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JP-7854724-B2 - Combinations of pharmaceuticals and their use

JP7854724B2JP 7854724 B2JP7854724 B2JP 7854724B2JP-7854724-B2

Inventors

  • 王晨光
  • 張暁嬌
  • 党暁萌
  • 張晋
  • 付雨▲テイ▼
  • 王一涵
  • 王超

Assignees

  • 天津立博美華基因科技有限責任公司

Dates

Publication Date
20260507
Application Date
20220520
Priority Date
20210521

Claims (5)

  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 R B000 4 ; the PD-L1 inhibitor comprises an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is R B000 5 ; 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.

Description

This application relates to the field of biomedicine, specifically to the development and use of drug combinations. Over the past decade, targeting PD-1 and PD-L1 has ushered in a new era for cancer clinical treatment. However, in many tumor types, immune checkpoint inhibitors are not well-received as monotherapy. Even against immune-responsive tumors, most patients do not experience sustained clinical benefit. The vast majority of patients develop primary or acquired treatment resistance. In most cases, resistance to immunotherapy is due to the presence of immunosuppressive TMEs and the insufficient reduction in immune cell counts in vivo to activate T-cell antitumor effects. Therefore, it is particularly important to actively pursue new therapeutic strategies that can reduce immunosuppression in the tumor environment or enhance the cytotoxic response against the tumor, compared to monotherapy. The PD-L1/PD-1 signaling pathway is a crucial co-inhibitory signaling pathway in immune responses. Studies have shown that when PD-L1 binds to PD-1, it replenishes the SH2-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2. These two phosphatases reduce the phosphorylation of the CD3ζ chain's immune receptor tyrosine activation motif (ITAM), weakening ZAP-70 activation and inhibiting signal transduction downstream of the TCR. This co-inhibitory effect on T cell activation, and this negative regulatory effect prevents autoimmune damage caused by excessive activation of effector T cells. 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 ultimately killing tumor cells. The STING pathway can also be activated by synthesized cyclic dinucleotides (CDNs) to trigger a specific immune response. The combined use of PD-L1/PD-1 inhibitors and STING pathway agonists releases inhibitory signals, enhances T cell activation, and promotes adaptive immune responses. Simultaneously, it induces INF and cytokine expression, promotes T cell aggregation, and activates innate immune responses. This combined effect enhances the cytotoxic response of cells against tumors and other pathogens, demonstrating significant clinical potential and application value. 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 HIV-specific CD8+ T cells. The virus activates the PD-L1/PD-1 signaling pathway, inhibiting the activity of HIV-specific CD8+ T cells, significantly weakening cytokine secretion and T cell proliferation, and leading to adaptive immune dysfunction. Therefore, this treatment method may have considerable potential applications in the treatment of this type of disease. 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: In vivo efficacy study of the drug combination of the PD-L1 inhibitor RB0005 and 2',3'-cGAMP described in this application - showing the change in body weight of mice in each group during the administration period. 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. 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. 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. In vivo efficacy study of the drug combination of the PD-1 inhibitor RB0004 and 2',3'-cGAMP described in this application - showing tumor growth changes in mice in each group during the administration period. 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 i