T cell exhaustion prevents effective immune responses against many tumors and chronic infectious diseases. Several antibody drugs termed ?checkpoint inhibitors? target receptors (e.g. PD-1, PD-L1, CTLA4) on exhausted T cells and can reverse their phenotype, leading to re-activation and the ability to function as killer cells. While molecules such as PD-1, PD-L1, LAG-3, Tim-3, TIGIT and ICOS have been described as markers of exhausted T cells, the cell surface phenotype is insufficiently defined; thus, more markers and possible drug targets may exist on the surface of exhausted T cells. Cluster of Differentiation (or ?CD?) molecules were traditionally defined based on the reactivity of monoclonal antibodies to the cell surface of leukocytes. These antibodies were identified by immunizing rodents with preparations of white blood cells. It has recently become clear that the antibody repertoires of different species are dramatically different with regards to their structural diversity. Cows, in particular, have heavy chain complementarity determining regions (CDR H3s) of up to 70 amino acids in length comprised of novel ?-ribbon ?stalk? and disulfide bonded ?knob? mini domain structures. This contrasts with rodents, where antibodies for most CD molecules were discovered, whose antibodies have flat binding surfaces comprised of very short (10 amino acids) CDR H3 loops. Cow antibodies have the ability to bind epitopes that are relatively refractory to other species? repertoires, and provide a novel opportunity to further define the exhausted T cell surface. To this end, we will immunize cattle with exhausted T cells and identify unique antibody:antigen pairs and demonstrate functional activity of the antibodies by in vitro and in vivo reversal of the exhausted T cell phenotype. Antibodies from this research could serve as experimental therapeutics for cancer or chronic infection, diagnostics, or important research tools to further define exhausted T cell subsets and differentiation pathways.
T cell exhaustion is a feature of several cancers and chronic infections that can be treated by monoclonal antibodies targeting ?checkpoint inhibitor? proteins on the cell surface. Defining exhausted T cell surface biology, and discovering new targets for therapy, is a major goal in cancer immunotherapy. We have discovered a very unique structural feature specific to cow antibodies that enables antibody binding to certain challenging epitopes, and will apply this novel cow antibody repertoire to discover new antigens and their cognate antibodies to the exhausted T cell surface to ultimately discover new therapeutic antibodies for cancer and infectious diseases.