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 ANTISENSE 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to PD-L1 antibodies as exemplified by durable complete tumor regression and establishment of anti-tumor immunity (unpublished data).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 signaling 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.

Secarna has successfully identified ASOs that potently reduce NRP1 expression in vitro at low concentrations. In vivo, NRP1-specific LNAplus^TM ASOs as monotherapy led to reduced tumor growth or even tumor regression in different mouse tumor models after systemic administration. Tumor tissue analysis revealed potent target knockdown in all analysed cell types that are postulated to mediate the tumor promoting roles of NRP1.

FIRST-IN-CLASS ANTISENSE 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 ANTISENSE 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.