Recent advances indicate that new therapeutic strategies for the treatment of malignancies will be realized from combined radiation treatment and immune checkpoint modulation. Numerous biophysical properties must be considered for effective biologic development, including affinity, selectivity, oligomeric state and valency. High-resolution structural characterization contributes to our understanding of these properties and can lead to the realization of proteins with unique in vitro activities and novel in vivo therapeutic functions. In this article we focus on the importance of these factors for new potential biologics and consider these in the context of combination therapies with physical modalities, including radiation therapy. In particular, we examine the consequences of altered avidities and subset-specific ligand density on the rational modification of biological function in the immunoglobulin and tumor necrosis factor superfamilies and for new optimized combination therapies.