Poster abstracts
Poster number 33 submitted by Nicholas Long
Engineering Polyvalent DLL1 Ligands for Cancer Immunotherapy
Nicholas E. Long (Ohio State Biochemistry Program), Ming Poi (The Ohio State University College of Pharmacy), Mikhail M. Dikov (The Ohio State University College of Medicine), Thomas J. Magliery (The Ohio State University Department of Chemistry and Biochemistry)
Abstract:
Currently, immunotherapy is one of the most promising forms of cancer therapy. This treatment method relies on the host immune system’s natural ability to fight aberrant cell development and growth (i.e. cancer). However, in many cases a tumor finds ways to evade immune cell detection. Undeterred, these cancers can continue to grow and metastasize, leading to progression of the disease and poor patient prognosis. Previous proof-of-concept experiments performed in the Dikov lab have shown promise in “re-energizing” immune T-cell function even after cancer has previously evaded detection. Through activation of the Notch signaling pathway in T-cells using clustered DLL1 ligands, mouse model studies have shown overall decreased tumor growth and longer survival time. Unfortunately, this DLL1 cluster does not satisfy requirements for FDA approval, cannot be patent protected, and is economically unfeasible for large-scaled industrial production. For these reasons, an alternative protein therapeutic is needed which has the same potency (and mode of Notch activation) as the DLL1 cluster, but without its restrictions.
In a collaborative effort directed by The Ohio State Drug Development Institute, the Dikov, Poi, and Magliery Labs have successfully engineered and characterized a new multivalent DLL1 ligand based Notch activator. This was accomplished by truncation studies of DLL1 which indicated the minimum domains required for function and various genetic and chemical methods to make multivalent conjugates thereof. This protein therapeutic has been shown in vitro to activate the Notch signaling pathway in mouse EL4 T Cells, is novel intellectual property, and can be reliably and cheaply produced in E. coli. It is our hope that with the addition of in vivo tumor studies, we will have created a novel immunotherapy cancer drug with broad applications.
Keywords: Immunotherapy, Protein Engineering, Cancer