OUR PLATFORMS
Harnessing the Potential
of Cytokines
We are applying multiple protein engineering platforms to create a pipeline of cytokine therapeutics for cancer and inflammatory disease.
Copyright 2023 – Synthekine
Cytokine
[sīdəˌkīn] noun
Cytokines are small proteins that facilitate communication among immune cells and orchestrate the body’s response to infections and tumors as well as its maintenance of overall immune homeostasis. Cytokines, such as interleukins, act by binding to cytokine receptors that are present on the surface of various immune cells. The binding of a cytokine on its receptors results in a cascade of intracellular signaling. However, cytokines are pleiotropic and a given cytokine can have divergent activity on multiple cell types, simultaneously resulting in both efficacious and toxic effects.
Our three protein engineering platforms
To engineer our selective cytokine partial agonists, we alter or tune the wild-type cytokine’s receptor-binding surface to enhance binding to receptors on efficacy-driving cell types and simultaneously diminish binding to receptors on toxicity-driving cell types. The result is a modified cytokine, or mutein, that allows for the selective agonism of cytokine signaling on specific cells to maximize efficacy and minimize toxicity.
For example, our data suggests that the efficacy of IL-2 is the result of the proliferation and activation of certain immune cells, namely tumor antigen-activated T cells. Furthermore, our data suggests that the toxicity of IL-2 is primarily driven by non-specific activation of a wide range of lymphocytes, such as NK cells. To address the therapeutic index challenges of IL-2, we have designed our IL-2 partial agonist, STK-012, to bias its activity towards tumor antigen-activated T cells.
We are also developing partial agonists of other cytokines, such as IL-12 for the treatment of cancer and IL-10 for the treatment of inflammatory diseases.
In order to facilitate selective in vivo activation and expansion of adoptive cell therapies, or ACTs, we have developed a novel cell therapy platform which utilizes engineered derivatives of naturally occurring cytokines that act as selective ligands for complementary, engineered cytokine receptors. This orthogonal ligand-receptor signaling platform uses a lock-and-key approach, wherein a modified cytokine receptor (the “lock”) is engineered into the ACT and can be selectively stimulated by a modified cytokine ligand (the “key”). This approach allows for cytokine-receptor binding completely independent of the endogenous cytokine system, allowing for controlled and enhanced in vivo expansion of cells of interest without toxicities emerging from the uncontrolled expansion of the infused ACT or the indiscriminate activation of the endogenous immune system.
We have designed STK-009, our orthogonal IL-2, to deliver a highly selective signal in vivo to increase the durability and potency of ACTs that are engineered to express the orthogonal IL-2 beta receptor (hoRß, the lock). Our first application for STK-009 is SYNCAR-001, a CD19-targeting chimeric antigen receptor, or CAR, T cell, which expresses hoRß to selectively receive a signal from STK-009. We believe that this technology will drive deeper and more durable responses with reduced toxicities across various cell therapy modalities.
Designing surrogate cytokine agonists represents a novel engineering approach to create a completely new pharmacologic class of cytokine therapeutics. Extracellular receptor dimerization is a fundamental mechanism by which most cytokines initiate signal transduction. Native cytokines bind to the extracellular domain of two or more cell surface cytokine receptor subunits and dimerize or multimerize the receptor to drive signaling within the cell. We have demonstrated that this intracellular signaling can be tuned by altering dimerization proximity or geometry of the cytokine receptor subunits.
Unlike our partial agonist platform, where we employ targeted mutagenesis, our surrogate cytokine agonist platform enables us to combinatorially dimerize or multimerize receptor subunits in ways wild-type cytokines or mutein-based approaches cannot. This gives our surrogate cytokine agonist platform the potential for an almost unlimited array of biased signaling possibilities, including non-natural pairing of cytokine receptor subunits to create new biology and drive novel cell selectivity and signaling. We are exploring our first sets of surrogate cytokine agonists in preclinical studies and continuing to expand our library of surrogate cytokine receptor binders.
Cytokine Partial Agonists
With this platform we aim to bias the activity of our cytokines to certain immune cell types to deliver therapeutic specificity. We do that by altering or tuning the wild-type cytokine’s receptor-binding surface to either enhance binding to efficacy-driving immune cell types or diminish binding to toxicity-driving immune cell types.
To engineer our selective cytokine partial agonists, we alter or tune the wild-type cytokine’s receptor-binding surface to enhance binding to receptors on efficacy-driving cell types and simultaneously diminish binding to receptors on toxicity-driving cell types. The result is a modified cytokine, or mutein, that allows for the selective agonism of cytokine signaling on specific cells to maximize efficacy and minimize toxicity.
For example, our data suggests that the efficacy of IL-2 is the result of the proliferation and activation of certain immune cells, namely tumor antigen-activated T cells. Furthermore, our data suggests that the toxicity of IL-2 is primarily driven by non-specific activation of a wide range of lymphocytes, such as NK cells. To address the therapeutic index challenges of IL-2, we have designed our IL-2 partial agonist, STK-012, to bias its activity towards tumor antigen-activated T cells.
We are also developing partial agonists of other cytokines, such as IL-12 for the treatment of cancer and IL-10 for the treatment of inflammatory diseases.
Orthogonal Cytokines + Cell Therapy
Our novel cell therapy platform utilizes engineered derivatives of naturally occurring cytokines and their receptors to selectively activate and expand adoptive cell therapies (ACTs) with an orthogonal ligand-receptor signaling system to overcome the limitations of cell therapies.
In order to facilitate selective in vivo activation and expansion of adoptive cell therapies, or ACTs, we have developed a novel cell therapy platform which utilizes engineered derivatives of naturally occurring cytokines that act as selective ligands for complementary, engineered cytokine receptors. This orthogonal ligand-receptor signaling platform uses a lock-and-key approach, wherein a modified cytokine receptor (the “lock”) is engineered into the ACT and can be selectively stimulated by a modified cytokine ligand (the “key”). This approach allows for cytokine-receptor binding completely independent of the endogenous cytokine system, allowing for controlled and enhanced in vivo expansion of cells of interest without toxicities emerging from the uncontrolled expansion of the infused ACT or the indiscriminate activation of the endogenous immune system.
We have designed STK-009, our orthogonal IL-2, to deliver a highly selective signal in vivo to increase the durability and potency of ACTs that are engineered to express the orthogonal IL-2 beta receptor (hoRß, the lock). Our first application for STK-009 is SYNCAR-001, a CD19-targeting chimeric antigen receptor, or CAR, T cell, which expresses hoRß to selectively receive a signal from STK-009. We believe that this technology will drive deeper and more durable responses with reduced toxicities across various cell therapy modalities.
Surrogate Cytokine Agonists
Our surrogate cytokine agonist platform does not rely on native cytokine structure. Instead, surrogate cytokine agonists are engineered as de novo structures specifically designed to dimerize or multimerize receptor subunits in ways wild-type cytokines or mutein-based approaches cannot.
Designing surrogate cytokine agonists represents a novel engineering approach to create a completely new pharmacologic class of cytokine therapeutics. Extracellular receptor dimerization is a fundamental mechanism by which most cytokines initiate signal transduction. Native cytokines bind to the extracellular domain of two or more cell surface cytokine receptor subunits and dimerize or multimerize the receptor to drive signaling within the cell. We have demonstrated that this intracellular signaling can be tuned by altering dimerization proximity or geometry of the cytokine receptor subunits.
Unlike our partial agonist platform, where we employ targeted mutagenesis, our surrogate cytokine agonist platform enables us to combinatorially dimerize or multimerize receptor subunits in ways wild-type cytokines or mutein-based approaches cannot. This gives our surrogate cytokine agonist platform the potential for an almost unlimited array of biased signaling possibilities, including non-natural pairing of cytokine receptor subunits to create new biology and drive novel cell selectivity and signaling. We are exploring our first sets of surrogate cytokine agonists in preclinical studies and continuing to expand our library of surrogate cytokine receptor binders.
Posters and Publications
IL-2
2022 – AACR
2021 – AACR
Orthogonal IL-2
2023 – Keystone Symposia
2022 – AACR
2022 – AACR
2021 – Science Translational Medicine
2021 – SITC Pre-Conference Program
2021 – The Journal of Clinical Investigation
2021 – AACR
2020 – ASH
2020 – AACR
2018 – Science
IL-12
2021 – Cell
IL-10
2021 – Science
IL-22
2021 – Immunity
IFN-gamma
2019 – Nature
IFN-lambda
2017 – Immunity
Surrogate Cytokine Agonists
2022 – Cytokines
2022 – AACR
2022 – AACR
2022 – Cell
2017 – eLife
2015 – Cell