Antibody – VX5 Autoimmune Disease

The target of VX5 therapeutic is CXCL13, a lymphoid chemokine expressed by follicular dendritic cells (FDC) and macrophages. During a normal immune response, CXCL13 and its receptor, CXCR5, on B cells and T follicular helper cells (Tfh) direct homing of these cells to primary follicles in lymph nodes and spleen and are involved in germinal center (GC) formation and lymphoid organogenesis. In a chronically-inflamed environment, ectopic germinal centers form within affected (often non-lymphoid) tissues. CXCL13 over-expression in these tertiary lymphoid organs, accompanied by dysregulation of the interactions among FDC, B and Tfh cells, enables survival of autoreactive B cells and the generation of high affinity IgG autoantibodies which contribute to development of autoimmune diseases (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis).

The CXCL13 signaling pathway represents an attractive target for the treatment of autoimmune disorders.

An ideal therapeutic would prevent CXCL13 from interacting with its receptor resulting in interference with B and T follicular helper cell migration into inflamed tissues and ultimately the reduction of autoimmune response. We have generated a high affinity human IgG1 antibody, VX5, capable of binding specifically to CXCL13 of multiple species (human, mouse, cynomolgus monkey). We have demonstrated that VX5 can effectively neutralize the activity of CXCL13 in mouse and human in vitro functional assays. Importantly, VX5 antibody inhibits development of disease in a mouse model of rheumatoid arthritis (collagen-induced arthritis; Figure 1).

VX5 antibody is currently in pre-clinical development with a Phase I clinical trial planned in 2012.

Figure 1. Treatment with VX5 antibody significantly reduced severity of murine collagen-induced arthritis. Arthritis was induced in DBA1/J mice by s.c. immunization with 100 mg of bovine type II collagen in CFA enhanced with 100 mg of heat-killed M. tuberculosis H37Ra, following by boost immunization on Day 21 with 100 mg of bovine type II collagen in Incomplete Freunds’ Adjuvant (IFA). Starting on Day 20 post-induction, the mice were given biweekly i.p. injections of 0.6 mg (30 mg/kg) of either Mouse Isotype control or an antibody comprised of the VX5 variable region and a mouse constant region. Arthritic Index (AI) was calculated by addition of the scores of individual paws (the maximum arthritic index that could be achieved in any given animal is 16). Each data point represents a mean of scores taken from 10 mice. Group means were compared by using one-way ANOVA followed by Bonferroni’s multiple comparison post test. Statistically significant differences were observed between Mouse Isotype Control and VX5 antibody treated groups (P<0.05).