Development of a novel safe and efficacious biologic drug for the treatment of AML

PROJECT SUMMARY There is a clear unmet need for effective treatments for acute myeloid leukemiaAMLAn exciting new mechanism for targeting cancer cells involves the activation of the extrinsic apoptotic pathway by administering the soluble domain of TNF related apoptosis inducing ligandTRAILcalled dulanerminMuch hope has been placed on this drug since TRAIL has been shown to bind to death receptors and activate the extrinsic apoptotic pathway in cancer cells while having little impact on normal tissueDulanermin has completed several clinical trialsand while showing little toxicityit has also disappointingly shown little efficacyThe main reasons attributed to dulanermin s failure have been its low in vivo stability and several resistance mechanismsTo counter these issueswe propose a molecule that is composed of three tandem TRAIL domainsTRlinked to an engineered safer version of L asparaginasecalled Aspthat we previously reportedFor dulanermin to activate the death receptorsit must assemble into a trimerUnlike monomeric dulanerminTRby virtue of having theTRAIL domains on a single polypeptideresults in a stabilized trimer that can better engage the death receptorsIn addition to bindingclustering of the death receptors is also a key factor required for their activationAsp is a tetrameric enzymeso the linking of TRto Aspwhich we refer to as TRAspresults in a molecule that assembles into a tetramer with Asp at its core andTRAIL trimers extending outside of itIn addition to increasing the clustering power of the biologicthe depletion of asparagine by the Asp reduces the amount of key TRAIL resistance factors such as cFLIPXIAP and simultaneously increases the expression of death receptorAdditionallyseveral AML subtypes are inherently sensitive to asparagine depletionso the addition of Asp to TRAIL also serves to directly target those L asparaginase sensitive AML subtypesOf particular noteby engineering out the toxicity related L glutaminase activityour improved safer versionAsp is very much compatible with the proven safety profile of TRAILOur strong preliminary data demonstrated that TRAsp has exceptional AML cell killing power both in vitro and in miceNotablythe mice under prolonged drug treatment exhibited no clinical signs of toxicity or weight lossTo build upon these exciting results we propose to further develop and evaluate TRAspSpecificallyin Aimwe will optimize the production of TRAsp and use the identified conditions to manufacture the drug for the biological studiesIn Aimwe will evaluate the pharmacokinetic properties and maximum tolerable dose of TRAspThese data will inform the dosing of the in vivo evaluation of the molecule in patient derived xenograftswhich are accepted as superior models of the human disease compared to cell line xenograftsSuccess in this work would provide the rationale for further development of TRAsp as a novel AML therapeuticas well as in other cancerssuch as pancreatic cancerthat have shown sensitivity to the individual TRAIL and L asparaginase components PROJECT NARRATIVE The ultimate goal of the proposed work is to extend survival and improve quality of life for individuals diagnosed with acute myeloid leukemiaAMLa disease that has a dismalyear survival rate due to the lack of effective treatmentsEnzyme by Design s strategy to achieve this goal centers on combining two wellcharacterized biologic drugs into a single therapeutic molecule whose synergistic activity is efficacious against AML and exhibits minimal toxicityIn this proposalwe will conduct pre clinical studies of our novel agent in order to start accumulating the data required for an Investigational New Drug filing