在胸腔镜手术过程中在患者的胸壁中形成的孔进行注射；
(vi)大肠和直肠的癌或肉瘤，并且所述药物组合通过结肠镜检查用针注射到瘤体内，或通过在腹腔镜手术过程中在患者的腹壁中形成的孔使用注射器进行注射；或
(vii)肺和气管的癌或肉瘤，并且所述药物组合使用纤维支气管镜的针注射到瘤体内；或
(viii)肺的癌，并且所述药物组合在超声、x射线、CT扫描或MR扫描的使用下用注射器进行注射，或通过在胸腔镜手术过程中在患者的胸壁中形成的孔进行注射；或
(ix)膀胱的癌或肉瘤，并且所述药物组合通过膀胱镜用针注射到瘤体内，或通过在腹腔镜手术过程中在患者的腹壁中形成的孔进行注射；或
(x)子宫的癌或肉瘤，并且所述药物组合的可注射制剂用注射器或宫腔镜的针注射到瘤体内；或通过在腹腔镜手术过程中在患者的腹壁中形成的孔进行注射；或
(xi)鼻咽和喉的癌或肉瘤，并且所述药物组合通过喉镜用针注射到瘤体内；或
(xii)脑的癌，并且所述药物组合在X射线、CT扫描或MR扫描的使用下，在相应的颅骨中钻洞后，用注射器或纤维镜的针注射到瘤体内；或
(xiii)恶性淋巴瘤或具有转移的淋巴结，并且所述药物组合使用针通过患者的皮肤注射到瘤体内，或者通过在腹腔镜手术过程中在患者的腹壁中形成的孔、或通过在胸腔镜手术过程中在患者的胸壁中形成的孔进行注射。
在某些实施方式中，所述赘生物包括疣，并且所述药物组合使用针通过患者的皮肤注射到疣体内。
在某些实施方式中，其中采取相同或不同的给药途径施用所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)STING通路激动剂。
在某些实施方式中，其包括向赘生物中注射所述STING通路激动剂。
在某些实施方式中，其还包括向赘生物中注射或全身输注(例如静脉注射、静脉滴注)所述PD-1抑制剂或PD-L1抑制剂。
在某些实施方式中，其包括向赘生物中注射所述药物组合中的i)所述PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂。
在某些实施方式中，其中同时或不同时施用所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂。
在某些实施方式中，其中在所述STING通路激动剂施用之前和/或施用之后施用所述PD-1抑制剂或PD-L1抑制剂。
例如，在STING通路激动剂施用之前和/或施用之后至少5min，10min，20min，40min，1h，2h，4h，8h，12h，16h，1天，2天，3天，4天，5天，6天，7天或2周，施用所述PD-1/PD-L1抑制剂。
在某些实施方式中，所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂通过赘生物内注射方式同时施用。
在某些实施方式中，所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂通过赘生物内注射方式同时施用，且i)所述PD-1抑制剂或PD-L1抑制剂与ii)所述STING通路激动剂位于同一剂型内。
在某些实施方式中，其中所述药物组合中的PD-1抑制剂或PD-L1抑制剂通过静脉注射方式，且所述STING通路激动剂通过赘生物内注射方式同时施用，且所述PD-1抑制剂或PD-L1抑制剂与所述STING通路激动剂位于分开剂型内。
另一方面，本申请提供了一种药盒，其包含前述药物组合。
在某些实施方式中，所述药盒中的药物组合的每种组分可以在分离的单独容器中提供。或者，本文所述药物组合的组分可以在单个容器中提供。在此类情况下，容器可以是准备好施用至有需要的患者的容器，例如IV袋、安瓿或注射器。在一些实施例中，药盒中的STING通路激动剂被配制用于瘤内或疣内注射施用。PD-1/PD-L1抑制剂可以例如粉末(例如冻干粉末)或肠胃外施用的溶液的形式提供。在某些情况下，PD-1/PD-L1抑制剂可以是如本文所述的抗PD-1/PD-L1抗体，其配制用于通过例如静脉内施用或瘤内或疣内注射施用。在一些实施例中，所述STING通路激动剂与PD-1/PD-L1抑制剂被配置为复方制剂，且用于瘤内或疣内注射施用。
本文所述的药盒的内容物可以无菌形式提供。药盒和其内容物可以准备好向有需要的对象施用的形式提供。在此类情况下，药盒中的组分作为制剂提供，并且任选地在施用装置中提供，使得施用对于使用者几乎不需要进一步的行动。在药盒包括施用装置的情况下，此类装置包括本领域技术人员已知和理解的用于本文所述的施用途径的装置，如但不限于注射器、泵、袋、杯、吸入器、滴管、贴片、乳膏或注入器。
本文所述的药盒的还可以包含说明书，其含有关于例如用法、剂量、施用、禁忌症和/或 关于使用此类药物的警告的信息。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的药物组合和用途等，而不用于限制本申请发明的范围。
实施例
动物种属、品系、性别、体重、来源、合格证
C57/BL6JNifdc小鼠，雌性，体重17-22g，6-8周龄，SPF级，购于北京维通利华实验动物技术有限公司[实验动物质量合格证号：SCXK(京)2016-0006]。
饲养条件
所有小鼠均自由觅食和饮水，在室温(25±2)℃下饲养。饲料及水均经高压灭菌处理，全部实验饲养过程为SPF级。
肿瘤细胞株
小鼠结直肠癌细胞株MC38，小鼠肺癌Lewis瘤株LLC1，小鼠黑色素瘤细胞株B16，小鼠前列腺癌细胞株RM-1、TRAMP-C1，小鼠乳腺癌细胞株4T1、NAFA等。
皮下移植瘤模型的建立
肿瘤细胞株选自：小鼠结直肠癌细胞株CT26、MC38，小鼠肺癌Lewis瘤株LLC1，小鼠黑色素瘤细胞株B16，小鼠前列腺癌细胞株RM-1、TRAMP-C1，小鼠乳腺癌细胞株4T1、NAFA等
肿瘤细胞培养，传代，在细胞对数期收集细胞，做成浓度为(1.0×107)每毫升的细胞悬液，小鼠右侧胁肋部下注射0.1ml细胞悬液(细胞数目为1.0×106个/只)，10天左右肿瘤长至直径约5mm，模型建立成功，随机均分为8组，每组8只。
药物评价指标
小鼠体重、肿瘤体积变化趋势，小鼠生存率，解剖瘤重抑制率。
瘤重抑制率＝[1-实验组(G2/G3/G4)平均瘤重/阴性对照组G1组平均瘤重)]×100％。
药物相互作用系数：CDI(CI)＝AB/A*B。根据解剖瘤重进行计算，AB是两药联合组与对照组的比值。A或B是各药单独使用组与对照组的比值。如CDI＜1，证明两药作用性质为协同；如CDI＝1，则两药作用性质为相加；如CDI>1，则两药作用性质为拮抗。
统计分析
数据用x±s表示，利用SPSS10.0软件进行处理，采用单因素方差分析(one-way ANOVA)。经统计学处理各组间数据差异性P值大小，P<0.05判定为组间具有显著性差异。
实施例1
采用移植瘤模型测试PD-L1抑制剂RB0005与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
试验主要步骤
1.1小鼠移植瘤模型
成功建立小鼠皮下结直肠癌MC38移植瘤模型后，随机分组，每组6～8只。每两天给药1次，共计给药3次后观察至15天。
Figure PCTCN2022094047-appb-000001
1.2结果
图1-4显示，新型药物组合及各单药均可明显抑制肿瘤生长，解剖瘤重均显著低于阴性对照组(P<0.01，P<0.001)，新型药物组合药效优于2’,3’-cGAMP或PD-L1抗体RB0005单独用药，表明新型药物组合具有更大优势。
如图2所示，溶剂对照组小鼠在第9天开始出现“死亡(当单只小鼠肿瘤体积超过2000mm 3时，在小鼠生存率统计分析过程中可将该只小鼠视为死亡(肿瘤体积变化曲线分析中并未将其排除))”，在第11-13天期间，溶剂对照组小鼠生存率下降最明显；各单药组小鼠均在第15天出现“死亡”，二者相差不大；G4试验组小鼠有1只小鼠肿瘤消失、1只几乎消失(肿瘤体积<100mm 3)。实验终点时，各组小鼠生存率分别为0％、37.5％、75％、87.5％。
如图3A-3B所示，G1溶剂对照组小鼠肿瘤体积随时间逐渐增大；G4试验组(RB0005+2’,3’-cGAMP)小鼠肿瘤体积增长明显减缓且整体体积出现降低现象。
如图4所示，G4试验组小鼠肿瘤重量明显减小，瘤重抑制率为73％，统计学上具有显著性差异(P<0.001)。
实施例2
采用移植瘤模型测试PD-1抑制剂RB0004与STING类激动剂2’,3’-cGAMP组成的药物 组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
2.1小鼠移植瘤模型
成功建立人源化PD-1小鼠结直肠癌MC38皮下移植瘤模型后，随机分组，每组8只，每两天给药1次。
Figure PCTCN2022094047-appb-000002
2.2结果
图5-图6显示，新型药物组合(分开剂型)及各单药均可抑制肿瘤生长，解剖瘤重均显著低于阴性对照组(P<0.05，P<0.001)，新型药物组合药效优于2’,3’-cGAMP或PD-1抗体RB0004单独用药，表明新型药物组合具有更大优势。
如图5所示，溶剂对照组(G1)小鼠肿瘤体积随时间逐渐增大；单药组(G2/G3)小鼠经过处理后，小鼠肿瘤体积增长较溶剂对照组减慢，且肿瘤体积较小；试验组(G4)小鼠肿瘤体积增长明显减缓，整体体积出现降低现象。
如图6所示，试验组(G4)小鼠肿瘤重量明显减小，瘤重抑制率为96％，统计学上具有显著性差异(P<0.001)。
实施例3
采用小鼠结直肠癌MC38移植瘤模型测试PD-L1抑制剂RB0005与不同剂量的STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
3.1小鼠移植瘤模型
成功建立小鼠皮下移植瘤模型后，随机分组，每组8只，每两天给药1次。
Figure PCTCN2022094047-appb-000003
Figure PCTCN2022094047-appb-000004
3.2结果
图7显示，三种药物组合及单药均可抑制肿瘤生长，药物组合抑制效果更加明显，瘤重抑制率均在90％以上(P<0.001)，新型药物组合药效优于PD-L1抗体RB0005及2’,3’-cGAMP单独用药，表明新型药物组合具有更大优势。
实施例4
采用移植瘤模型测试PD-1抑制剂RB0004与不同剂量的STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
4.1小鼠移植瘤模型
成功建立小鼠皮下移植瘤模型后，随机分组，每组8只，每两天给药1次。
Figure PCTCN2022094047-appb-000005
4.2结果
图8-9显示，三种药物组合均可抑制肿瘤生长，瘤重抑制率均在70％以上，尤其是复合 2’,3’-cGAMP 0.1mpk剂量组，肿瘤抑制效果明显，且生存率高(P<0.05)，新型药物组合药效优于PD-1抗体RB0004单独用药，表明新型药物组合具有更大优势。
实施例5
采用移植瘤模型测试PD-1/PD-L1抑制剂与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
5.1小鼠移植瘤模型
成功建立小鼠结直肠癌MC38人源化CD274细胞皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
Figure PCTCN2022094047-appb-000006
5.2结果
表1各组平均肿瘤质量及肿瘤抑制率
组别 Tumor Weight(g) IR TW％ CDI(相互作用指数)
G1 4.43 -  
G2 3.24 26.8  
G3 3.55 19.9  
G4 3.48 21.5  
G5 1.84 58.5  
G6 2.40 45.9 0.94(＜1)
G7 0.81 81.7 0.55(＜1)
G8 0.97 78.1 0.72(＜1)
结果如表1和图10至图12所示：
RB0005单药腹腔和瘤内(G2\G3)给药方式瘤重抑制率为26.8％、19.9％；cGAMP单药腹腔和瘤内(G4\G5)给药方式相比，瘤内给药效果较好，瘤重抑制率为58.5％，腹腔给药肿瘤抑制作用不明显，瘤内与对照组相比，差异有统计学意义(P＜0.001)；
新型复合制剂单一剂型(G6\G7)复合制剂腹腔和瘤内给药，瘤内给药瘤重抑制率为81.7％，肿瘤抑制作用优与腹腔给药，试验终点小鼠生存率为100％。
新型复合制剂分开剂型(G8)也表现出肿瘤抑制作用，瘤重抑制率为78.1％，试验终点小鼠生存率为100％。
无论是分开的剂型或者单一剂型，无论是腹腔给药还是瘤内给药，本申请的新型的药物组合均表现了良好的药物协同效应，其中复合制剂单一剂型瘤内给药表现出显著的协同药物作用效果，CDI相互作用值为0.55。
实施例6
采用移植瘤模型测试PD-1抑制剂RB0004与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
6.1小鼠移植瘤模型
成功建立人源化PD-1小鼠结直肠癌MC38皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
6.2分组
Figure PCTCN2022094047-appb-000007
6.3结果
表2各组平均肿瘤质量及肿瘤抑制率
组别 Tumor Weight(g) IR TW％ CDI(相互作用指数)
G1 2.21 -  
G2 0.87 60.8  
G3 0.84 61.9  
G4 0.15 93.2 0.45
结果如表2和图13至图15所示：
RB0004单药瘤重抑制率为60.8％；cGAMP单药瘤重抑制率为61.9％；
复合制剂(单一剂型)(G4)肿瘤增值抑制效果显著，给药后肿瘤增值缓慢，瘤重抑制率为93.2％，与对照组相比，差异有统计学意义(P＜0.001)，实验终点小鼠生存率为100％，且表现出显著的药物协同作用效果(CDI值＝0.45)。
综上，2’,3’-cGAMP与PD-1单抗的单一剂型，肿瘤抑制效果明显，生存率高(P<0.05)，且协同药物作用显著，新型药物组合药效优于PD-1抗体RB0004单独用药，表明新型药物组合具有更大优势。
实施例7
采用移植瘤模型测试已上市PD-1\PD-L1抑制剂与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
7.1小鼠移植瘤模型
成功建立小鼠结直肠癌MC38皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
7.2.1分组1(PD-1抑制剂)
Figure PCTCN2022094047-appb-000008
7.3.1结果1(PD-1抑制剂)
表3各组平均肿瘤质量及肿瘤抑制率
Figure PCTCN2022094047-appb-000009
Figure PCTCN2022094047-appb-000010
结果如表3和图16至图18所示：
cGAMP与已上市PD1抑制剂复合制剂G4\6\8\10与对照组相比，差异有统计学意义(P＜0.001)，瘤重抑制率分别为88.2％、79.1％、93.5％、77.1％。四种复合制剂均表现出协同药物作用效果，其中G8组(信迪利)复合制剂药物协同效应最为显著。
实验终点，单药组中G2(LPG1501)\G3(替雷)\G9(特瑞)生存率在60％以上；复合制剂G4\G6\G8\G10S生存率均为100％，显著提高生存率。
综上，2’,3’-cGAMP与已上市的4种PD-1单抗的复合制剂(单一剂型)，肿瘤抑制效果明显，生存率高(P<0.05)，且表现出协同药物作用效果。
7.2.2分组2(PD-L1抑制剂Durvalumab)
Figure PCTCN2022094047-appb-000011
7.3.2结果(PD-L1抑制剂Durvalumab)
表4各组平均肿瘤质量及肿瘤抑制率
Figure PCTCN2022094047-appb-000012
结果如表4和图19至图21所示：
cGAMP与已上市PD-L1抑制剂Durvalumab复合制剂(G4)有抑制肿瘤增值作用，药效优于cGAMP或PD-L1抗体单独用药，统计学上有显著性差异(P＜0.001)，瘤重抑制率为63.6％。实验终点，复合制剂组小鼠生存率在80％以上，显著提高生存率。
综上，2’,3’-cGAMP与已上市的PD-L1单抗的复合制剂(单一剂型)，肿瘤抑制效果明显，生存率高(P<0.05)，且表现出协同药物作用效果。
7.2.3分组3(PD-L1抑制剂Tecentriq)
Figure PCTCN2022094047-appb-000013
Figure PCTCN2022094047-appb-000014
7.3.3结果(PD-L1抑制剂Tecentriq)
表5各组平均肿瘤质量及肿瘤抑制率
组别 Tumor Weight(g) IR TW％
G1 1.86  
G2 0.7 62.4
G3 0.9 51.6
G4 0.7 62.4
G5 0.8 56.9
G6 0.5 73.1
结果如表5及图22至图25所示：
cGAMP与RB0005复合制剂(G6)瘤重抑制率为73.1％，与对照组相比，差异有统计学意义(p＜0.05)；与已上市PD-L1抑制剂Tecentriq复合制剂(G4)瘤重抑制率为62.4％，复合制剂药效优于cGAMP或PD-L1抗体单独用药。
给药期间，复合制剂组肿瘤增值缓慢甚至消失，实验终点，复合制剂组小鼠50％肿瘤消失(Tv＜80mm3)。
综上，2’,3’-cGAMP与RB0005及已上市的PD-L1单抗的复合制剂(单一剂型)，肿瘤抑制效果明显，且生存率高(P<0.05)。
实施例8
采用移植瘤模型测试PD-L1抑制剂RB0005与STING类激动剂2’,3’-cGAMP组成的药物组合不同肿瘤增殖期内的抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
8.1小鼠移植瘤模型
成功建立小鼠结直肠癌人源化CD274的MC38皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
8.2分组
Figure PCTCN2022094047-appb-000015
Figure PCTCN2022094047-appb-000016
8.3结果
如图26所示，
肿瘤增值初期(平均体积为250mm 3)给药后复合制剂的肿瘤体积抑制率为49.9％，与对照组相比，有显著的统计学差异(P＜0.01)；
肿瘤快速增殖期(平均体积为500mm 3)给药后复合制剂的肿瘤体积抑制率为55.5％，与对照组相比，有统计学差异(P＜0.05)；
肿瘤增值晚期(平均体积为1000mm 3)给药后复合制剂的肿瘤体积抑制率为26.4％，与对照组相比，无统计学差异(P＞0.05)；
结论：新型复合制剂(单一剂型)对肿瘤增值初期、快速肿瘤增殖期均有肿瘤抑制作用，尤其是肿瘤增值初期，抑制作用更加显著。
实施例9
采用移植瘤模型测试先给药小分子STING类激动剂2’,3’-cGAMP，48h后给与PD-L1抑制剂RB0005，对MC38移植瘤模型生长的抑制作用。
9.1小鼠移植瘤模型
成功建立人源化PD-1小鼠结直肠癌MC38皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
9.2分组
Figure PCTCN2022094047-appb-000017
Figure PCTCN2022094047-appb-000018
9.3结果
表6各组平均肿瘤质量及肿瘤抑制率
Figure PCTCN2022094047-appb-000019
结果如表6及图27至图29所示：
序贯给药组(G4)肿瘤增值抑制作用明显，给药结束后观察期内，肿瘤体积持续减小甚至消失。序贯给药组(G4)与对照及RB0005单药组相比，差异有统计学意义(ANOVA，P＜0.001)，瘤重抑制率为95.5％。
序贯联合(先给小分子即2’,3’-cGAMP，后给大分子即PD-L1单抗)，肿瘤抑制作用显著，且表现出协同药物作用效果，CDI＝0.17。
实验终点，序贯联合给药组小鼠生存率为100％，与对照组及RB0005单药组相比，显著提高了小鼠生存率。
综上，2’,3’-cGAMP与PD-L1单抗，以先给小分子，后给PD-L1抑制剂的方式给药，肿瘤抑制效果明显，提高了小鼠生存率，且表现出协同药物作用效果。
实施例10
采用移植瘤模型测试PD-L1抑制剂与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
10.1小鼠移植瘤模型
成功建立BALBc小鼠乳腺癌CT26人源化CD274细胞皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
10.2分组
Figure PCTCN2022094047-appb-000020
10.3结果
表7各组平均肿瘤体积及肿瘤抑制率
组别 Tv(mm 3) TGI(％)
G1 1499.1 -
G2 974.7 35.0
G3 868.0 42.1
G4 486.7 67.5
G5 142.5 90.5
结果如表7及图30至33所示：
不同剂量的cGAMP与RB0005复合制剂给药观察期间肿瘤增值缓慢，其中与LPG1501-1mpk复合制剂组(G4)肿瘤减小甚至消失，试验终点肿瘤体积与对照组相比，差异均有统计学意义(p＜0.05)；
溶剂对照组，Day11小鼠生存率为0，复合制剂G3、G4组试验终点，小鼠生存率在50％以上。
综上，不同剂量的2’,3’-cGAMP与RB0005复合制剂(单一剂型)，肿瘤抑制效果明显，且提高生存率(P<0.05)。
实施例11
采用移植瘤模型测试PD-L1抑制剂RB0005与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
11.1小鼠移植瘤模型
成功建立BALBc小鼠乳腺癌4T1人源化CD274细胞皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
11.2分组
Figure PCTCN2022094047-appb-000021
11.3结果
表8各组平均肿瘤质量及肿瘤抑制率
Figure PCTCN2022094047-appb-000022
结果如表8及图34至图36所示：
4T1模型对RB0005单药反应性较差，RB0005单药对肿瘤抑制作用不明显；
cGAMP单药对该模型有一定的抑制肿瘤增值作用，瘤重移植瘤为34％，但组内差异较大，实验终点生存率为66.7％；
复合制剂瘤重抑制率为37.5％，与对照组及RB0005单药组相比，差异有统计学意义(P＜0.05)，且表现出协同药物作用效果，CDI值＜1，实验终点生存率为83.3％；
综上，2’,3’-cGAMP与PD-L1单抗的复合制剂(单一剂型)，有一定的肿瘤抑制作用，提高小鼠生存率，且2’,3’-cGAMP提高了RB0005对4T1模型的反应性。
实施例12
采用移植瘤模型测试PD-1抑制剂RB0004与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
12.1小鼠移植瘤模型
成功建立人源化PD-1小鼠黑色素瘤B16皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
12.2分组
Figure PCTCN2022094047-appb-000023
12.3结果
表9各组平均肿瘤体积及肿瘤抑制率
Figure PCTCN2022094047-appb-000024
结果如表9及图37至40所示：
cGAMP单药给药后第7天，肿瘤抑制率为59％；
复合制剂(单一剂型)(G4)肿瘤增值抑制效果显著，给药后肿瘤增值缓慢，第7天肿瘤抑制率为84.9％，与对照组相比，差异有统计学意义(P＜0.001)，实验终点小鼠生存率为100％，且表现出显著的药物协同作用效果(金氏Q值＝1.8)
综上，2’,3’-cGAMP与PD-1单抗的单一剂型，肿瘤抑制效果明显，生存率高(P<0.05)，且协同药物作用显著，新型药物组合药效优于PD-1抗体RB0004单独用药，表明新型药物组合具有更大优势。
实施例13
采用移植瘤模型测试PD-1抑制剂RB0004与STING类激动剂2’,3’-cGAMP组成的药物组合抗肿瘤作用即对小鼠皮下移植瘤生长的抑制作用。
13.1小鼠移植瘤模型
成功建立人源化PD-1小鼠肺癌LLC-1皮下移植瘤模型后，随机分组，每组6～8只，每两天给药1次，共计给药3次。
13.2分组
Figure PCTCN2022094047-appb-000025
13.3结果
表10各组平均肿瘤抑制率
组别 TGI％ CDI(相互作用指数)
G1 -  
G2 -  
G3 47  
G4 72 0.55(＜1)
结果如表10及图41至43所示：
RB0004单药对该模型无明显的肿瘤抑制效果；cGAMP单药对肿瘤有抑制作用，瘤重抑制率为47％；
复合制剂(单一剂型)(G4)有肿瘤增值抑制效果，给药后肿瘤增值缓慢，瘤重抑制率为72％，与对照组相比，差异有统计学意义(P＜0.001)，且表现出显著的药物协同作用效果(CDI＝0.55)
综上，2’,3’-cGAMP与PD-1单抗的单一剂型，肿瘤抑制效果明显，生存率高(P<0.05)，且有协同药物作用，新型药物组合药效优于PD-1抗体RB0004单独用药，表明新型药物组合具有更大优势。

Claims (108)

  1. 药物组合，其包含程序性细胞死亡蛋白1(PD-1)抑制剂和/或程序性死亡配体1(PD-L1)抑制剂，以及STING通路激动剂。
  2. 根据权利要求1所述的药物组合，其中所述STING通路激动剂包括环状二核苷酸。
  3. 根据权利要求2所述的组合物，其中所述环状二核苷酸选自c-di-AMP、c-di-GMP、c-di-GMP-F、3’,3’-cGAMP、3’,3’-cGAMP-F、2’,3’-cGAMP、Rp/Sp(CL656)、ADU-S100、ADU-S100二钠、其衍生物及其组合。
  4. 根据权利要求3所述的药物组合，其中所述STING通路激动剂包括2’,3’-cGAMP或其衍生物。
  5. 根据权利要求1所述的药物组合，其中所述STING通路激动剂包括类黄酮。
  6. 根据权利要求5所述的药物组合，其中所述类黄酮包括CMA、DMXAA、甲氧酮、6,4’-二甲氧基黄酮、4’-甲氧基黄酮、3’,6’-二羟基黄酮、7,2’-二羟基黄酮、黄豆苷元、Formononetin，视黄素7-甲基醚、吨酮和/或其任意组合。
  7. 根据权利要求1所述的药物组合，其中所述STING通路激动剂包括DNA。
  8. 根据权利要求1所述的药物组合，其中所述STING通路激动剂包括I型干扰素(IFN)。
  9. 根据权利要求8所述的药物组合，其中所述I型干扰素包括IFN-α或IFN-β。
  10. 根据权利要求1-9中任一项所述的药物组合，其中所述PD-1抑制剂具有以下一个或多个特征：
    a.抑制或减少PD-1表达，例如PD-1的转录或翻译；
    b.抑制或降低PD-1活性，例如抑制或降低PD-1与其同源配体，例如PD-L1或PD-L2的结合；和
    c.结合PD-1或其一个或多个配体，例如PD-L1或PD-L2。
  11. 根据权利要求1-9中任一项所述的药物组合，其中所述PD-1抑制剂包括抗PD-1抗体或其抗原结合片段。
  12. 根据权利要求11所述的药物组合，其中所述抗PD-1抗体选自Pembrolizumab、Nivolumab、Pidilizumab、SHR-1210、MEDI0680、BGB-A317、TSR-042、REGN2810、PF-06801591、RB0004、Tislelizumab、Camrelizumab、Toripalimab、Sintilimab、其生物类似物、其生物增强物、其生物等效物及它们的组合。
  13. 根据权利要求11-12中任一项所述的药物组合，其中所述抗PD-1抗体包含抗体重链可变区(VH)中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列。
  14. 根据权利要求11-13中任一项所述的药物组合，其中所述抗PD-1抗体包含VH，所述VH 包含HCDR3，所述HCDR3包含SEQ ID NO:3所示的氨基酸序列。
  15. 根据权利要求14所述的药物组合，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:2所示的氨基酸序列。
  16. 根据权利要求14-15中任一项所述的药物组合，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:1所示的氨基酸序列。
  17. 根据权利要求14-16中任一项所述的药物组合，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列。
  18. 根据权利要求14-17中任一项所述的药物组合，其中所述VH包括框架区HFR1，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:4所示的氨基酸序列或与SEQ ID NO:4所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  19. 根据权利要求14-18中任一项所述的药物组合，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连；且所述HFR2包含SEQ ID NO:5所示的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  20. 根据权利要求14-19中任一项所述的药物组合，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连；且所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  21. 根据权利要求14-20中任一项所述的药物组合，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  22. 根据权利要求14-21中任一项所述的药物组合，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO: 4所示的氨基酸序列或与SEQ ID NO:4所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:5所示的氨基酸序列或与SEQ ID NO:5所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  23. 根据权利要求11-22中任一项所述的药物组合，其中所述抗PD-1抗体包含VH，所述VH包含SEQ ID NO:8所示的氨基酸序列。
  24. 根据权利要求11-23中任一项所述的药物组合，其中所述抗PD-1抗体包含抗体重链(HC)，所述HC包含SEQ ID NO:9所示氨基酸序列。
  25. 根据权利要求11-24中任一项所述的药物组合，其中所述抗PD-1抗体包含抗体轻链可变区(VL)中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
  26. 根据权利要求11-25中任一项所述的药物组合，其中所述抗PD-1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:8所示的氨基酸序列，且所述抗PD-1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:17所示的氨基酸序列。
  27. 根据权利要求11-26中任一项所述的药物组合，其中所述抗PD-1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:10所示的氨基酸序列。
  28. 根据权利要求27所述的药物组合，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:11所示的氨基酸序列。
  29. 根据权利要求27-28中任一项所述的药物组合，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
  30. 根据权利要求27-29中任一项所述的药物组合，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
  31. 根据权利要求11-30中任一项所述的药物组合，其中所述抗PD-1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:3所示的氨基酸序列，所述HCDR2包含SEQ ID NO:2所示的氨基酸序列，所述HCDR1包含SEQ ID NO:1所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:10所示的氨基酸序列，所述LCDR2包含SEQ ID NO:11所示的氨基酸序列，所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
  32. 根据权利要求27-31中任一项所述的药物组合，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID NO:13所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  33. 根据权利要求27-32中任一项所述的药物组合，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  34. 根据权利要求27-33中任一项所述的药物组合，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  35. 根据权利要求27-34中任一项所述的药物组合，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  36. 根据权利要求27-35中任一项所述的药物组合，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:13所示的氨基酸序列或与SEQ ID NO:13所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:14所示的氨基酸序列或与SEQ ID NO:14所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:15所示的氨基酸序列或与SEQ ID NO:15所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:16所示的氨基酸序列或与SEQ ID NO:16所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  37. 根据权利要求11-36中任一项所述的药物组合，其中所述抗PD-1抗体包含VL，所述VL包含SEQ ID NO:17所示的氨基酸序列。
  38. 根据权利要求11-37中任一项所述的药物组合，其中所述抗PD-1抗体包含VH以及VL，所述VH包含SEQ ID NO:8所示的氨基酸序列，且所述VL包含SEQ ID NO:17所示的氨基酸序列。
  39. 根据权利要求11-38中任一项所述的药物组合，其中所述抗PD-1抗体包含抗体轻链(LC)，所述LC包含SEQ ID NO:18所示氨基酸序列。
  40. 根据权利要求11-39中任一项所述的药物组合，其中所述抗PD-1抗体包含HC和LC，所述HC包含SEQ ID NO:9所示氨基酸序列，且所述LC包含如SEQ ID NO:18所示氨基酸序列。
  41. 根据权利要求1所述的药物组合，其中所述PD-L1抑制剂具有以下一个或多个特征：
    a.抑制或减少PD-L1表达，例如PD-L1的转录或翻译；
    b.抑制或降低PD-L1活性，例如抑制或降低PD-L1与其关联受体，例如PD-1的结合；和
    c.结合PD-L1或其受体，例如PD-1。
  42. 根据权利要求1-41中任一项所述的药物组合，其中所述PD-L1抑制剂包括抗PD-L1抗体或其抗原结合片段。
  43. 根据权利要求42所述的药物组合，其中所述抗PD-L1抗体选自Durvalumab、Atezolizumab、Envafolimab、Avelumab、MDX-1105、YW243.55.S70、MDPL3280A、AMP-224、LY3300054、RB0005、其生物类似物、其生物增强物、其生物等效物及它们的组合。
  44. 根据权利要求42-43中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列。
  45. 根据权利要求42-44中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH，所述VH包含HCDR3，所述HCDR3包含SEQ ID NO:21所示的氨基酸序列。
  46. 根据权利要求45所述的药物组合，其中所述VH还包含HCDR2，其中所述HCDR2包含SEQ ID NO:20所示的氨基酸序列。
  47. 根据权利要求45-46中任一项所述的药物组合，其中所述VH还包含HCDR1，其中所述HCDR1包含SEQ ID NO:19所示的氨基酸序列。
  48. 根据权利要求45-47中任一项所述的药物组合，其中所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列。
  49. 根据权利要求45-48中任一项所述的药物组合，其中所述VH包括框架区HFR1，所述 HFR1的C末端与所述HCDR1的N末端直接或间接相连，且所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  50. 根据权利要求45-49中任一项所述的药物组合，其中所述VH包括框架区HFR2，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连；且所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  51. 根据权利要求45-50中任一项所述的药物组合，其中所述VH包括框架区HFR3，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连；且所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  52. 根据权利要求45-51中任一项所述的药物组合，其中所述VH包括框架区HFR4，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连，且所述HFR4包含SEQ ID NO:7所示的氨基酸序列或SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  53. 根据权利要求45-52中任一项所述的药物组合，其中所述VH包括框架区HFR1，HFR2，HFR3和HFR4，所述HFR1的C末端与所述HCDR1的N末端直接或间接相连，所述HFR2的N末端与所述HCDR1的C末端直接或间接相连，且所述HFR2的C末端与所述HCDR2的N末端直接或间接相连，所述HFR3的N末端与所述HCDR2的C末端直接或间接相连，且所述HFR3的C末端与所述HCDR3的N末端直接或间接相连，所述HFR4的N末端与所述HCDR3的C末端直接或间接相连；其中，所述HFR1包含SEQ ID NO:22所示的氨基酸序列或与SEQ ID NO:22所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR2包含SEQ ID NO:23所示的氨基酸序列或与SEQ ID NO:23所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR3包含SEQ ID NO:24所示的氨基酸序列或与SEQ ID NO:24所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述HFR4包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  54. 根据权利要求42-53中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH，所述VH包含SEQ ID NO:25所示的氨基酸序列。
  55. 根据权利要求42-54中任一项所述的药物组合，其中所述抗PD-L1抗体包含HC，所述HC 包含SEQ ID NO:26所示氨基酸序列。
  56. 根据权利要求42-55中任一项所述的药物组合，其中所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
  57. 根据权利要求42-56中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:37所示的氨基酸序列。
  58. 根据权利要求42-57中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH中的至少一个CDR，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述抗PD-L1抗体包含VL中的至少一个CDR，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
  59. 根据权利要求42-58中任一项所述的药物组合，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:27所示的氨基酸序列。
  60. 根据权利要求59所述的药物组合，其中所述抗PD-L1抗体包含VL，所述VL包含LCDR1，所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列。
  61. 根据权利要求59-60中任一项所述的药物组合，其中所述VL还包含LCDR2，其中所述LCDR2包含SEQ ID NO:31所示的氨基酸序列。
  62. 根据权利要求59-61中任一项所述的药物组合，其中所述VL还包含LCDR3，其中所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
  63. 根据权利要求59-62中任一项所述的药物组合，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
  64. 根据权利要求63所述的药物组合，其中所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列；
    所述LCDR1包含SEQ ID NO:29所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列；或
    所述LCDR1包含SEQ ID NO:30所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
  65. 根据权利要求42-64中任一项所述的药物组合，其中抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示 的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:27所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
  66. 根据权利要求65所述的药物组合，其中所述抗PD-L1抗体包含VH以及抗体VL，所述VH包含HCDR1，HCDR2和HCDR3，其中所述HCDR3包含SEQ ID NO:21所示的氨基酸序列，所述HCDR2包含SEQ ID NO:20所示的氨基酸序列，所述HCDR1包含SEQ ID NO:19所示的氨基酸序列；且所述VL包含LCDR1，LCDR2和LCDR3，其中所述LCDR1包含SEQ ID NO:28、SEQ ID NO:29或SEQ ID NO:30所示的氨基酸序列，所述LCDR2包含SEQ ID NO:31所示的氨基酸序列，所述LCDR3包含SEQ ID NO:32所示的氨基酸序列。
  67. 根据权利要求59-66中任一项所述的药物组合，其中所述VL包括框架区LFR1，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，且所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID NO:33所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  68. 根据权利要求59-67中任一项所述的药物组合，其中所述VL包括框架区LFR2，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2的N末端直接或间接相连；且所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  69. 根据权利要求59-68中任一项所述的药物组合，其中所述VL包括框架区LFR3，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连；且所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  70. 根据权利要求59-69中任一项所述的药物组合，其中所述VL包括框架区LFR4，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连，且所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  71. 根据权利要求59-70中任一项所述的药物组合，其中所述VL包括框架区LFR1，LFR2，LFR3和LFR4，所述LFR1的C末端与所述LCDR1的N末端直接或间接相连，所述LFR2的N末端与所述LCDR1的C末端直接或间接相连，且所述LFR2的C末端与所述LCDR2 的N末端直接或间接相连，所述LFR3的N末端与所述LCDR2的C末端直接或间接相连，且所述LFR3的C末端与所述LCDR3的N末端直接或间接相连，所述LFR4的N末端与所述LCDR3的C末端直接或间接相连；其中，所述LFR1包含SEQ ID NO:33所示的氨基酸序列或与SEQ ID NO:33所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR2包含SEQ ID NO:34所示的氨基酸序列或与SEQ ID NO:34所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR3包含SEQ ID NO:35所示的氨基酸序列或与SEQ ID NO:35所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列，所述LFR4包含SEQ ID NO:36所示的氨基酸序列或与SEQ ID NO:36所示的氨基酸序列具有至少约70％序列同一性的氨基酸序列。
  72. 根据权利要求42-71中任一项所述的药物组合，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:37所示的氨基酸序列。
  73. 根据权利要求72所述的药物组合，其中所述抗PD-L1抗体包含VL，所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
  74. 根据权利要求42-73中任一项所述的药物组合，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述VL包含SEQ ID NO:37所示的氨基酸序列。
  75. 根据权利要求74所述的药物组合，其中所述抗PD-L1抗体包含VH以及VL，所述VH包含SEQ ID NO:25所示的氨基酸序列，且所述VL包含SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40所示的氨基酸序列。
  76. 根据权利要求42-75中任一项所述的药物组合，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:41所示氨基酸序列。
  77. 根据权利要求76所述的药物组合，其中所述抗PD-L1抗体包含LC，所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列。
  78. 根据权利要求42-77中任一项所述的药物组合，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列，且所述LC包含SEQ ID NO:41所示氨基酸序列。
  79. 根据权利要求78所述的药物组合，其中所述抗PD-L1抗体包含HC和LC，所述HC包含SEQ ID NO:26所示氨基酸序列，且所述LC包含SEQ ID NO:42、SEQ ID NO:43或SEQ ID NO:44所示氨基酸序列。
  80. 根据权利要求1-79中任一项所述的药物组合，所述药物组合中的i)所述PD-1抑制剂和/ 或PD-L1抑制剂，与ii)所述STING通路激动剂在所述药物组合中彼此不混合。
  81. 根据权利要求1-79中任一项所述的药物组合，所述药物组合中的i)所述PD-1抑制剂和/或PD-L1抑制剂，与ii)所述STING通路激动剂位于单一的剂型中。
  82. 根据权利要求81所述的药物组合，其中所述药物组合被配制成药物组合物。
  83. 根据权利要求82所述的药物组合，其中所述药物组合物包括PD-1抑制剂或PD-L1抑制剂，以及STING通路激动剂。
  84. 根据权利要求82-83中任一项所述的药物组合，其中所述STING通路激动剂的存在量为约0.0001mg/kg至约200mg/kg。
  85. 根据权利要求82-84中任一项所述的药物组合，其中所述PD-1抑制剂或PD-L1抑制剂的存在量为约0.0001mg/kg至约200mg/kg。
  86. 根据权利要求82-85中任一项所述的药物组合，其中所述药物组合物还包含一种或多种药学上可接受的载体。
  87. 权利要求1-86中任一项所述的药物组合在制备药物中的用途，所述药物用于治疗赘生性疾病。
  88. 根据权利要求87所述的用途，其中所述赘生性疾病包括肿瘤和/或疣类疾病。
  89. 权利要求1-86中任一项所述的药物组合用于治疗赘生性疾病。
  90. 治疗赘生性疾病的药物，其包含权利要求1-86中任一项所述的药物组合。
  91. 治疗赘生性疾病的方法，其包括向有需要的受试者施用有效量的权利要求1-86中任一项所述的药物组合。
  92. 根据权利要求91所述的方法，其中所述受试者患有赘生物。
  93. 根据权利要求92所述的方法，其中所述赘生物包括肿瘤和/或疣。
  94. 根据权利要求91-93中任一项所述的方法，其中所述施用包括局部、赘生物内或全身性施用。
  95. 根据权利要求91-94中任一项所述的方法，其中所述施用包括静脉注射、静脉滴注、肌肉注射、皮下注射和/或赘生物内注射。
  96. 根据权利要求91-95中任一项所述的方法，其中采取相同或不同的给药途径施用所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)STING通路激动剂。
  97. 根据权利要求91-96中任一项所述的方法，其包括向赘生物中注射所述STING通路激动剂。
  98. 根据权利要求91-97中任一项所述的方法，其还包括向赘生物中注射或全身输注所述 PD-1抑制剂或PD-L1抑制剂。
  99. 根据权利要求98所述的方法，包括向赘生物中注射所述STING通路激动剂和全身输注所述PD-1抑制剂或PD-L1抑制剂。
  100. 根据权利要求91-98中任一项所述的方法，其包括向赘生物中注射所述药物组合中的i)所述PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂。
  101. 根据权利要求91-100中任一项所述的方法，其中同时或不同时施用所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂。
  102. 根据权利要求101所述的方法，其中在所述STING通路激动剂施用之前和/或施用之后施用所述PD-1抑制剂或PD-L1抑制剂。
  103. 根据权利要求102所述的方法，所述方法包括在所述STING通路激动剂施用之后施用所述PD-1抑制剂或PD-L1抑制剂。
  104. 根据权利要求103所述的方法，所述方法包括：i)向赘生物中注射所述STING通路激动剂；ii)在施用所述STING通路激动剂之后向赘生物中注射或全身输注所述PD-1抑制剂或PD-L1抑制剂。
  105. 根据权利要求104所述的方法，所述方法包括：i)向赘生物中注射所述STING通路激动剂；ii)在施用所述STING通路激动剂之后全身输注所述PD-1抑制剂或PD-L1抑制剂。
  106. 根据权利要求101所述的方法，其中所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂同时施用。
  107. 根据权利要求106所述的方法，其中所述药物组合中的i)PD-1抑制剂或PD-L1抑制剂，与ii)所述STING通路激动剂通过赘生物内注射方式同时施用，且所述PD-1抑制剂或PD-L1抑制剂与所述STING通路激动剂位于同一剂型内。
  108. 药盒，其包含权利要求1-86中任一项所述的药物组合。
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