Bioavailability, Pharmacokinetics, and Safety of Belimumab Administered Subcutaneously in Healthy Subjects.

This Phase 1 study evaluated the absolute bioavailability, pharmacokinetics (PK), tolerability, and safety of belimumab 200 mg/mL administered subcutaneously (SC) to healthy subjects as a single dose and as multiple doses up to 240 mg. In all, 118 subjects (age range 18-55 years; body weight 51-115 kg) were enrolled. Seventy-eight subjects received a single dose of belimumab 240 mg intravenously, or 2 × 120, 1 × 240, or 1 × 200 mg SC. Forty subjects received 4 weekly injections of belimumab 2 × 120 or 1 × 200 mg SC. Randomization was stratified by weight (<75 kg vs. ≥75 kg) and injection site (abdomen vs. thigh). Following single belimumab SC doses, bioavailability was 74-82%, indicating that belimumab SC was well absorbed, and bioavailability was similar among the three SC groups. Following 4 weekly belimumab SC doses, bioavailability was similar to that following single SC administration. Four subjects had persistent positive immune responses; neutralizing antibodies in these subjects were not detected and there was no apparent impact on PK. Belimumab was generally well tolerated after single and multiple SC dosing, and 200 mg SC weekly dosing is expected to provide an exposure similar to 10 mg/kg intravenously every 28 days.

Aspartyl aminopeptidase, encoded by an evolutionarily conserved syntenic gene, is colocalized with its cluster in secretory granules of pancreatic islet cells.

Aspartyl aminopeptidase (DAP), encoded by the DNPEP gene, is believed to be a cytosolic protein with high enzymatic activity in the neuroendocrine tissues. Bioinformatic analysis revealed that the genomic segment spanning the DNPEP gene is evolutionarily conserved from Caenorhabditis elegans to humans. In the present study, we sought to determine whether the expression of DAP is associated with its clustered genes when expressed in pancreatic islet cells. Using anti-DAP specific antibody in immunofluorescent stainings, we found that DAP was specifically expressed in islet alpha cells but not in exocrine acinar cells. Moreover, using electron microscopy, we found that DAP was associated with a lysosomal-like structure and secretory granules, suggesting that it plays an important role in post-translational processing and the secretion of hormones in islet cells. The identification and characterization of DNPEP syntenic genes confirm that conserved clustered genes can preferentially be expressed in the same signaling pathway.