Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a member of the CD28 superfamily and is a negative regulator of T cell-mediated immune responses. CTLA-4 expression is induced on the surface of T cells after CD28 binding and activation, and is constitutively expressed on T-regulatory cells, acting as an immune checkpoint inhibitor, downregulating T cell activity. (1-3). CTLA-4 primarily inactivates T-cell activity by competing with the CD28 costimulatory molecule (1,3). CD28 and CTLA-4 share the identical ligands of CD80 and CD86 on antigenpresenting cells; and thus CTLA-4 competes with CD28 function in T-cell survival, proliferation, and recruitment (3,4). In particular, CTLA-4 down-modulates CD4+ helper T-cell activity and enhances Treg immunosuppressive functions (5).
CTLA-4 has been shown to play a role in human diseases (1,3). CTLA-4 acts as a physiological brake on the activated immune system in order to maintain immune homeostasis. Several suppressive mechanisms for T-cell functions have been attributed to CTLA-4. FDA approved Ipilimumab (IgG1 isotype), a monoclonal antibody to CTLA-4, was the first immunotherapeutic drug directed toward CTLA-4 inhibition to demonstrate overall survival benefit in metastatic melanoma (1,6). Another CTLA-4 inhibitor, tremelimumab (IgG2 isotype), has also proven successful in metastatic melanoma and other malignancies (1,6).