Tony Georgiev, Francesca Migliorini, Andrea Ciamarone, Marco Mueller, Ilaria Biancofiore, Pinuccia Faviana, Francesco Bartoli, Young Seo Park Kim, Lucrezia Principi, Ettore Gilardoni, Gabriele Bassi, Nicholas Favalli, Emanuele Puca, Dario Neri, Sebastian Oehler & Samuele Cazzamalli 
Nature Biomedical Engineering (2025)

DOI: 10.1038/s41551-025-01432-6

Abstract

Improving the specificity of prostate cancer treatment requires ligands that bind selectively and with ultra-high affinity to tumour-associated targets absent from healthy tissues. Prostatic acid phosphatase has emerged as an alternative target to prostate-specific membrane antigen, as it is expressed in a broader subset of prostate cancers and is not detected in healthy organs such as the salivary glands and kidneys. Here, to discover selective binders to prostatic acid phosphatase, we constructed two DNA-encoded chemical libraries comprising over 6.7 million small molecules based on proline and phenylalanine scaffolds. Screening against the purified human prostatic acid phosphatase yielded OncoACP3, a small organic ligand with picomolar binding affinity. When radiolabelled with lutetium-177, OncoACP3 selectively accumulated in enzyme-expressing tumours with a long residence time (biological half-life greater than 72 h) and a high tumour-to-blood ratio (>148 at 2 h after administration). Lutetium-177-labelled OncoACP3 cured tumours in mice at low, well-tolerated doses. Its conjugation to the cytotoxic agent monomethyl auristatin E facilitated tumour-selective payload deposition, resulting in potent anti-tumour activity. The modular structure of OncoACP3 supports flexible payload delivery for the targeted treatment of metastatic prostate cancer.

Summary

Philochem’s research team successfully identified high-affinity ligands targeting prostate-specific membrane antigen (ACP3) using DNA-encoded library (DEL) technology. The study demonstrates a rapid and efficient path from hit identification to preclinical validation, highlighting DEL’s utility in accelerating radioligand therapy development.

Highlights

1. High-Affinity Ligand Discovery

- Two phosphonate-focused DELs were screened against ACP3, yielding enriched hits with strong binding motifs.

- Optimized compounds achieved sub-nanomolar inhibition (SPR-confirmed) and >100-fold improved affinity versus the original ligand.

- Fluorophore-conjugated ligands selectively stained ACP3-expressing prostate cancer cells, confirming target engagement.

2. Therapeutic Efficacy in Preclinical Models

- 177Lu-labeled conjugates showed ~70 %ID/g tumor uptake in xenografts with minimal off-target accumulation and slow washout.

- Significant tumor regression was observed, outperforming a reference radioligand derived from earlier inhibitors.

- Small-molecule drug conjugates (cleavable linker + MMAE payload) also demonstrated potent antitumor activity.

Conclusion

Philochem’s work delivers a robust pipeline of ACP3-targeting ligands with translational potential in radioligand therapy and antibody-free drug conjugates. It validates DEL as a key enabling technology for accelerating cancer therapeutic discovery.