A Different Kind of Cytokine Therapy
We are building a pipeline of novel immunotherapies that we believe will deliver on the promise of cytokine therapeutics for patients with cancer and inflammatory diseases.
CD19 expressing cancers
GPC3 expressing cancers
Cytokine Partial Agonists
Orthogonal Cytokine Cell Therapy
Surrogate Cytokine Agonist Platform
The IL-2 receptor is expressed on the surface of most lymphocytes, in particular T cells, NK cells and B cells, and contains three possible protein chains: (i) IL-2Rα, or CD25; (ii) IL-2Rß, or CD122; and (iii) IL-2Rγ, or CD132. The trimeric, high-affinity IL-2 receptor employs all three of these chains while the dimeric, intermediate-affinity IL-2 receptor employs only the IL-2Rβ and IL-2Rγ chains. Tumor antigen-activated T cells express the high-affinity IL-2 receptor at significantly higher concentrations than any other lymphocyte.
We believe the efficacy of IL-2 is primarily driven by the proliferation and activation of tumor antigen-activated T cells, and we have engineered STK-012 to preferentially stimulate these tumor-killing T cells. In contrast, inactive, or naïve, T cells and NK cells do not express IL-2Rα and express only the intermediate affinity IL-2 receptor. We and others have demonstrated that IL-2-related toxicities, in particular CLS, are mainly driven by the non-specific activation of various lymphocytes such as NK cells. Therefore, we designed STK-012 as an α/ß-biased IL-2 partial agonist with the following three characteristics:
In syngeneic mouse efficacy models, the mouse surrogate of STK-012 demonstrated superior tumor regression compared to both wild-type mouse IL-2 and a non-α-IL-2 agent. Moreover, in mouse toxicity models, the mouse surrogate of STK-012 was well tolerated, with no cases of CLS. In contrast, wild-type IL-2 and non-α-IL-2 agents induced CLS and led to significant lethality. In non-human primates, or NHPs, STK-012 demonstrated significantly improved pharmacokinetics, or PK, and toxicity profile versus both aldesleukin and and a non-a IL-2 agent, representing a different approach by biasing IL-2 towards the dimeric, intermediate-affinity IL-2 receptor. STK-012 is now being investigated in a Phase 1a/1b study.
Unlike other CD19 CAR T therapies, SYNCAR-001 also expresses an engineered IL-2 receptor beta subunit, or hoRß, that is designed to only receive a signal from STK-009, our engineered IL-2 cytokine. STK-009 was designed specifically to stimulate hoRß-expressing cells. In the absence of STK-009, SYNCAR-001 functions as a current generation CD19 CAR T cell. However, in the presence of STK-009, a unique IL-2 signal is delivered to the adoptively transferred cells engineered to express hoRß with high specificity while avoiding stimulation of normal lymphocytes expressing the endogenous IL-2 receptors, such as NK cells, native T cells or Tregs.
We believe SYNCAR-001 + STK-009 has the potential to address the key limitations of current CD19 CAR-T cell therapies by:
In xenograft efficacy models, SYNCAR-001, followed by multiple doses of STK-009, led to significantly more complete responses, or CRs, compared to a conventional CD19 CAR T cell therapy. STK-009 + SYNCAR-001 also demonstrated CRs in bulky lymphoma models that are typically refractory to CD19 CAR T therapies. In NHP studies, STK-009 did not induce toxicity or immune activation of native lymphocytes. STK-009 + SYNCAR-001 are in IND enabling studies.
In addition to our lead programs, we have several programs in the early stages of preclinical development, including our IL-12 partial agonist for the treatment of cancer and our IL-10 partial agonist for the treatment of inflammatory disease. We are also extending our orthogonal cytokine cell therapy platform to CARs against solid tumor targets, such as GPC3, to pair with STK-009. Finally, we have multiple surrogate cytokine agonists in preclinical exploration.