HPN424, a Half-Life Extended, PSMA/CD3-Specific TriTAC for the Treatment of Metastatic Prostate Cancer

摘要

Metastatic castration-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients annually in the US alone, and roughly 27,000 patients succumb to it each year. Once metastasized beyond regional lymph nodes, the 5-year survival rate is 30%. While novel therapeutics like abiraterone and enzalutamide have improved treatment options for mCRPC, a curative therapy is urgently needed. HPN424 is a single polypeptide antibody derivative called TriTAC (Tri-specific T cell Activating Construct) which is being developed for the treatment of mCRPC. The TriTAC platform addresses shortcomings of other T cell engagers including short serum half-life, limited tissue penetration, and manufacturability. HPN424 is designed to bind simultaneously to CD3epsilon on T cells and to prostate specific membrane antigen (PSMA, FOLH1) on prostate cancer cells. PSMA is expressed in >90% of malignant lesions and, outside the central nervous system, its normal tissue expression is largely restricted to prostate. A third domain of HPN424 binds to serum albumin providing half-life extension. With a molecular weight of approximately 50 KDa, TriTACs are expected to diffuse faster into human tumor tissues than is possible with antibodies given the high interstitial pressure and dense extracellular matrix in solid tumors. HPN424 binds human PSMA with sub-nanomolar affinity in the presence of serum albumin and efficiently targets PSMA in model systems. When incubated in co-cultures with resting, human T cells and prostate cancer cells, HPN424 activates T cells, induces cytokine production, T cell proliferation, and redirected target cell killing with single digit picomolar EC[50] values. When administered to mice bearing human prostate cancer xenografts and human T cells, HPN424 eradicates subcutaneous tumors. HPN424 affinity for CD3 and albumin are comparable for human and cynomolgus monkey proteins; however, HPN424 binds poorly to cynomolgus PSMA. HPN424 was very well tolerated in non-human primates (NHP) with doses of up to 3 mg/kg given weekly four times. Although on-target mediated findings may be under-represented in NHP, dose-dependent transient pharmacodynamic changes in cytokines and T cell activation markers were observed, consistent with T cell engagement. Pharmacokinetic analysis and serum half-life supports weekly administration in humans.