BMS-931699, a domain antibody (dAb) conjugated with 40 kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development. The minimal anticipated biological effect level (MABEL) was determined for by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated PK/PD analysis using antihCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 L/kg) were employed to calculate the MABEL (0.01mg) in humans, with a CD28 RO predicted to be ≤10%. It was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys dosed weekly for 5 weeks. The MABEL dose was successfully used as the first-in-human starting dose for BMS-931699.
See article at J Pharmacol Exp Ther 2015 355:506-515.
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