Anti CD19/CD11c Bi-Specific Antibodies Target a Subset of B Cells to Treat Autoimmune Diseases
NJH ID: #09-03
It is estimated that 23.5 million Americans suffer from autoimmune disease (AD) and that the prevalence is rising. Researchers have identified 80-100 different ADs and suspect at least 40 additional diseases of having an autoimmune basis. These diseases are chronic and can be life-threatening with an annual direct health care costs in the range of $100 billion. AD is one of the top 10 leading causes of death in female children and women in all age groups up to 64 years.
Current therapies for autoimmune diseases such as immunosuppressant treatments, anti-CD20 and anti-TNF monoclonal antibodies (mAb) have very profound effects on the whole immune system leading to substantial long-term side effects. These therapies deplete patients of large populations of immune cells that are important for maintaining the integrity of the host response to pathogens.
Researchers at National Jewish Health have identified a new population of autoimmune associated B cells (ABCs) that appears in the blood and lymphoid organs as the mice develop an autoimmune disease.
They further demonstrated that ABCs secrete autoantibodies and depletion of these cells in mice with ongoing autoimmunity leads to reduction of autoreactive antibodies, suggesting that ABCs play a direct role in the development of autoimmunity. This population of cells also increase in female mice as they get older, possibly explaining why females are more likely to develop autoimmunity compared to males. Furthermore, they were able to identify B cells in the blood of autoimmnune patients with a phenotype almost identical to those of ABCs in mice.
Diagnostic: early detection of ABCs in blood will make possible for physicians to identify patients developing autoimmunity before the onset of symptoms, allowing for earlier and more successful therapeutic interventions.
Therapeutic: targeted depletion of ABC cells with a bispecific (CD19/CD11c) mAb could lead to the development of a treatment for autoimmune diseases.
State of Development
Fusion hybridomas have been created and the best bispecific antibodies will be isolated and tested for their binding capacity and then for ability to deplete ABCs. These antibodies recognize two different proteins (CD19 and CD11c) on the surface of ABCs and will be tested in a mouse model of autoimmunity. This therapeutic approach will lead to the specific elimination of ABCs with no effect over other B cells, modeling a potential treatment in which the individuals being treated are much less immune compromised than with current treatments where all B cells are depleted.
Rubtsov, A. V., K. Rubtsova, A. Fischer, R. T. Meehan, J. Z. Gillis, J. W. Kappler, and P. Marrack. "Toll-like Receptor 7 (TLR7)-driven Accumulation of a Novel CD11c B-cell Population Is Important for the Development of Autoimmunity." Blood 118.5 (2011): 1305-315. PMID: 21543762.
Rubtsov, Anatoly V., Kira Rubtsova, John W. Kappler, and Philippa Marrack. "TLR7 Drives Accumulation of ABCs and Autoantibody Production in Autoimmune-prone Mice."Immunologic Research 55.1-3 (2013): 210-16. PMID: 22945807.
Rubtsova, K., A. V. Rubtsov, L. F. Van Dyk, J. W. Kappler, and P. Marrack. "T-box Transcription Factor T-bet, a Key Player in a Unique Type of B-cell Activation Essential for Effective Viral Clearance." Proceedings of the National Academy of Sciences 110.34 (2013): E3216-3224. PMID: 23922396.
Rubtsova, Kira, Philippa Marrack, and Anatoly V. Rubtsov. "Age-associated B Cells: Are They the Key to Understanding Why Autoimmune Diseases Are More Prevalent in Women?" Expert Review of Clinical Immunology 8.1 (2012): 5-7. PMID: 22149332.
Published international patent WO 2010/054288.
John W. Kappler Ph.D., Philippa Marrack Ph.D., Anatoly Rubtsov, Ph.D. and Julia Rhiannon, M.D.
This technology is available for licensing.
For Further Information, Contact:
Emmanuel Hilaire, PhD
Technology Transfer Office
National Jewish Health
1400 Jackson Street, Room M206b
Denver, CO 80206