Immunomodulating agents engineered from Notch receptor ligand extracellular domains
T2017-177 Immunomodulating agents have been engineered from Notch receptor ligand extracelluar domains. These are useful for stimulating the immune system.
The Notch signaling pathway is important in immune cell differentiation and maturation. As a result, it has been shown that Notch receptor signaling can promote or suppress adaptive immune responses depending on the particular ligands and receptors involved. A set of native protein-inspired biologics that elicit predictable effects on the immune system could be harnessed for diverse therapeutic uses such as promoting immunosurveillance to treat cancer or achieving immunosuppression for the treatment of conditions featuring undesired immune activation.
Modulation of Notch signaling in immune cells may allow therapeutic tuning of the immune response in both cancer and non-cancer indications. In published research, a multivalent Notch agonist, clustered DLL1, resuscitates immunosurveillance of tumors in vivo. Prompted by the proof of concept work with this tool compound, multiple biological constructs have been designed and are under evaluation by researchers at The Ohio State University in order to selectively stimulate or inhibit Notch signaling in immune cells for therapeutic benefit. The researchers will continue to generate and evaluate new protein constructs for further development as immune stimulators and inhibitors. An assay could be developed to allow more complete characterization of the effects of these constructs on Notch signaling and immune cell function.
- Modulators of Notch Signaling to Increase Immune Response:
- Hematological Malignancies
- Solid Tumors
- Modulators of Notch Signaling to Decrease Immune Response:
- Acute Graft-Versus-Host Disease
- Native protein-inspired biological ligands may have the potential to elicit agonist or antagonist effects at specific sets of Notch receptor isoforms.
- Combination therapy with approved therapeutics may provide a synergistic effect.