Considering B7-CD28 as a family through sequence and structure.

With the emergence of immuno-oncology, new therapeutic agents that modulate immune activation and regulation are being used to treat cancer patients with durable response. It is well known that following T-cell receptor (TCR) activation, many co-receptors can augment or suppress the TCR signal, and therapeutically targeting these co-receptors has proven effective. The B7-CD28 family is comprised of such immune-regulatory receptors, and antibodies against its members programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer treatment. These therapies promote an immune response against tumor cells, which demonstrated better long-term survival and tolerability compared to traditional cancer treatments. In this review we describe the history of the expanding B7-CD28 family, and by comparison of sequence and structure reveal that it is a non-traditional family. The family has grown to include proteins that share low sequence identity, generally grouped by regulation of immune response, which utilize the common immunoglobulin fold. This low level of commonality has provided additional challenges to the drug discovery process as the mechanisms and therapeutic potency between family members can vary greatly. Impact statement Immunotherapy as a field has dramatically expanded in the last decade in the area of oncology with efficacy demonstrated by PD-1, PD-L1, and CTLA-4 blockade. With all three "checkpoint blockade" receptors being in the B7-CD28 family, there has been increased interest in targeting other members in this family due to redundancy in immune regulation, i.e., the combination of therapeutic agents targeting multiple co-inhibitory receptors may yield additional antitumor efficacy. Therefore significant resources are being dedicated to developing additional B7-CD28 treatment options.