Briobacept

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Current understanding centralises B cells in SLE pathogenesis with clinical features resulting from autoantibody formation, immune complex deposition, antigen presentation and cytokine activation. Existing standard of care therapies generates adverse side effects; secondary to corticosteroid use and untargeted immunosuppression. The inability to uphold remission and abolish the disease process, in addition to the increasing numbers of patients seen with refractory disease with these therapies, has provoked the development of novel B cell biologics targeting specific pathogenic pathways fundamental to the SLE disease process. Current evidence highlighting the efficacy of Rituximab, Ocrelizumab and Epratuzumab in inducing B cell depletion and achieving disease amelioration through specific B cell surface receptor antagonism is discussed. We review the efficacy of Atacicept, Briobacept and Belimumab in antagonising B lymphocyte stimulator (BLyS) and A proliferation inducing ligand (APRIL), two stimulatory cytokines crucial to B cell survival, growth and function. Two large multicentre randomised controlled trials, BLISS-52 and BLISS-76, have led to FDA approval of Belimumab. Following this breakthrough, other anti-BLyS therapies, Blisibimod and Tabalumab, are currently under Phase III evaluation. Similarly, murine models and Phase I/II trials have demonstrated significant efficacy of Rituximab, Epratuzumab, Briobacept and Atacicept as potential future therapies and we now eagerly await results from Phase III trials. Future research must compare the efficacy of different biologics amongst different patient subpopulations and SLE manifestations, in order to develop clinically and cost effective therapies.

We examined the biodistribution and pharmacokinetics of (111)In-labeled rGel/BLyS, a gelonin toxin (rGel)-B lymphocyte stimulator (BLyS) fusion protein.

rGel/BLyS was labeled with In-111 through DTPA with a labeling efficiency >95%. Biodistribution/imaging studies were obtained in severe-combined immunodeficiency mice bearing diffuse large B cell lymphoma OCI-Ly10. Pharmacokinetic studies were performed in BALB/c mice.

In vitro, DTPA-conjugated rGel/BLyS displayed selective cytotoxicity against OCI-Ly10 cells and mantle cell lymphoma JeKo cells. In vivo, rGel/BLyS exhibited a tri-exponential disposition with a rapid initial mean distribution followed by an extensive mean distribution and a long terminal elimination phase. At 48 h after injection, uptake of the radiotracer in tumors was 1.25 %ID/g, with a tumor-to-blood ratio of 13. Tumors were clearly visualized at 24-72 h post-injection. Micro-SPECT-CT images and ex vivo analyses confirmed the accumulation of rGel/BLyS in OCI-Ly10 tumors.

(111)In-DTPA-rGel/BLyS are distributed to B cell tumors and induce apoptosis in tumors. Preclinical antitumor studies using rGel/BLyS should use a twice-per-week treatment schedule.