Anti-Human CTLA-4 (Tremelimumab) (C980-GRP)

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 1. 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 2. 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 1. 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 2. 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 1. Additionally, tremelimumab activity is mainly mediated by direct activation of T effector cells rather than by affecting T regulatory cells 3. 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 2. Tremelimumab has been approved for use in the treatment of unresectable hepatocellular carcinoma and some metastatic non-small cell lung cancers.