Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an activation induced, type I transmembrane protein of the Ig superfamily that is expressed as a covalent homodimer . CTLA-4 functions as an inhibitory receptor for the costimulatory molecules B7.1 (CD80) and B7.2 (CD86), inhibiting T cell activation and proliferation as well as IL-2 gene transcription by directly inhibiting TCR signal transduction.
Immune checkpoint blockade of CTLA-4 is a well-established treatment for cancer . Since CTLA-4 inhibits T cell activation, blocking CTLA-4 function enhances T cell activation as well as the immune response. Additionally, tremelimumab activity enhances the production of interleukin-2 and interferon-γ in human T cell blasts stimulated with B7-positive Raji cells. Tremelimumab also stimulates upregulation of the Th1/Th2 pathway, activates the Th17 pathway, and reduces expression of genes involved in epithelial-mesenchymal transition, angiogenesis, and cancer stemness. The mechanism of action includes antibody-dependent cell cytotoxicity.
Tremelimumab was generated by recombinant DNA technology using engineered XenoMice . Tremelimumab binds to CTLA-4 and blocks interaction with its ligands B7.1 (CD80) and B7.2 (CD86), thereby activating an enhanced T cell response against tumors . Additionally, tremelimumab inhibits binding of CTLA-4-Ig to immobilized B7.1 and B7.2. In vitro, binding of tremelimumab to CTLA-4 is >500 fold more selective than for human CD28-Ig, B7.2-Ig and IgG1. Tremelimumab does not initiate a nonspecific cytokine release or bind to Fc receptors . Additionally, tremelimumab activity is mainly mediated by direct activation of T effector cells rather than by affecting T regulatory cells .
Tremelimumab has been tested in a variety of therapeutic trials, including for hepatocellular, non-small cell lung, small cell lung, urothelial, biliary tract, thyroid, renal, gastrointestinal, and cervical cancers . Tremelimumab has been approved for use in the treatment of unresectable hepatocellular carcinoma and some metastatic non-small cell lung cancers.
