Monoclonal Antibodies to CTLA-4 with Focus on Ipilimumab.

The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) is a negative regulator of T-cell-mediated immune responses which plays a critical role in suppressing autoimmunity and maintaining immune homeostasis. Because of its inhibitory activity on T cells, CTLA-4 has been investigated as a drug target to induce immunostimulation, blocking the interaction with its ligands. The antitumor effects mediated by CTLA-4 blockade have been attributed to a sustained active immune response against cancer cells, due to the release of a brake on T cell activation. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human anti-CTLA-4 IgG1κ monoclonal antibody (mAb) that represents the first immune checkpoint inhibitor approved as monotherapy by FDA and EMA in 2011 for the treatment of unresectable/metastatic melanoma. In 2015, FDA also granted approval to ipilimumab monotherapy as adjuvant treatment of stage III melanoma to reduce the risk of tumour recurrence. The subsequent approved indications of ipilimumab for metastatic melanoma, regardless of BRAF mutational status, and other advanced/metastatic solid tumours always involve its use in association with the anti-programmed cell death protein 1 (PD-1) mAb nivolumab. Currently, ipilimumab is evaluated in ongoing clinical trials for refractory/advanced solid tumours mainly in combination with additional immunostimulating agents.