Description:
OBJECTIVE: Develop innovative approaches to substantially improved serum half-life of the protective monoclonal antibodies for prophylaxis and/or therapy against ricin intoxication. DESCRIPTION: Ricin from the castor oil plant Ricinus communis, is a highly toxic, naturally occurring protein. A dose the size of a few grains of table salt can kill an adult human. Although estimates vary, the LD50 of ricin is approximately 25 micrograms per kilogram in humans if exposure is from injection or inhalation. In light of the abundant availability and relatively simple methods required to obtain ricin from castor oil plants, this toxin is considered a biological warfare threat agent. Moreover, the Department of Defense identified a capability gap to protect against exposure to the ricin toxin in the Initial Capabilities Document for Joint Medical Biological Warfare Agent Prophylaxes, approved 14 September 2004. Currently, there are no licensed, specific medical prophylactic or therapeutic measures against the ricin toxin. To that end, the goal of this SBIR topic is to solicit innovative approaches to improved serum half-life of the protective monoclonal antibodies (mAbs) for prophylaxis and/or therapy against ricin intoxication. The approaches may include but are not restricted to methods to reduce mAb degradation, use of genetically derived immunoglobulin glycoforms, methods to reduce hepatic turnover of mAbs, methods to create slow-release mAb depots and combinations thereof. The specific improvements in duration should be determined using baseline values and ideally technologies will be developed to improve mAb duration 2-fold or more. PHASE I: Phase I studies will focus on development of proof-of-concept in vitro and in vivo models and prototyping systems to modify ricin-specific mAbs. PHASE II: Studies in Phase II will include small scale process development, production of material for in vivo potency and pharmokinetic/pharmodynamic studies in small animals and culminate in a pharmokinetic/pharmodynamic study in a non-human primate (NHP) model. PHASE III: Studies in this phase will focus on scale-up manufacturing, toxicity and potency assessment in appropriate animal models, followed by cGMP manufacturing, pivotal efficacy studies in NHPs and clinical trials. PHASE III Dual Use Applications: It is anticipated that successful development of a platform strategy to improved mAb half-life will have dual use in both improved mAb countermeasures for the warfighter and improved therapeutic mAbs for use as pharmaceutics.
