LEAD CANDIDATES IN IMMUNO-ONCOLOGY
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 that triggers immunosuppressive Aryl Hydrocarbon Receptor signaling.
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. 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 CD39 AND CD73 INHIBITORS
CD39 is a key component within the adenosine axis. Targeting CD39 with ASOs holds several advantages compared with targeting other components. For example, it allows for accumulation of immune-stimulatory extracellular ATP (eATP) and in contrast to small molecule inhibitors of the A2A receptor it also reverses A2A receptor-independent immune suppression.
Secarna has demonstrated in syngeneic mouse models that ASOs targeting CD39 potently suppress expression of CD39 in tumor 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). Using ASOs targeting CD39 and CD73, Secarna has also demonstrated in human immune cells that relevant immunosuppressive effects are mediated in an A2Ar-independent fashion, strengthening the role of CD39 and CD73 as promising drug targets (PMID: 32739778).
FIRST-IN-CLASS IDO1 and TDO2 INHIBITORS
Within the kynurenine pathway, Secarna has shown that ASOs targeting IDO1 and TDO2 prevent kynurenine production and prevented kynurenine-mediated suppression of T cell proliferation. Combination of IDO1 ASOs with the small molecule inhibitor Epacadostat resulted in suppression of kynurenine production in a synergistic manner (PMID: 31802183).
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. 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.