Combinations of pharmaceuticals and their use

Abstract

A pharmaceutical combination and its use, comprising a PD-1 inhibitor and / or a PD-L1 immune checkpoint inhibitor and a STING pathway agonist, the antitumor efficacy of the pharmaceutical combination is better than that of an immune checkpoint inhibitor alone or a STING pathway agonist alone, and realizes treatment by both activating the body's inherent immune pathway and preventing immune escape, and has the potential for clinical application with high efficiency and low toxicity.

Description

Technical Field

[0001] This application relates to the field of biomedicine, and specifically to the development and use of pharmaceutical combinations.

Background Art

[0002] Over the past decade, targeting PD-1 and PD-L1 has opened a new era for the clinical treatment of cancer. However, in many tumor types, immune checkpoint inhibitors are not effective as monotherapies. Even for immunoresponsive tumors, most patients do not have sustained clinical benefits. The vast majority of patients develop primary or acquired treatment resistance. In most cases, resistance to immunotherapy is due to the presence of an immunosuppressive TME and a decrease in the number of immune cells in vivo that is insufficient to activate the T cell anti-tumor effect. Therefore, compared with monotherapy, it is particularly important to actively pursue new treatment strategies that can reduce immune inhibition in the tumor environment or enhance the response of cytotoxic cells to tumors.

[0003] The PD-L1 / PD-1 signaling pathway is a very important co-inhibitory signaling pathway in the immune response. According to research, it has been shown that when PD-L1 binds to PD-1, the protein tyrosine phosphatases SHP-1 and SHP-2 having SH2 domains are recruited. These two phosphatases can reduce the degree of phosphorylation of the immunoreceptor tyrosine activation motif (ITAM) of the CD3ζ chain, weaken ZAP-70 activation, and inhibit signal transduction downstream of the TCR, thereby exerting a co-inhibitory effect on T cell activation and preventing autoimmune damage caused by overactivation of effector T cells by this negative regulatory effect.

[0004] Interferon gene-stimulating proteins (STINGs) are immunostimulatory small molecule targets primarily distributed in immune-related tissue cells, such as the thymus, spleen, and peripheral blood leukocytes, where they are highly expressed. cGAMP can bind to and activate STINGs in the endoplasmic reticulum when tumor cells undergo necrosis. STING activation leads to the nuclear translocation of transcription factors, inducing the expression of interferon (INF) and cytokines, promoting T cell aggregation and activation, and further killing tumor cells. The STING pathway can also be activated by synthesized cyclic dinucleotides (CDNs) to trigger a unique immune response.

[0005] The combined use of PD-L1 / PD-1 inhibitors and STING pathway agonists has very high clinical potential and application value, as it releases inhibitory signals, enhances T cell activation, and promotes adaptive immune responses, while simultaneously inducing INF and cytokine expression, promoting T cell aggregation, and activating innate immune responses, thereby enhancing the cytotoxic response of cells against tumors and other pathogens through the combined effects of both.

[0006] Furthermore, studies have shown that several viral infections are also associated with the PD-L1 / PD-1 signaling pathway. For example, in chronic HIV infection, high expression of PD-1 has been found on the surface of CD8+ T cells that specifically recognize HIV. The virus activates the PD-L1 / PD-1 signaling pathway, inhibiting the activity of CD8+ T cells that specifically recognize HIV, significantly weakening cytokine secretion and the proliferation ability of the T cells themselves, leading to adaptive immune dysfunction. Therefore, this treatment method may have considerable potential applications in the treatment of this type of disease. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] This application provides a combination of pharmaceuticals and its use in antitumor drugs. The combination of pharmaceuticals is primarily, The present invention comprises two parts: (1) an immune checkpoint inhibitor (e.g., PD-1 / PD-L1) and (2) a STING pathway agonist (e.g., cyclic dinucleotide cGAMP and its derivatives). The present invention enables the production of highly efficient and low-toxicity antitumor drugs. [Means for solving the problem]

[0008] In one embodiment, the present application provides a combination of pharmaceuticals comprising a programmed cell death protein 1 (PD-1) inhibitor and / or a programmed cell death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist.

[0009] In one embodiment, the STING pathway agonist here comprises a cyclic dinucleotide.

[0010] In one embodiment, the 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, their derivatives, and combinations thereof.

[0011] In one embodiment, the STING pathway agonist here comprises 2',3'-cGAMP or a derivative thereof.

[0012] In one embodiment, the STING pathway agonist here comprises a flavonoid.

[0013] In one embodiment, the flavonoids herein include CMA, DMXAA, methoxyflavone, 6,4'-dimethoxyflavone, 4'-methoxyflavone, 3',6'-dihydroxyflavone, 7,2'-dihydroxyflavone, daidzein, formononetin, retinoid 7-methyl ether, xanthone, and / or any combination thereof.

[0014] In one embodiment, the STING pathway agonist here comprises DNA.

[0015] In one embodiment, the STING pathway agonist here comprises a type I interferon (IFN).

[0016] In one embodiment, the type I interferon here comprises IFN-α or IFN-β.

[0017] In one embodiment, the PD-1 inhibitor is used here. a. Inhibiting or reducing PD-1 expression, for example, PD-1 transcription or translation. b. Inhibiting or reducing PD-1 activity, for example, inhibiting or reducing the binding of PD-1 to its homologous ligand, such as PD-L1 or PD-L2, and c. Having one or more of the following characteristics: binding to PD-1 or one or more ligands thereof, such as PD-L1 or PD-L2.

[0018] In one embodiment, the PD-1 inhibitor here comprises an anti-PD-1 antibody or its antigen-binding fragment.

[0019] In one embodiment, 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, their bioanalogs, their bioenhancements, their bioequivalences, and combinations thereof.

[0020] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in the antibody heavy chain variable region (VH), wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 8.

[0021] In certain embodiments, the anti-PD-1 antibody herein comprises a VH comprising an HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3.

[0022] In certain embodiments, the VH herein further comprises an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0023] In certain embodiments, the VH herein further comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1.

[0024] In certain embodiments, the VH herein comprises an HCDR1, an HCDR2, and an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3, the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2, and the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1.

[0025] In certain embodiments, the VH herein comprises a framework region HFR1, the C-terminus of the HFR1 is directly or indirectly linked to the N-terminus of the HCDR1, and the HFR1 comprises the amino acid sequence set forth in SEQ ID NO: 4 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence set forth in SEQ ID NO: 4.

[0026] In certain embodiments, the VH herein comprises a framework region HFR2, the N-terminus of the HFR2 is directly or indirectly linked to the C-terminus of the HCDR1, the C-terminus of the HFR2 is directly or indirectly linked to the N-terminus of the HCDR2, and the HFR2 comprises the amino acid sequence set forth in SEQ ID NO: 5 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence set forth in SEQ ID NO: 5.

[0027] In one embodiment, the VH comprises a framework region HFR3, the N-terminus of the HFR3 is directly or indirectly bound to the C-terminus of the HCDR2, and the C-terminus of the HFR3 is directly or indirectly bound to the N-terminus of the HCDR3, and 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.

[0028] In one embodiment, the VH comprises a framework region HFR4, the N-terminus of the HFR4 is directly or indirectly bound to the C-terminus 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 with the amino acid sequence shown in SEQ ID NO: 7.

[0029] In one embodiment, the VH comprises a framework region HFR1, HFR2, HFR3, and HFR4, wherein the C-terminus of HFR1 is directly or indirectly coupled to the N-terminus of HCDR1, the N-terminus of HFR2 is directly or indirectly coupled to the C-terminus of HCDR1, and the C-terminus of HFR2 is directly or indirectly coupled to the N-terminus of HCDR2, the N-terminus of HFR3 is directly or indirectly coupled to the C-terminus of HCDR2, and the C-terminus of HFR3 is directly or indirectly coupled to the N-terminus of HCDR3, and the N-terminus of HFR4 is directly or indirectly coupled to the C-terminus of HCDR3. Hereinafter, HFR1 includes the amino acid sequence shown in SEQ ID NO: 4 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 4; HFR2 includes 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; HFR3 includes 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; and HFR4 includes the amino acid sequence shown in SEQ ID NO: 7 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 7.

[0030] In one embodiment, the anti-PD-1 antibody here comprises a VH having the amino acid sequence shown in SEQ ID NO: 8.

[0031] In one embodiment, the anti-PD-1 antibody here comprises an antibody heavy chain (HC) having the amino acid sequence shown in SEQ ID NO: 9.

[0032] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in the antibody light chain variable region (VL), wherein the VL comprises the amino acid sequence shown in SEQ ID NO: 17.

[0033] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 8, and the anti-PD-1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 17.

[0034] In one embodiment, the anti-PD-1 antibody comprises a VL containing LCDR1, wherein the LCDR1 contains the amino acid sequence shown in SEQ ID NO: 10.

[0035] In one embodiment, the VL further comprises an LCDR2 having the amino acid sequence shown in SEQ ID NO: 11.

[0036] In one embodiment, the VL further comprises an LCDR3 having the amino acid sequence shown in SEQ ID NO: 12.

[0037] In one embodiment, the VL hereby includes LCDR1 containing the amino acid sequence shown in SEQ ID NO: 10, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 12.

[0038] In one embodiment, the anti-PD-1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, where HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 3, HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2, HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1, and VL comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 10, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 11, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 12.

[0039] In one embodiment, the VL comprises a framework region LFR1, the C-terminus of the LFR1 is directly or indirectly bound to the N-terminus of the LCDR1, and the LFR1 comprises an amino acid sequence represented by SEQ ID NO: 13 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence represented by SEQ ID NO: 13.

[0040] In one embodiment, the VL hereof includes a framework region LFR2, the N-terminus of the LFR2 is directly or indirectly bound to the C-terminus of the LCDR1, and the C-terminus of the LFR2 is directly or indirectly bound to the N-terminus of the LCDR2, and the LFR2 includes 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.

[0041] In one embodiment, the VL comprises a framework region LFR3, the N-terminus of the LFR3 is directly or indirectly bound to the C-terminus of the LCDR2, and the C-terminus of the LFR3 is directly or indirectly bound to the N-terminus of the LCDR3, and the LFR3 comprises an amino acid sequence represented by SEQ ID NO: 15 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence represented by SEQ ID NO: 15.

[0042] In one embodiment, the VL comprises a framework region LFR4, the N-terminus of the LFR4 is directly or indirectly bound to the C-terminus 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 with the amino acid sequence shown in SEQ ID NO: 16.

[0043] In one embodiment, the VL here comprises a framework region LFR1, LFR2, LFR3, and LFR4, wherein the C-terminus of LFR1 is directly or indirectly coupled to the N-terminus of LCDR1, the N-terminus of LFR2 is directly or indirectly coupled to the C-terminus of LCDR1, and the C-terminus of LFR2 is directly or indirectly coupled to the N-terminus of LCDR2, the N-terminus of LFR3 is directly or indirectly coupled to the C-terminus of LCDR2, and the C-terminus of LFR3 is directly or indirectly coupled to the N-terminus of LCDR3, and the N-terminus of LFR4 is directly or indirectly coupled to the C-terminus of LCDR3, and here, LFR1 includes the amino acid sequence shown in SEQ ID NO: 13 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 13; LFR2 includes 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; LFR3 includes 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; and LFR4 includes the amino acid sequence shown in SEQ ID NO: 16 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 16.

[0044] In one embodiment, the anti-PD-1 antibody here comprises a VL containing the amino acid sequence shown in SEQ ID NO: 17.

[0045] In one embodiment, the anti-PD-1 antibody comprises VH and VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 8, and VL comprises the amino acid sequence shown in SEQ ID NO: 17.

[0046] In one embodiment, the anti-PD-1 antibody here comprises an antibody light chain (LC) having the amino acid sequence shown in SEQ ID NO: 18.

[0047] In one embodiment, the anti-PD-1 antibody comprises HC and LC, wherein HC comprises the amino acid sequence shown in SEQ ID NO: 9, and LC comprises the amino acid sequence shown in SEQ ID NO: 18.

[0048] In one embodiment, the PD-L1 inhibitor is used here. a. Inhibiting or reducing PD-L1 expression, for example, PD-L1 transcription or translation. b. Inhibiting or reducing PD-L1 activity, for example, inhibiting or reducing the binding of PD-L1 to its associated receptor, for example, PD-1, and c. Having one or more of the following characteristics: binding to PD-L1 or its receptor, such as PD-1.

[0049] In one embodiment, the PD-L1 inhibitor here comprises an anti-PD-L1 antibody or its antigen-binding fragment.

[0050] In one embodiment, the anti-PD-L1 antibody is selected from Durvalumab, Atezolizumab, Avelumab, Envafolimab, MDX-1105, YW243.55.S70, MDPL3280A, AMP-224, LY3300054, RB0005, their bioanalogs, their bioenhancements, their bioequivalences, and combinations thereof.

[0051] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25.

[0052] In one embodiment, the anti-PD-L1 antibody comprises a VH containing HCDR3, wherein the HCDR3 contains the amino acid sequence shown in SEQ ID NO: 21.

[0053] In one embodiment, the VH further comprises an HCDR2 having the amino acid sequence shown in SEQ ID NO: 20.

[0054] In one embodiment, the VH further comprises HCDR1 having the amino acid sequence shown in SEQ ID NO: 19.

[0055] In one embodiment, VH comprises HCDR1, HCDR2, and HCDR3, wherein HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, and HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19.

[0056] In one embodiment, the VH comprises a framework region HFR1, the C-terminus of the HFR1 is directly or indirectly bound to the N-terminus of the HCDR1, and the HFR1 comprises an amino acid sequence that has at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 22 or the amino acid sequence shown in SEQ ID NO: 22.

[0057] In one embodiment, the VH comprises a framework region HFR2, the N-terminus of the HFR2 is directly or indirectly bound to the C-terminus of the HCDR1, and the C-terminus of the HFR2 is directly or indirectly bound to the N-terminus of the HCDR2, and the HFR2 comprises an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 23 or the amino acid sequence shown in SEQ ID NO: 23.

[0058] In one embodiment, the VH comprises a framework region HFR3, the N-terminus of the HFR3 is directly or indirectly bound to the C-terminus of the HCDR2, and the C-terminus of the HFR3 is directly or indirectly bound to the N-terminus of the HCDR3, and the HFR3 comprises an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 24 or the amino acid sequence shown in SEQ ID NO: 24.

[0059] In one embodiment, the VH comprises a framework region HFR4, the N-terminus of the HFR4 is directly or indirectly bound to the C-terminus 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 with the amino acid sequence shown in SEQ ID NO: 7.

[0060] In one embodiment, the VH comprises a framework region HFR1, HFR2, HFR3, and HFR4, wherein the C-terminus of HFR1 is directly or indirectly coupled to the N-terminus of HCDR1, the N-terminus of HFR2 is directly or indirectly coupled to the C-terminus of HCDR1, and the C-terminus of HFR2 is directly or indirectly coupled to the N-terminus of HCDR2, the N-terminus of HFR3 is directly or indirectly coupled to the C-terminus of HCDR2, and the C-terminus of HFR3 is directly or indirectly coupled to the N-terminus of HCDR3, and the N-terminus of HFR4 is directly or indirectly coupled to the C-terminus of HCDR3, where HFR1 includes the amino acid sequence shown in SEQ ID NO: 22 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 22; HFR2 includes 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; HFR3 includes 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; and HFR4 includes the amino acid sequence shown in SEQ ID NO: 7 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 7.

[0061] In one embodiment, the anti-PD-L1 antibody here comprises a VH having the amino acid sequence shown in SEQ ID NO: 25.

[0062] In one embodiment, the anti-PD-L1 antibody here comprises an HC having the amino acid sequence shown in SEQ ID NO: 26.

[0063] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in the VL, and the VL comprises the amino acid sequence shown in SEQ ID NO: 37.

[0064] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and the anti-PD-L1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 37.

[0065] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and the anti-PD-L1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0066] In one embodiment, the anti-PD-L1 antibody comprises a VL containing LCDR1, wherein the LCDR1 contains the amino acid sequence shown in SEQ ID NO: 27.

[0067] In one embodiment, the anti-PD-L1 antibody comprises a VL containing LCDR1, wherein LCDR1 contains the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30.

[0068] In one embodiment, the VL further comprises an LCDR2 having the amino acid sequence shown in SEQ ID NO: 31.

[0069] In one embodiment, the VL further comprises an LCDR3 having the amino acid sequence shown in SEQ ID NO: 32.

[0070] In one embodiment, the VL here comprises LCDR1 containing the amino acid sequence shown in SEQ ID NO: 27, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 32.

[0071] In one embodiment, the VL hereby includes LCDR1, LCDR2, and LCDR3, wherein LCDR1 includes the amino acid sequence shown in SEQ ID NO: 28, LCDR2 includes the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 includes the amino acid sequence shown in SEQ ID NO: 32. The LCDR1 includes the amino acid sequence shown in SEQ ID NO: 29, the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 31, the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 32, or LCDR1 includes the amino acid sequence shown in SEQ ID NO: 30, LCDR2 includes the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 includes the amino acid sequence shown in SEQ ID NO: 32.

[0072] In one embodiment, the anti-PD-L1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, wherein HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19, and VL comprises LCDR1, LCDR2, and LCDR3, wherein LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO: 32.

[0073] In one embodiment, the anti-PD-L1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, where HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 21, HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 20, HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 19, and VL comprises LCDR1, LCDR2, and LCDR3, where LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO: 32.

[0074] In one embodiment, the VL comprises a framework region LFR1, the C-terminus of the LFR1 is directly or indirectly bound 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 with the amino acid sequence shown in SEQ ID NO: 33.

[0075] In one embodiment, the VL hereof includes a framework region LFR2, the N-terminus of the LFR2 is directly or indirectly bound to the C-terminus of the LCDR1, and the C-terminus of the LFR2 is directly or indirectly bound to the N-terminus of the LCDR2, and the LFR2 includes 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.

[0076] In one embodiment, the VL hereof includes a framework region LFR3, the N-terminus of the LFR3 is directly or indirectly bound to the C-terminus of the LCDR2, and the C-terminus of the LFR3 is directly or indirectly bound to the N-terminus of the LCDR3, and the LFR3 includes 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.

[0077] In one embodiment, the VL comprises a framework region LFR4, the N-terminus of the LFR4 is directly or indirectly bound to the C-terminus 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 with the amino acid sequence shown in SEQ ID NO: 36.

[0078] In one embodiment, the VL here comprises a framework region LFR1, LFR2, LFR3, and LFR4, wherein the C-terminus of LFR1 is directly or indirectly coupled to the N-terminus of LCDR1, the N-terminus of LFR2 is directly or indirectly coupled to the C-terminus of LCDR1, and the C-terminus of LFR2 is directly or indirectly coupled to the N-terminus of LCDR2, the N-terminus of LFR3 is directly or indirectly coupled to the C-terminus of LCDR2, and the C-terminus of LFR3 is directly or indirectly coupled to the N-terminus of LCDR3, and the N-terminus of LFR4 is directly or indirectly coupled to the C-terminus of LCDR3, and here, LFR1 includes the amino acid sequence shown in SEQ ID NO: 33 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 33; LFR2 includes 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; LFR3 includes 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; and LFR4 includes the amino acid sequence shown in SEQ ID NO: 36 or an amino acid sequence having at least about 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 36.

[0079] In one embodiment, the anti-PD-L1 antibody here comprises a VL having the amino acid sequence shown in SEQ ID NO: 37.

[0080] In one embodiment, the anti-PD-L1 antibody here comprises a VL containing the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0081] In one embodiment, the anti-PD-L1 antibody comprises VH and VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and VL comprises the amino acid sequence shown in SEQ ID NO: 37.

[0082] In one embodiment, the anti-PD-L1 antibody comprises VH and VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and VL comprises the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0083] In one embodiment, the anti-PD-L1 antibody here comprises an LC having the amino acid sequence shown in SEQ ID NO: 41.

[0084] In one embodiment, the anti-PD-L1 antibody here comprises an LC having the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.

[0085] In one embodiment, the anti-PD-L1 antibody comprises HC and LC, wherein HC comprises the amino acid sequence shown in SEQ ID NO: 26, and LC comprises the amino acid sequence shown in SEQ ID NO: 41.

[0086] In one embodiment, the anti-PD-L1 antibody comprises HC and LC, wherein HC comprises the amino acid sequence shown in SEQ ID NO: 26, and LC comprises the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.

[0087] In one embodiment, i) the PD-1 inhibitor and / or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination do not mix with each other in the drug combination.

[0088] In one embodiment, the drug combination consists of i) the PD-1 inhibitor and / or PD-L1 inhibitor and ii) the STING pathway agonist, all in a single dosage form.

[0089] In one embodiment, the combination of pharmaceuticals is formulated as a pharmaceutical composition.

[0090] In one embodiment, the pharmaceutical composition comprises a PD-1 inhibitor or a PD-L1 inhibitor and a STING pathway agonist.

[0091] In one embodiment, the amount of the STING pathway agonist present is approximately 0.0001 mg / kg to approximately 200 mg / kg.

[0092] In one embodiment, the amount of the PD-1 inhibitor or PD-L1 inhibitor present is between 0.0001 mg / kg and approximately 200 mg / kg.

[0093] In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0094] In another embodiment, the present invention further provides the use of the aforementioned drug combination in the manufacture of a drug for the treatment of neoplastic diseases.

[0095] In one embodiment, the neoplastic disease here includes tumors and / or verrucous diseases.

[0096] In another embodiment, the present invention further provides the use of the aforementioned drug combination in the treatment of neoplastic diseases.

[0097] In another embodiment, the present invention further provides a pharmaceutical product for treating a neoplastic disease, including the aforementioned combination of pharmaceutical products.

[0098] In another embodiment, the present invention further provides a method for treating a neoplastic disease, comprising administering an effective amount of the aforementioned drug combination to a subject in need thereof.

[0099] In one embodiment, the subject is suffering from a neoplasm.

[0100] In one embodiment, the neoplasm hereby includes tumors and / or warts.

[0101] In one embodiment, the administration here includes local, intracellular (e.g., intratumor or intravesical) or systemic administration.

[0102] In one embodiment, the administration hereby includes intravenous injection, intravenous drip infusion, intramuscular injection, subcutaneous injection and / or neoplasm injection.

[0103] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) a STING pathway agonist in the drug combination are administered via the same or different routes of administration.

[0104] In one embodiment, the STING pathway agonist is injected into the neoplasm.

[0105] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor is further injected or systemically administered to the neoplasm.

[0106] In one embodiment, the method includes injecting the STING pathway agonist into the neoplasm and systemically injecting the PD-1 inhibitor or PD-L1 inhibitor.

[0107] In one embodiment, i) the PD-1 inhibitor or PD-L1 inhibitor in a drug combination Agent and ii) The STING pathway agonist is injected into the neoplasm.

[0108] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously or separately.

[0109] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor is administered before and / or after the administration of the STING pathway agonist.

[0110] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor is administered after the administration of the STING pathway agonist.

[0111] In one embodiment, the method comprises i) injecting the STING pathway agonist into the neoplasm, and ii) injecting or systemically infusing the PD-1 inhibitor or PD-L1 inhibitor into the neoplasm after administration of the STING pathway agonist.

[0112] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously.

[0113] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously by intracellular injection, and the PD-1 inhibitor or PD-L1 inhibitor and the STING pathway agonist are in the same dosage form.

[0114] In another embodiment, the present application provides a pharmaceutical kit including the aforementioned combination of pharmaceuticals. [Effects of the Invention]

[0115] Those skilled in the art will readily be able to infer other aspects and advantages of the Application from the following detailed description. Only exemplary embodiments of the Application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of the Application allows those skilled in the art to modify the specific embodiments disclosed without departing from the spirit and scope of the invention covered by the Application. Accordingly, the drawings and description of the Application are illustrative and not limiting. [Brief explanation of the drawing]

[0116] The specific features of the invention relating to this application are as set forth in the attached claims. The features and advantages of the invention relating to this application can be better understood by referring to the exemplary embodiments and attached drawings described in detail below. A brief description of the drawings is as follows: [Figure 1] This paper presents an in vivo efficacy study of the drug combination of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP, showing the changes in body weight of mice in each group during the administration period. [Figure 2] This study presents an in vivo efficacy study of the drug combination of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP, showing the changes in the survival rate of mice in each group during the administration period. [Figure 3] A: In vivo efficacy study of the drug combination of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP described in this application - shows tumor growth changes in each group of mice during the administration period. B: In vivo efficacy study of the drug combination of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP described in this application - shows tumor growth changes in each group of mice 17 days after treatment. [Figure 4] This shows the tumor weight inhibition rate of mice obtained by dissection after the completion of an in vivo drug efficacy study of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP combination described in this application. [Figure 5] This study presents an in vivo efficacy study of the drug combination of the PD-1 inhibitor RB0004 and 2',3'-cGAMP, showing the tumor growth changes in mice in each group during the administration period. [Figure 6] This shows the tumor weight inhibition rate of mice obtained by dissection after the completion of an in vivo drug efficacy study of the PD-1 inhibitor RB0004 and 2',3'-cGAMP combination described in this application. [Figure 7] This shows the tumor weight inhibition rate of mice obtained by dissection after the completion of an in vivo efficacy study of a drug combination of the PD-L1 inhibitor RB0005 of this application and 2',3'-cGAMP at different doses. [Figure 8]In vivo efficacy studies of drug combinations of the PD-1 inhibitor RB0004 and 2',3'-cGAMP at different doses - showing tumor growth changes in mice in each group during the administration period. [Figure 9] This study presents an in vivo efficacy study of drug combinations of the PD-1 inhibitor RB0004 and 2',3'-cGAMP at different doses, showing the changes in survival rates of mice in each group during the administration period. [Figure 10] The tumor growth tendency of each group of mice during the administration period in Example 5 of this application is shown. [Figure 11] The survival curves of each group of mice during the administration period in Example 5 of this application are shown. [Figure 12] The average tumor mass of each group of mice during the administration period in Example 5 of this application is shown. [Figure 13] The tumor growth tendency of each group of mice during the administration period in Example 6 of this application is shown. [Figure 14] The survival curves of each group of mice during the administration period in Example 6 of this application are shown. [Figure 15] The average tumor mass of each group of mice during the administration period in Example 6 of this application is shown. [Figure 16] The tumor growth tendency of mice in each group during the administration period in Example 7.2.1 of this application is shown. [Figure 17] The survival curves of each group of mice during the administration period in Example 7.2.1 of this application are shown. [Figure 18] The average tumor mass of each group of mice during the administration period in Example 7.2.1 of this application is shown. [Figure 19] The tumor growth tendency of each group of mice during the administration period in Example 7.2.2 of this application is shown. [Figure 20] The survival curves for each group of mice during the administration period in Example 7.2.2 of this application are shown. [Figure 21] This shows the average tumor mass of each group of mice during the administration period in Example 7.2.2 of the present application. [Figure 22] The tumor growth tendency of each group of mice during the administration period in Example 7.2.3 of this application is shown. [Figure 23] The survival curves of each group of mice during the administration period in Example 7.2.3 of this application are shown. [Figure 24] This shows the trend of tumor volume changes in one mouse in the combined formulation group during the administration period in Example 7.2.3 of the present application. [Figure 25] The average tumor mass of each group of mice during the administration period in Example 7.2.3 of this application is shown. [Figure 26] The relative tumor volume inhibition rates for each group of mice during the administration period in Example 8 of this application are shown. [Figure 27] The tumor growth tendency of each group of mice during the administration period in Example 9 of this application is shown. [Figure 28] The survival curves of each group of mice during the administration period in Example 9 of this application are shown. [Figure 29] The average tumor mass of each group of mice during the administration period in Example 9 of this application is shown. [Figure 30] The tumor growth tendency of each group of mice during the administration period in Example 10 of this application is shown. [Figure 31] The average tumor volume of each group of mice at the end of the test in Example 10 of this application is shown. [Figure 32] The survival curves of each group of mice during the administration period in Example 10 of this application are shown. [Figure 33] This shows the trend of tumor volume changes in one mouse in group G5 during the administration period in Example 10 of the present invention. [Figure 34] The tumor growth tendency of each group of mice during the administration period in Example 11 of this application is shown. [Figure 35] The survival curves of each group of mice during the administration period in Example 11 of this application are shown. [Figure 36] The average tumor mass of each group of mice during the administration period in Example 11 of this application is shown. [Figure 37] The tumor growth tendency of each group of mice during the administration period in Example 12 of this application is shown. [Figure 38] The survival curves of each group of mice during the administration period in Example 12 of this application are shown. [Figure 39]The average tumor volume of each group of mice on day 7 in Example 12 of this application is shown. [Figure 40] The average tumor mass of each group of mice during the administration period in Example 12 of this application is shown. [Figure 41] The tumor growth tendency of each group of mice during the administration period in Example 13 of this application is shown. [Figure 42] The survival curves of each group of mice during the administration period in Example 13 of this application are shown. [Figure 43] The average tumor mass of each group of mice during the administration period in Example 13 of this application is shown. [Modes for carrying out the invention]

[0117] The embodiments of the present invention will be described below with specific examples, but those familiar with this technology will be able to easily understand other advantages and effects of the present invention from the disclosures herein.

[0118] Term definition In this application, the term "PD-1" generally refers to apoptotic cell 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 T cell regulatory factor family and has two ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). The structure of the protein includes an extracellular IgV domain, followed by a transmembrane domain and an intracellular tail. The intracellular tail contains two phosphorylation sites located at the tyrosine-based inhibitory motif and tyrosine-based conversion motif in the immune receptor, suggesting that PD-1 negatively modulates TCR signaling. This is consistent with the binding of ligand-bound SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1. PD-1 is not expressed on naive T cells but is upregulated after T cell receptor (TCR) mediated activation and is observed in both activated and depleted T cells (Agata et al., Int. Immunology 8 (1996), 765-772). These depleted T cells have a dysfunctional phenotype and are unable to respond properly. Although PD-1 has a relatively broad expression pattern, its most important role is likely that of a co-inhibitory receptor on T cells (Chinai et al., Trends in Pharmacological Sciences 36 (2015), 587-595). Current therapies focus on blocking the interaction between PD-1 and its ligands to enhance the T cell response. In this application, PD-1 may include human PD-1 (hPD-1) or its mutants, isoforms and species homologs, as well as analogs having at least one common epitope with hPD-1. An example amino acid sequence of hPD-1 can be found at GenBank accession number U64863.

[0119] In this application, the term “PD-L1” generally refers to programmed cell death ligand 1, also known as B7 homolog 1, B7-H1, differentiation cluster 274, (3)274, or CD274, which downregulates T cell activation and cytokine secretion after binding to PD-1. “PD-L1” includes any native PD-L1 from any vertebrate, including mammals such as primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). The term encompasses “full-length” PD-L1, untreated PD-L1, and any form of PD-L1 produced by cell processing. PD-L1 can exist as a transmembrane protein or as a soluble protein. “PD-L1” includes complete PD-L1 and its fragments, as well as functional mutants, isoforms, species homologs, derivatives, analogs, and analogs having at least one epitope in common with PD-L1. The basic structure of PD-L1 includes four domains: an extracellular Ig-like V domain, an Ig-like C2 domain, a transmembrane domain, and a cytoplasmic domain. An exemplary human PD-L1 amino acid sequence can be found at NCBI accession number NP_001254653 or UniProt accession number Q9NZQ7.

[0120] In this application, the term “inhibitor” generally refers to a compound / substance or composition that can completely or partially prevent or reduce the physiological function of one or more specific biomolecules (e.g., proteins (e.g., PD-1 or PD-L1), polypeptides, lipopolysaccharides, glycoproteins, ribonucleoprotein complexes, etc.). The reduction of the physiological function of the one or more specific proteins may include a reduction in the activity of the protein itself (e.g., its ability to bind to other molecules) or a reduction in its abundance. Suitable inhibitor molecules may include antagonist antibodies or antibody fragments, small molecule fragments or derivatives, peptides, antisense oligonucleotides, small organic molecules, etc. In some embodiments, the inhibitor may interfere with the activation of a cellular signaling pathway. In some embodiments, the PD-1 / PD-L1 inhibitor is an anti-PD-1 / PD-L1 antibody or its antigen-binding fragment.

[0121] In this application, the terms "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," and "Sintilimab" are used in accordance with their general and ordinary meanings as understood in the art.

[0122] In this application, the term "STING (an interferon gene stimulator, also known as THEM173, MITA, ERIS, and MPYS)" generally refers to an endoplasmic reticulum (ER) transmembrane protein expressed in the thymus, spleen, placenta, and THP1 human monocytes. Human STING is encoded by the gene TMEM173. The STING pathway can be activated by exogenous cyclic dinucleotides (CDNs) produced by bacterial infection or structurally different endogenous CDNs (e.g., cyclic GMP-AMP (cGAMP) produced in response to the sensing of cytoplasmic double-stranded DNA (dsDNA) by cyclic GMP-AMP synthase (cGAS)) (Ablasser et al., 2013; Diner et al., 2013). The cytoplasmic domain of STING forms a dimer, and CDNs bind at the dimer interface (Burdette, DL et al., 2011). After ligand binding, the cytoplasmic tail of STING acts as an adapter for TBK-1 and IRF-3, thereby inducing their phosphorylation. Phosphorylated IRF-3 enters the nucleus to induce transcription of genes encoding type I IFNs and cytokines that promote intercellular host immune defense (Keating et al., 2011). Activation of STING can lead to the production of type I interferons (e.g., IFN-α and IFN-β) via the IRF3 (interferon regulator 3) pathway and the production of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-6, TNF-α, etc.) via the tumorigenic transcription factor NF-κB (activated B-cell nuclear factor κ-light chain enhancer) pathway. The STING pathway may regulate innate immune recognition of immunogenic tumors and enhance the antitumor effects of interferons. IFN-γ exerts antitumor effects in vivo through TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), promoting apoptosis in tumor cells.

[0123] In this application, the term "STING pathway agonist" generally refers to a molecule that binds to STING (an interferon gene stimulant, or TMEM173), activates STING, and induces activation of the IRF3-TBK1 pathway, resulting in increased transcription of type I interferon and other genes.

[0124] In this application, the term “cyclic dinucleotide (CDN)” generally refers to a class of cyclic molecules having two phosphate diester bonds, or two phosphorothioate diester bonds, or one phosphate diester bond and one phosphorothioate diester 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, which is a product of Vibrio cholerae DncV protein), 3',3'-cGAMP-F, 2',3'-cGAMP (also known as 2'-5',3'-5'cGAMP, which is a product of human cGAS protein), Rp / Sp(CL656), ADU-S100, ADU-S100 disodium, and combinations thereof.

[0125] In this application, the term "nucleoside" generally refers to a glycosylamine containing a nitrogen-containing base and a pentose sugar, where the nitrogen-containing base is bonded to the pentose sugar via a β-glycosidic bond. The term "nucleotide" generally refers to any nucleoside in which a phosphate ester group is bonded at the 5', 3', or 2' position of the sugar moiety.

[0126] In this application, the term "antibody" is used in its broadest sense, and specifically includes monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, insofar as they exhibit the desired biological activity (Milleretal (2003) Journal of Immunology 170:4854-4861). Antibodies may be mouse, human, humanized, chimeric, or derived from other species.

[0127] 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 of an antibody heavy chain variable domain (VH), antibody constant heavy chain domain 1 (CH1), antibody hinge region (HR), antibody heavy chain constant domain 2 (CH2), and antibody heavy chain constant domain 3 (CH3) in the direction from the N-terminus to the C-terminus, and is abbreviated as VH-CH1-HR-CH2-CH3. In the case of an IgE subclass antibody, it optionally further includes antibody heavy chain constant domain 4 (CH4). In some embodiments, the "full-length antibody heavy chain" is a polypeptide consisting of VH, CH1, HR, CH2, and CH3 in the direction from the N-terminus to the C-terminus. 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 direction from the N-terminus to the C-terminus, and is abbreviated as VL-CL. The constant domain (CL) of the antibody light chain may be kappa (κ) or lambda (λ). Two full-length antibody chains are linked by an interpolypeptide disulfide bond between the CL domain and the CH1 domain, and by an interpolypeptide disulfide bond between the hinge regions of the full-length antibody heavy chain. Typical examples of full-length antibodies are native antibodies such as IgG (e.g., IgG1 and IgG2), IgM, IgA, IgD, and IgE.

[0128] In this application, the term "antigen-binding fragment" generally refers to a portion of an antibody molecule containing amino acids that are responsible for specific binding between the antibody and the antigen. The portion of the antigen that is specifically recognized and bound by the antibody is called an "epitope," as described above. The antigen-binding domain may typically include the antibody light chain variable region (VL) and the antibody heavy chain variable region (VH), but does not necessarily have to include both. An Fd fragment, for example, has two VH regions and generally retains part of the antigen-binding function of a complete antigen-binding domain. Examples of antibody antigen-binding fragments include: (1) Fab fragments, which are monovalent fragments having VL, VH, constant light chain (CL), and CH1 domains; (2) F(ab')2 fragments, which are bivalent fragments having two Fab fragments linked by disulfide crosslinks in the hinge region; (3) Fd fragments having two VH and CH1 domains; (4) Fv fragments having VL and VH domains on the single arm of the antibody; and (5) dAb fragments having a VH domain. (Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli," Nature) 341:544-546 (1989), which is incorporated into this application by reference as a whole), (6) an isolated complementarity-determining region (CDR), (7) a single-chain Fv (scFv) derived from, for example, an scFV library, where the two domains VL and VH of the Fv fragment are encoded by independent genes but can be joined using recombination by synthesizing a linker, and by synthesizing the linker, the VL and VH regions pair up to form a monovalent molecule, which is prepared as a single protein chain (called a single-chain Fv (scFv)) (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. Natl. Acad. Sci.(See USA 85:5879-5883 (1988)), and (8) VHH, where "VHH" is involved in a variable antigen-binding domain derived from heavy chain antibodies of camelids (camels, dromedaries, llamas, alpacas, etc.) (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), and VHH also includes nanobody (Nb) and / or single-domain antibodies. These antibody fragments are obtained using prior art known to those skilled in the art, and the function of the fragments is evaluated in the same way as that of a complete antibody.

[0129] In this application, the terms “variable region” or “variable domain” generally refer to a region in the variable domain where a segment of the variable domain may differ significantly in sequence between antibodies. The “variable region” of the light chain may include the light chain variable region VL, and the “variable region” of the heavy chain may include the heavy chain variable region VH. The variable domain mediates antigen binding and determines the specificity of a particular antibody to a particular antigen. However, variability is not uniformly distributed across the entire range of the variable domain. It is generally concentrated in three segments called the hypervariable regions (CDRs or HVRs) of the light and heavy chain variable domains. The more highly conserved portion of the variable domain is called the framework region (FR). The natural heavy and light chain variable domains each contain four FR regions, most of which adopt a β-sheet configuration, linked by three CDRs to form a cyclic linkage, and in some cases forming part of a β-sheet structure. The CDRs in each chain are held in close proximity to each other by the FR region, and the CDRs from the other chain jointly promote 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 its antigen-binding molecule.

[0130] In this application, the term "CDR" generally refers to the complementarity-determining region within the variable sequence of an antibody. Each variable region of the heavy and light chains contains three CDRs, referred to as CDR1, CDR2, and CDR3 for each variable region. The precise limits of these CDRs are defined differently depending on the system. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides a clear residue numbering system suitable for any variable region of an antibody, but also provides precise residue boundaries that define these three CDRs. These CDRs can be called Kabat CDRs. Chothia and his colleagues (Chothia & Lesk, J.MoI. Biol. 196:901-917 (1987) and Chothia et al., Nature 342:877-883 (1989)) found that some sub-parts within the Kabat CDR adopt nearly identical peptide skeletal conformations despite significant differences at the amino acid sequence level. These sub-parts are designated as L1, L2, and L3, or H1, H2, and H3, where "L" and "H" refer to the light chain and heavy chain regions, respectively. These regions are Kabat These can be called Chothia CDRs, which have boundaries that overlap with the CDR. Padlan (FASEB J.9:133-139 (1995)) and MacCallum (JMoI Biol 262(5):732-45 (1996)) have described other boundaries that define CDRs that overlap with the Kabat CDR. Other CDR limits may not strictly conform to the above system, but still overlap with the Kabat CDR, and, according to the following predictions or experiments, have been found to have no significant effect on antigen binding, even if they are shortened or lengthened, as can be expressed by specific residues, groups of residues, or even the entire CDR.Unless otherwise expressly stated herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3,” as used in this application, include CDRs as defined by any of the methods described above (Kabat, Chothia, or IMGT).

[0131] In this application, the term “sequence identity percentage (%)” generally refers to the number of amino acid matches ("hits") between two or more aligned amino acid sequences compared to the total number of amino acid residues that make up the entire length of these sequences. In other words, when using alignment to compare and align two or more sequences for the maximum correspondence (measured, for example, using sequence comparison algorithms known in the art), or when manually aligning and visually inspecting, a percentage of identical amino acid residues (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity) can be determined. Thus, sequences to be compared for determining sequence identity may be distinguished by one or more amino acid substitutions, additions, or deletions. Appropriate procedures for aligning protein sequences are known to those skilled in the art. The percentage sequence identity of protein sequences can be determined using methods such as CLUSTALW, Clustal Omega, FASTA, or BLAST, and can also be determined using the NCBI BLAST algorithm (AltschulSF et al. (1997), Nucleic Acids Res. [Nucleic Acid Research] 25:3389-3402).

[0132] In this application, the terms “combination,” “therapeutic combination,” “combination therapy,” or “pharmaceutical combination” generally refer to a combination comprising at least two active ingredients / therapeutic agents, where the STING pathway agonist and the PD-1 / PD-L1 inhibitor may be administered simultaneously and independently or separately within a time interval that allows them to exert a synergistic effect with their combination partner. In some embodiments, each active ingredient / therapeutic agent may be prepared as an independent formulation (solid, liquid, gel, etc.), in some embodiments, each active ingredient / therapeutic agent may be present in different containers and, if necessary, may be formulated simultaneously or each with a suitable carrier into a desired formulation, in some embodiments, each active ingredient / therapeutic agent may be of different origin (e.g., manufactured or sold by different companies), and in some embodiments, each active ingredient / therapeutic agent may form a pharmaceutical composition in mixed form.

[0133] In this application, the term “pharmaceutical composition” generally refers to a formulation that is an effective form allowing the biological activity of an active ingredient and does not contain additional ingredients that are toxic and unacceptable to the subject to whom the composition is to be administered. Such a composition may be sterile and may contain a pharmaceutically acceptable carrier, such as saline. A suitable pharmaceutical composition may contain one or more buffers (e.g., acetate, phosphate, or citrate buffers), surfactants (e.g., polysorbates), stabilizers (e.g., human albumin), preservatives (e.g., benzyl alcohol), absorption enhancers for enhancing bioavailability, and / or other conventional solubilizers or dispersants. Pharmaceutical compositions in this application include, but are not limited to, liquid, freeze-dried, and lyophilized compositions.

[0134] In this application, the term “pharmaceutically acceptable carrier” generally refers to one or more non-toxic materials that do not interfere with the efficacy of the biological activity of the active ingredient. Such formulations may conventionally include salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. Such pharmaceutically acceptable formulations may also include compatible solid or liquid fillers, diluents, or encapsulants suitable for administration to humans. Other possible carriers, excipients, and / or additives that may be used in the formulations described herein may include, but are not limited to, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients (e.g., serum albumin, gelatin, casein), salt-forming counterions (e.g., sodium), etc. These and other known pharmaceutically acceptable carriers, excipients, and / or additives suitable for use in the formulations described herein are known in the art.

[0135] In this application, the term “neoplastic” generally means novel and abnormally growing cells that, in particular, grow uncontrolled and progress, causing neoplastic disease. Neoplastic cells may be malignant, i.e., invasive and metastatic, or benign.

[0136] In this application, the term “neoplasm” generally refers to an abnormal growth of tissue in which the growth of the tumor exceeds and is not in harmony with the growth of normal tissue. A “neoplasm” may be defined as “benign” or “malignant” depending on its characteristics, including morphology and function, growth rate, and degree of cellular differentiation, including local invasion and metastasis. A “benign neoplasm” is generally well-differentiated, grows characteristically slower than a malignant neoplasm, and remains localized at the site of origin. Furthermore, a benign tumor does not have the ability to penetrate, invade, or metastasize to distal sites. A “malignant neoplasm” is generally poorly differentiated (degenerate) and has characteristic rapid growth accompanied by progressive penetration, invasion, and destruction of surrounding tissue. Furthermore, a malignant neoplasm has the ability to metastasize to distal sites.

[0137] In this application, the terms “tumor” or “cancer” generally refer to any medical disease characterized by the growth, proliferation, or metastasis of neoplastic or malignant cells, and a tumor may be a solid tumor or a non-solid tumor.

[0138] In this application, the term "wart" generally refers to a class of benign neoplasms of the cutaneous surface that are primarily cell proliferation reactions caused by human papillomavirus (HPV). HPV is a DNA virus belonging to the genus A of the family Papovaviridae, and there are more than 80 subtypes of HPV, which are associated with different types of warts. Unless otherwise specified, the term "wart" generally refers to all types of warts, including but not limited to plantar warts, common warts, and genital warts.

[0139] In this application, the term “administer” and similar terms are not generally limited to physical administration, and suitable methods include in vitro, in vitro followed by in vivo, or in vivo methods. For example, any administration method known to those skilled in the art for bringing cells, organs, or tissues into contact with the composition may be used. For example, the compound may be introduced into the body of a subject in need of treatment by any introduction or delivery route. In some embodiments, the compositions of this application may be administered orally, topically, intranasally, intramuscularly, subcutaneously, intradermally, intrathecally, intraperitoneally, transdermally, or intratumorally.

[0140] In this application, the term “effective amount” or “effective dose” generally refers to an amount sufficient to achieve, or at least partially achieve, the desired effect. The “therapeutic effective amount” or “therapeutic effective dose” of a drug or therapeutic agent is generally any amount of the drug, when used alone or in combination with another therapeutic agent, that promotes disease regression (as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods of the disease, or the prevention of damage or disability caused by having the disease).

[0141] In this application, the term “treatment” generally refers to the delay or improvement of the progression, severity, and / or duration of a proliferative disorder, or the improvement of one or more symptoms of a proliferative disorder (e.g., one or more recognizable symptoms), by the administration of one or more therapies (e.g., one or more therapeutic agents, such as the pharmaceutical compositions of this application). In this application, the term “treatment” may also refer to the improvement of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, which is not necessarily recognizable to the patient. In this application, the term “treatment” may also refer to inhibiting the progression of a proliferative disorder, for example, physically by stabilizing recognizable symptoms, for example, physiologically by stabilizing physical parameters, or both. In some cases, the term “treatment” may refer to reducing or stabilizing tumor size or the number of cancer cells.

[0142] In this application, the term "synergistic" generally means that the effectiveness of the combination of two or more active drugs is greater than the combined effect of each active drug used alone. Therefore, when the combination of two or more drugs results in "synergistic inhibition" of an activity or process such as tumor growth, it means that the inhibitory effect on that activity or process is greater than the sum of the inhibitory effects of each active drug. In this application, the synergistic effect of drug combinations can be evaluated using the coefficient of drug interaction (CDI / CI). CDI(CI) is calculated according to the formula CDI(CI)=AB / A*B. It is calculated based on anatomical tumor weight, where AB is the ratio of the combined drug group to the control group. A or B is the ratio of each drug group to the control group. If CDI<1, the synergistic effects of both drugs are proven; if CDI=1, the additive effects of both drugs; and if CDI>1, the antagonistic effects of both drugs. (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.) In this application, the term "subject" generally refers to a human or a non-human animal, including but not limited to a cat, dog, horse, pig, cattle, sheep, rabbit, mouse, rat, or monkey.

[0143] In this application, the term "approximately" generally refers to fluctuations within a range of 0.5%-10% above or below the specified value, for example, fluctuations within a range of approximately 0.5%, approximately 1%, approximately 1.5%, approximately 2%, approximately 2.5%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4.5%, approximately 5%, approximately 5.5%, approximately 6%, approximately 6.5%, approximately 7%, approximately 7.5%, approximately 8%, approximately 8.5%, approximately 9%, approximately 9.5%, or approximately 10% above or below the specified value.

[0144] In this application, the term "includes" and its variations include other forms such as "contains" and "includes," and generally refers to including other components, elements, values, steps, etc.

[0145] This application provides a combination of agonists and immune checkpoint inhibitors used to induce INF and cytokine expression and activate innate immune system responses, including STING agonists (e.g., cyclic dinucleotides 2'3'-cGAMP and its derivatives) and immune checkpoint inhibitors (PD-1 / PD-L1), etc.

[0146] In one embodiment, the present application provides a combination of pharmaceuticals which may include a programmed cell death protein 1 (PD-1) inhibitor and / or a programmed cell death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist.

[0147] In one embodiment, the STING pathway agonist here comprises a cyclic dinucleotide.

[0148] In one embodiment, the 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, their derivatives, and combinations thereof.

[0149] In one embodiment, the STING pathway agonist here comprises 2'3'-cGAMP or a derivative thereof.

[0150] In one embodiment, the STING pathway agonist here comprises a flavonoid.

[0151] In one embodiment, the flavonoids herein include CMA, DMXAA, methoxyflavone, 6,4'-dimethoxyflavone, 4'-methoxyflavone, 3',6'-dihydroxyflavone, 7,2'-dihydroxyflavone, daidzein, formononetin, retinoid 7-methyl ether, xanthone, and / or any combination thereof.

[0152] In one embodiment, the STING pathway agonist here comprises DNA.

[0153] In one embodiment, the STING pathway agonist here comprises a type I interferon (IFN).

[0154] In one embodiment, the type I interferon here comprises IFN-α or IFN-β.

[0155] In one embodiment, the PD-1 inhibitor is used here. a. Inhibiting or reducing PD-1 expression, for example, PD-1 transcription or translation. b. Inhibiting or reducing PD-1 activity, for example, inhibiting or reducing the binding of PD-1 to its homologous ligand, such as PD-L1 or PD-L2, and c. Having one or more of the following characteristics: binding to PD-1 or one or more ligands thereof, such as PD-L1 or PD-L2.

[0156] In one embodiment, the PD-1 inhibitor here comprises an anti-PD-1 antibody or its antigen-binding fragment.

[0157] For example, the pharmaceutical combination may include 1) an anti-PD-1 antibody or its antigen-binding fragment, and 2) a cyclic dinucleotide.

[0158] In one embodiment, the anti-PD-1 antibody is selected from Pembrolizumab, 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, Tislelizumab, Camrelizumab, Toripalimab, Sintilimab, their bioanalogs, their bioenhancements, their bioequivalences, and combinations thereof.

[0159] For example, the aforementioned drug combination is: 1) Pembrolizumab, 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 1) Anti-PD-1 antibodies selected from PF-06801591 (Pfizer), RB0004, their bioanalytes, their bioenhancements, their bioequivalences, and combinations thereof; and 2) cyclic dinucleotides 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, and combinations thereof.

[0160] In some embodiments, the anti-PD-1 antibody is RB0004. RB0004 and other humanized anti-PD-1 monoclonal antibodies are disclosed in CN201610345750.1 and WO2017201766A1. For example, the pharmaceutical combination comprises 1) an anti-PD-1 antibody which is RB0004 or its bioenhancement, and its bioequivalence, and a combination thereof, and 2) a STING pathway agonist which comprises 2',3'-cGAMP or a derivative thereof.

[0161] In some other embodiments, the anti-P D-1 antibody This is Pembrolizumab (trade name Keytruda, formerly known as Lambrolizumab, Merck 3745, MK-3475 or SCH-900475), a humanized IgG4 monoclonal antibody that binds to PD-1. 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. For example, the drug combination comprises 1) an anti-PD-1 antibody that is Pembrolizumab or its bioenhancement, and its bioequivalence, and a combination thereof, and 2) a STING pathway agonist containing 2',3'-cGAMP or a derivative thereof.

[0162] In several other embodiments, the anti-PD-1 antibody is Nivolumab (CAS registry number: 946414-94-4, including alternative names MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. US8,008,449 and WO2006 / 121168 disclose Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1. For example, the pharmaceutical combination comprises 1) an anti-PD-1 antibody which is Nivolumab or its bioenhancement, and its bioequivalence, and a combination thereof, and 2) a STING pathway agonist which comprises 2',3'-cGAMP or a derivative thereof.

[0163] In several other embodiments, the anti-PD-1 antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1 monoclonal antibody that binds to PD-1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009 / 101611. Other anti-PD-1 antibodies are disclosed in US 8,609,089, US2010028330 and / or US20120114649. Other anti-PD-1 antibodies include AMP514 (Amplimmune). For example, the pharmaceutical combination comprises 1) an anti-PD-1 antibody which is pidilizumab or its bioenhancement and its bioequivalence and combination thereof, and 2) a STING pathway agonist which comprises 2',3'-cGAMP or a derivative thereof.

[0164] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in the antibody heavy chain variable region (VH), wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 8.

[0165] In one embodiment, the anti-PD-1 antibody comprises a VH containing HCDR3, wherein the HCDR3 contains an amino acid sequence represented by SEQ ID NO: 3 or an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 3.

[0166] In one embodiment, the VH further comprises an HCDR2 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 2.

[0167] In one embodiment, the VH further comprises an HCDR1 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 1.

[0168] In one embodiment, the VH hereby comprises HCDR1, HCDR2, and HCDR3, wherein the HCDR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 3, and the HCDR2 comprises at least the amino acid sequence represented by SEQ ID NO: 2, or the amino acid sequence represented by SEQ ID NO: 2 The HCDR1 contains an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 1 or the amino acid sequence indicated by SEQ ID NO: 1.

[0169] In one embodiment, the VH comprises a framework region HFR1, the C-terminus of the HFR1 is directly or indirectly bound to the N-terminus of the HCDR1, and the HFR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 4.

[0170] In one embodiment, the VH comprises a framework region HFR2, the N-terminus of the HFR2 is directly or indirectly bound to the C-terminus of the HCDR1, and the C-terminus of the HFR2 is directly or indirectly bound to the N-terminus of the HCDR2, and the HFR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 5.

[0171] In one embodiment, the VH comprises a framework region HFR3, the N-terminus of the HFR3 is directly or indirectly bound to the C-terminus of the HCDR2, and the C-terminus of the HFR3 is directly or indirectly bound to the N-terminus of the HCDR3, and the HFR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 6.

[0172] In one embodiment, the VH comprises a framework region HFR4, the N-terminus of the HFR4 is directly or indirectly bound to the C-terminus of the HCDR3, and the HFR4 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 7.

[0173] In one embodiment, the VH hereby includes a framework region HFR1, HFR2, HFR3, and HFR4, wherein the C-terminus of HFR1 is directly or indirectly coupled to the N-terminus of HCDR1, the N-terminus of HFR2 is directly or indirectly coupled to the C-terminus of HCDR1, and the C-terminus of HFR2 is directly or indirectly coupled to the N-terminus of HCDR2, and the N-terminus of HFR3 is directly or indirectly coupled to the C-terminus of HCDR2, and The C-terminus of HFR3 is directly or indirectly bound to the N-terminus of HCDR3, and the N-terminus of HFR4 is directly or indirectly bound to the C-terminus of HCDR3, wherein HFR1 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 with the amino acid sequence shown in SEQ ID NO: 4. The HFR2 contains an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO. 5, and the HFR3 has at least about 70%, about 75%, about 80%, about 8% sequence identity with the amino acid sequence shown in SEQ ID NO. 6. The HFR4 contains an amino acid sequence having 5%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity, wherein the HFR4 contains an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 7.

[0174] In one embodiment, the anti-PD-1 antibody hereby comprises the amino acid sequence shown in SEQ ID NO: 8 or a VH 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 8.

[0175] In one embodiment, the anti-PD-1 antibody comprises an antibody heavy chain (HC) having an amino acid sequence that is 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 with the amino acid sequence that is shown in SEQ ID NO: 9.

[0176] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in the antibody light chain variable region (VL), wherein the VL comprises the amino acid sequence shown in SEQ ID NO: 17.

[0177] In one embodiment, the anti-PD-1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 8, and the anti-PD-1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 17.

[0178] In one embodiment, the anti-PD-1 antibody comprises a VL containing LCDR1, wherein LCDR1 contains an amino acid sequence that is 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 with the amino acid sequence that is shown in SEQ ID NO: 10.

[0179] In one embodiment, the VL further comprises an LCDR2 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 11.

[0180] In one embodiment, the VL further comprises an LCDR3 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 12.

[0181] In one embodiment, the VL hereby comprises an LCDR1 containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 10, and an amino acid sequence having at least about 70%, about 75%, about 80%, or about 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 11. It includes LCDR2 containing an amino acid sequence having approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 containing an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 12.

[0182] In one embodiment, the anti-PD-1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, wherein HCDR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 3, and HCDR2 comprises an amino acid sequence shown in SEQ ID NO: 2 The HCDR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 1 or SEQ ID NO: 1, and the HCDR1 comprises an amino acid sequence 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%, or about 97% sequence identity with the amino acid sequence represented by SEQ ID NO: 1 or SEQ ID NO: 1, LCDR1 contains an amino acid sequence having approximately 98% or approximately 99% sequence identity, and the VL contains an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 11 or approximately 70%, approximately 75%, It includes LCDR2 containing an amino acid sequence having approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 containing an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 12.

[0183] For example, the anti-PD-1 antibody may include VH and antibody VL, where VH may include HCDR1, HCDR2, and HCDR3, where HCDR3 may include the amino acid sequence shown in SEQ ID NO: 3, HCDR2 may include the amino acid sequence shown in SEQ ID NO: 2, HCDR1 may include the amino acid sequence shown in SEQ ID NO: 1, and VL may include LCDR1 which may include the amino acid sequence shown in SEQ ID NO: 10, LCDR2 which may include the amino acid sequence shown in SEQ ID NO: 11, and LCDR3 which may include the amino acid sequence shown in SEQ ID NO: 12.

[0184] Furthermore, for example, the pharmaceutical combination may include: 1) an anti-PD-1 antibody that may include VH and antibody VL, wherein VH may include HCDR1, HCDR2, and HCDR3, where HCDR3 may include the amino acid sequence shown in SEQ ID NO: 3, HCDR2 may include the amino acid sequence shown in SEQ ID NO: 2, HCDR1 may include the amino acid sequence shown in SEQ ID NO: 1, and VL may include LCDR1 which may include the amino acid sequence shown in SEQ ID NO: 10, LCDR2 which may include the amino acid sequence shown in SEQ ID NO: 11, and LCDR3 which may include the amino acid sequence shown in SEQ ID NO: 12; and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0185] In one embodiment, the VL comprises a framework region LFR1, the C-terminus of the LFR1 is directly or indirectly bound to the N-terminus of the LCDR1, and the LFR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 13.

[0186] In one embodiment, the VL, wherein the VL includes a framework region LFR2, the N-terminus of the LFR2 is directly or indirectly bound to the C-terminus of the LCDR1, and the C-terminus of the LFR2 is directly or indirectly bound to the N-terminus of the LCDR2, and the LFR2 includes an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 14.

[0187] In one embodiment, the VL, wherein the VL comprises a framework region LFR3, the N-terminus of the LFR3 directly or indirectly bound to the C-terminus of the LCDR2, and the C-terminus of the LFR3 directly or indirectly bound to the N-terminus of the LCDR3, and the LFR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 15.

[0188] In one embodiment, the VL comprises a framework region LFR4, the N-terminus of the LFR4 is directly or indirectly bound to the C-terminus of the LCDR3, and the LFR4 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 16.

[0189] In one embodiment, the VL hereby includes a framework region LFR1, LFR2, LFR3, and LFR4, wherein the C-terminus of LFR1 is directly or indirectly coupled to the N-terminus of LCDR1, the N-terminus of LFR2 is directly or indirectly coupled to the C-terminus of LCDR1, and the C-terminus of LFR2 is directly or indirectly coupled to the N-terminus of LCDR2, and the N-terminus of LFR3 is directly or indirectly coupled to the C-terminus of LCDR2, and The C-terminus of LFR3 is directly or indirectly bound to the N-terminus of LCDR3, and the N-terminus of LFR4 is directly or indirectly bound to the C-terminus of LCDR3, wherein LFR1 is an amino acid 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 13. The sequence includes, and the LFR2 includes an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 14 or the amino acid sequence shown in SEQ ID NO: 15 or the amino acid sequence shown in SEQ ID NO: 15 The LFR4 contains an amino acid sequence having 5%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity, wherein the LFR4 contains an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 16.

[0190] In one embodiment, the anti-PD-1 antibody hereby comprises a VL containing the amino acid sequence shown in SEQ ID NO: 17 or an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 17.

[0191] In one embodiment, the anti-PD-1 antibody comprises VH and VL, wherein VH comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 8, and VL comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 17.

[0192] For example, the anti-PD-1 antibody may include VH and VL, where VH may include the amino acid sequence shown in SEQ ID NO: 8, and VL may include the amino acid sequence shown in SEQ ID NO: 17.

[0193] For example, the drug combination may include 1) an anti-PD-1 antibody that may contain VH and VL, wherein VH may contain the amino acid sequence shown in SEQ ID NO: 8, and VL may contain the amino acid sequence shown in SEQ ID NO: 17, and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0194] In one embodiment, the anti-PD-1 antibody comprises an antibody light chain (LC) having an amino acid sequence that is 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 with the amino acid sequence shown in SEQ ID NO: 18.

[0195] In one embodiment, the anti-PD-1 antibody comprises HC and LC, wherein HC comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 9, and LC comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 18.

[0196] For example, the anti-PD-1 antibody may comprise HC and LC, wherein HC may comprise the amino acid sequence shown in SEQ ID NO: 9, and LC may comprise the amino acid sequence shown in SEQ ID NO: 18.

[0197] For example, the pharmaceutical combination may include 1) an anti-PD-1 antibody that comprises HC and LC, wherein HC may comprise the amino acid sequence shown in SEQ ID NO: 9, and LC may comprise the amino acid sequence shown in SEQ ID NO: 18, and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0198] In one embodiment, the PD-L1 inhibitor is used here. a. Inhibiting or reducing PD-L1 expression, for example, PD-L1 transcription or translation. b. Inhibiting or reducing PD-L1 activity, for example, inhibiting or reducing the binding of PD-L1 to its associated receptor, for example, PD-1, and c. Having one or more of the following characteristics: binding to PD-L1 or its receptor, such as PD-1.

[0199] In one embodiment, the PD-L1 inhibitor here comprises an anti-PD-L1 antibody or its antigen-binding fragment.

[0200] For example, the pharmaceutical combination includes 1) an anti-PD-L1 antibody or its antigen-binding fragment, and 2) a cyclic dinucleotide.

[0201] In one embodiment, the anti-PD-L1 antibody is selected from Durvalumab (disclosed in MEDI4736, US2013 / 0034559A1), Atezolizumab (MPDL3280A, US8,217,149), Avelumab (MSB0010718C, US2014 / 0341917A1), MDX-1105, YW243.55.S70, MDPL3280A, AMP-224 (Amplimmune, GlaxoSmithKline), LY3300054 (Eli Lilly and Co.), RB0005, their bioanalogs, their bioenhancements, their bioequivalents, and combinations thereof.

[0202] For example, the aforementioned drug combination may include: 1) Durvalumab (disclosed in MEDI4736, US2013 / 0034559A1), Atezolizumab (MPDL3280A, US8,217,149), Avelumab (MSB0010718C, US2014 / 0341917A1), MDX-1105, YW243.55.S70, MDPL3280A, AMP-224, LY3300054, RB 0005) Anti-PD-L1 antibodies selected from their bioanalytes, bioenhancements, bioequivalents and combinations thereof, and 2) Cyclic dinucleotides 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 and combinations thereof.

[0203] In some embodiments, the anti-PD-L1 antibody is RB0005. RB0005 and other humanized anti-PD-L1 monoclonal antibodies are disclosed in CN201610340678.3 and WO2017197667A1. For example, the pharmaceutical combination comprises 1) an anti-PD-L1 antibody which is RB0005 or its bioenhancement, and its bioequivalence, and a combination thereof, and 2) a STING pathway agonist which comprises 2',3'-cGAMP or a derivative thereof.

[0204] In some other embodiments, the PD-L1 inhibitor is MDX-1105, also known as BMS-936559, and is an anti-PD-L1 antibody described in W02007 / 005874. For example, the pharmaceutical combination comprises 1) an anti-PD-L1 antibody which is MDX-1105 or its bioenhancement and its bioequivalence and combination thereof, and 2) a STING pathway agonist which comprises 2',3'-cGAMP or a derivative thereof.

[0205] In some other embodiments, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PD-L1 antibody described in W02010 / 077634.

[0206] In several other embodiments, the PD-L1 inhibitor is MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. U.S. Patent No. 7,943,743 and U.S. Patent Disclosure No. 20120039906 disclose MDPL3280A and other human monoclonal antibodies against PD-L1.

[0207] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25.

[0208] In one embodiment, the anti-PD-L1 antibody comprises a VH containing HCDR3, wherein the HCDR3 contains an amino acid sequence represented by SEQ ID NO: 21 or an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 21.

[0209] In one embodiment, the VH further comprises an HCDR2 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 20.

[0210] In one embodiment, the VH further comprises an HCDR1 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 19.

[0211] In one embodiment, the VH comprises HCDR1, HCDR2, and HCDR3, wherein the HCDR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 21, and the HCDR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 20. The HCDR1 contains an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 19 or the amino acid sequence indicated by SEQ ID NO: 19 having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 19.

[0212] For example, VH here may include HCDR1, HCDR2, and HCDR3, where HCDR3 includes the amino acid sequence shown in SEQ ID NO: 21, HCDR2 includes the amino acid sequence shown in SEQ ID NO: 20, and HCDR1 includes the amino acid sequence shown in SEQ ID NO: 19.

[0213] In one embodiment, the VH comprises a framework region HFR1, the C-terminus of the HFR1 is directly or indirectly bound to the N-terminus of the HCDR1, and the HFR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 22.

[0214] In one embodiment, the VH comprises a framework region HFR2, the N-terminus of the HFR2 is directly or indirectly bound to the C-terminus of the HCDR1, and the C-terminus of the HFR2 is directly or indirectly bound to the N-terminus of the HCDR2, and the HFR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 23.

[0215] In one embodiment, the VH comprises a framework region HFR3, the N-terminus of the HFR3 is directly or indirectly bound to the C-terminus of the HCDR2, and the C-terminus of the HFR3 is directly or indirectly bound to the N-terminus of the HCDR3, and the HFR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 24.

[0216] In one embodiment, the VH comprises a framework region HFR4, the N-terminus of the HFR4 is directly or indirectly bound to the C-terminus of the HCDR3, and the HFR4 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 7.

[0217] In one embodiment, the VH hereby includes a framework region HFR1, HFR2, HFR3, and HFR4, wherein the C-terminus of HFR1 is directly or indirectly coupled to the N-terminus of HCDR1, the N-terminus of HFR2 is directly or indirectly coupled to the C-terminus of HCDR1, and the C-terminus of HFR2 is directly or indirectly coupled to the N-terminus of HCDR2, and the N-terminus of HFR3 is directly or indirectly coupled to the C-terminus of HCDR2, and The C-terminus of HFR3 is directly or indirectly bound to the N-terminus of HCDR3, and the N-terminus of HFR4 is directly or indirectly bound to the C-terminus of HCDR3, wherein HFR1 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 with the amino acid sequence shown in SEQ ID NO: 22. The HFR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 23, and the HFR3 comprises an amino acid sequence having at least about 70%, about 75%, about 80%, about The HFR4 contains an amino acid sequence having 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity, wherein the HFR4 contains an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 7.

[0218] In one embodiment, the anti-PD-L1 antibody hereby comprises the amino acid sequence shown in SEQ ID NO: 25 or a VH 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 25.

[0219] In one embodiment, the anti-PD-L1 antibody comprises an HC 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 26.

[0220] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in the VL, and the VL comprises the amino acid sequence shown in SEQ ID NO: 37.

[0221] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and the anti-PD-L1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 37.

[0222] In one embodiment, the anti-PD-L1 antibody comprises at least one CDR in VH, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and the anti-PD-L1 antibody comprises at least one CDR in VL, wherein VL comprises the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0223] In one embodiment, the anti-PD-L1 antibody comprises a VL containing LCDR1, wherein LCDR1 contains an amino acid sequence represented by SEQ ID NO: 27 or an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 27.

[0224] In one embodiment, the anti-PD-L1 antibody comprises a VL containing LCDR1, wherein LCDR1 contains an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30.

[0225] In one embodiment, the VL further comprises an LCDR2 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 31.

[0226] In one embodiment, the VL further comprises an LCDR3 comprising an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 32.

[0227] In one embodiment, the VL hereby comprises an LCDR1 containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 31 or about 80%, about 85% It includes LCDR2 containing an amino acid sequence having approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 containing an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 32.

[0228] In one embodiment, the VL hereby comprises an LCDR1 containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 31 or about 80%, about 85% LCDR2 includes an amino acid sequence having approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 includes an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 32. In one embodiment, the VL hereby comprises an LCDR1 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 31 or about 80%, about 85%, LCDR2 includes an amino acid sequence having approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 includes an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 32, or In one embodiment, the VL hereby comprises an LCDR1 containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 31 or about 80%, about 85% It includes LCDR2 containing an amino acid sequence having approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 containing an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 32.

[0229] In one embodiment, the anti-PD-L1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, wherein HCDR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 21, and HCDR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 20 The HCDR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 19 or SEQ ID NO: 19, and the HCDR1 comprises an amino acid sequence 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 LCDR1 includes an amino acid sequence having 97%, approximately 98%, or approximately 99% sequence identity, and the VL includes an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 31 or approximately 75% LCDR2 includes an amino acid sequence having sequence identity of approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and LCDR3 includes an amino acid sequence having sequence identity of at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with the amino acid sequence shown in SEQ ID NO: 32.

[0230] For example, the anti-PD-L1 antibody may include VH and antibody VL, and VH may include HCDR1, HCDR2, and HCDR3, where HCDR3 may include the amino acid sequence shown in SEQ ID NO: 21, HCDR2 may include the amino acid sequence shown in SEQ ID NO: 20, HCDR1 may include the amino acid sequence shown in SEQ ID NO: 19, and VL may include LCDR1 which may include the amino acid sequence shown in SEQ ID NO: 27, LCDR2 which may include the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 which may include the amino acid sequence shown in SEQ ID NO: 32.

[0231] For example, the drug combination may include: 1) an anti-PD-L1 antibody that may include VH and antibody VL, wherein VH may include HCDR1, HCDR2, and HCDR3, where HCDR3 may include the amino acid sequence shown in SEQ ID NO: 21, HCDR2 may include the amino acid sequence shown in SEQ ID NO: 20, HCDR1 may include the amino acid sequence shown in SEQ ID NO: 19, and VL may include LCDR1 which may include the amino acid sequence shown in SEQ ID NO: 27, LCDR2 which may include the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 which may include the amino acid sequence shown in SEQ ID NO: 32; and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0232] In one embodiment, the anti-PD-L1 antibody comprises VH and antibody VL, wherein VH comprises HCDR1, HCDR2, and HCDR3, wherein HCDR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 21, and HCDR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 20 The HCDR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in sequence number 19 or the amino acid sequence shown in sequence number 19. LCDR1 includes an amino acid sequence having sequence identity, and VL includes an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, and the amino acid sequence shown in SEQ ID NO: 31 or the amino acid sequence shown in SEQ ID NO: 31 and at It includes LCDR2 containing an amino acid sequence having approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, and LCDR3 containing an amino acid sequence having at least approximately 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 32.

[0233] For example, the anti-PD-L1 antibody may include VH and antibody VL, where VH may include HCDR1, HCDR2, and HCDR3, where HCDR3 may include the amino acid sequence shown in SEQ ID NO: 21, HCDR2 may include the amino acid sequence shown in SEQ ID NO: 20, HCDR1 may include the amino acid sequence shown in SEQ ID NO: 19, and VL may include LCDR1 which may include the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, LCDR2 which may include the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 which may include the amino acid sequence shown in SEQ ID NO: 32.

[0234] For example, the drug combination may include: 1) an anti-PD-L1 antibody comprising VH and antibody VL, wherein VH may comprise HCDR1, HCDR2, and HCDR3, where HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 21, HCDR2 may comprise the amino acid sequence shown in SEQ ID NO: 20, HCDR1 may comprise the amino acid sequence shown in SEQ ID NO: 19, and VL may comprise LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0235] In one embodiment, the VL comprises a framework region LFR1, the C-terminus of the LFR1 is directly or indirectly bound to the N-terminus of the LCDR1, and the LFR1 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 33.

[0236] In one embodiment, the VL, wherein the VL comprises a framework region LFR2, the N-terminus of the LFR2 is directly or indirectly bound to the C-terminus of the LCDR1, and the C-terminus of the LFR2 is directly or indirectly bound to the N-terminus of the LCDR2, and the LFR2 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 34.

[0237] In one embodiment, the VL, wherein the VL comprises a framework region LFR3, the N-terminus of the LFR3 directly or indirectly bound to the C-terminus of the LCDR2, and the C-terminus of the LFR3 directly or indirectly bound to the N-terminus of the LCDR3, and the LFR3 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 35.

[0238] In one embodiment, the VL comprises a framework region LFR4, the N-terminus of the LFR4 is directly or indirectly bound to the C-terminus of the LCDR3, and the LFR4 comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence represented by SEQ ID NO: 36.

[0239] In one embodiment, the VL hereby includes a framework region LFR1, LFR2, LFR3, and LFR4, wherein the C-terminus of LFR1 is directly or indirectly coupled to the N-terminus of LCDR1, the N-terminus of LFR2 is directly or indirectly coupled to the C-terminus of LCDR1, and the C-terminus of LFR2 is directly or indirectly coupled to the N-terminus of LCDR2, and the N-terminus of LFR3 is directly or indirectly coupled to the C-terminus of LCDR2, and The C-terminus of LFR3 is directly or indirectly bound to the N-terminus of LCDR3, and the N-terminus of LFR4 is directly or indirectly bound to the C-terminus of LCDR3, wherein LFR1 is an amino acid 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 33. The sequence includes, and LFR2 includes an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 34, and LFR3 includes an amino acid sequence having at least about 70%, about 75%, about 80%, about 8% sequence identity with the amino acid sequence shown in SEQ ID NO: 35 The LFR4 contains an amino acid sequence having 5%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity, wherein the LFR4 contains an amino acid sequence having at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99% sequence identity with the amino acid sequence indicated by SEQ ID NO: 36.

[0240] In one embodiment, the anti-PD-L1 antibody hereby comprises the amino acid sequence shown in SEQ ID NO: 37 or a VL 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 37.

[0241] In one embodiment, the anti-PD-L1 antibody hereof comprises a VL containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0242] In one embodiment, the anti-PD-L1 antibody comprises VH and VL, wherein VH comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 25, and VL comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 37.

[0243] For example, the anti-PD-L1 antibody may include VH and VL, where VH may include the amino acid sequence shown in SEQ ID NO: 25, and VL may include the amino acid sequence shown in SEQ ID NO: 37.

[0244] For example, the drug combination may include 1) an anti-PD-L1 antibody that may contain VH and VL, wherein VH may contain the amino acid sequence shown in SEQ ID NO: 25, and VL may contain the amino acid sequence shown in SEQ ID NO: 37, and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0245] In one embodiment, the anti-PD-L1 antibody comprises VH and VL, wherein VH comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 25, and VL comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, and VL comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0246] For example, the anti-PD-L1 antibody may include VH and VL, where VH may include the amino acid sequence shown in SEQ ID NO: 25, and VL may include the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40.

[0247] For example, the drug combination may include 1) an anti-PD-L1 antibody that may contain VH and VL, wherein VH may contain the amino acid sequence shown in SEQ ID NO: 25, and VL may contain the amino acid sequence shown in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, and 2) a STING pathway agonist which may be 2',3'-cGAMP or a derivative thereof.

[0248] In one embodiment, the anti-PD-L1 antibody hereof comprises an LC comprising the amino acid sequence shown in SEQ ID NO: 41 or an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 41.

[0249] In one embodiment, the anti-PD-L1 antibody hereof comprises an LC containing an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.

[0250] In one embodiment, the anti-PD-L1 antibody comprises HC and LC, wherein HC comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 26, and LC comprises an amino acid sequence 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%, about 98%, or about 99% sequence identity with the amino acid sequence shown in SEQ ID NO: 41.

[0251] For example, the anti-PD-L1 antibody may comprise HC and LC, wherein HC may comprise the amino acid sequence shown in SEQ ID NO: 26, and LC may comprise the amino acid sequence shown in SEQ ID NO: 41.

[0252] For example, the pharmaceutical combination may include 1) an anti-PD-L1 antibody that may include a heavy chain (HC) and a light chain (LC), where the HC may include the amino acid sequence shown in SEQ ID NO: 26 and the LC may include the amino acid sequence shown in SEQ ID NO: 41, and 2) a STING pathway agonist that may be 2’,3’-cGAMP or a derivative thereof.

[0253] In certain embodiments, where the anti-PD-L1 antibody includes a HC and a LC, the HC includes the amino acid sequence shown in SEQ ID NO: 26 or an amino acid sequence 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%, about 98%, or about 99% sequence identity to the amino acid sequence shown in SEQ ID NO: 26, and the LC includes the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44 or an amino acid sequence 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%, about 98%, or about 99% sequence identity to the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.

[0254] For example, where the anti-PD-L1 antibody may include a HC and a LC, the HC may include the amino acid sequence shown in SEQ ID NO: 26 and the LC may include the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.

[0255] For example, the pharmaceutical combination may include 1) an anti-PD-L1 antibody that may include a HC and a LC, where the HC may include the amino acid sequence shown in SEQ ID NO: 26 and the LC may include the amino acid sequence shown in SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, and 2) a STING pathway agonist that may be 2’,3’-cGAMP or a derivative thereof.

[0256] In one embodiment, i) the PD-1 inhibitor and / or PD-L1 inhibitor and ii) the STING pathway agonist in the pharmaceutical combination do not mix with each other in the pharmaceutical combination, i.e., i) the PD-1 inhibitor and / or ii) the PD-L1 inhibitor and the STING pathway agonist are in separate dosage forms.

[0257] In one embodiment, i) 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.

[0258] In one embodiment, here the pharmaceutical combination is formulated as a pharmaceutical composition (e.g., a combined preparation or a compound preparation). The pharmaceutical composition can be directly injected into a large tumor without affecting normal (surrounding) tissues, kill cancer cells, prevent or delay the growth of malignant tumors (e.g., shrink a swelling or reduce a tumor), and enable a patient with advanced cancer to live with the tumor (in a manner similar to a human patient living with a parasite). When the pharmaceutical combination is injected into a tumor, the drug can flow along blood vessels or lymphatic vessels to metastatic foci and kill metastatic cells. Injection of the pharmaceutical combination into the tumor causes little trauma to the patient and can be repeated, for example, multiple times per month. The direct injection can also be administered simultaneously to the primary tumor and secondary tumors where the cancer has metastasized.

[0259] In one embodiment, here the pharmaceutical composition contains a PD-1 inhibitor or a PD-L1 inhibitor and a STING pathway agonist.

[0260] For example, the pharmaceutical composition may contain a PD-1 inhibitor and a STING pathway agonist. Also for example, the pharmaceutical composition may contain an anti-PD-1 antibody or an antigen-binding fragment thereof and a cyclic dinucleotide.

[0261] For example, the pharmaceutical composition may include a PD-L1 inhibitor and a STING pathway agonist. Alternatively, for example, the pharmaceutical composition may include an anti-PD-L1 antibody or its antigen-binding fragment and a cyclic dinucleotide.

[0262] In one embodiment, the amount of the STING pathway agonist present is approximately 0.0001 mg / kg to approximately 200 mg / kg. For example, the STING pathway agonist may be present in the combinations (i.e., mg / kg) specified herein relative to the body weight of the subject. In some cases, the amount of the STING pathway agonist may be approximately 0.0001 mg / kg to approximately 200 mg / kg, 0.001 mg / kg to approximately 200 mg / kg, 0.01 mg / kg to approximately 200 mg / kg, 0.01 mg / kg to approximately 150 mg / kg, 0.01 mg / kg to approximately 100 mg / kg, 0.01 mg / kg to approximately 50 mg / kg, 0.01 mg / kg to approximately 25 mg / kg, 0.01 mg / kg to approximately 10 mg / kg, or 0.01 mg / kg to approximately 5 mg / kg, 0.05 mg / kg to approximately 200 mg / kg, or approximately The dosages are 150 mg / kg, 0.05 mg / kg to approximately 100 mg / kg, 0.05 mg / kg to approximately 50 mg / kg, 0.05 mg / kg to approximately 25 mg / kg, 0.05 mg / kg to approximately 10 mg / kg, or 0.05 mg / kg to approximately 5 mg / kg, 0.5 mg / kg to approximately 200 mg / kg, 0.5 mg / kg to approximately 150 mg / kg, 0.5 mg / kg to approximately 100 mg / kg, 0.5 mg / kg to approximately 50 mg / kg, 0.5 mg / kg to approximately 25 mg / kg, 0.5 mg / kg to approximately 10 mg / kg, or 0.5 mg / kg to approximately 5 mg / kg. In other cases, the amount of STING pathway agonist present is approximately 1 mg / kg to 200 mg / kg, 1 mg / kg to 150 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 25 mg / kg, 1 mg / kg to 10 mg / kg, or 1 mg / kg to 5 mg / kg.

[0263] For example, STING pathway agonists may be present in combinations in amounts of approximately 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. STING pathway agonists may be present in combinations in amounts of approximately 1 mg to 10 mg, 10 mg to 20 mg, 25 mg to 50 mg, 30 mg to 60 mg, 40 mg to 50 mg, 50 mg to 100 mg, 75 mg to 150 mg, 100 mg to 200 mg, 200 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1200 mg to 1500 mg, or 1500 mg to 2000 mg.

[0264] For example, STING pathway agonists may be present in combinations at amounts of approximately 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, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 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. In some examples, the STING pathway agonist is present in combination in amounts of approximately 1 mg / mL to 10 mg / mL, 5 mg / mL to 10 mg / mL, 5 mg / mL to 15 mg / mL, 10 mg / mL to 25 mg / mL, 20 mg / mL to 30 mg / mL, 25 mg / mL to 50 mg / mL, or 50 mg / mL to 100 mg / mL.

[0265] In one embodiment, the amount of the PD-1 inhibitor or PD-L1 inhibitor (e.g., anti-PD-1 / PD-L1 antibody) present is approximately 0.0001 mg / kg to approximately 200 mg / kg. For example, the PD-1 inhibitor or PD-L1 inhibitor may be present in the combinations (i.e., mg / kg) described herein relative to the body weight of the subject. In some cases, the amount of PD-1 inhibitor or PD-L1 inhibitor present may range from approximately 0.0001 mg / kg to approximately 200 mg / kg, 0.001 mg / kg to approximately 200 mg / kg, 0.01 mg / kg to approximately 200 mg / kg, 0.01 mg / kg to approximately 150 mg / kg, 0.01 mg / kg to approximately 100 mg / kg, 0.01 mg / kg to approximately 50 mg / kg, 0.01 mg / kg to approximately 25 mg / kg, 0.01 mg / kg to approximately 10 mg / kg, or 0.01 mg / kg to approximately 5 mg / kg, 0.05 mg / kg to approximately 200 mg / kg, or 0.05 mg / kg. The dosages are approximately 150 mg / kg for g, 100 mg / kg for 0.05 mg / kg, 50 mg / kg for 0.05 mg / kg, 25 mg / kg for 0.05 mg / kg, 10 mg / kg for 0.05 mg / kg, 5 mg / kg for 0.05 mg / kg, 200 mg / kg for 0.5 mg / kg, 150 mg / kg for 0.5 mg / kg, 100 mg / kg for 0.5 mg / kg, 50 mg / kg for 0.5 mg / kg, 25 mg / kg for 0.5 mg / kg, 10 mg / kg for 0.5 mg / kg, or 5 mg / kg. In other cases, the amount of PD-1 inhibitor or PD-L1 inhibitor present is approximately 1 mg / kg to 200 mg / kg, 1 mg / kg to 150 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 25 mg / kg, 1 mg / kg to 10 mg / kg, or 1 mg / kg to 5 mg / kg.

[0266] For example, anti-PD-1 / PD-L1 antibodies may be present in combinations in amounts of approximately 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. Anti-PD-1 / PD-L1 antibodies may be present in combinations in amounts of approximately 1 mg to 10 mg, 10 mg to 20 mg, 25 mg to 50 mg, 30 mg to 60 mg, 40 mg to 50 mg, 50 mg to 100 mg, 75 mg to 150 mg, 100 mg to 200 mg, 200 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1200 mg to 1500 mg, or 1500 mg to 2000 mg.

[0267] For example, anti-PD-1 / PD-L1 antibodies may be present in combinations in amounts of approximately 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, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 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. In some examples, anti-PD-1 / PD-L1 antibodies are present in combinations in amounts of approximately 1 mg / mL to 10 mg / mL, 5 mg / mL to 10 mg / mL, 5 mg / mL to 15 mg / mL, 10 mg / mL to 25 mg / mL, 20 mg / mL to 30 mg / mL, 25 mg / mL to 50 mg / mL, or 50 mg / mL to 100 mg / mL.

[0268] In one embodiment, the STING pathway agonist may be provided in a synergistic amount with the amount of the PD-1 / PD-L1 inhibitor. The dose administered will undoubtedly vary depending on known factors such as the pharmacokinetic properties of the particular reagent, its mode and route of administration, the age, health status, and weight of the receptor, the nature and severity of symptoms, the type of concomitant symptoms, the frequency of treatment, and the desired effect.

[0269] In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0270] In another embodiment, the present invention further provides the use of the aforementioned drug combination in the manufacture of a drug for the treatment of neoplastic diseases.

[0271] In one embodiment, the neoplastic disease here includes tumors and / or verrucous diseases.

[0272] In one embodiment, the tumor (or cancer) includes, but is not limited to, hepatocellular carcinoma, metastatic liver 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, nephroblastoma, ovarian cancer, bone cancer, osteosarcoma, kidney cancer, or head and neck cancer, oral cancer, laryngeal cancer, or oropharyngeal cancer, breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermal carcinoma, and melanoma.

[0273] In another embodiment, the present invention further provides the aforementioned drug combinations for the treatment of neoplastic diseases.

[0274] In another embodiment, the present invention further provides a pharmaceutical product for treating neoplastic diseases, including the aforementioned combination of pharmaceutical products.

[0275] In another embodiment, the present invention further provides a method for treating a neoplastic disease, comprising administering an effective amount of the aforementioned drug combination to a subject in need thereof.

[0276] In one embodiment, the subject is suffering from a neoplasm here.

[0277] In one embodiment, the neoplasm is in a mammal here. It is located at a position selected from the brain, head, eye, nasopharynx, mouth, tongue, neck, thyroid, gastrointestinal system, liver, pancreas, gallbladder, lung, respiratory system, urogenital system, kidney, bladder, breast, lymphatic system, cardiovascular system, nervous system, skin, chest cavity, pleura, skeletal system, abdomen, and has a primary or secondary nature.

[0278] In one embodiment, the neoplasm includes a tumor and / or a wart here.

[0279] In one embodiment, the administration includes local, intraneoplastic (e.g., intratumoral or intralesional) or systemic administration here. For example, intratumoral or intralesional injection is employed, and the method enables both reducing trauma to the patient and killing cancer cells rather than normal cells. Direct injection of the pharmaceutical combination into malignant tumors also greatly reduces or eliminates many common side effects.

[0280] In one embodiment, the administration includes intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection, and / or intraneoplastic injection here.

[0281] In one embodiment, the tumor includes the following: (i) Superficial malignant diseases of the skin, eye, tongue, mouth, thyroid, breast, cervix, uterus, anus, prostate, vagina, osteosarcoma, urethral cancer, penis, testis, and epididymis, and the pharmaceutical combination is directly injected into the tumor using a syringe without dilution, or (ii) Nasopharyngeal cancer, and the pharmaceutical combination is injected into the tumor by a syringe or needle through a nasopharyngoscope, or (iii) Cancers of the liver, kidney, and gallbladder, and the pharmaceutical combination is injected into the tumor through the skin using a syringe under ultrasonic assistance or through a hole formed in the abdominal wall of the patient during laparoscopic surgery, or (iv) Cancer of the ovaries, fallopian tubes, pancreas, lymph node metastases, or direct intraperitoneal invasion into the abdominal cavity, or abdominal lymphoma, and the combination of drugs is injected into the tumor using a syringe through an opening made in the patient's abdominal wall during laparoscopic surgery, or (v) Cancer or sarcoma of the esophagus, stomach, duodenum, or small intestine, and the drug combination is injected into the tumor by a transloscopic needle, or injected into the tumor via a long syringe through an opening made in the patient's abdominal wall during laparoscopic surgery, or injected through an opening made in the patient's chest wall during thoracoscopic surgery, (vi) Cancer or sarcoma of the large intestine and rectum, wherein the drug combination is injected into the tumor by a colonoscopy needle, or injected into the tumor using a syringe through an opening made in the patient's abdominal wall during laparoscopic surgery, (vii) Cancer or sarcoma of the lung and trachea, wherein the drug combination is injected into the tumor using a bronchoscope needle, (viii) Lung cancer, and the drug combination is injected using a syringe under the use of ultrasound, X-ray, CT scan or MRI scan, or injected through an opening made in the patient's chest wall during thoracoscopic surgery, (ix) Cancer or sarcoma of the bladder, and the drug combination is injected into the tumor by a cystoscopic needle, or injected through an opening made in the patient's abdominal wall during laparoscopic surgery, (x) Uterine cancer or sarcoma, wherein the injectable formulation of the drug combination is injected into the tumor using a syringe or hysteroscopic needle, or injected through an opening made in the patient's abdominal wall during laparoscopic surgery, (xi) Cancer or sarcoma of the nasopharynx and larynx, and the drug combination is injected into the tumor by a laryngoscope needle, (xii) Brain cancer, and the drug combination is injected into the tumor using a syringe or fiberscope needle after drilling a hole in the corresponding skull under the use of X-ray, CT scan or MRI scan, or (xiii) Malignant lymphoma or metastatic lymph nodes, wherein the drug combination is injected into the tumor through the patient's skin using a needle, or through an incision made in the patient's abdominal wall during laparoscopic surgery, or through an incision made in the patient's chest wall during thoracoscopic surgery.

[0282] In one embodiment, the neoplasm comprises a wart, and the drug combination is injected into the wart through the patient's skin using a needle.

[0283] In one embodiment, the i) PD-1 inhibitor or PD-L1 inhibitor and ii) STING pathway agonist in the drug combination are administered using the same or different administration routes.

[0284] In one embodiment, the STING pathway agonist is injected into the neoplasm.

[0285] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor is further injected into the neoplasm or administered systemically (e.g., intravenous injection, intravenous infusion).

[0286] In one embodiment, the combination of the pharmaceuticals includes injecting i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist into the neoplasm.

[0287] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously or not simultaneously.

[0288] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor is administered before and / or after the administration of the STING pathway agonist.

[0289] For example, administer the PD-1 / PD-L1 inhibitor for at least 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h, 16 h, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 2 weeks before and / or after administration of a STING pathway agonist.

[0290] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously by intracellular injection.

[0291] In one embodiment, i) a PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the drug combination are administered simultaneously by intracellular injection, and i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist are in the same dosage form.

[0292] In one embodiment, the PD-1 inhibitor or PD-L1 inhibitor in the drug combination is administered by intravenous injection, and the STING pathway agonist is administered by intracellular injection, and the PD-1 inhibitor or PD-L1 inhibitor and the STING pathway agonist are in separate dosage forms.

[0293] In another embodiment, the present application provides a pharmaceutical kit including the aforementioned combination of pharmaceuticals.

[0294] In some embodiments, each component of the pharmaceutical combination in the pharmaceutical kit may be provided in separate, separate containers. Alternatively, the components of the pharmaceutical combination described herein may be provided in a single container. In such cases, the container may be a ready-to-administer container to a patient requiring it, such as an IV bag, ampoule, or syringe. In some embodiments, the STING pathway agonist in the pharmaceutical kit is formulated for intratumoral or intraverrucous injection. The PD-1 / PD-L1 inhibitor may be provided, for example, in the form of a powder (e.g., lyophilized powder) or a parenteral administration solution. In some cases, the PD-1 / PD-L1 inhibitor may be the anti-PD-1 / PD-L1 antibody described herein, formulated for administration, for example, by intravenous administration, intratumoral injection, or intraverrucous injection. In some embodiments, the STING pathway agonist and the PD-1 / PD-L1 inhibitor are formulated as a compound formulation for use in intratumoral or intraverrucous injection.

[0295] The contents of the pharmaceutical kits described herein may be provided in a sterile form. The pharmaceutical kits and their contents may be prepared to be provided in the form of administration to the desired subject. In such cases, the components in the pharmaceutical kit are provided as formulations and optionally in an administration device so that administration requires little further action from the user. If the pharmaceutical kit includes an administration device, such device may include, but is not limited to, syringes, pumps, bags, cups, inhalers, droppers, patches, creams, or injectors, which are known and understood by those skilled in the art for the administration routes described herein.

[0296] The pharmaceutical kits described herein may further include, for example, instructions for use, dosage, administration, contraindications and / or warnings relating to the use of such drugs.

[0297] The following examples are not intended to be limited by any theory, and are merely illustrative of the combinations and uses of the pharmaceuticals of the present application, and do not limit the scope of the present invention.

[0298] (Example) Genus, strain, sex, body weight, origin, certificate of conformity of animal species C57 / BL6JNifdc mice, female, body weight 17 - 22 g, 6 - 8 weeks old, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. [Experimental Animal Quality Conformity Certificate Number: SCXK(Beijing) 2016 - 0006].

[0299] Rearing conditions All mice had free access to food and water and were reared at room temperature (25 ± 2)°C. Both the feed and water were autoclaved, and the entire experimental rearing process was at the SPF grade.

[0300] Tumor cell lines 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.

[0301] Construction of subcutaneous transplanted tumor model The tumor cell lines were selected from the group consisting of 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 breast cancer cell lines 4T1, NAFA, etc. ?

[0302] The tumor cells were cultured, passaged, and the cells were collected during the logarithmic growth phase of the cells to prepare a cell suspension with a concentration of (1.0×10 7 ) A 1 - milliliter cell suspension was prepared, and 0.1 ml of the cell suspension (cell number 1.0×10 6 cells / mouse) was injected under the right rib of the mouse. The tumor grew to a diameter of about 5 mm in about 10 days, and the model was successfully constructed. The mice were randomly divided into 8 groups of 8 mice each.

[0303] Drug evaluation indicators Mouse body weight, tumor volume change trend, mouse survival rate, anatomical tumor weight inhibition rate.

[0304] Tumor weight inhibition rate = [1 - average tumor weight of experimental group (G2 / G3 / G4) / average tumor weight of negative control group G1] × 100%.

[0305] Drug interaction coefficient: CDI (CI) = AB / A * B. Calculated based on anatomical tumor weight, where AB is the ratio of the combined drug group to the control group. A or B is the ratio of each drug alone to the control group. If CDI < 1, the synergistic effects of both drugs are proven; if CDI = 1, the additive effects of both drugs; and if CDI > 1, the antagonistic effects of both drugs.

[0306] statistical analysis The data were represented as x±s, processed using SPSS 10.0 software, and one-way ANOVA was performed. A statistically significant difference between groups was determined if the p-value (P-value) was P<0.05.

[0307] (Example 1) Using a transplanted tumor model, we tested the inhibitory effect of a combination of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP on the growth of subcutaneous transplanted tumors in mice.

[0308] Main Exam Procedures 1.1 Mouse transplant tumor model After successfully constructing a mouse subcutaneous colorectal cancer (MC38) transplanted tumor model, the mice were randomly divided into groups of 6-8. They were administered the drug every two days for a total of three doses, followed by 15 days of observation. [Table 1] 1.2 Results As is clear from Figures 1-4, both the novel drug combination and each individual drug significantly inhibited tumor growth, and anatomical tumor weights were significantly lower than in the negative control group (P<0.01, P<0.001). The efficacy of the novel drug combination was superior to that of 2',3'-cGAMP or PD-L1 antibody RB0005 administered alone, demonstrating that the novel drug combination has superior advantages.

[0309] As shown in Figure 2, mice in the solvent control group died from day 9 (when the tumor volume of a single mouse reached 2000 mm³). 3 If the tumor volume exceeds a certain threshold, the mouse can be considered dead during the statistical analysis of mouse survival rates (this is not excluded in the tumor volume change curve analysis). The decline in survival rate was most pronounced in the solvent control group of mice between days 11 and 13, while "death" was observed in all mice in each monotherapy group on day 15, and the difference between the two groups was not significant. In the G4 test group, there was one mouse with complete tumor disappearance and one mouse with almost complete tumor disappearance (tumor volume < 100 mm²). 3 At the end of the experiment, the survival rates of the mice in each group were 0%, 37.5%, 75%, and 87.5%, respectively.

[0310] As shown in Figures 3A-3B, the tumor volume of mice in the G1 solvent control group gradually increased over time, while the increase in tumor volume in the G4 test group (RB0005+2',3'-cGAMP) mice was significantly slower, and a decrease in overall volume was observed.

[0311] As shown in Figure 4, the tumor weight of mice in the G4 test group was clearly reduced, with a tumor weight reduction rate of 73%, which was statistically significant (P<0.001).

[0312] (Example 2) The antitumor effect of a drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0313] 2.1 Mouse transplant tumor model After successfully constructing a humanized PD-1 mouse colorectal cancer (MC38) subcutaneous transplant tumor model, the mice were randomly divided into groups of 8 and administered the drug every two days. [Table 2] 2.2 Results As is clear from Figures 5 and 6, both the novel drug combination (separate dosage forms) and each monotherapy agent were able to inhibit tumor growth, and anatomical tumor weights were significantly lower in both cases than in the negative control group (P<0.05, P<0.001). This demonstrated that the efficacy of the novel drug combination was superior to that of 2',3'-cGAMP or PD-1 antibody RB0004 administered alone, indicating that the novel drug combination has superior advantages.

[0314] As shown in Figure 5, the tumor volume of mice in the solvent control group (G1) gradually increased over time, while in the monotherapy groups (G2 / G3), the increase in tumor volume was slower and smaller than in the solvent control group after treatment. In the test group (G4), the increase in tumor volume was significantly slower, and a decrease in overall volume was observed.

[0315] As shown in Figure 6, the tumor weight of the mice in the test group (G4) was clearly reduced, with a tumor weight inhibition rate of 96%, which was statistically significant (P<0.001).

[0316] (Example 3) The antitumor effect of drug combinations consisting of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP at different doses was tested using a mouse colorectal cancer MC38 transplanted tumor model to investigate its inhibitory effect on the growth of subcutaneous transplanted mouse tumors.

[0317] 3.1 Mouse transplant tumor model After successfully constructing a mouse subcutaneous tumor model, the mice were randomly divided into groups of eight and administered the treatment every two days. [Table 3] 3.2 Results As is clear from Figure 7, all three drug combinations and single agents were able to inhibit tumor growth, but the inhibitory effect of the drug combinations was more pronounced, with tumor weight inhibition rates of 90% or more in all cases (P<0.001). This indicates that the efficacy of the novel drug combinations is superior to that of PD-L1 antibody RB0005 and 2',3'-cGAMP administered alone, demonstrating that the novel drug combinations have superior advantages.

[0318] (Example 4) Using a transplanted tumor model, we tested the antitumor effect of drug combinations consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP at different doses, specifically their inhibitory effect on the growth of subcutaneous transplanted tumors in mice.

[0319] 4.1 Mouse transplant tumor model After successfully constructing a mouse subcutaneous tumor model, the mice were randomly divided into groups of eight and administered the treatment every two days. [Table 4] 4.2 Results As is clear from Figures 8-9, all three drug combinations were able to inhibit tumor growth, and the tumor weight inhibition rate was 70% or higher in all cases. In particular, the tumor inhibitory effect of the combined 2',3'-cGAMP 0.1mpk dose group was clear, and the survival rate was high (P<0.05). This indicates that the efficacy of the novel drug combination is superior to that of PD-1 antibody RB0004 administered alone, demonstrating that the novel drug combination has superior advantages.

[0320] (Example 5) The antitumor effect of a drug combination consisting of a PD-1 / PD-L1 inhibitor and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0321] 5.1 Mouse transplant tumor model After successfully constructing a mouse colorectal cancer MC38 humanized CD274 cell subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the cells every two days for a total of three doses. [Table 5] 5.2 Results

[0322] [Table 6] The results are shown in Table 1 and Figures 10 to 12.

[0323] The tumor weight inhibition rates for RB0005 monotherapy administered intraperitoneally and intratumorally (G2\G3) were 26.8% and 19.9%, respectively. When comparing cGAMP monotherapy administered intraperitoneally and intratumorally (G4\G5), intratumor administration showed better efficacy, with a tumor weight inhibition rate of 58.5%. The tumor inhibitory effect of intraperitoneal administration was not clear, and the intratumor administration showed a statistically significant difference compared to the control group (P<0.001).

[0324] The novel combination formulation (G6 / G7) was administered intraperitoneally and intratumorally. Intratumor administration showed a tumor weight inhibition rate of 81.7%, demonstrating superior tumor inhibitory activity compared to intraperitoneal administration, and the survival rate of mice at the end of the study was 100%.

[0325] The separate dosage form (G8) of the new compound formulation also showed tumor inhibitory activity, with a tumor weight inhibition rate of 78.1%, and the survival rate of mice at the end of the study was 100%.

[0326] Whether administered as separate dosage forms or single dosage forms, and whether administered intraperitoneally or intratumorally, all novel drug combinations of this application exhibited good drug synergistic effects. In this case, intratumor administration of the single dosage form of the compound formulation showed a remarkable synergistic drug effect, with a CDI interaction value of 0.55.

[0327] (Example 6) The antitumor effect of a drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0328] 6.1 Mouse transplant tumor model After successfully constructing a humanized PD-1 mouse colorectal cancer (MC38) subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0329] 6.2 Grouping [Table 7] 6.3 Results

[0330] [Table 8] The results are shown in Table 2 and Figures 13 to 15.

[0331] The tumor weight inhibition rate with RB0004 monotherapy was 60.8%, while the tumor weight inhibition rate with cGAMP monotherapy was 61.9%.

[0332] The combined formulation (single dosage form) (G4) showed remarkable tumor growth inhibitory effects, with slowed tumor growth after administration and a tumor weight inhibition rate of 93.2%, which was statistically significant compared to the control group (P<0.001). The survival rate of mice at the end of the experiment was 100%, and a remarkable synergistic drug effect was observed (CDI value = 0.45).

[0333] In summary, the single formulations of 2',3'-cGAMP and PD-1 monoclonal antibody demonstrated clear tumor inhibitory effects, high survival rates (P<0.05), and significant synergistic drug effects. The efficacy of the novel drug combination was superior to that of PD-1 antibody RB0004 alone, indicating that the novel drug combination offers superior advantages.

[0334] (Example 7) Using a transplanted tumor model, we tested the antitumor effect of a drug combination consisting of a commercially available PD-1 / PD-L1 inhibitor and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneous transplanted tumors in mice.

[0335] 7.1 Mouse transplant tumor model After successfully constructing a mouse colorectal cancer (MC38) subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0336] 7.2.1 Group 1 (PD-1 inhibitors) [Table 9] 7.3.1 Results 1 (PD-1 inhibitors)

[0337] [Table 10] The results are shown in Table 3 and Figures 16-18.

[0338] The combination formulations G4, G6, G8, and G10 of cGAMP and commercially available PD1 inhibitors showed statistically significant differences compared to the control group (P<0.001), with tumor weight inhibition rates of 88.2%, 79.1%, 93.5%, and 77.1%, respectively. All four combination formulations showed synergistic drug effects, with the G8 (scintirimab) combination formulation exhibiting the most pronounced drug synergy.

[0339] At the end of the experiment, the survival rates for the single-agent groups G2 (LPG1501), G3 (tislerizumab), and G9 (tripalimab) were over 60%, while the survival rates for the combination formulations G4, G6, G8, and G10S were all 100%, demonstrating a significant improvement in survival rates.

[0340] In summary, a combination formulation (single dosage form) of 2',3'-cGAMP and four commercially available PD-1 monoclonal antibodies demonstrated clear tumor inhibitory effects, high survival rates (P<0.05), and synergistic drug effects.

[0341] 7.2.2 Group 2 (PD-L1 inhibitor Durvalumab) [Table 11] 7.3.2 Results (PD-L1 inhibitor Durvalumab)

[0342] [Table 12] The results are shown in Table 4 and Figures 19 to 21.

[0343] A combination formulation (G4) of cGAMP and the commercially available PD-L1 inhibitor Durvalumab exhibited tumor growth inhibitory effects, demonstrating superior efficacy compared to the monotherapy of cGAMP or PD-L1 antibody, with a statistically significant difference (P<0.001), and a tumor weight reduction rate of 63.6%. At the end of the experiment, the survival rate of mice in the combination formulation group was over 80%, indicating a significant improvement in survival rate.

[0344] In summary, a combination formulation (single dosage form) of 2',3'-cGAMP and a commercially available PD-L1 monoclonal antibody demonstrated clear tumor inhibitory effects, high survival rates (P<0.05), and synergistic drug effects.

[0345] 7.2.3 Group 3 (PD-L1 inhibitor Tecentriq) [Table 13] 7.3.3 Results (PD-L1 inhibitor Tecentriq)

[0346] [Table 14] The results are shown in Table 5 and Figures 22-25.

[0347] The tumor weight inhibition rate of the combination formulation of cGAMP and RB0005 (G6) was 73.1%, which was statistically significant compared to the control group (p<0.05). The tumor weight inhibition rate of the combination formulation with the commercially available PD-L1 inhibitor Tecentriq (G4) was 62.4%, indicating that the efficacy of the combination formulation was superior to that of cGAMP or PD-L1 antibody administered alone.

[0348] During the administration period, tumor growth in the combined formulation group was slow and eventually disappeared, and at the end of the experiment, 50% of the tumors in the mice in the combined formulation group had disappeared (Tv < 80 mm). 3 ).

[0349] In summary, a combination formulation (single dosage form) of 2',3'-cGAMP, RB0005, and a commercially available PD-L1 monoclonal antibody demonstrated clear tumor inhibitory effects and high survival rates (P<0.05).

[0350] (Example 8) Using a transplanted tumor model, we tested the inhibitory effects of different drug combinations consisting of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP on the growth of subcutaneous transplanted mouse tumors during different tumor growth phases.

[0351] 8.1 Mouse transplant tumor model After successfully constructing a subcutaneous MC38 transplant tumor model of humanized CD274 for mouse colorectal cancer, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0352] 8.2 Grouping [Table 15] 8.3 Results As shown in Figure 26, Early stage of tumor growth (average volume 250 mm) 3 The tumor volume inhibition rate of the combined formulation after administration was 49.9%, which was a statistically significant difference compared to the control group (P<0.01).

[0353] Rapid tumor growth phase (average volume 500 mm) 3 The tumor volume inhibition rate of the combined formulation after administration was 55.5%, which was statistically different from the control group (P<0.05).

[0354] End-stage tumor growth (average volume 1000 mm³) 3 The tumor volume inhibition rate of the combined formulation after administration was 26.4%, which was not statistically significant compared to the control group (P>0.05).

[0355] Conclusion: The novel combination formulation (single dosage form) exhibits tumor inhibitory effects against both the early and rapid stages of tumor growth, with the inhibitory effect being particularly pronounced during the early stages of tumor growth.

[0356] (Example 9) We investigated the inhibitory effect on the growth of MC38 transplanted tumors when the small molecule STING agonist 2',3'-cGAMP was administered first, followed by the PD-L1 inhibitor RB0005 48 hours later, using a transplanted tumor model.

[0357] 9.1 Mouse transplant tumor model After successfully constructing a humanized PD-1 mouse colorectal cancer (MC38) subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0358] 9.2 Grouping [Table 16] 9.3 Results

[0359] [Table 17] The results are shown in Table 6 and Figures 27-29.

[0360] The tumor growth inhibitory effect in the sequential administration group (G4) was evident, with tumor volume continuously decreasing and eventually disappearing during the observation period after the end of administration. The sequential administration group (G4) showed a statistically significant difference compared to the control and the RB0005 monotherapy group (ANOVA, P<0.001), with a tumor weight inhibition rate of 95.5%.

[0361] When administered sequentially (small molecule, i.e., 2',3'-cGAMP, administered first, followed by the large molecule, i.e., PD-L1 monoclonal antibody), the tumor inhibitory effect was significant, and a synergistic drug effect was observed, with a CDI of 0.17.

[0362] At the end of the experiment, the survival rate of mice in the sequential combination therapy group was 100%, demonstrating a significant improvement in mouse survival compared to the control group and the RB0005 monotherapy group.

[0363] In summary, when 2',3'-cGAMP and PD-L1 monoclonal antibody were administered by first administering the small molecule and then the PD-L1 inhibitor, a clear tumor inhibitory effect was observed, improving mouse survival rates and demonstrating a synergistic drug effect.

[0364] (Example 10) The antitumor effect of a drug combination consisting of a PD-L1 inhibitor and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0365] 10.1 Mouse transplant tumor model After successfully constructing a BALBc mouse mammary cancer CT26 humanized CD274 cell subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0366] 10.2 Grouping [Table 18] 10.3 Results

[0367] [Table 19] The results are shown in Table 7 and Figures 30-33.

[0368] Tumor growth was slower during the observation period for combined formulations of different doses of cGAMP and RB0005. In the group using the combined formulation with LPG1501-1mpk, tumors (G4) decreased and eventually disappeared. At the end of the study, tumor volume was statistically significant compared to the control group (p<0.05).

[0369] In the solvent control group, the survival rate of mice on Day 11 was 0, while in the combined formulation G3 and G4 groups, the survival rate of mice was 50% or higher at the end of the study.

[0370] In summary, combination formulations (single dosage form) of 2',3'-cGAMP and RB0005 at different doses demonstrated tumor inhibitory effects and improved survival rates (P<0.05).

[0371] (Example 11) The antitumor effect of a drug combination consisting of the PD-L1 inhibitor RB0005 and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0372] 11.1 Mouse transplant tumor model After successfully constructing a BALBc mouse mammary cancer 4T1 humanized CD274 cell subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0373] 11.2 Grouping [Table 20] 11.3 Results

[0374] [Table 21] The results are shown in Table 8 and Figures 34-36.

[0375] The 4T1 model showed poor response to RB0005 monotherapy, and RB0005 monotherapy did not demonstrate a clear inhibitory effect on tumors.

[0376] cGAMP monotherapy exhibited a certain degree of tumor growth inhibitory effect in this model, with a tumor weight reduction rate of 34%. However, there was significant variation within the group, and the survival rate at the end of the experiment was 66.7%.

[0377] The tumor weight inhibition rate of the combination drug was 37.5%, which was statistically significant (P<0.05) compared to the control group and the RB0005 monotherapy group. It also showed a synergistic drug effect, with a CDI value of <1 and a survival rate of 83.3% at the end of the experiment.

[0378] In summary, a combination formulation (single dosage form) of 2',3'-cGAMP and PD-L1 monoclonal antibody exhibited a certain tumor inhibitory effect, improved mouse survival rates, and 2',3'-cGAMP enhanced the responsiveness of RB0005 to the 4T1 model.

[0379] (Example 12) The antitumor effect of a drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0380] 12.1 Mouse transplant tumor model After successfully constructing a humanized PD-1 mouse melanoma B16 subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0381] 12.2 Grouping [Table 22] 12.3 Results

[0382] [Table 23] The results are shown in Table 9 and Figures 37-40.

[0383] On day 7 after administration of cGAMP monotherapy, the tumor inhibition rate was 59%. The combined formulation (single dosage form) (G4) showed a remarkable tumor growth inhibitory effect, with tumor growth slowed after administration. The tumor inhibition rate on day 7 was 84.9%, which was statistically significant compared to the control group (P<0.001). The survival rate of mice at the end of the experiment was 100%, and a remarkable synergistic drug effect was observed (Kin's Q value = 1.8).

[0384] In summary, the single formulations of 2',3'-cGAMP and PD-1 monoclonal antibody demonstrated clear tumor inhibitory effects, high survival rates (P<0.05), and significant synergistic drug effects. The efficacy of the novel drug combination was superior to that of PD-1 antibody RB0004 alone, indicating that the novel drug combination offers superior advantages.

[0385] (Example 13) The antitumor effect of a drug combination consisting of the PD-1 inhibitor RB0004 and the STING agonist 2',3'-cGAMP, specifically its inhibitory effect on the growth of subcutaneously transplanted mouse tumors, was tested using a transplanted tumor model.

[0386] 13.1 Mouse transplant tumor model After successfully constructing a humanized PD-1 mouse lung cancer LLC-1 subcutaneous transplant tumor model, the mice were randomly divided into groups of 6-8 and administered the drug every two days for a total of three doses.

[0387] 13.2 Grouping [Table 24] 13.3 Results

[0388] [Table 25] The results are shown in Table 10 and Figures 41-43.

[0389] RB0004 monotherapy did not show any clear tumor inhibitory effect in this model, while cGAMP monotherapy did have an inhibitory effect on tumors, with a tumor weight reduction rate of 47%. The combined formulation (single dosage form) (G4) exhibited tumor growth inhibitory effects, slowing tumor growth after administration and showing a tumor weight inhibition rate of 72%, which was statistically significant compared to the control group (P<0.001), and also demonstrated a remarkable drug synergistic effect (CDI=0.55).

[0390] In summary, the single formulations of 2',3'-cGAMP and PD-1 monoclonal antibody demonstrated clear tumor inhibitory effects, high survival rates (P<0.05), and synergistic drug effects. The efficacy of the novel drug combination was superior to that of PD-1 antibody RB0004 alone, indicating that the novel drug combination offers significant advantages.

Claims

1. A combination of pharmaceuticals comprising a programmed cell death protein 1 (PD-1) inhibitor or a programmed cell death ligand 1 (PD-L1) inhibitor, and a STING pathway agonist, The PD-1 inhibitor comprises an anti-PD-1 antibody, wherein the anti-PD-1 antibody is RB0004; the PD-L1 inhibitor comprises an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is RB0005; and the STING pathway agonist is 2',3'-cGAMP. The RB0004 comprises VH and VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 8, and VL comprises the amino acid sequence shown in SEQ ID NO:

17. A combination of pharmaceuticals in which RB0005 comprises VH and VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 25, and VL comprises the amino acid sequence shown in SEQ ID NO:

37.

2. i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist in the aforementioned drug combination do not mix with each other in the drug combination. The pharmaceutical combination according to claim 1, wherein i) the PD-1 inhibitor or PD-L1 inhibitor and ii) the STING pathway agonist are in a single dosage form.

3. The pharmaceutical combination according to claim 1, wherein the amount of the STING pathway agonist present is approximately 0.0001 mg / kg to approximately 200 mg / kg.

4. The amount of the PD-1 inhibitor or PD-L1 inhibitor present is approximately 0.0001 mg / kg to approximately 200 mg / kg; The pharmaceutical combination according to claim 1, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

5. The use of the drug combination described in claim 1 in the manufacture of a drug for the treatment of neoplastic diseases, Uses in which the aforementioned neoplastic disease includes tumors and / or verrucous diseases.

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