Radiopharmaceuticals span modalities from small molecules to antibodies and antibody fragments, aiming to balance clearance and tumor penetration to maximize therapeutic window. Full length antibodies benefit from FcRn recycling but risk prolonged systemic exposure and retention throughout the reticuloendothelial system (RES). Antibody fragments clear faster yet accumulate at clearance organs. We present engineering strategies that elucidate RES endocytosis mechanisms and a methodology to reduce nonspecific uptake of antibody fragments in healthy tissues.

Radionuclide Drug Conjugates (RDCs), applying radioisotopes, both alpha (α) and beta (β) emitters, are able to precisely kill tumor cells with high efficiency and lower toxicity. We have created a potential best-in-class radioligand by increasing tumor uptake, tumor retention time, and tumor/normal organs ratio through our computational approaches. Meanwhile, we are building our first-in-class agents based on AI, experienced medicinal chemistry, and proven optimization.

Antibody is traditionally not a good ligand for developing radioligand therapy due to its large size, liver retention, and long half-life. This presentation intends to report on our efforts in applying antibody engineering and novel conjugation strategies to reduce the hepatic and blood retention and also simultaneously increase the specific targeting of the radioligand therapy to the tumor to achieve enhanced efficacy and improved safety profile. Specific case study will be presented.

DARPins are small, high affinity binding proteins with intrinsic properties well suited for use as radioligands. Using MP0712, a 212Pb based Radio DARPin targeting DLL3, we illustrate the path from target selection to first in human data. We further discuss opportunities for next generation Radio DARPin candidates, leveraging DARPin flexibility to address target and disease biology.

Radioligand therapy is governed by ligand performance, yet pharmacokinetic constraints of existing modalities limit biodistribution and target access. We present peptidomimetic DNA ligands as a programmable approach to engineering pharmacokinetics through modulation of size, valency, chemistry, and albumin binding. Using CD127 as a representative high-value, underexploited solid tumor target, we show preclinical data demonstrating radiolabeling, stability, and in vivo target engagement, and outline progression toward clinical candidate selection.

To address the dose-limiting bone marrow toxicity in radioimmunotherapy, Tagworks applies its Click-to-Release platform to enable chemically triggered off-target deactivation of radioimmunotherapeutics directed against internalizing cancer targets. In this approach, upon sufficient tumor internalization of a click-cleavable radioimmunoconjugate, a non-cell permeable trigger molecule is administered i.v. that that selectively cleaves circulating radioimmunoconjugate, leading to rapid clearance of the radiolabel and a strong increase of the tumor-nontumor dose ratio.

Lumina Pharmaceuticals is developing first in class radioligand theranostics (RLT) to address the high unmet need in solid tumor cancers. This presentation will discuss the advantages of a novel RLT targeting fibrin, a component of the extracellular matrix that is abundant in solid tumors and metastatic lesions but absent in healthy tissue.

Pre-targeted radioimmunotherapy (PRIT) separates tumor targeting from radionuclide delivery. This strategy has the potential to overcome the limitations of conventional radioimmunotherapy. OncoOne has developed its proprietary PreTarg-it platform, a modular, two-step PRIT approach designed to achieve a high therapeutic index. We demonstrate the generation of radiotherapies tailored to different tumor targets, enabling diagnostic and therapeutic radionuclide applications across multiple oncology indications.

The role of new targets to expand RLT use beyond prostate and neuroendocrine tumors will be covered in addition to maximizing therapeutic index by limiting kidney, bone marrow uptakes, and hematological toxicities.

This talk will present quantitative frameworks for reduced time-point dosimetry in radioconjugate therapy, linking preclinical biodistribution and PK/PD modeling to clinical dose estimation. Approaches to optimize sampling schedules, preserve dosimetric accuracy, and address interspecies scaling and variability will be discussed, with implications for improving feasibility and robustness in clinical implementation.

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.

Personalized dosimetry is central to unlocking the full therapeutic potential of radioligand therapy. This presentation outlines practical frameworks for integrating quantitative imaging, pharmacokinetics, and patient specific modeling into clinical development and clinical practice. Emphasis will be placed on scalable workflows, time activity characterization, and strategies to balance clinical feasibility with biological accuracy to support individualized treatment planning and improved therapeutic outcomes.

We present ALDH1A1-targeted radiotheranostics for therapy-resistant cancer. [18F]NTx-10 selectively images ALDH1A1-high tumors and resistant subpopulations in vivo, supported by genetic/pharmacologic controls and tissue validation. The therapeutic analogue [131I]NTx-11 shows prolonged tumor retention and strong efficacy with favorable tolerability in lung and ovarian models, linking response to ALDH1A1 status.

¹88Re-AX-188 (Tozaride) is a generator-produced rhenium-188-labeled somatostatin analog targeting SSTR2-overexpressing neuroendocrine tumors and lung cancers. Uniquely exploiting SSTR2 upregulation in tumor vasculature and stroma, it expands the addressable patient population beyond conventionally SSTR2-high tumors. The compound delivers high-energy beta-particle therapy (Eßmax 2.12 MeV) with simultaneous gamma-camera/SPECT imaging via a single agent, eliminating a separate diagnostic tracer. Across four Phase I/II studies enrolling 75 patients, Tozaride demonstrated favorable dosimetry, tolerability, and meaningful clinical activity in SCLC, including a median OS of 11.5 months and 25% objective tumor reduction, supporting accelerated advancement into Phase II efficacy trials. 

This presentation introduces Bicycle Radionuclide Conjugates (BRCs) as a next-generation theranostic platform for precision oncology. We will unveil how our proprietary screening technology identifies novel peptide binders against challenging cancer targets, and how these are engineered into high-affinity, selective BRCs with highly favorable biodistribution. The session will feature preclinical and early clinical data for programs targeting MT1-MMP and EphA2.

Radioligand therapies have demonstrated therapeutic benefits including extension of overall survival in patients with metastatic disease. However, these agents may have their greatest potential for clinical impact as a component of combined modality regimens where they may contribute to advancing the curative potential of cancer treatment. This talk will highlight preclinical and early clinical data from studies investigating optimal approaches to combining radioligand therapies with external beam radiation and/or immunotherapies.