New preclinical data show long-term antitumor effects of Secarna Pharmaceuticals’ antisense oligonucleotide (ASO) therapies
The findings from in vivo and in vitro studies were published in the peer-reviewed Journal for ImmunoTherapy of Cancer (JITC)
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Malignant cancer cells under microscope
“These data further support the versatility of our LNAplus™ ASO platform and its ability to offer novel therapeutic solutions to overcome cancer treatment resistance.”
Alexander Gebauer, M.D., Ph.D., CEO of Secarna Pharmaceuticals
Secarna Pharmaceuticals, an IZB-based biopharmaceutical company focusing on the discovery and development of next-generation antisense oligonucleotide (ASO) therapies to address challenging or previously undruggable targets via its LNAplus™ platform, announced the publication of striking new preclinical data demonstrating that bimodal ASOs can enable efficacious long-term antitumor immunity in tumor models compared to current immune checkpoint inhibitors. The data were published in the peer-reviewed publication, Journal for ImmunoTherapy of Cancer.
The article, “Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity,” discusses the joint work of the teams of Prof. Alfred Zippelius, Department of Biomedicine, Basel University; Prof. Mikael Pittet, Department of Pathology and Immunology, University of Geneva; and Secarna and can be found here.
The publication describes the preclinical activity of Secarna’s high-affinity bimodal LNAplus™-based ASO, IM-T9P1, that simultaneously triggers toll-like receptor 9 (TLR9) signaling and downregulates programmed cell death ligand 1 (PD-L1) expression, a protein involved in the suppression of the adaptive immune system, in one molecular entity. TLR9 signaling is an important innate immune pathway that is relevant as a first-line defense mechanism against pathogens. It is activated by DNA that contains motifs, which are frequently present in bacterial DNA. Activation of TLR9 signaling can also be achieved by synthetic oligonucleotides and hold strong potential for treating cancer; several such compounds are in clinical testing. A drawback to this approach is that the TLR9 –mediated immune response is blunted by immediate upregulation of immune checkpoints such as PD-L1. The combined downregulation of PD-L1 expression in a single-molecule approach resulted in exceptional antitumor activity in different tumor models.
Frank Jaschinski, Ph.D., Chief Scientific Officer of Secarna Pharmaceuticals, said: “The promising preclinical results seen with our bimodal ASO, IM-T9P1, pave the way for the development of combination therapies targeting TLR9 and PD-L1 for the treatment of cancer. Collectively, these data show that IM-T9P1 leads to long-lasting, adaptive antitumor immunity that can be further improved when combined with T cell-targeting immune checkpoint inhibitors and can have efficacy against large, established tumors in preclinical tumor models. These studies provide critical insight for moving forward to develop our ASOs for the treatment of cancer patients.”
Overcoming resistance to immune checkpoint inhibitors (ICIs) through ASO therapies
ICIs have transformed the treatment of cancer, producing responses in patients with various types of metastatic disease. These drugs inhibit immune-suppressive signals and reinstate cancer immunosurveillance. However, many patients either don’t respond or develop resistance to treatment, with only a minority of them showing a durable response.
The studies described in the publication evaluated the use of ASOs as potential immunomodulators and their role in overcoming immune checkpoint inhibitor resistance through its dual mechanism of action. The activity of IM-T9P1 was tested in cancer cell lines and tumor models. Treatment with IM-T9P1 resulted in the sustained activation of a specific type of tumor infiltrating cell, dendritic cells 3 (DC3s), which can promote antitumor immunity by supporting T cells with survival signals and enabling them to perform their effector functions. These results demonstrate the importance of DCs in overcoming ICI resistance and achieving effective and durable antitumor responses and, in many cases, antitumor immunity. The general concept that PD-L1 is induced after TLR9 stimulation is conserved between mice and humans. Therefore, these studies serve as a roadmap for translation to the human situation for treatment of cancer patients.
Treatment with IM-T9P1
Notably, IM-T9P1 triggered complete tumor regression in 39% (7/18) of MC38 tumor-bearing mice (compared with the 0% regression rate following PD-L1 monoclonal antibody treatment), and in 77% (30/39) of EMT6 tumor-bearing mice (compared with the 28% response rate following PD-L1 monoclonal antibody treatment). Additionally, Secarna observed a significant antitumor effect of IM-T9P1 in the D4M.3A melanoma model, which is considered poorly immunogenic and unresponsive to anti-PD-1 monoclonal antibody therapy. In addition, IM-T9P1 induced the formation of protective antitumor memory, as mice that survived the initial treatment remained tumor-free after being exposed a second time to the same tumor cell line.
“The development of novel cancer therapeutics, such as immune checkpoint inhibitors, are being advanced at unprecedented speed. However, low response rates and the increase of resistance mechanisms in patients continues to pose a challenge for the scientific and medical communities,” commented Alexander Gebauer, M.D., Ph.D., CEO of Secarna Pharmaceuticals. “Our recently published data demonstrate the potential therapeutic effect of simultaneously targeting TLR9 and PD-L1, key modulators of the innate and adaptive immune system, respectively, with a bimodal ASO. These data further support the versatility of our LNAplus™ ASO platform and its ability to offer novel therapeutic solutions to overcome cancer treatment resistance.”
About Secarna’s proprietary drug discovery and development platform, LNAplus™
Secarna’s proprietary, customized LNAplus™ platform is being applied to the discovery, testing and selection of antisense oligonucleotides (ASOs) for pre-clinical and clinical development. LNAplus™ encompasses all aspects of drug discovery and pre-clinical development and has proven to be fast, reliable, scalable and efficient, enabling the discovery of novel antisense-based therapies for challenging or currently undruggable targets. The platform includes the powerful proprietary Oligofyer™ bioinformatics pipeline, a streamlined, high efficiency screening process, including Secarna’s proprietary LNA-Vit(r)ox™ safety test system, as well as target-specific functional assays. Secarna’s platform and ASOs have been validated by numerous in-house projects as well as in several academic and industry collaborations.
Secarna Pharmaceuticals specialises in the research and development of next-generation antisense drugs
Secarna Pharmaceuticals is the leading independent European next-generation antisense drug discovery and development company addressing high unmet medical needs in immuno-oncology and immunology, as well as viral, neurodegenerative and cardiometabolic diseases. Secarna’s mission is to maximize the performance and output of its proprietary LNAplus™ antisense oligonucleotide discovery platform, as well as to develop highly specific, safe, and efficacious best-in-class antisense therapies. With over 20 discovery and development programs, including both proprietary pipeline projects and partnered programs, Secarna focuses on targets in indications where antisense-based approaches have clear potential benefits over other therapeutic modalities. www.secarna.com