Development of anti-CXCL13 monoclonal antibody for the treatment of autoimmune and immuno-oncological disorders (THER2P.950)

Abstract

Abstract The chemokine CXCL13 is expressed in secondary lymphoid organs by follicular dendritic cells and macrophages and is also expressed by TH17 cells. It is the only known ligand for the CXCR5 receptor expressed on mature B cells, multiple subsets of T cells, macrophages and endothelial cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune and cancer-promoting inflammatory disorders. Over-expression of CXCR5 receptor in certain cancers has been reported to induce CXCL13-dependent cell proliferation and metastasis. We developed a human IgG1 monoclonal antibody that specifically binds to human, rodent and primate CXCL13 and is capable of neutralizing CXCL13 function of these various species in in vitro functional assays. For preclinical in vivo studies we have engineered a chimeric antibody that contains the same human heavy and light chain variable genes as the human antibody along with mouse constant regions. This antibody has demonstrated efficacy in murine models of autoimmunity (Experimental Autoimmune Encephalomyelitis, Collagen-Induced Arthritis) and immuno-oncology (MALT lymphoma). In adoptive transfer and immunization studies, treatment with this antibody reduced B cell trafficking to the spleen and lymph nodes and interfered with the formation and expansion of germinal centers. The human antibody is currently undergoing pre-clinical development to support a future FDA Investigational New Drug application.