NEW YORK — Progress toward unraveling the complexities of the B cell and its role in autoimmunity continues, with identification of potential new therapeutic targets for lupus nephritis and early clinical investigations providing insights on what B-cell depletion does—and does not—do.
The most experience with B-cell depletion in lupus thus far is with rituximab. This drug selectively targets the intermediate-stage B cells, though not stem or plasma cells, and causes significant decreases in markers of T-cell activation. “The risk of infection is limited because IgG is conserved,” Dr. Gregg Silverman said at a rheumatology meeting sponsored by New York University.
A recent open study of rituximab that included 10 patients with biopsy-proven proliferative glomerulonephritis showed “very impressive” results, Dr. Silverman said. Patients received four weekly infusions of 375 mg/m
Another ongoing investigation involves the autoreactive B-cell survival factor BAFF (also known as BLyS). BAFF, a tumor necrosis factor, can be blocked a number of ways, such as through decoy receptors and with anti-BAFF monoclonal antibodies, explained Dr. Silverman, professor of medicine at the University of California, San Diego.
One anti-BAFF monoclonal antibody, belimumab (LymphoStat-B, Human Genome Sciences, Rockville, Md.) has been tested in a phase I trial that included 70 lupus patients, and found to be safe, with no clinically significant differences from placebo in adverse events. It also significantly reduced levels of circulating B cells and anti-double stranded (ds) DNA antibodies, which are seen in high titers in lupus nephritis. A phase II trial that includes 449 patients now has been initiated, according to the company's Web site.
Abetimus (LJP 394, Riquent, La Jolla Pharmaceutical Co., San Diego), an agent that induces tolerance in B cells against anti-ds-DNA antibodies was investigated in a 76-week blinded study that randomized 230 patients to 16 weekly doses of 100 mg of the active drug or placebo, then alternating 8-week drug holidays and 12 weekly doses of 50 mg of the drug or placebo.
In this trial the primary efficacy outcome—prevention or delay of subsequent renal flare in patients with a history of lupus renal disease—was not met (Arthritis Rheum. 2003;48:442–54). But an ad hoc retrospective analysis found that in the subset of patients with high levels of anti-ds-DNA antibodies there were 67% fewer renal flares and time to renal flare was longer. A new multicenter trial is planned that will test three different doses of abetimus, he said.