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.
