Basic Research on B Cells in Lupus
Future clinical successes in SLE may be related to the development of more drugs aimed at treating molecular characteristics that are more specifically related to the disease. “I think one of the reasons that there is a measure of excitement in lupus and in other complex diseases that we've been confronted with for a long time is the advent of a whole series of new molecular tools that allow us to address basic issues,” commented Salk Institute neurobiology professor Greg E. Lemke, Ph.D.
For example, Petar Lenert, M.D., Ph.D., and colleagues, authors of a 2009 paper published in Arthritis Research and Therapy, said that more selective approaches to weeding out B cells that promote lupus may be better than nonselective B-cell depletion. Autoreactive B cells produce the autoantibodies characteristic of lupus but also contribute to disease pathogenesis by presenting autoantigens to T cells and secreting proinflammatory cytokines.
Dr. Lenert and other scientists have shown that intracellular nucleic acid sensing receptors that function in innate immunity, like toll-like receptor (TLR) 7 and TLR9, may play an important role in SLE. Dual engagement of rheumatoid factor-specific AM14 B cells through the B-cell receptor and TLR7/9 results in proliferation of autoimmune B cells. Therefore, Dr. Lenert explained, strategies that preferentially block innate immune activation through TLRs in autoimmune B cells may be preferred over nonselective B-cell depletion.
Dr. Lenert’s group found that a certain type of double-stranded DNA-like molecule that carries autoimmune-inhibitory sequences could selectively reduce the activity of autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage. The authors concluded that use of this specific class of nucleotides could result in a new approach to autoimmune disease therapeutics. Dr. Lenert was more circumspect in a conversation with GEN about the role of TLRs in autoimmunity. “It’s an area that requires much more research,” he said.
The search for and development of a lupus drug that induced tolerance in B cells directed against double-stranded DNA by cross-linking surface antibodies, however, proved to be La Jolla Pharmaceuticals’ undoing. The firm had to discontinue development of Riquent in February 2009 after it failed in lupus nephritis. La Jolla was delisted from NASDAQ this March, and Adamis Pharmaceuticals terminated its proposed merger with the firm; Riquent was La Jolla's only clinical-stage drug.
Dr. Lenert’s concerns that the field requires further research remains the defining characteristic of current drug development efforts for SLE. Perhaps the Phase III success of Benlysta will encourage companies to keep on trying against tough odds.