Frontiers in Radiopharmaceutical Therapy

Radiopharmaceutical trials, which involve developing and testing agents that combine radioactive isotopes with targeting molecules for diagnostic imaging or targeted radionuclide therapy (e.g., in oncology), face several persistent challenges. These unmet needs span logistical, regulatory, biological, and equity-related domains, hindering efficient trial execution, patient access, and broader therapeutic impact. Addressing these needs requires global collaboration for isotope production, AI integration for workflows, inclusive trial designs, and policy reforms for equitable access. Ongoing phase III trials (e.g., PSMAfore, COMPETE) show promise but underscore the urgency for innovation in these areas to realize radiopharmaceuticals' full potential in precision oncology.

Radiopharmaceutical therapy (RPT) shows promise for cancer treatment, but challenges in dose delivery and off-target effects remain. Quantitative digital autoradiography provides real-time visualization of radiopharmaceutical distribution in ex vivo tissue sections, improving the assessment of alpha/beta therapies. This approach is crucial for evaluating micro-scale dose estimates in tumors and normal organs. It enables evaluation of combination alpha/beta therapies and validating the biological equivalence of alpha RPT and PET theranostic surrogates.

Radioligand therapy is rapidly advancing toward the clinic, driven by recent approvals that highlight its therapeutic promise. Advancing next-generation agents demands rigorous application of principles that govern target engagement, radionuclide selection, stability, and safety. This presentation will focus on the foundational considerations that shape clinical performance, emphasizing how molecular design influences successful patient outcomes in diverse cancer therapeutic settings today.

ROVEr is a novel platform for RLT development. We entered clinical development with our first clinical program targeting DLL3 (ABD147) in 2025 and are beginning to reveal the PK and biodistribution profile of using a VHH-Fc binder format to tune these therapies. We are poised to share the translation of the platform from no clinical to clinical and share insights from a next generation platform on next generation targets.

DARPins are promising small-sized protein-based delivery vectors for radiopharmaceutical for targeted cancer therapy. This presentation summarizes preclinical strategies to advance Radio-DARPin Therapeutics (RDT) toward clinical evaluation, focusing on improving tumor uptake and minimizing kidney exposure for optimized therapeutic windows. Initial patient images from a compassionate care program with MP0712, our DLL3-targeting lead RDT candidate show selective uptake in primary and metastatic SCLC lesions providing first-in-human proof-of-concept for RDTs.

Multiple candidates targeting Transient Receptor Potential - Vanilloid Six (TRPV6) were explored in vivo and in vitro using a proprietary peptide backbone to identify top leads for radioligand therapy. This lead optimization journey will be presented.

Radiotheranostics are advancing beyond traditional targets and tumor types through the integration of novel ligands, promising new radionuclides, and imaging-biomarker strategies. This talk will discuss innovative clinical-trial frameworks tailored for radiopharmaceuticals, emphasizing adaptive designs, dosimetry-informed endpoints, and multidisciplinary collaboration. Key themes include radionuclide selection and supply, novel targeting vectors, theranostic pair development, and strategies to seamlessly bridge preclinical and clinical research, accelerating the translation of radiotherapeutics into effective patient care.

PreTarg-it is OncoOne’s modular pretargeting platform designed to expand therapeutic windows in radioligand therapies by decoupling tumor targeting from radiopeptide administration. Biodistribution and pharmacokinetic data demonstrate high tumor-to-background ratios, supported by proof-of-concept efficacy findings in preclinical tumor models. These results position PreTarg-it as a next-generation strategy for safer, more effective radiotheranostics and outline its path toward clinical translation.

4B043 exhibits strong binding affinity to human CAIX with a KD of ~ 90 pM. In VMRC-RCW tumor-bearing mice, ⁶⁸Ga-4B043 showed high tumor retention, achieving >50% ID/g tumor uptake at 4 hours post-injection. Encouraged by these results, we initiated a human investigator-initiated trial (IIT) of ⁶⁸Ga-4B043. In three patients with renal tumors, ⁶⁸Ga-4B043 demonstrated high tumor uptake and low kidney uptake at 1 hour post-injection, with SUVₘₐₓ of approximately 100 and a tumor-to-kidney ratio of ~8.