Our peptide-MHC (pMHC) targeting DARPins® represent the next level of immune cell targeting in our DARPin® platform. These highly differentiated and complex therapeutic candidates are designed to engage specific pMHC complexes and attack tumors, while avoiding off-target attacks on healthy tissue, potentially delivering greater efficacy with fewer side effects. The small size and rigid binding surfaces of DARPins® make them well suited for binding to pMHC targets tucked away within dense tumor microenvironments that have been difficult to access for the large, flexible structures of antibodies.
pMHC complexes display the intracellular proteome on the surface of cells and thereby can show specific peptides for virus-infected cells or tumor cells. So far no technology, including antibodies and soluble T-cell receptors, has been able to recognize pMHC complexes with high specificity and high affinity. The need is for a molecule that can act as a bridge between specific pMHC complexes and immune cells to bring about highly-targeted destruction.
The flat binding surface of a DARPin® protein is ideally suited for binding to the small and flat target surface of the peptide held within a groove of the MHC. DARPin® proteins have shown promise at binding to pMHC complexes with high affinity and specificity.
We have demonstrated proof-of-concept for the ability of DARPin® therapeutics to effectively drug peptide-MHC complexes. We are actively screening single domain DARPin® proteins for optimal binding to a range of pMHC complexes to then design potent multi-domain DARPin® product candidates with specific and potent tumor killing effects.