This week I was arguing that PIRA is a terrible concept because a significant element is due to actions outside the CNS…I suggested that most antibody delivered never reach the CNS.
To the average of 80Kg volunteers they give 6mg/kg = 480mg (more than any MS antibody except ocrelizumab and 24 times the ofatumumab dose), 18mg/kg = 1040mg (more than rituximab and any approved MS antibody) and 36mg/kg = 2880mg. Even at the low dose there was over 100 times more antibody circulating than reported with ofatumumab. at about a maximum of about 1microgramme/microlitre so at 99.9% exclusion that is 1ng/mL which is not a lot
Curtin F, Vidal V, Bernard C, Kromminga A, Lang AB, Porchet H. Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: A Phase 1 study. MAbs. 2016;8:854-60. doi: 10.1080/19420862.2016.1168956. Epub 2016 Mar 30. PMID: 27030142; PMCID: PMC4968100.
GNbAC1 is a humanized IgG4 monoclonal antibody antagonist of Mulitple Sclerosis Retrovirus Envelope (MSRV-Env), a protein that could play a critical role in multiple sclerosis. This randomized placebo-controlled dose-escalation study evaluated the safety and pharmacokinetics of GNbAC1 in 21 healthy volunteers after single intravenous infusion at doses of 6, 18 and 36 mg/kg. Lumbar punctures were performed at days 2, 15 or 29 to measure GNbAC1 concentrations in cerebrospinal fluid (CSF). GNbAC1 was well tolerated. Serum data show a dose-linear pharmacokinetics. A mean CSF/serum ratio of 0.12% (~99.9% excluded) was observed at Day 2, increasing to 0.39% (99.6% excluded….but if the half-life is different between the blood and the brain this may not be the case…) at Day 15 and 0.42% at Day 29 (Still more than 99% excluded, when there is 75% less antibody circulating). A relationship between GNbAC1 CSF/serum ratio and albumin CSF/serum ratio and a relationship at the limit of statistical significance with the timing of CSF sampling was shown
Source: multiple-sclerosis-research.org