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. Targeted, locally activated cytokine drugs will be more effective than systemically active native or attenuated cytokines.
Our portfolio includes five regulated immunocytokine programs, each with blockbuster potential:
Program & Rationale Stages: | Discovery | Lead Optimization | Preclinical Development | Upcoming Milestones |
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IL-2 active only on T cells targeted by PD-1 antibody
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Clinical candidate (1H22); IND (1H24)
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Maturation of APCs by IFNα and polarization towards immune responsiveness
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Clinical candidate (2H22)
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CEA-IFNα
Regulated IFNα activity in CEA-tumors
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LRRC15-TGFBR2
Inhibit TGF-β using a marker of CAFs
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ATP-IFNα
Extracellular ATP is elevated in solid tumors
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An IL-2 therapeutic that is active on PD-1+ tumor-specific T-cells and has the capacity to simultaneously inhibit PD1
PD-1 expression identifies activated tumor-reactive T cells, whereas it is absent on the majority of T cells in circulation. Directing IL-2 activity specifically to PD-1+ T cells has the potential to stimulate the anti-tumor T cell response while minimizing systemic toxicity.
IL-2 promotes the growth and differentiation of activated T-cells and natural killer (NK) cells. High-dose IL-2 is approved for the treatment of cancer, but its clinical usage is limited by toxic side effects.
PDL1-dependent IFN-α will target tumor-localized immune cells while limiting adverse systemic effects.
Elevated and dysregulated expression of PD-L1 allows tumors to evade the
anti-tumor
immune response. PD-L1 is expressed on both tumor cells and immune
cells within the tumor microenvironment. Elevated PD-L1 expression is
correlated with a poor prognosis in a variety of solid tumors.
IFN-α increases MHC-I expression on tumor cells, drives innate immune cell activation and cross-presentation, and potentiates
T-cell
effector function. Recombinant IFN-α has demonstrated efficacy in
melanoma and renal cell carcinoma, but its clinical usage is limited by
adverse side effects.