SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pathogenesis of a variety of autoimmune diseases has implicated autoantibodies as contributing to the disease process. Many of the specific autoantibodies associated with autoimmune diseases appear to be antigen selected and require T lymphocyte help associated with conventional B lymphocyte antibody responses. The mechanism as to how these autoantibody responses are initiated is unclear. However, prolonged survival of B lymphocytes (BLyS), molecular mimicry, altered tolerance to self-antigens or abnormal apoptosis have been proposed as potential triggering mechanisms. SLE is a chronic autoimmune disorder characterized by autoantibody production and abnormal B lymphocyte (BlyS) function. SLE can lead to arthritis, kidney failure, heart, lung, and central nervous system inflammation, vasculitis, and hemopoeitic changes such as anemia, leukopenia, and thrombocytopenia. The current paradigm of SLE pathogenesis begins with a genetic predisposition leading to the production of pathogenic autoantibodies and autoreactive effector B (Blys) and T lymphocytes. In SLE, a variety of autoantibodies (usually oligoclonal) directed against DNA, histones, the nucleosome, chromatin, ribonucleoproteins, ribosomes, RNA and phospholipids have been characterized. The rationale for developing a BLyS antagonist for treatment of autoimmune disease is supported in the current literature. Constitutive overexpression of BLyS in transgenic mice results in the development of autoimmune-like disease characterized by hypergammaglobulinemia, autoantibody production (e.g., anti-double stranded-DNA [anti-dsDNA] antibodies), and glomerulonephritis (GLEN) (Gross et al., 2000, Khare et al., 2000, and Mackay et al., 1999). Soluble BLyS receptor (TACI-Fc) used as a BLyS antagonist in an animal model of autoimmune disease shows that TACI-Fc inhibits proteinuria in and prolongs the survival of NZBWF1 mice (Gross et al., 2000). TACI-Fc also reduces disease severity in an animal model of RA (Wang et al., 2001). Elevated BLyS levels are evident in the serum and synovial fluid of some RA patients and the serum of SLE patients. A positive correlation exists between serum BLyS and serum IgG levels and autoantibody (anti-dsDNA and RF) levels (Zhang et al, 2001 and Cheema et al, 2001). Taken together, these data provide evidence that BLyS antagonism has potential therapeutic benefit in SLE. Non-clinical studies demonstrated that LymphoStat-B has high affinity for BlyS and inhibits the activity of BLyS in a murine splenocyte proliferation assay. LymphoStat-B recognizes both human and cynomolgus (Macaca fasicularis) monkey BLyS; LymphoStat-B recognizes soluble, but not membrane bound BLyS. LymphoStat-B has been found to be well-tolerated in mice and monkeys at doses up to 50 mg/kg. LymphoStat-B, given intravenously, inhibits an increase in mature B lymphocytes and serum IgA induced by administration of rhuBLyS in a mouse model. LymphoStat-B is a recombinant, fully human, IgG1? monoclonal antibody that binds BLyS with high affinity and inhibits its biological activity. LymphoStat-B was derived by affinity maturation of a parental antibody, D08, which itself was derived from screening a phage display library for high affinity binding to BLyS. LymphoStat-B is expressed in the NSO mouse myeloma cell line, secreted into culture media, and purified by a series of chromatography and filtration steps. In vitro and in vivo studies of LymphoStat-B have demonstrated its ability to bind BLyS, and animal models and preclinical data in SLE patients indicate elevated BLyS levels may be associated with the pathogenesis of SLE. A Phase 1, multi-center, double blind clinical trial of LymphoStat-B completed enrollment and the treatment phase in December 2002. The trial (Protocol LBSL01) was a single and double dose-escalation study in subjects with SLE. The study was designed to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of 4 doses (1, 4, 10, 20 mg/kg) of LymphoStat-B administered as a single intravenous infusion (Cohorts 1 to 4) or 2 infusions 21 days apart (Cohorts 5 to 8). A total of 57 subjects received LymphoStat-B and 13 subjects received placebo across 8 cohorts. LymphoStat-B was generally well tolerated at all dose levels. There does not appear to be a significant increase in adverse events (AEs) that correlates with increasing dose. More detailed results are in the preclinical studies/progress report.