Abstract 311: Long-term tumor growth inhibition and extended survival with TD001, a novel optimized PSMA-targeting ADC, in PSMA-expressing CRPC CDX castrated mouse models

Abstract Patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on androgen deprivation therapy (ADT) have limited therapeutic options. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed in mCRPC and is a validated target for precision medicine approaches. TD001 is a novel antibody-drug conjugate (ADC) composed of a deimmunized anti-PSMA IgG1 monoclonal antibody (HuJ591) conjugated to a highly stable protease-cleavable topoisomerase I inhibitor (exatecan) proprietary linker-payload (LD038) with a drug-to-antibody ratio (DAR) of 8. TD001 was evaluated in vivo in human cell line-derived xenograft (CDX) models with high PSMA expression (LNCaP-abl; ∼104 ligands/cell) or intermediate/heterogeneous PSMA expression (22Rv1; ∼102-104 ligands/cell) in castrated NRG mice, and in the high PSMA-expressing (∼105 ligands/cell) patient-derived xenograft (PDX) model C5 in non-castrated NRG mice. Of note, PSMA expression increased upon castration in both CDX models, mimicking the clinical condition of the target patient population. After single IV administration across a wide range of doses (up to 20 mg/kg), TD001 achieved dose-dependent, potent tumor growth inhibition (TGI) not only in the high-PSMA LNCaP-abl CDX and C5 PDX models but also in the intermediate-PSMA 22Rv1 CDX model. Rapid responses and high TGI (>90%) after a single administration at optimal doses were seen across all models. Upon tumor regrowth, PSMA expression was unchanged between treated and vehicle control groups, indicating no impact on target expression. Recurrent tumors remained similarly responsive to rechallenge with TD001. Of note, fractionation of a single TD001 dose into 2 or 3 doses administered every 10 days resulted in persistent tumor regression (TGI ≥90% for 60-70 days) and extended survival compared to the equivalent higher single dose. TD001 was well tolerated with no body weight loss or other signs of toxicity, nor mortality at all doses after single and repeated dosing regimens. Alternative dosing schedules, dose response, and tumor/plasma ratio result in a 2-3 fold increase in therapeutic index (TGI ≥90% for up to 60 days). TD001 appears as a best-in-class anti-PSMA ADC with its novel linker-payload (LD038) and exhibits potent antitumor activity in preclinical models with a broad range of PSMA expression, representing a highly promising treatment for PSMA-expressing CRPC patients. The efficacy of TD001 in preclinical in vivo castrated CDX and PDX models supports further investigation in clinical settings. Citation Format: Daniela Impellizzieri, Elisa Storelli, Atik Balla, Simone Mosole, Cristina Dongilli, Federico Jauk, Roberta Frapolli, Lavinia Morosi, Maurizio D'Incalci, Jemila Houacine, Morris Rosenberg, Mohamed Bekradda, Esteban Cvitkovic, Carlo V. Catapano. Long-term tumor growth inhibition and extended survival with TD001, a novel optimized PSMA-targeting ADC, in PSMA-expressing CRPC CDX castrated mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 311.