Engineered CD80 as a promising approach to block CTLA-4 for cancer immunotherapy

Immune checkpoint inhibitors, such as monoclonal antibodies or engineered small molecules, are a novel approach to cancer immunotherapy and are being used to treat several types of cancer. CTLA-4, an immune checkpoint, is expressed on the surface of activated T cells where it downregulates immune responses. CD80, also known as B7-1, is a common ligand for CTLA-4 and the T cell co-stimulatory protein CD28. In this study, to inhibit CTLA-4, a variant of the extracellular domain of CD80 (mCD80) carrying the A29Y, Y31R, and Q33K mutations to increase its binding affinity to CTLA-4 was recombinantly expressed in Escherichia coli. The equilibrium dissociation constant (K_D) for the binding of mCD80 to both CD28 and CTLA-4 was also calculated using surface plasmon resonance (SPR) technology. The results showed a significant increase in the binding affinity of mCD80 to CTLA-4, with a 69.76-fold increase compared to wild-type CD80. In contrast, the binding affinity of mCD80 to CD28 showed a significant decrease compared to its wild-type counterpart. These findings suggest that mCD80 may serve as a promising candidate for inhibiting the CTLA-4 on the surface of T cells. Consequently, it may be developed in the future as a potential pharmaceutical agent for cancer immunotherapy.