Abstract 315: Dose-response and tumor size at time of treatment with TD001, a novel ADC against PSMA, drive potent tumor growth inhibition in a CRPC CDX castrated mouse model

Abstract Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein belonging to the folate receptor family, is highly expressed in metastatic castrate-resistant prostate cancer (CRPC), and increases following androgen deprivation therapy. TD001 is a novel antibody-drug conjugate (ADC) composed of a deimmunized anti-PSMA IgG1 monoclonal antibody (HuJ591), which binds to the extracellular domain of PSMA, conjugated to a proprietary cleavable topoisomerase I inhibitor exatecan linker-payload (LD038), with a drug-to-antibody ratio (DAR) of 8. Flow cytometry and immunofluorescence microscopy show TD001 is internalized and cleaved rapidly, colocalizing with lysosomes in PSMA-expressing tumor cells. TD001 (10-20 mg/kg IV) was evaluated in a human CRPC cell line-derived xenograft (CDX) model, LNCaP-abl with high PSMA expression, in castrated NSG mice, with a range of tumor sizes (from 150 to 700 mm3) at the time of treatment. TD001 gave dose-dependent and sustained potent activity (tumor growth inhibition [TGI] >80%) with single dosing. Sustained inhibition of regrowth for 20 days was observed after TD001 10 mg/kg even in large tumors up to 400 mm3. Strong antitumoral activity of a single dose of TD001 10 mg/kg was also observed even in tumors >400 mm3 at the time of treatment. Tumor regrowth was faster in larger tumors (mean volume ∼300-400 mm3) compared to smaller tumors (mean volume ∼200 mm3). PSMA expression was unchanged in tumor regrowth between treated and vehicle control in the CDX castrated mouse model after treatment with TD001 up to 20 mg/kg, indicating no impact on target expression. Fractionation of a single TD001 dose into 2 or 3 doses administered every 10 days resulted in a 2-3 fold higher therapeutic index (TGI >90%) compared to the equivalent higher single isodose. No mortality or weight loss was reported. Pharmacokinetics/pharmacodynamic correlations of TD001 are described separately. TD001 appears as a best-in-class anti-PSMA Topo I inhibitor ADC (exatecan payload), and exhibited potent and sustained antitumor activity, including in large tumors, and represents a promising new treatment for PSMA-expressing CRPC patients. Citation Format: Roberta Frapolli, Ezia Bello, Marina Meroni, Daniela Impellizzieri, Elisa Storelli, Carlo V. Catapano, Lavinia Morosi, Maurizio D'Incalci, Jemila Houacine, Esteban Cvitkovic. Dose-response and tumor size at time of treatment with TD001, a novel ADC against PSMA, drive potent tumor growth inhibition in a CRPC CDX castrated mouse model [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 315.