A Phase IIa, randomized, double-blind, placebo-controlled, study of HIV-1 Vaccines MVA.HTI and ChAdOx1.HTI with TLR7 agonist vesatolimod (GS-9620), in early treated HIV-1 infection

开始日期2019-05-09

申办/合作机构

Aelix Therapeutics SL

100 项与 TLR7 agonists(Punjabi University) 相关的临床结果

登录后查看更多信息

100 项与 TLR7 agonists(Punjabi University) 相关的转化医学

登录后查看更多信息

100 项与 TLR7 agonists(Punjabi University) 相关的专利（医药）

登录后查看更多信息

290

项与 TLR7 agonists(Punjabi University) 相关的文献（医药）

2026-01-01·JOURNAL OF PHARMACEUTICAL SCIENCES

Investigation of synergistic effects of β-defensin, vesatolimod and resiquimod in increasing the potency of a therapeutic HIV-1 vaccine candidate

Article

作者: Bolhassani, Azam ; Nekouian, Reza ; Agi, Elnaz ; Alarzi, Seyedeh Somayeh Hosseini

Improvement of therapeutic vaccination strategies is critical to control the human immunodeficiency virus-1 (HIV-1) infection. The goal of this study is to determine the immunostimulatory effects of toll-like receptor (TLR) agonists including β-defensin (TLR4 agonist), vesatolimod (GS-9620: TLR7 agonist) and resiquimod (R848: TLR7/8 agonist) as individual or combined with the Nef^mut-Tat antigen candidate in BALB/c mice. The results of immune responses for groups receiving the recombinant Nef^mut-Tat protein (∼ 35 kDa) and the recombinant β-defensin-Nef^mut-Tat protein (∼ 45 kDa) showed that the linkage of β-defensin to Nef^mut-Tat protein could significantly increase the secretion of IFN-γ, TNF-α and Granzyme B. Furthermore, the highest levels of IFN-γ, TNF-α and Granzyme B was observed in group receiving β-defensin-Nef^mut-Tat protein + GS-9620 + R848 regimen indicating the potent synergistic effects of TLR agonists on induction of cellular immunity (i.e., stimulation of T-helper 1 cells and cytotoxic T lymphocytes). This regimen could significantly induce IFN-γ and TNF-α in splenocytes infected with single-cycle replicable (SCR) HIV-1 in vitro, as well. It was interesting that no significant differences in TNF-α and Granzyme B secretion were observed between groups receiving β-defensin-Nef^mut-Tat protein + GS-9620 and β-defensin-Nef^mut-Tat protein + R848; although group receiving β-defensin-Nef^mut-Tat protein + R848 could significantly induce IFN-γ secretion in uninfected and infected splenocytes compared to group receiving β-defensin-Nef^mut-Tat protein + GS-9620. These findings demonstrated that the simultaneous use of TLR 4, 7 and 8 agonists could improve and maintain cellular immunity against SCR HIV-1 infection suggesting an effective approach for eradication of latent HIV reservoir.

2025-11-01·Infectious Diseases and Therapy

The Effects of Cobicistat and Voriconazole on the Safety, Pharmacokinetics, and Pharmacodynamics of the TLR7 Agonist Vesatolimod in People with HIV

Article

作者: Wen, Anita ; Cruz, Kimberly ; Cai, Yanhui ; Wallin, Jeffrey J ; deVries, Christiaan R ; Omange, Robert Were ; Hassman, Howard ; Zheng, Yanan ; Rondon, Juan Carlos ; Zhang, Liao ; West, Steve ; Chen, Buyun ; Huang, Susie S Y ; Lim, Daina ; Osiyemi, Olayemi ; Wire, Mary ; SenGupta, Devi

INTRODUCTION:

Vesatolimod (VES), a toll-like receptor 7 agonist, is being investigated as part of a strategy for human immunodeficiency virus (HIV) cure. VES is metabolized through the CYP3A pathway and is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This study evaluated the impact of coadministration of VES with cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor) or voriconazole (VOR; a strong CYP3A inhibitor with no effect on transporters) on the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VES in people with HIV (PWH).

METHODS:

A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2 mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150 mg COBI once daily for 5 days in period 2, and 400 mg VOR on day 1 and 200 mg twice daily on days 2-6 in period 3. Blood samples were collected to measure VES PK, expression of interferon-stimulated genes (ISGs), cytokine/chemokine levels, and immune-cell phenotyping.

RESULTS:

Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (C_max), area under the concentration-time curve extrapolated to infinity (AUC_inf), and half-life (t_1/2) 7.5-, 4.3-, and 1.2-fold, respectively, but did not increase the mRNA expression levels of ISGs, serum cytokines/chemokines, or expression of activation markers on peripheral natural killer or T cells compared with VES alone. There were no serious adverse events, and no participants discontinued study drugs due to study-drug-related adverse events.

CONCLUSIONS:

VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A).

TRIAL REGISTRATION:

ClinicalTrials.gov NCT05458102.

2025-10-01·COLLOIDS AND SURFACES B-BIOINTERFACES

Synergistic anti-tumor effects of mRNA vaccine and PERK inhibitor combination in melanoma treatment

Article

作者: Gou, Guojing ; Guo, Jueshuo ; Wei, Yaya ; Ma, Shijie ; Li, Xiaolong ; Mai, Yaping ; Ma, Lanlan ; Zuo, Wenbao ; Yang, Jianhong

Melanoma is a highly aggressive form of skin cancer. mRNA vaccines deliver genetic material encoding specific antigens into cells, thereby triggering the host immune system to produce the antigen. Gp-100, an antigenic protein expressed on the surface of melanoma cells, serves as a target mRNA to stimulate the cytotoxic T lymphocyte (CTL) response. However, the absence of natural killer (NK) cells can lead to significant tumor cell proliferation. Gardiquimod, a TLR7 agonist, enhances NK cell cytotoxicity, promoting tumor clearance. In advanced melanoma, the unfolded protein response (UPR) often becomes dysregulated. By inhibiting protein kinase R-like ER kinase (PERK), the UPR can be disrupted, inducing apoptosis in cancer cells and shifting the tumor microenvironment (TME) towards an increased M1/M2 macrophage ratio. This study developed a cationic liposome-based mRNA vaccine (GD-LPR) using DOTMA to co-deliver gp-100 mRNA and the TLR7 agonist Gardiquimod, combined with the PERK inhibitor GSK2656157 (GSK), for synergistic melanoma immunotherapy. GD-LPR achieved 95 % mRNA encapsulation efficiency and demonstrated enhanced dendritic cell maturation and NK cell activation both in vitro and in vivo. In subcutaneous melanoma models, GD-LPR+GSK reduced tumor volume and prolonged survival by modulating the tumor microenvironment (TME): increasing CD8⁺ T cells (Fig. 3 f), repolarizing M2 to M1 macrophages (Fig. 4 f), and suppressing IL-10 while elevating pro-inflammatory cytokines (IL-2, IFN-γ, TNF-α). Mechanistically, GSK inhibited PERK/ATF-4 signaling, synergizing with GD-LPR to suppress lung metastasis. The combination of the GD-LPR vaccine and GSK provides new potential strategies for treating melanoma, particularly in subcutaneous tumors and lung metastases.

项与 TLR7 agonists(Punjabi University) 相关的新闻（医药）

2023-12-29

·SYNAPSE

What are TLR7 agonists and how do you quickly get the latest development progress?

TLR7, or Toll-like receptor 7, is a crucial component of the innate immune system in humans. It is a pattern recognition receptor that recognizes viral RNA and triggers an immune response against viral infections. TLR7 is primarily expressed in immune cells such as dendritic cells and macrophages. Upon activation, TLR7 initiates a signaling cascade that leads to the production of pro-inflammatory cytokines and type I interferons, which are essential for antiviral defense. Understanding the role of TLR7 in the human body is vital for developing therapeutic interventions targeting viral infections and autoimmune diseases. The analysis of target TLR7 from various perspectives provides valuable insights into the current competitive landscape and future development. Companies such as Roche Holding AG, Viatris Inc., and Bausch Health Cos., Inc. have shown significant progress in the development of drugs targeting TLR7. Indications such as hepatitis B, various types of cancer, and infectious diseases have received attention in the development of drugs under target TLR7. The presence of small molecule drugs and monoclonal antibodies indicates intense competition, while the involvement of biosimilar research and development institutions should be monitored. The United States, European Union, and China are leading in terms of research and development activities for target TLR7. Overall, the analysis suggests a promising future for the development of drugs targeting TLR7, with potential breakthroughs in the treatment of various diseases. How do they work?TLR7 agonists are a type of compounds that activate Toll-like receptor 7 (TLR7) in the immune system. Toll-like receptors are proteins that play a crucial role in recognizing and responding to pathogens, such as viruses and bacteria. TLR7 specifically recognizes viral RNA, triggering an immune response to eliminate the invading virus. TLR7 agonists are designed to mimic viral RNA and activate TLR7, thereby stimulating the immune system to mount a robust antiviral response. They can enhance the production of cytokines, such as interferons and pro-inflammatory molecules, which help in the elimination of viral infections. Additionally, TLR7 agonists can promote the maturation and activation of immune cells, such as dendritic cells, which are essential for initiating and coordinating immune responses. From a biomedical perspective, TLR7 agonists have gained attention as potential therapeutic agents for viral infections, including respiratory viruses like influenza and SARS-CoV-2 (the virus causing COVID-19). By activating TLR7, these agonists can boost the immune response against the virus, potentially reducing viral replication and improving clinical outcomes. It is important to note that TLR7 agonists are still under investigation and development, and their safety and efficacy need to be thoroughly evaluated through preclinical and clinical studies before they can be used as approved treatments. List of TLR7 AgonistsThe currently marketed TLR7 agonists include: ImiquimodAfimetoranAL-034BDB-001(Seven and Eight Biopharm)BDC-1001BNT-411DSP-0509EnpatoranNKTR-262ResiquimodFor more information, please click on the image below. What are TLR7 agonists used for?TLR7 agonists are primarily being studied for their role in immunotherapy, specifically in oncological indications. For more information, please click on the image below to log in and search. How to obtain the latest development progress of TLR7 agonists?In the Synapse database, you can keep abreast of the latest research and development advances of TLR7 agonists anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与 TLR7 agonists(Punjabi University) 相关的药物交易

登录后查看更多信息