OUR PIPELINE

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.

Program

Platform

Discovery
Pre-clinical

IND Enabling

Phase 1

Phase 2

Phase 3

Worldwide
Rights

Oncology

STK-012: IL-2 Partial Agonist

Phase 1

STK-009 + SYNCAR-001 (OrthoIL2 + CD19 OrthoCAR)

Phase 1

± lymphodepletion

STK-026: IL-12 Partial Agonist

IND Enabling

STK-009 + SYNCAR-002 (OrthoIL2 + GPC3 OrthoCAR)

IND Enabling

Undisclosed

Discovery
Pre-clinical

Autoimmune & Inflammation

STK-009 + SYNCAR-001 (OrthoIL2 + CD19 OrthoCAR)

Phase 1

no lymphodepletion

IL-10 Program

+

Discovery
Pre-clinical

IL-22 Program

+

Discovery
Pre-clinical

Undisclosed

Discovery
Pre-clinical

Engineered Cytokine Partial Agonist

Surrogate Cytokine Agonist

Orthogonal Cytokine + Cell Therapy

STK-012

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 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:

  1. Proliferate and activate antigen-activated T cells
  2. Avoid NK cell-driven toxicity
  3. Improve the CD8+ T cell to regulatory T cell ratio in the tumor microenvironment

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.

STK-009 + SYNCAR-001

Several CAR T cell therapies targeting CD19, a cell-surface antigen that is present on B cells, are FDA-approved for the treatment of advanced, refractory hematologic malignancies such as lymphoma. These therapies can lead to long-term remissions and cures for patients. However, median progression-free survival, or PFS, is limited to less than six months in lymphoma patients, and approximately half of all patients who initially respond will relapse.

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:

  • Increasing the activity of CAR T cells to improve the magnitude of clinical responses
  • Increasing CAR T expansion and persistence, thereby improving the durability of clinical responses
  • Enabling lower initial doses of CAR T cells to reduce toxicity
  • Reducing or eliminating lymphodepletion to lower the risk of infection

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.

Additional Programs

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.