However, the effects of antibodies against CD137 on tumor are various depending on types and developmental stages of cancer as well as the immunotherapies that have been used. immunotherapies, anti-CD137 antibody therapy 1. Introduction Cancer immunotherapy is the type of treatment that restores or boosts the natural defence against tumor by the human immune system. Such therapy usually targets specific biological molecules on cancer cells surface such as tumor-associated antigens (TAAs). Anti-tumor activities are possibly achieved by directing the host immune system toward TAAs, which consequently establishes or induces adaptive immune Rovazolac responses against cancer cells. Over the past few decades, cancer treatment using monoclonal antibodies (mAbs) has achieved great success and many of them have been approved for cancer treatment or clinical trials. Some great examples of approved mAbs are alemtuzumab (anti-CD52), ipilimumab (anti-CTLA4), nivolumab (anti-PD1), rituximab (anti-CD20), urelumab, and utomilumab or PF-05082566 (anti-CD137 antibody). CD137 (4-1BB/TNFRSF9) was identified in 1989 as Rovazolac an inducible gene that was expressed on antigen-primed T cells but not on resting ones [1]. In addition, it is known to be expressed in dendritic (DCs), natural killer cells (NKs) [2], activated CD4+ and CD8+ T lymphocytes, eosinophils, natural killer T cells (NKTs), and mast cells [1,3,4,5], but myeloid-derived suppressor cells (MDSCs) were investigated to not express this molecule on their surfaces [6]. The anti-CD137 antibodies show great potential in anti-cancer activities due to its ability to activate cytotoxic T cells and to increase the production of interferon gamma (IFN-) [7,8]. Here, we will update and discuss the recent findings regarding clinical development of anti-CD137 antibodies (Table 1) as a cancer immunotherapy, either as monotherapy or combined treatment with other mAbs and/or reagents. Table 1 The list of anti-CD137 antibodies, their different properties and binding sites.
Urelumab (BMS-663513)AgonistHuman IgG4 mAbCRD IUtomilumab (PF-05082566)AgonistHumanized IgG2 mAbCRDs III and IV Open in a separate window 2. TNF Family Members and CD137 (L) Biology The tumor necrosis factor Mouse Monoclonal to 14-3-3 receptor superfamily (TNFRSF) is usually a protein superfamily consists of 29 members [9] and plays important roles in human immune system [10]. This family of molecules is classified into two groups: death receptors (8 members) and activating receptors. All of them contain an intracellular signaling pathway activation domain name and an extracellular receptor site. These receptor sites can be activated by binding to corresponding ligands of the tumor necrosis factor superfamily (TNFSF) [11,12]. It has been demonstrated that this ligand-receptor (e.g., CD40-CD40L, CD27-CD70 or OX40-OX40L) signaling pathways of TNFSF-TNFRSF can modulate many important processes in the body such as cell development and death of cells or induction of cytokines and chemokines [11]. Growing evidence also suggests that the TNFRSF and TNFSF members are involved in inflammatory and pathology in several diseases including cancer [13,14,15]. Consequently, immunotherapeutic developments targeting the ligand-receptor interactions of TNFSF and TNFRSF are highly potential for treatment of cancer. In immunotherapy, an effective immune Rovazolac response requires two types of biological signal to fully activate T cells and other immune cells. The first signal, namely antigen-specific signal, is generated by the conversation of lymphocyte receptor with specific peptides bound to major histocompatibility complexes (MHC) molecules on antigen-presenting cells (APCs). Co-stimulation signal is the second signal and antigen-nonspecific. This type of signal is provided through the conversation between T cells and co-stimulatory molecules expressed on APCs [16]. CD137 is usually a co-stimulatory molecule belonging to the TNFRSF. It was discovered in the late Rovazolac 80s during T-cell-factor-screening on mouse helper and cytotoxic cells stimulated by concanavalin A [1]. In Rovazolac 1993, the human homologue of murine CD137 was identified [17]. CD137 can be activated by binding to its ligand (CD137L; 4-1BBL). The human CD137L was first isolated in 1994 using direct expression cloning from an activated CD4+ T lymphocyte population [18]. The lymphocytes were stimulated by immobilized CD3 monoclonal antibodies which bind to a fusion protein consisted of the extracellular portion of human CD137 coupled to the Fc region of human immunoglobin G1 [18]. The CD137L is usually expressed mostly on DCs, B cells or macrophages [19]. In mice, CD137 ligation results in recruitment of TNFR factors (TRAF1 and TRAF2) consequently leads to the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), Jun amino-terminal kinases/Stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinases (p38 MAPK) pathways [20]. This generates co-stimulatory signals to induce the activities of.