Notch Technology

Using both allergy and transplantation model systems, it has been shown in pre-clinical research studies that activation of the Notch signaling pathway in immune cells results in antigen-specific immune suppression selective for the co-administered antigen.

During the course of immune activation, APCs present antigen to T-cells. During this interaction, Notch receptors on T-cells are activated by Notch binding proteins (Delta or Jagged) resulting in a signal important to induction of an immune response. However, when a properly modified Notch binding protein is used, the immune response to the activating antigen is suppressed (See Figure below). Our CDX-S03 product candidate, based on the Notch binding protein Delta, is designed to selectively suppress the immune response to antigen. By using antigens relevant for different diseases, CDX-S03 forms the basis of a platform for the development of selective immunomodulatory products.

Physiological triggering of Notch receptor on T-cells during antigen activation naturally modulates their response to antigen (A). Pharmacological stimulation of Notch on T cells results in suppression of the response to antigen (B).

Activation of T-cells in vitro results in the production of both inflammatory and anti-inflammatory cytokines such as TNFα and IL-10, respectively. Stimulation of the Notch signaling pathway in activated T-cells results in a marked reduction in TNFα (and other inflammatory cytokines such as interferon-γ, IL-5 and IL-13), while at the same time enhancing the production of the regulatory and anti-inflammatory cytokine IL-10. Further pre-clinical efficacy studies have shown that, when used with antigen immunization, such Notch ligand stimulation can induce antigen-specific hyporesponsiveness. Thus, this kind of Notch signaling in the presence of antigen induces antigen specific immunosuppression.

Immune enhancement via Notch

Blockade of physiological Notch signaling between immune cells can also lead to enhanced immune activation, providing further product development opportunities for the treatment of infectious diseases and cancers.