CXCL13 is secreted by cells of the immune system to trigger formation of organized lymphoid tissues at sites of inflammation and is linked to the development of autoimmunity. VX5 is a monoclonal antibody that specifically binds human, primate and rodent CXCL13, neutralizes its activity and exhibits therapeutic benefit in mouse models of human autoimmune diseases (e.g. rheumatoid arthritis and multiple sclerosis).
Pre-clinical development of VX5/5261 antibody has been initiated in preparation for filing an FDA Investigational New Drug (IND) application for the treatment of autoimmune disorders. Antibody manufacturing and purification processes were developed. VX5/5261 was evaluated in a single-dose pharmacokinetic study in rats in which no clinical toxicity was observed. Additional preclinical pharmacokinetic/pharmacodynamic studies are planned.
In mouse models of autoimmunity, anti-CXCL13 treatment blocks recruitment of immune cells and formation of germinal centers in inflammatory follicles (sites in which generation of anti-self antibodies can take place). The effect on germinal center formation translates into therapeutic benefit in mouse models of rheumatoid arthritis and multiple sclerosis where administration of anti-CXCL13 antibody provides symptom relief in arthritic mice and mice with MS-like disease.
CXCL13, also known as B-cell attracting chemokine, is expressed by follicular dendritic cells (FDC) and macrophages. Through its receptor expressed on a variety of immune cells (B cells, follicular helper T cells (Thf), recently activated T cells, Th17 cells), it induces intracellular changes necessary for maintenance of immune system homeostasis, lymphoid organogenesis, leukocyte trafficking and chemotactic migration. In a chronically-inflamed environment, ectopic germinal centers form within affected (often non-lymphoid) tissues. CXCL13 over-expression in these germinal centers, accompanied by dysregulation in the interactions among FDC, B and Thf cells, is thought to interfere with elimination of autoreactive B cells and can result in generation of high affinity IgG autoantibodies which may give rise to autoimmune diseases.
The CXCL13-mediated signaling pathway, therefore, represents an attractive target for the treatment of autoimmune disorders. Our VX5/5261 antibody efficiently neutralizes both mouse and human CXCL13 activity in several in vitro functional assays. A murine version of VX5/5261 antibody, VX5/5261-muIg (engineered to contain same human heavy and light chain variable genes along with mouse constant regions), effectively inhibited CXCL13-mediated recruitment of lymphocytes into secondary lymphoid organs of mice immunized with thymus-dependent antigen thus interfering with germinal center formation (Figure 1). In a murine model of rheumatoid arthritis (collagen-induced arthritis (CIA)), VX5/5261-muIg alleviated symptoms of arthritis in mice immunized with Type II collagen (Figure 2A). Similarly, in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), VX5/5261-muIg inhibited the severity of relapsing-remitting EAE (Figure 2B). BMC Immunology 16:6-23, 2015.
Anti-CXCL13 antibody suppresses Germinal Center Formation in Gastric Lymphoid Follicles Induced by H. suis infection
In addition to autoimmunity, collaborative research between Vaccinex and scientists at Kobe University in Japan have linked overexpression of CXCL13 to inflammatory events that can lead to mucosa-associated lymphoid tissue (MALT) lymphomas. This suggests that blockade of CXCL13 may reduce the risk of cancer is certain chronic inflammatory conditions. Mucosal Immunol 7:1244-54, 2014.
Vaccinex publications describing preclinical studies with anti-CXCL13:
Klimatcheva, et al. BMC Immunology. 2015;16(1):6. (link)
Yamamoto, et al. Mucosal Immunology. 2014;7:1244-54. (link).
Figure 1: Effect of VX5/5261-muIg on germinal center formation in C57BL/6 mice challenged with NP-KLH.
Mice were treated with 30 mg/kg of VX5/5261-muIg antibody and corresponding mouse isotype control, on days -3, 0 (the day of the challenge), 4 and 7 (n=9/group). Number of PNA+ germinal centers in relation to total number of follicles per group was calculated using ImagePro software. *P = 0.01
Figure 2: Effect of treatment with VX5/5261-muIg on CIA (A) and relapsing-remitting EAE (B).
(A) Male DBA1/J mice were subjected to therapeutic treatment regimen that was initiated when the group mean arthritic index (AI) reached 3-4 (approximately on day 30 post-initial immunization) and consisted of bi-weekly intraperitoneal injections of 30 mg/kg of the antibodies.
(B) Starting on day 7 post-immunization with PLP139-151, female SJL/J mice were treated with weekly intraperitoneal injections of 30mg/kg of the antibodies.