Programs

Cytokines As Therapeutics

The cytokines IL-2 and IFN-α received FDA approval three decades ago. Although efficacious in a subset of cancer patients, widespread usage of these treatments has been limited by toxicity. Additionally, a growing body of data has implicated TGF-β as a central regulator of the tumor microenvironment. We believe targeted inhibition of this pathway may help overcome resistance to checkpoint blockade therapy.

We are developing cytokine drugs that are only active following binding to a specified target. Our therapeutics have the potential to be more effective than systemically active native or attenuated cytokines.

ATP-IFNα
ATP-IL12
LAG3-IL2
LRRC15-IFNα
LRRC15-antiTGFβR2
PD1-IL12
PDL1-IFNα

ATP-IFNα

ATP-dependent IFN-α is designed to avoid the systemic toxicity associated with recombinant IFN-α therapy. While in circulation, the therapeutic remains in an inactive conformation. Upon binding to extracellular ATP in the tumor microenvironment, ATP-dependent IFN-α undergoes a conformational change, and the IFN-α component becomes accessible to its cell surface receptor. IFN-α then drives anti-tumor immunity through signaling in multiple tumor-resident immune cell populations.

ATP-IL12

ATP-dependent IL-12 is engineered to remain inactive in circulation to avoid the systemic toxicity associated with recombinant IL-12 therapy. Following binding to extracellular ATP present in the tumor, ATP-dependent IL-12 undergoes a conformational change, and the active IL-12 component becomes accessible to IL-12R. IL-12 signaling then drives anti-cancer immunity through effector immune cell differentiation and induction of IFN-y production.

LAG3-IL2

LAG3-dependent IL-2 is designed to direct IL-2 activity to tumor-reactive T cells. LAG3 is absent on the majority of T cells in circulation. Directing IL-2 activity specifically to LAG3+ T cells has the potential to stimulate the anti-tumor T cell response while minimizing systemic toxicity.

LRRC15-IFNα

LRRC15-dependent IFN-⍺ is designed to avoid the systemic toxicity associated with recombinant IFN-⍺ therapy. LRRC15 is highly expressed on suppressive cancer-associated fibroblasts (CAFs). Upon binding to LRRC15, LRRC15-dependent IFN-⍺ undergoes a conformational change, and the IFN-⍺ component becomes accessible to receptor binding in the tumor microenvironment.

LRRC15-antiTGFβR2

LRRC15-dependent anti-TGFβR2 is designed to be inactive in circulation and avoid systemic TGF-β inhibition. LRRC15 is highly expressed on suppressive cancer-associated fibroblasts (CAFs). Upon binding to LRRC15, the therapeutic undergoes a conformational change to reveal the anti-TGFβR2 component, which will block the TGFβR2. Inhibition of the TGF-β signaling in LRRC15-expressing CAFs has the potential to reverse CAF-mediated immunosuppression, reduce tumor collagen content, and allow increased T cell infiltration.

PD1-IL12

PD-1-dependent IL-12 is designed to circulate in an inactive form, thereby reducing IL-12-driven toxicity. Upon binding to PD-1 on a tumor-reactive T cell, PD-1-dependent IL-12 undergoes a conformational change to reveal active IL-12, which can then signal in cis. In addition to selectively delivering IL-12, PD-1-dependent IL-12 functionally blocks PD-1/PD-L1 signaling.

PDL1-IFNα

PD-L1-dependent IFN-α is designed to avoid the systemic toxicity associated with recombinant IFN-α therapy. Upon binding to PD-L1, PD-L1-dependent IFN-α undergoes a conformational change, and the IFN-α component becomes accessible to its cell surface receptor.

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