Abstract 318: Optimal free exatecan payload tumor/plasma ratio of TD001, a new ADC against PSMA, in CRPC CDX mouse models

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Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein folate receptor, is highly expressed in metastatic castrate-resistant prostate cancer (CRPC) and expression increases following androgen deprivation therapy. 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 proprietary Topo I inhibitor exatecan linker-payload (LD038), with a drug-to-antibody ratio (DAR) of 8. Free payload and total ADC were evaluated in mouse plasma, tumor, and liver, after TD001 10 mg/kg IV (which has potent antitumor activity in vivo) in 2 human CRPC cell line-derived xenograft (CDX) models, LNCaP-abl (high PSMA expression ∼104 ligands/cell) and 22Rv1 (intermediate/heterogeneous PSMA ∼102-104 ligands/cell) in castrated NRG/NSG mice. The TD001 PK profile was characterized across a wide temporal span post treatment, in LNCaP-abl (5 min to 10 days) and 22Rv1 (2 h to 6 days). The PK/PD profile of a range of doses (3-20 mg/kg) was characterized in both models. Dose proportional free exatecan concentrations were observed in tumor and plasma, and a consistently high tumor/plasma (T/P) ratio (∼70-100 fold) was seen in both tumor models across the range of TD001 doses tested. Potent tumor growth inhibition (TGI) was dose dependent up to 20 mg/kg. PK/PD and the high therapeutic index with different dosing schedules are presented separately. Free exatecan was detected in tumors 5 min post treatment in LNCaP-abl. Free exatecan concentrations were approximately 80x higher in tumor compared to plasma 2 h post treatment, and at least 100x higher from 6 h to 6 days post treatment, showing rapid and high distribution of TD001 to the targeted tumor tissue regardless of PSMA expression levels. The concentration of total ADC (assuming constant DAR 8) was ∼200 µg/mL (5 min post treatment), remained high for up to 6 days post treatment, while decreasing gradually from 24 h allowing for prolonged tumor exposure to TD001. The high and prolonged T/P ratio supports the excellent therapeutic index observed in TGI studies in both CDX castrated mice models, with TGI >90% and good tolerance (described separately). Of note, exatecan plasma levels rapidly declined under 0.5 ng/mL (from 24 h) and were under the limit of quantification (0.1 ng/mL) 10 days post treatment, preventing systemic toxicity. No free exatecan accumulation was observed after repeat dosing (described separately). TD001 effectively and preferentially delivers the potent exatecan payload to tumor tissue, with minimal systemic exposure, contributing to an excellent therapeutic index and strong antitumor activity in multiple CRPC models with high or intermediate PSMA expression. Our preclinical PK data support clinical development of TD001 in PSMA-expressing CRPC patients. Citation Format: Lavinia Morosi, Daniela Impellizzieri, Roberta Frapolli, Elisa Storelli, Atik Balla, Carlo V. Catapano, Jemila Houacine, Esteban Cvitkovic, Maurizio D’Incalci. Optimal free exatecan payload tumor/plasma ratio of TD001, a new ADC against PSMA, in CRPC CDX 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 318.

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