WCLC 2025 - Posters & ePosters-P3.13.05 First-In-Human Study of 225Ac-ABD147 for SCLC and LCNEC Post-Chemotherapy: Pharmacokinetics, Biodistribution and Safety Insights

P3.13.05 First-In-Human Study of 225Ac-ABD147 for SCLC and LCNEC Post-Chemotherapy: Pharmacokinetics, Biodistribution and Safety Insights

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This first-in-human Phase 1a study evaluates 225Ac-ABD147, a novel biologic radioligand targeting delta-like ligand 3 (DLL3), in patients with Small Cell Lung Cancer (SCLC) and Large Cell Neuroendocrine Carcinoma (LCNEC) post-chemotherapy. 225Ac-ABD147 combines a single-domain antibody (VHH) for high specificity and tumor penetration with an engineered Fc domain for optimized half-life and effector silencing, enabling selective delivery of potent alpha-emitting radiation from actinium-225 to DLL3-expressing tumor cells. DLL3 is minimally expressed in normal tissues but aberrant in SCLC and LCNEC, making it an attractive therapeutic target.<br /><br />The study enrolled six patients in the initial cohort at a 1.6 MBq dose level, with safety, pharmacokinetics (PK), biodistribution, and dosimetry assessed using the surrogate tracer 111In-ABD147 via SPECT imaging. PK analysis showed rapid systemic clearance with an elimination half-life of approximately 22 hours, shorter than IgG antibodies, implying lower systemic and red marrow radiation exposure. Biodistribution studies revealed expected organ uptake patterns, with low renal retention and preferential hepatic clearance. SPECT-CT confirmed lesion-specific uptake, supporting effective tumor targeting.<br /><br />No dose-limiting toxicities (DLTs) or dose modifications were observed, and adverse events were minimal and treatment-unrelated in most cases. Dosimetry projections indicated favorable safety margins for kidney, liver, and red marrow at doses up to 6.4 MBq, supporting planned dose escalations. One patient received multiple doses with stable disease over four months, indicating potential therapeutic benefit.<br /><br />Overall, 225Ac-ABD147 demonstrates a favorable safety profile, specific tumor targeting, and manageable organ dosimetry, warranting further dose escalation and clinical development. These findings support its promise as a targeted alpha therapy for DLL3-expressing neuroendocrine lung cancers. The trial is registered under NCT06736418.

Asset Subtitle

Sean Carlin

Meta Tag

Speaker Sean Carlin

Topic Small Cell Lung Cancer and Neuroendocrine Tumors

Keywords

225Ac-ABD147

delta-like ligand 3

DLL3

Small Cell Lung Cancer

SCLC

Large Cell Neuroendocrine Carcinoma

LCNEC

alpha-emitting radioligand

phase 1a clinical trial

targeted alpha therapy