Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma

Abstract

Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape.

Keywords: checkpoint inhibitors; durvalumab; metastatic urothelial carcinoma.

Figure 1

Immune checkpoint paths and interactions. Notes: Major inhibitory and stimulatory pathways through the TCR. CTLA4, PD-1 and PD-L1, OX40 (tumor necrosis factor receptor superfamily, member 4), and OX40L, PI3K-AKT, SHP2, and TRAF pathways. Abbreviations: TCR, T-cell receptor; CTLA4, Cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; OX40L, OX40 ligand; PI3K-AKT, phosphoinositide 3-kinase-protein kinase B; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase; TRAFs, tumor necrosis factor receptor-associated factors.

Figure 2

Mechanism of durvalumab. Notes: Durvalumab antibody blocks PD-1 and PD-L1 interaction, which prevents a SHP2-mediated co-inhibitory signal, allowing the neoepitope expressed by MHC-I to act as signal in stimulating an immune response, leading to the release of perforins and granzymes, theoretically leading to destruction of the tumor cell. Abbreviations: PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase; MHC, major histocompatibility complex; TCR, T-cell receptor.