Abstract 580: 111In/225Ac-ABD320, a novel 5T4-targeted radiopharmaceutical with favorable tumor-to-normal tissue biodistribution and single-dose efficacy in preclinical cancer models

Abstract Radiopharmaceutical therapies offer a promising, targeted approach for treating cancers with limited options. The 5T4/trophoblast glycoprotein (encoded by TPBG) is an oncofetal cell surface antigen found on various cancer cells, including gastrointestinal, head and neck, and non-small cell lung cancers. 5T4 is associated with cancer stem cell properties, metastatic spread and poor clinical outcomes in cancer patients, while it is minimally expressed or absent in healthy adult tissue. Hence, 5T4 is an ideal target for tumor-directed radiotherapy, particularly since targeting 5T4 has no clear therapeutic benefit without a cytotoxic payload in preclinical models. ABD320, a humanized camelid heavy chain only antibody (VHH) fused to an engineered Fc with altered Fc-gamma and neonatal Fc receptor binding, uses a novel linker-chelator to deliver targeted 111In and 225Ac to 5T4 positive cancer cells. The ABD320 VHHFc binds human 5T4 with high affinity and specificity and is internalized by 5T4-expressing cancer cells. ABD320 is designed to minimize systemic and whole-body exposure through fast blood clearance and minimal normal tissue exposure. Tumor targeting was evaluated using 111In-ABD320 in murine models bearing human xenografts. In the NCI-H1975 non-small cell lung cancer model, a single intravenous administration of 111In-ABD320 was rapidly cleared from blood and normal tissues. Tumor accumulation peaked at 40% ID/g, despite low expression (29, 000 receptors/cell) corresponding to high tumor to normal tissue exposure ratios (kidney 6, liver 11) assessed between 1 to 240 hours after 111In-ABD320 administration. ABD320 was well tolerated when used to deliver 12 to 20 kBq of the therapeutic radionuclide 225Ac to 5T4-expressing tumors. 225 Ac-ABD320 achieved significant tumor regression, suppression of regrowth and extension of survival. Within-mouse dosimetry estimates a tumor inferred dose of 50 to 80 Gy corresponding to efficacious doses of 225 Ac-ABD320. In conclusion, ABD320, which employs a novel VHH-binder and linker-chelator, selectively and preferentially delivers radionuclides to 5T4 expressing tumors, demonstrates potent anticancer activity and is a promising candidate for further development. Citation Format: Etienne Sylvain Melese, Emma Cummins, Alex Mandel, Lily Li, Dhananjay Namjoshi, Milena Čučuk, Namrata Menon, Bryant Harbourne, Paula Tao, Brandon McLeod, Tess Osborne, Andrei Roman, Kristiana Lassueur, Anthony McDonagh, Michael Abrams, Adam Judge, Lana Janes, Iva Kulić. 111In/225Ac-ABD320, a novel 5T4-targeted radiopharmaceutical with favorable tumor-to-normal tissue biodistribution and single-dose efficacy in preclinical cancer 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 580.