Development of a PSMA-Targeted Small-Molecule Drug Conjugate for Prostate Cancer

PROJECT SUMMARY ABSTRACTProstate Specific Membrane AntigenPSMAis an andapos ideal biomarkerandaposfor tumor targeting as it exhibits restricted expression on prostate tumor cells and the neovasculature of a number of other solid tumorsCancer Targeted Technology has developed unique phosphoramidate based PSMA inhibitor scaffolds that irreversibly bind to the enzyme target and selectively penetrate prostate tumor cells through the internalization of the PSMA enzyme inhibitor complexaccumulating in endosomes and lysosomesWe recently demonstrated that the addition of an albumin binding motif to our PSMA targeted agents dramatically slows clearance in miceresulting in tumor uptake of nearlyinjected dose gFurthermoreCTT has licensed a novel pH triggered linker systemPhos Amthat is stable under physiological conditionsbut can be tuned to rapidly release amine containing drugs at endosomal lysosomal pHTogetherthese advances support the development of a PSMA targeted drug conjugate that can be trafficked to and selectively liberated within PSMAtumor cellsThe objective of this Phase I application is to design and prove the effectiveness of a PSMA targeted Small Molecule Drug ConjugateSMDCCTTCTTwill incorporate these crucial componentsphosphoramidate based PSMA targeting moleculealbumin binderPhos Am linker systemand Monomethyl Auristatin EMMAEas the conjugated drug payloadWe expect that CTTwill exhibit the following key in vitro and in vivo performance characteristicsspecificity for and rapid internalization by PSMAprostate tumor cellsstability in plasmarapid subcellular drug releaseappropriate biodistribution and circulation halflife and potent anti tumor activityOur aims for this Phase I application are as followsAimDetermine the stability and in vitro performance of CTTWe will prepare CTTand assess its stability and drug release kinetics in bufferpHas well as in mouse and human plasmaConcentration dependent in vitro cytotoxicity and specificity will be assessed with PSMAand PSMAcells linesAimDetermine the in vivo efficacy of CTTWe will determine the biodistribution of CTTand its released drugMMAEin blood and key organsIn vivo performance will be evaluated using a PSMAtumor xenograft mouse model dosed once per week forweeks and monitoring tumor volume forweeksThis innovative work harnesses the ideal performance properties of a cell penetrating irreversible smallmolecule PSMA inhibitor that possesses the desirable pharmacokinetics of antibodies without the additional manufacturing costs associated with antibodiesFurtherCTTshould have considerable significance for prostate cancer therapy by reducing chemotherapy associated toxic side effects to non target tissuesIt is expected that CTTwill represent a breakthrough in targeted chemotherapy for prostate cancer and other tumors that are characterized by PSMA expression PROJECT NARRATIVE The development and characterization of a unique Prostate Specific Membrane AntigenPSMAtargeted chemotherapy that can be specifically delivered to tumor cells and released intracellularly is innovativeThis work will lay the foundation for future definitive IND enabling studies that will translate this new agent into a clinically relevant and safe therapeutic option for prostate cancer and other cancers that express PSMA