Structural Properties of Unique Antibodies with TCR-Like Specificity Utilized for Cancer and Autoimmune Disease Therapy

For over a decade, our lab and others have been producing and characterizing a new family of antibodies (Abs) against cancerous and autoimmune diseases. These Abs are uniquely capable of recognizing MHC-restricted targets with a T cell receptor-like (TCRL) specificity, within a binding range of micro to nano molar disassociation constant affinity. These can be exceptionally utilized in different modes of action for therapeutic modalities. In this study, our aim is to understand the structural properties of the cognate ligand binding of the TCRLs at the atom level with X-ray Crystallography. The study considers both classes of the MHC, i.e. class I and class II. In class I-MHC, a massive over-presentation of Tyrosinase peptide has been observed on Melanoma lines in the context of HLA-A2 complex. As a therapeutic candidate target, many TCR-Like Abs have been produced against HLA-A2-Tyosrinase by utilizing phage-display and hybridoma techniques, thus yielding Abs with different amino-acid sequences that are translated into different binding affinities and specificity qualities. Our purpose is to solve structures of TCRL Abs selected from a scale of high to low affinity levels, in their bound state, to analyze their modes of binding with diverged affinities and understand the structural basis for this .In class II-MHC, novel TCRL Abs have been isolated and characterized in our lab towards MHC-peptide complexes associated with Multiple sclerosis autoimmune disease. Structural analysis of class II-MHC TCRL Abs is considered novel and thus may provide pivotal insights into an undiscovered family of immune-modulatory therapeutic TCRL Abs.