Abstract 7197: Molecular characteristics of MP0712, a clinical stage 212Pb-based Radio-DARPin candidate for targeted anti-DLL3 radiotherapy of small cell lung cancer (SCLC)

Abstract Introduction: Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand aberrantly expressed on SCLC cells and largely absent in healthy tissues, making it a promising therapeutic target. However, low DLL3 surface density may limit tumor accumulation of a targeted radiopharmaceutical. MP0712, a half-life extended DLL3-targeting DARPin (Designed Ankyrin Repeat Protein) molecule combined with the short-lived alpha-emitting therapeutic isotope 212Pb, showed favorable safety, biodistribution, and antitumor efficacy in mice (Croset et al. AACR 2025). Under South Africa’s Section 21 compassionate care framework, MP0712 was administered for imaging with 203Pb to patients with SCLC and other DLL3-positive neuroendocrine cancers (NECs). Initial human imaging data indicate specific tumor uptake, supporting MP0712’s intended mode of action (Steiner et al. TRP EU 2025). Here, we describe MP0712’s molecular features, focusing on binding properties, internalization, and circulatory half-life. Methods: DLL3-expressing SCLC cell lines and xenograft models were used to evaluate MP0712 biodistribution in vivo. Internalization was assessed using flow cytometry and confocal microscopy. PK/PD properties were determined in mice. The affinity to DLL3 protein was determined by Surface Plasmon Resonance. Results: We identified sub-nanomolar affinity as a critical parameter for achieving efficient tumor uptake. MP0712 comprises a high-affinity, DLL3-specific DARPin (KD of 0.2 nM) that binds efficiently and selectively to DLL3+ SCLC cells. Given the low surface density of DLL3, we reasoned that to maximize accumulation in tumor, rapid and repeated internalization of a Radio-DARPin would be beneficial. Consistent with this hypothesis, we could demonstrate that up to 80% of surface-bound DLL3-DARPin internalizes within 30 min into SCLC cells in vitro. Importantly, we observed progressive intracellular accumulation over time upon continuous supply of DLL3-targeting DARPins, suggesting that repeated cycles of internalization occur. Finally, we hypothesized that extending systemic exposure of the DLL3-targeting DARPin would further enhance tumor uptake by leveraging these internalization dynamics. Indeed, we observed that intermediate half-life extension with an albumin-binding moiety improved tumor accumulation in xenograft models compared to non-half-life extended molecules. Conclusions: MP0712 demonstrates a compelling preclinical profile that suggests it may benefit from rapid receptor turnover-mediated intracellular accumulation, offsetting the effects of low DLL3 surface density. Together with emerging 203Pb-imaging data from compassionate care, these findings support further clinical evaluation of MP0712 therapeutic application with 212Pb-payload in patients with SCLC and other DLL3-positive NECs. Citation Format: Stefanie Riesenberg, Amal Saidi, Francesca Malvezzi, Aaron Schatzmann, Christian Reichen, Tania Stallons, Nicole Pina, Aline Eggenschwiler, Amy Wong, Madlaina Mettier, Jitka Rantanen, Marcela Guzman-Ayala, Julien Torgue, Daniel Steiner. Molecular characteristics of MP0712, a clinical stage 212Pb-based Radio-DARPin candidate for targeted anti-DLL3 radiotherapy of small cell lung cancer (SCLC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7197.