ES014: Clinical-Stage First-in-Class Anti-CD39xTGF-β BsAb

ES014 is a first-in-class anti-CD39xTGF-β bispecific antibody (bsAb) that simultaneously targets the adenosine and TGF-β pathways, two major immunosuppressive mechanisms in the tumor microenvironment (TME).

Solid tumors frequently express TGF-β, which suppresses T cell activation and induces CD39 expression, the rate-limiting enzyme in the ATP-adenosine pathway. The anti-CD39 target is designed to selectively direct ES014 to the TME where the anti-TGF-β activity promotes effector T cell function and immune activation, while avoiding or minimizing systemic immunotoxicity. ES014’s anti-CD39 activity further aims to reverse TME immunosuppression by reducing suppressive adenosine, while maintaining high levels of immune-stimulatory extracellular ATP.

The combined removal of immune suppression and immune stimulating effects of ES014 were recently demonstrated in a PD-1 antibody non-responsive in vivo animal model where tumor growth was significantly inhibited after treatment.

ES014 received FDA IND clearance in May 2022 and Elpiscience plans to initiate a first-in-human trial for patients with advanced solid tumors in the U.S. in the second half of 2022.

Mechanism of Action

• Solid tumors frequently express TGF-β, which suppresses T cell activation and induces CD39 expression, the rate-limiting enzyme in the adenosine pathway
• The anti-CD39 target is designed to selectively direct ES014 to the TME where the anti-TGF-β activity promotes immune-favorable T cell activation and cytokine release, while avoiding or minimizing systemic immunotoxicity
• ES014’s anti-CD39 activity further aims to reverse TME immunosuppression by reducing suppressive adenosine, while maintaining high levels of immune-stimulatory extracellular ATP

Key Differentiation

• Unique MOA: Simultaneously targets two major TME immunosuppressive pathways
• Designed to effectively promote T cell function and activation as well as reverse immunosuppression in the TME
• Superior anti-tumor activity in PD-(L)1 non-responsive in vivo model

In vitro and In vivo Properties

In vitro:

• Inhibits CD39 expression and reverses Treg cell differentiation
• Effectively promotes T cell survival and expansion by anti- CD3/CD28 stimulation
• Promotes IL-2 and IFN-γ cytokine production leading to higher T cell activation

In vivo:

• Significantly anti-tumor activity in SK-MEL-5 anti-PD-1 resistant model

Clinical Plan Highlights

• US IND clearance received in May 2022 and expect to initiate first-in-human study in the second half of 2022

Publications

• ES014 achieved a strong single agent anti-tumor efficacy in a PD-(L)1 unresponsive mouse model. SITC 2021, P792

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