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. 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	Discovery	Lead Optimization	Preclinical Development	Upcoming Milestones
PD1-IL2 IL-2 active only on T cells targeted by PD-1 antibody				Clinical candidate (1H22); IND (1H24)
PDL1-IFNα Maturation of APCs by IFNα and polarization towards immune responsiveness				Clinical candidate (2H22)
CEA-IFNα Regulated IFNα activity in CEA-tumors
LRRC15-TGFBR2 Inhibit TGF-β using a marker of CAFs
ATP-IFNα Extracellular ATP is elevated in solid tumors

Program & Rationale Stages:	Discovery	Lead Optimization	Preclinical Development	Upcoming Milestones
PD1-IL2 IL-2 active only on T cells targeted by PD-1 antibody				Clinical candidate (1H22); IND (1H24)
PDL1-IFNα Maturation of APCs by IFNα and polarization towards immune responsiveness				Clinical candidate (2H22)
CEA-IFNα Regulated IFNα activity in CEA-tumors
LRRC15-TGFBR2 Inhibit TGF-β using a marker of CAFs
ATP-IFNα Extracellular ATP is elevated in solid tumors

PD1-Dependent IL-2

An IL-2 therapeutic that is active on PD-1+ tumor-specific T-cells and has the capacity to simultaneously inhibit PD1

Sensor component:

Antibody binding domain directed against PD-1

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.

Therapeutic component:

Interleukin 2 (IL-2)

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

PDL1-dependent IFN-α will target tumor-localized immune cells while limiting adverse systemic effects.

Sensor component:

Antibody binding domain directed against PD-L1

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.

Therapeutic component:

Interferon alpha (IFN-α)

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.