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ES002: Clinical-Stage Anti-CD39 Antibody with Best-in-Class Potential

 

ES002’s dual ATP-adenosine mechanism is a potentially powerful TME regulator and transformative cancer immunotherapy. In preclinical studies ES002 demonstrated significant single agent anti-tumor activity as well as an excellent tolerability profile. ES002 has also shown superior enzymatic inhibition and binding affinity.

The ecto-ATPase CD39 is the rate-limiting enzyme in the ATP-adenosine pathway that plays an important immune regulatory role. The dual ES002 mechanism is designed to reverse immunosuppression by maintaining high levels of immune-stimulatory extracellular ATP while reducing suppressive adenosine. Blocking CD39 is expected to have a strong effect on the inhibition of Treg function, enhancing the killing function of effector T cells. 

An ES002 monotherapy Phase 1 clinical study started in the US in January 2022 and IND clearance from CDE was received in February 2022. We also plan to combine ES002 with chemotherapy in future studies.

 

CD39 Dual ATP-Adenosine Mechanism of Action

  • CD39 is pivotal in the conversion of extracellular ATP into AMP, which is then converted downstream by CD73 into immunosuppressive adenosine
  • CD39 blockade is expected to maintain extracellular ATP, a key TME inflammatory signal stimulating the immune response
  • Blocking CD39 is expected to have a strong effect on the inhibition of Treg function, enhancing the killing function of effector T cells

 

Key Differentiation

  • Differentiated dual ATP-adenosine mechanism of action versus targeting CD73
  • Demonstrated high binding affinity and enzymatic inhibition
  • Significant in vivo single agent anti-tumor activity and excellent GLP tolerability profile

 

In vitro and In vivo Properties

In vitro:
  • High binding affinity against human and cyno CD39
  • Strong enzyme inhibition effect
  • Efficient reversal of immunosuppression by adenosine mediated inhibition
    • Promotes IL-18 and IL-1β secretion (anti-CD73 antibodies have not shown this effect)
    • Promotes monocyte maturation and activation
    • Promotes NK cell activation

In vivo:

  • Demonstrated a significant single-agent anti-tumor activity in MOLP-8 PBMC humanized mice model

 

Anti-tumor activity in PBMC humanized mice

Statistically significant reduction in tumor volume observed in all groups treated with ES002 with a dose as low as 0.03mg/kg

 

Clinical Plan Highlights
  • First in human study: an open-label, phase 1 study of ES002 monotherapy (NCT05075564) is currently enrolling patients in the US. The primary objective is to determine the MTD/MAD, OBD, RP2D, safety, and tolerability with planned enrollment of approximately 60 participants
  • Plans to explore ES002 clinical activity in combination with chemotherapy
  • Indications: NSCLC, CRC, PDAC and GC

 

Publications

The anti-tumor activity of an anti-CD39 antibody (ES002) in a multiple myeloma xenograft model is dependent on NK cells and myeloid cells. SITC 2021, P790

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