CD80-Fc fusion protein ALPN-202

A fusion protein composed of the N-terminal Ig variable-like (IgV) domain of CD80 fused to a human immunoglobulin G1 (IgG1) Fc fragment, with potential immunostimulatory, immune checkpoint inhibitory and antineoplastic activities. Upon administration, CD80-Fc fusion protein ALPN-202 targets and binds to programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274) expressed on tumor cells, which blocks its binding to and activation of its receptor programmed cell death 1 (PD-1; cluster of differentiation 279; CD279), and leads to PD-L1-dependent CD28 binding and co-stimulation in the local tumor microenvironment (TME). This reverses T-cell inactivation caused by PD-1/PD-L1 signaling, leads to the co-stimulation of T-cell responses including the activation of naïve and memory T cells in the TME and enhances the cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response against PD-L1-expressing tumor cells. In addition, ALPN-202 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, thereby enabling CD80-CD28 engagement, CD28 signaling, and T-cell activation. This further promotes T-cell activity. PD-L1 is overexpressed by many human cancer cell types. PD-L1 binding to PD-1 on T cells suppresses the immune system and results in immune evasion. 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.