Definition

A bi-specific Fc fusion protein composed of the N-terminal extracellular domain (ECD) of human CD80 (B7.1) fused to a human immunoglobulin G4 (IgG4) Fc fragment and linked to an interleukin (IL)-2 variant (IL-2v) as a C-terminal moiety, with potential immunostimulatory, immune checkpoint inhibitory and antineoplastic activities. Upon administration of bispecific CD80-IgG4Fc-IL-2v fusion protein GI-101, the CD80 moiety targets and binds to CTL-associated antigen 4 (CTLA4; CTLA-4) expressed on T cells. This prevents the binding of CTLA-4 to endogenous CD80, enables the binding of CD80 to CD28, which leads to CD28-mediated signaling, and results in the activation of T cells in the tumor microenvironment (TME). This promotes T-cell activity. The IL-2 moiety may stimulate a local immune response and activate natural killer (NK) cells and cytotoxic T cells. This may enhance the activity of neoantigen specific T cells and potentiates the T-cell-mediated immune response against tumor cells. CD80 is a co-stimulatory molecule expressed on activated antigen presenting cells (APCs) that plays a key role in T-cell activation upon binding to CD28 on T cells. On the other hand, binding of CD80 to CTLA-4 prevents CD80-CD28 engagement, thereby inhibiting T-cell activity and immune activation. CTLA-4 is a member of the immunoglobulin superfamily (IgSF) and an inhibitory molecule upregulated by T cells following T-cell activation. It plays a key role in the downregulation of the immune system. IL-2v cannot bind to IL-2 receptor-alpha (CD25, IL2Ra) and does not activate regulatory T cells (Tregs).