Post-exposure immunotherapy for ricin exposure

PROJECT SUMMARYRicin is a category B toxin due to its ease of acquisitiondisseminationand the high potential for morbidity and mortality after exposureRicin is naturally produced by the castor bean plantRicinus communiswhich is cultivated on industrial levels worldwideRicin constitutes up toof the total dry weight of the castor bean and can be extracted using several simple enrichment stepsRicin in semi purified or purified form is extremely toxic to humans following injectioninhalationor ingestion and has been used as an agent of bioterrorismRicin was previously weaponized by the United Statesthe former Soviet UnionIraq and likely other countrieshas been used in assassinations and was recently detected in a number of U Sgovernment facilitiesThere are currently no methods of preventing or treating ricin exposurethis represents a major unmet need for protection of civilians and military forcesThe Mapp teamin collaboration with DrNicholas MantisWadsworth CenterAlbanyNYand DrChad RoyTulane National Primate Research CenterCovingtonLAhas identified a number of highly potent anti ricin monoclonal antibodiesmAbsThese mAbseither in their original fully murine statewhen chimerized with human constant regionsor when fully humanizedhave demonstrated protection of mice when administered prior to and after ricin challengeFurtherone of these mAbshumanized PBhPBhas been shown to protect non human primatesNHPsfrom aerosol challenge therapeuticallythis is the first demonstration of protection of NHPs by a therapeutic against a lethal aerosol challengeWe have now generated evidence that a mAb cocktail consisting of one RTA and one RTB mAb may provide improved potency and extend the therapeutic windowThe in vitro and in vivo potency of the mAb cocktails we have tested is superior to any individual mAb previously describedwhich is consistent with the combination of mAbs functioning at different steps in the intoxication processAnti RTB mAbs interfere with ricin attachment to target cellswhile anti RTA mAbs are proposed to block ricin intracellular traffickingThe Specific Aims to advance a ricin medical countermeasure to the clinic areEngineerproduceand down select from the panel of RTA RTB mAbsHumanize the lead RTA RTB mAb cocktail and manufacture to support AimDetermine the prophylactic and therapeutic efficacy of the lead RTA RTB combination in the rhesus macaque aerosol challenge modelThese data combined with the ChemistryManufacturing and ControlCMCinformation will form the basis of a preInvestigational New DrugINDmeeting with the FDA to solicit guidance on continued development of the product PROJECT NARRATIVE Ricin is a category B toxin due to its ease of dissemination and the potential for morbidity and mortality after exposureBased partially on analyses of the accessibility of ricin and its ease of disseminationthe U Sgovernment has designated ricin amaterial threatand it is classified as a Select AgentThere are currently no vaccines or treatments for ricin exposureOur long term goal is to develop a safe and effective drug for the prevention and treatment of poisoning by ricin