An immunosuppressive interest

Newly published data support the potential of LNA-modified ASOs to block important immunosuppressive pathway

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MUNICH & MARTINSRIED, Germany—Secarna Pharmaceuticals GmbH has announced that data from one of its immuno-oncology programs have recently been published in Cancer Immunology, Immunotherapy in an article entitled “A highly efficient modality to block the degradation of tryptophan for cancer immunotherapy: locked nucleic acid-modified antisense oligonucleotides to inhibit human indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase expression.”
The data demonstrate that locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) efficiently block the expression of TDO2 and IDO1, which are overexpressed in a variety of tumors and have been associated with poor prognosis. Both targets are catalytic enzymes that play a key role in the degradation of tryptophan into kynurenine, which is a key immunosuppressive pathway.
“These in-vitro data support that our novel LNAplus ASOs inhibit an important immunotherapy pathway—namely, the degradation of tryptophan into kynurenine—that has not been effectively blocked by other approaches. As the majority of patients do not respond to currently available immunotherapies, new options to prevent tumors from evading the immune system are urgently needed,” said Jonas Renz, managing director and co-founder of Secarna Pharmaceuticals. “We look forward to advancing our approach, and as a next step in development, we will investigate the efficacy of these ASOs in in-vivo tumor models.”
Secarna’s approach was shown to be synergistic with epacadostat, one of the most clinically advanced IDO1-specific small-molecule inhibitors. The article concludes that the combination of IDO1- and TDO2-specific LNA-modified ASOs and small-molecule inhibitors should be considered as a strategy to reduce the degradation of tryptophan and production of kynurenine in cancer immunotherapy.
Recent attempts to target the pathway’s key enzymes IDO1 and TDO2 using small-molecule inhibitors have failed to show therapeutic benefit. But despite these results, Secarna says that there is strong support in the scientific community for both IDO1 and TDO2 as relevant targets for immunotherapy of cancer.
While conventional approaches aim to suppress a specific function of an already expressed target, Secarna’s ASO approach aims to suppress the expression of a target. The company applied its proprietary third-generation antisense drug discovery platform LNAplus to identify ASOs with specificity for IDO1 and TDO2. These ASOs have a phosphorothioated backbone and various chemical modifications. This design results in an increased stability as well as target affinity, and allows degradation of the target by a cellular enzyme named RNase H1.
The published data show that treatment of cancer cells with LNAplus-modified ASOs specific for IDO1 and TDO2 led to potent target knockdown in vitro. The degradation of tryptophan to immunosuppressive kynurenine by ASO-treated cancer cells is markedly decreased. With their unique pharmacokinetic properties that result in longer target exposure times and sustained target engagement, LNAplus-modified IDO1- and TDO2-specific ASOs offer a novel treatment modality that could efficiently reduce the degradation of tryptophan to kynurenine in cancer patients.
Secarna also recently signed a research, development and transfer agreement with Lipigon Pharmaceuticals AB. Under this agreement, Lipigon acquires certain antisense drug candidates developed with Secarna’s proprietary LNAplus platform, including the corresponding patent portfolio.
“For the past two years, we have collaborated with our colleagues at Lipigon under a highly productive discovery and research partnership. We are excited that Lipigon has selected therapeutic lead candidates generated from Secarna's LNAplus platform and will now swiftly progress them through the next stages of development,” Jonas Renz, managing director and co-founder of Secarna Pharmaceuticals, explained in a press release.
The antisense oligonucleotide candidates targeting the ANGPTL gene family were previously generated by Secarna and Lipigon under a target validation and drug discovery collaboration. Per the agreement, Lipigon will fund and continue the development of the acquired assets. Secarna will receive undisclosed payments, but further financial details were not disclosed.
“Antisense-based therapeutics have gained strong industry interest over the past five to seven years, as evidenced by major licensing and acquisitions transactions,” noted Stefan K. Nilsson, CEO and co-founder of Lipigon. “We are very pleased that our successful collaboration with Secarna has generated fully optimized, patented LNAplus antisense drug candidates ready to enter late-stage preclinical development and GMP manufacturing.”
Inhibiting the ANGPTL gene family members ANGPTL3 and ANGPTL4 with Secarna’s LNAplus-based ASOs has been shown to positively affect plasma lipid levels. Safe and effective drug candidates addressing these targets have the potential to become novel treatments of orphan diseases such as familial chylomicronemia syndrome or homozygote familial hypercholesterolemia, and more common cardiovascular, metabolic liver and kidney diseases.

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