Eldelumab (alternative identifier BMS-936557) is a fully human monoclonal antibody (type IgG1 kappa) that targets chemokine (CXC motif) ligand 10 (CXCL10)/Interferon-γ-inducible protein-10 (IP-10). This drug was developed by Bristol-Myers Squibb and Medarex and designed for the treatment of Crohn's disease and ulcerative colitis. To date, eldelumab has been investigated as an induction and maintenance therapy in active Crohn's disease, and its induction treatment demonstrated trends towards clinical and endoscopic efficacy with no new safety signal in a phase IIa study. Meanwhile, inhibiting IP-10 activity through the use of the monoclonal antibody, eldelumab, demonstrated efficacy in patients who achieved high serum concentrations in this phase II, randomized, controlled, proof-of-concept study of moderate-to-severe ulcerative colitis.
Ulcerative colitis (UC) is a chronic disease characterized by relapsing-remitting inflammation of the colonic mucosa, believed to be multifactorial in disease pathophysiology, including an aberrant immune response. However, not all patients with conventional treatment will achieve remission, and corticosteroids, immunomodulators and anti-TNF therapy can be associated with toxicities, including infection and malignancy, rendering treatment inappropriate for some patients. Interferon-γ-inducible protein-10 (IP-10), also referred to as CXCL10, is a chemokine that plays an important role in the integrin activation and migration of cells, including activated T cells, monocytes, eosinophils, natural killer, epithelial and endothelial cells. The receptor for IP-10 is chemokine (cys-x-cys motif) receptor 3 (CXCR3). Stimulation by IP-10 is directly and indirectly involved in the generation and recruitment of the pro-inflammatory cells that are responsible for inflammation and tissue destruction. IP-10 exerts its chemotactic activity on T helper (Th) 1 and Th17 cells, and blockade of IP-10 may skew cytokine activity from a Th1 to a Th2 profile. Thus, this chemokine can regulate inflammation by both induction of cellular migration and promotion of a Th1/Th17 response. IP-10 also appears to modulate cellular functions independently of CXCR3, including epithelial cell proliferation and migration as well as endothelial cell proliferation via heparan sulfate. These additional mechanisms of action may also contribute to the potential role of IP-10 in driving intestinal inflammation. Expression of IP-10 in colonic tissue and IP-10 plasma concentrations are greater in patients with UC compared with healthy controls. Eldelumab is a fully human monoclonal antibody that targets IP-10. Eldelumab binds to IP-10 with high affinity and specifically blocks its interaction with CXCR3. As a result, eldelumab is a potent inhibitor of IP-10-induced chemotaxis of activated T cells. Eldelumab does not bind to either Mig (CXCL9) or ITAC (CXCL11), the other ligands for CXCR3, and so is only expected to modulate IP-10-mediated functions.
Fig 1. Mechanism of Action of Eldelumab