NSCLC, RCC, and other select solid tumors
Phase 1
Solid tumors
IND Enabling
Inflammatory diseases
Discovery
Pre-clinical
Inflammatory and metabolic diseases
Discovery
Pre-clinical
Autoimmune diseases
Discovery
Pre-clinical
Undisclosed
Discovery
Pre-clinical
(CD19 orthoCAR-T + orthoIL-2)
CD19+ malignancies
Phase 1
(CD19 orthoCAR-T + orthoIL-2)
Systemic lupus erythematosus (SLE) and lupus nephritis (LN)
Phase 1
(GPC3 orthoCAR-T + orthoIL-2)
Hepatocellular carcinoma
IND Enabling
Undisclosed
Discovery
Pre-clinical
Our most advanced product candidate, STK-012, is a modified IL-2 cytokine. IL-2 is a master modulator of the immune system, stimulating cell proliferation, survival and differentiation in a diverse set of immune cells. A recombinant IL-2 therapy, aldesleukin (marketed as Proleukin), is approved for and has compelling efficacy in certain cancers, however it is not widely used because it can only be administered for a short course of therapy due to risk for severe toxicities such as capillary leak syndrome, or CLS.
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 trimeric, 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, NK cells and naïve T cells do not express IL-2Rα and express only the dimeric, 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 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 1b study (NCT05098132).
Our lead cytokine-inducible cell therapy candidate using orthoIL-2 technology is SYNCAR-001, an autologous CD19 orthoCAR-T cell combined with STK-009, our orthoIL-2 ligand. Several CAR T cell therapies targeting CD19 are FDA-approved for the treatment of advanced, refractory hematologic malignancies such as lymphoma, and can lead to long-term remissions and cures for patients. In addition, recently published data on the use of CD19 CAR-T cells in autoimmune disease has shown extraordinary efficacy and highlights both the unmet need and therapeutic potential of STK-009 + SYNCAR-001 in lupus and other B-cell mediated diseases.
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 orthogonal 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 SYNCAR-001 cells 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. Syngeneic mouse models also demonstrate the ability to clear tumors or eliminate B cells in the absence of lymphodepletion. In NHP studies, STK-009 did not induce toxicity or immune activation of native lymphocytes.
STK-009 + SYNCAR-001 is now being investigated in a Phase 1 study (NCT05665062). STK-009 dose escalation is ongoing and the fixed dose of SYNCAR-001 cells is significantly lower than traditional CD19 CAR-T therapies. The initial clinical investigation is in CD19+ hematologic malignancies. Given the promise for the mechanism of SYNCAR-001 in B-cell mediated autoimmune diseases, such as systemic lupus erythematosus (SLE), we plan to expand the development into non-renal SLE and lupus nephritis (LN). Across both cancer and autoimmune indications, we will treat patients without lymphodepletion.
In addition to our lead programs, we have several programs in preclinical development, including our IL-12 partial agonist for the treatment of cancer and our IL-22 partial agonist for the treatment of inflammatory and metabolic disease. We are also extending our orthogonal cytokine-inducible 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 internally as well as in partnerships.