Development of an Innovative PSMA-Targeted Small Molecule Prodrug for Prostate Cancer

ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancer death in American men.1 For metastatic castration resistant prostate cancer (mCRPC), therapeutic options include taxane drugs, docetaxel and cabazitaxel, Radium-223 chloride (Xofigo®) for bone disease, Sipuleucel- T immunotherapy (Provenge®), and 177Lu therapy (Pluvicto®).2–4 Unfortunately, each of these therapies only offers a short-term survival advantage, and mCRPC ultimately evades treatment. Like taxanes, monomethyl auristatin E (MMAE) is a potent tubulin disruptor and known to inhibit prostate cancer tumor growth.5 However, MMAE cannot be administered as a drug alone due to significant toxicity to normal cells.5,6 To overcome dose limiting toxicity, MMAE must be conjugated to a targeting moiety. Small molecule drug conjugates (SMDC) and antibody-drug conjugates (ADCs) deliver toxic therapeutic payloads to cancer cells through a cancer-specific biomarker or protein, sparing non-target cells and tissues that do not express the biomarker. SMDCs and ADCs can effectively increase the therapeutic index (i.e. increasing efficacy against tumor cells while decreasing toxic effects to normal tissues) of the drug payload.7 To date, four MMAE ADCs are FDA approved; however, no ADCs or SMDCs are approved for use in mCRPC. Prostate-specific membrane antigen (PSMA) is a well characterized biomarker for prostate cancer with great success in targeting drug payloads (including 18F for imaging and 177Lu for radiotherapy) for diagnostic and therapeutic approaches. PSMA is expressed at low levels on normal tissues but is overexpressed on >90% of prostate cancers, and expression increases as the cancer progresses to the mCRPC stage.8–14 Cancer Targeted Technology (CTT) has developed a unique high affinity PSMA-targeted scaffold that irreversibly binds to and is rapidly internalized by PSMA expressing cells.15,16 In addition, CTT has developed a unique PhosAm linker attached to the scaffold that acts as a prodrug (CTT2274) and releases active MMAE only in target PSMA+ tumor endo/lysosomes. Rapid drug release by the PhosAm linker is ideal to quickly concentrate drug payload inside of the tumor cells.17–19 Using this unique delivery mechanism, CTT’s novel backbone, and PSMA-targeting, CTT2274, has the potential to both decrease toxicity of MMAE and result in substantial anti-tumor efficacy, offering a novel therapeutic for the treatment of advanced prostate cancer. This Fast-Track SBIR will develop and validate CTT2274. In Phase I, CTT will (a) perform process development and optimization on CTT2274 synthetic procedures, (b) assess the pharmacokinetics of CTT2274, and (c) determine the minimum effective dose of CTT2274 in a relevant model of prostate cancer. In Phase II, CTT will (a) synthesize a non-GMP engineering batch and perform stability tests, (b) conduct a GLP acute rat safety/toxicity, and (c) conduct a GLP chronic rat safety/toxicity study, Successful completion of these studies will establish a therapeutic index for CTT2274, establish a future clinical dose and serve as the framework for downstream GMP synthesis, large animal safety/tox assessment, clinical protocol development, and IND submission.