Monoclonal Antibody Development Targeting OX40-OX40L for Autoimmune Diseases

OX40-OX40L Interaction

OX40, also known as CD134, is a tumor necrosis factor receptor (TNFR) that is mainly expressed on activated T cells, which was originally identified in 1987 as a T cell activation marker. As an important member of the TNFR-superfamily, human OX40 (TNFRSF4) is a 50 KD type-1 transmembrane glycoprotein with 277 amino acids. The extracellular portion of OX40 contains three cysteine-rich domains (CRDs) that are responsible for the binding to OX40 ligand (OX40L). OX40L, also known as CD252 and TNFSF4, is a 34 KD type II transmembrane glycoprotein expressed as trimers on the surface of multiple antigen-presenting cells (APCs), including macrophages, activated B cells, and dendritic cells.

Once the immune system was stimulated by antigens, the T cells are activated, thereby the OX40 expression is initiated and peaks about 48-72 hours after T cell activation. Simultaneously, the expression of OX40L is induced on APCs to react with the OX40 receptor. The OX40-OX40L engagement further results in activations of an array of downstream signaling pathways, such as the PI3 K/PKB pathway, NF-κB pathway, and NFAT pathway, all of which devote great contribution to the activation, proliferation, adhesion, survival, cytokine production, and other effector functions of T cells.

Fig.1 Effects of OX40 ligation on T cells. (Webb, 2015)

OX40-OX40L: A Pathogenic Factor in Autoimmune Diseases

Autoimmune diseases are a class of chronic conditions characterized by autoantibodies or autoimmunity reactive against self-antigens due to the abnormal immune self-tolerance. The critical costimulatory effect of OX40-OX40L interaction in T cell development and bio functions makes it an attractive target in autoimmunity and autoimmune disease research. Plenty of animal investigations have demonstrated the pathogenic roles of the OX40-OX40L interaction in autoimmune diseases, as well as therapeutic value for disease prevention and treatment.

• OX40-OX40L in experimental autoimmune encephalomyelitis (EAE)

It was first found in the EAE murine model that the OX40 expression was up-regulated by myelin-specific T cells at the site of inflammation and gradually decreased as the aggravation of the EAE. And using OX40L neutralizing monoclonal antibody to block OX40-OX40L interactions or OX40/OX40L knockout could reduce the infiltration of monocytes into the spinal cord and ameliorate EAE.

• OX40-OX40L in systemic lupus erythematosus (SLE)

The OX40 expression by CD4+ T lymphocytes in patients suffering from SLE was significantly higher than that on healthy individuals, and was positively correlated with serum creatinine and SLE disease activity index (SLEDAI). The circulating OX40L concentrations in SLE patients were also notably higher than in controls, but without relation to SLEDAI. The CD4+ T cell expressing OX40 combined with serum OX40L might serve as biomarkers for SLE diagnosis.

• OX40-OX40L in rheumatoid arthritis (RA)

Several studies have indicated that anti-OX40L monoclonal antibody administration remarkably ameliorated the severity in collagen-induced RA mice. The pathogenetic mechanism research revealed that the anti-OX40L antibody inhibited the secretion of IFN-γ and anti-collagen antibodies rather than inhibited the expansion of reactive T cells. So OX40-OX40L interactions play a pathogenetic role in collagen-induced RA through enhancing Th1-type autoimmune response.

• OX40-OX40L in other autoimmune diseases

Additionally, OX40-OX40L signaling is also implicated in the pathogenesis of multiple other autoimmune diseases, including type 1 diabetes mellitus, multiple sclerosis, ulcerative colitis, psoriasis, which may serve as promising biomarkers for disease diagnosis and potential targets for novel drug development.

Fig.2 OX40 ligand contributes to human lupus pathogenesis. (Jacquemin, 2015)

OX40-OX40L Monoclonal Antibody Development Services for Autoimmune Disease Treatment

Autoimmune diseases are a category of intractable immune disorders caused by abnormal autoimmune tolerance. Currently, new immunotherapies, including therapeutic monoclonal antibody, bispecific antibody, regulatory T cell therapy, and co-stimulation blockade, have been extensively explored and developed for the treatment of autoimmune diseases. As a recognized expert in the field of novel immunotherapy discovery, Creative Biolabs has accumulated abundant expertise and experience in pathogenetic research and novel therapy development of autoimmune diseases. Our specialized scientist team provides tailored anti- OX40/OX40L monoclonal antibody development services for autoimmune disease treatment.

Please feel free to contact us for more detailed information.

References

1. Webb, G.J.; et al. OX40, OX40L and Autoimmunity: A Comprehensive Review. Clinical Reviews in Allergy & Immunology. 2015, 50(3): 312-332.
2. Jacquemin, C.; et al. OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T follicular Helper Response. Immunity. 2015, 42(6): 1159-1170.

For Research Use Only | Not For Clinical Use