Secarna is addressing several targets within the ”immunosuppressive cloud” which enables the tumor to escape immune surveillance and destruction and that contributes to resistance to current immunotherapeutic approaches. Pathways include the adenosine axis (targeted by ASOs suppressing the expression of the ectonucleotidases CD39 and CD73) as well as the kynurenine pathway (targeted by ASOs supressing IDO1 and TDO2 expression) that triggers immunosuppressive Aryl Hydrocarbon Receptor signaling. Further promising targets addressed by Secarna are NRP1 that contributes to the immunosuppressive microenvironment via different mechanisms as well as the established target PD-L1.
Secarna has demonstrated that LNA-modified ASOs achieve a potent target knockdown in different cell types that shape the immunosuppressive tumor microenvironment after systemic administration. Secarna’s ASOs can be combined with – and allow or improve activity of – other treatment modalities such as antibody-based immune checkpoint inhibitor (ICI), cell therapies, anti-cancer vaccination and small molecule-based immune modulators. No delivery reagents are required for in vivo activity. Based on this, Secarna has established a strong pipeline of projects within the field of immune oncology.
FIRST-IN-CLASS PD-L1 INHIBITOR
PD-L1 plays a major role in suppressing the adaptive arm of the immune system, hence, we pursue an advanced program targeting PD-L1 by ASOs. The expression of PD-L1 is induced after an initial immune response and subsequently dampens further immune responses by binding to the PD-1 receptor that is expressed in effector immune cells and by triggering an immunosuppressive response. It is frequently overexpressed by cells within the tumor microenvironment and supports the tumor in evading anti-tumor immune responses. PD-L1 is a recognized tumor target as demonstrated by the clinical success of several antibody-based therapies targeting PD-L1.
Secarna has successfully demonstrated in various tumor models that PD-L1-specific ASOs have superior anti-tumor efficacy compared to PD-L1 antibodies as exemplified by durable complete tumor regression and establishment of anti-tumor immunity (unpublished data). This is most probably caused by the distinguished pharmacokinetic and pharmacodynamic properties of ASOs.
FIRST-IN-CLASS NRP1 INHIBITOR
NRP1 is a multifunctional multidomain receptor protein with multiple tumor-promoting roles that is involved in different signalling pathways. NRP1 exerts immunosuppressive functions in different immune cell types. On the one hand it supports immunosuppressive immune cells and on the other hand supresses effector immune cells. Furthermore it has l immune- independent tumor-promoting effects by induction of tumor angiogenesis and promotion of tumor metastasis and aggressiveness. These functions are mediated by different domains that cannot be simultaneously blocked by individual small molecules or monoclonal antibodies. LNAplusTM ASOs that prevent the expression of NRP1 are therefore highly suited as therapeutic modality to prevent all tumor-promoting functions of NRP1.
FIRST-IN-CLASS CD39 AND CD73 INHIBITORS
The ectonucleotidase CD39 is a key component within the adenosine axis. It converts extracellular ATP (eATP) that is released by dying cells in the tumor microenvironment into AMP. AMP is further converted by the ectonucleotidase CD73 into adenosine. While eATP can promote antitumor immune activity by activation of the innate immune system, adenosine has immunosuppressive functions. It can act directly by binding to the immunosuppressive A2A receptor that is expressed on many immune cells. Furthermore, using CD39- and CD73-specific ASOs, Secarna has demonstrated that downstream metabolites of adenosine can exert immunosuppressive activity independent of the A2A receptor (PMID: 32739778). Targeting CD39 with ASOs holds several advantages. In contrast to A2A- and CD73- inhibitors it enables the accumulation of immune-stimulatory extracellular ATP. Compared with A2A-inhibitors targeting of CD39 or CD73 also addresses the A2A receptor-independent effects of the adenosine axis by prevention of the formation of downstream metabolites.
Secarna has demonstrated in syngeneic mouse models that ASOs targeting CD39 potently suppress expression of CD39 in intratumoral regulatory T cells (Treg) and Tumor-associated macrophages. Furthermore, treatment resulted in a reduction of intratumoral Treg and suppression of tumor growth in combination with PD-1 antibody treatment (PMID: 30871609).
FIRST-IN-CLASS IDO1 AND TDO2 INHIBITORS
IDO1 and TDO2 create an immunosuppressive microenvironment by degradation of the essential amino acid tryptophan and by generation of immunosuppressive downstream metabolites like kynurenine. Secarna has identified ASOs that potently reduce TDO2 or IDO1 expression in vitro with IC50 values in the submicromolar or lower nanomolar range. In functional assays it was shown that ASOs targeting IDO1 and TDO2 prevent degradation of tryptophan and production of kynurenine resulting in reversal of suppression of T cell proliferation. Combination of IDO1 ASOs with the small molecule IDO1 inhibitor Epacadostat resulted in suppression of kynurenine production in a synergistic manner (PMID: 31802183. In vivo, IDO1-specific ASOs substantially reduced IDO1 expression in mouse tumors after systemic administration.
Fibrosis is a process characterized by excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, Fibrosis can lead to the disruption of organ architecture and ultimately result in organ failure. An important trigger for tissue injury is inflammation. Therefore, inflammation and fibrosis are processes that are frequently interconnected. Since inflammation can be triggered by tissue injury but also causes further tissue injury, often vicious cycles of persisting inflammation, frequently associated with fibrosis, are started. Aim of Secarna’s anti-inflammatory and anti-fibrotic programs is the disruption of these cycles and prevention or reversal of fibrosis.
Two mayor pathways within fibrosis and inflammation are addressed by Secarna:
1. The unfolded protein response (UPR) pathway that is triggered by endoplasmatic reticulum (ER) stress. This pathway is targeted by Secarna via ASOs suppressing the transcription factor CHOP, a key component of the UPR pathway.
2. The NLRP3 inflammasome, which is triggered by danger signals associated with infection or tissue damage and which mediates an inflammatory response by release of proinflammatory cytokines. This pathway is targeted by Secarna via ASOs suppressing the expression of NLRP3.
Organs frequently affected by inflammation and fibrosis are the liver and the kidney. ASOs are particularly suited for treatment of kidney and liver diseases, since these are the organs with the strongest biodistribution of unformulated and unconjugated ASOs after systemic administration. Furthermore efficient target knockdown in relevant target cell types within these organs is feasible.
FIRST-IN-CLASS CHOP INHIBITOR IN DIABETIC NEPHROPATHY
CHOP is a transcription factor, which is induced by ER stress. In a variety of diseases such as diabetic nephropathy, sustained activation of CHOP results in maladaptive gene expression causing fibrosis and apoptotic cell death that ultimately contribute to organ failure. As intracellular transcription factor without enzymatic function it is hard to target by conventional approaches such as antibodies or small molecules. Therefore suppression of CHOP expression by ASOs is a promising approach for treatment of diseases in which ER-stress-mediated CHOP induction plays a role.
Secarna has identified ASOs that potently reduce the expression of CHOP. In mouse models of diabetic kidney disease, treatment with Chop-specific LNAplusTM gapmers as monotherapy resulted in a significant therapeutic benefit. Furthermore, in combination with standard of care ACE inhibitor, an on top effect with regards to amelioration of glomerular and tubular damage was observed (PMID: 34479965).
FIRST-IN-CLASS NLRP3 INHIBITOR FOR TREATMENT OF INFLAMMATORY DISEASES
NLRP3 is the central component of the NLRP3 inflammasome complex, a part of the innate immune system that is – amongst others – responsible for pathogen defense. It is activated by pathogen associated molecular patterns (PAMP) during infection or damage associated molecular pattern (DAMP) after tissue injury. Stimulation of the inflammasome results in activation of Caspase-1 which promotes the maturation and release of the proinflammatory cytokines IL-1β and IL-18. Furthermore Caspase-1 activation can lead to pyroptotic cell death. In addition, Caspase-1 independent effects of NLRP3 are reported that contribute to pathology. Aberrant NLRP3 activity contributes to inflammation, issue damage and fibrosis in many diseases such as Non-Alcoholic SteatoHepatitis (NASH) or acute and chronic kidney diseases. Moreover, cryopyrin-associated periodic syndrome (CAPS) is a group of inherited autoinflammatory diseases that is directly caused by activating mutations within the NLRP3 gene.
Currently approved approaches for treatment of diseases mediated by the inflammasome consist in blocking IL-1β activity via antibodies, receptor antagonists or ligand traps. This however covers only one pathological aspect of the inflammasome. Direct targeting of NLRP3 by ASOs that prevent its expression is a more promising approach since this covers all aspects of the NLRP3 inflammasome.
Secarna has identified ASOs that potently reduce the expression of NLRP3. It was demonstrated that -after treatment with NLRP3-specific ASOs- Caspase-1 activity was potently reduced and maturation and release of mature IL-1β was practically completely blocked. In a mouse model for CAPS, systemic treatment with NLRP3-specific ASOs reduced NLRP3 expression and generation of mature IL-1β. A substantial prolongation of survival of mice could be achieved.
Within our high-value partnerships, we currently have a total of 19 high-impact programs in the areas of oncology and inflammatory/fibrotic, viral, neurodegenerative, neurodevelopmental, neuromuscular as well as cardiometabolic diseases. We are interested to expand our partnering approach by further collaborations in existing and new therapeutic areas, leveraging our validated approach to generate co-owned ASO pipelines.