What Radionuclide Drug Conjugates (RDC) are being developed?

Introduction to Radionuclide Drug Conjugates

Radionuclide Drug Conjugates (RDCs) represent a cutting‐edge class of agents designed to combine the targeting precision of biomolecules with the potent, localized effects of radioactivity. These RDCs are garnering increased interest in clinical oncology and other indications due to their unique capacity to deliver radionuclides directly to tumor cells, thereby enhancing tumor cell killing while minimizing systemic toxicity. In this review, we explore the definition, historical context, and current trends regarding RDCs, along with the diverse types being developed, notable examples from current research and clinical trials, and the technical and regulatory challenges that shape future innovation.

Definition and Mechanism

Radionuclide Drug Conjugates are complex compounds comprising three essential components: a targeting moiety (often an antibody, peptide, or small molecule ligand), a radioisotope serving as the payload, and a chemical or biological linker that covalently or non-covalently binds the two. The targeting component confers specificity by binding to antigens or receptors that are overexpressed on tumor cells, while the radionuclide emits ionizing radiation—such as alpha or beta particles—that induces DNA damage and cell death locally at the tumor site.
This mechanism exploits the principle of "magic bullet" therapy by delivering high radiotoxicity selectively to cancer cells with minimal collateral damage to normal tissue. Importantly, RDCs are designed to mediate both diagnostic imaging and therapeutic effects, a concept commonly referred to as “theranostics.” The specific decay characteristics of the radionuclide, including half-life and particle emission type, are critical determinants for their diagnostic or therapeutic utility. For example, isotopes like 131I can serve dual functions, offering both imaging capabilities and cytotoxic therapy, depending on their formulation and attached targeting agent.

Historical Development and Current Trends

The concept of using radionuclides linked to targeting vectors is not entirely new but has evolved significantly over the past few decades. Early studies in radioimmunotherapy demonstrated that radiolabelled antibodies could be used to treat hematological malignancies such as non-Hodgkin’s lymphoma; however, these initial attempts lacked the sophistication needed for solid tumors.
In recent years, advances in chemistry, ligand engineering, and conjugation technologies have revolutionized RDC development. The historical development of RDCs reflects tremendous progress in overcoming earlier challenges such as non-specific radiotoxicity and unstable linker chemistries. With enhanced chemical stability and site-specific conjugation methods borrowed from advances in the antibody-drug conjugates (ADC) field, researchers have been able to improve tumor penetration and optimize the pharmacokinetics of RDCs.
Current trends include a focus on targeting antigens such as DLL3, which are expressed in solid tumors like small-cell lung cancer (SCLC). Alongside the refinement of existing techniques, the development of RDCs now integrates novel radionuclide platforms and supermolecular assembly approaches, such as the construction of nanoplatform-based systems with clearly defined structures and improved quality control properties. Thus, RDC development is marked by an evolutionary shift, where historical lessons have informed the creation of more selective, safer, and clinically effective conjugates.

Types of Radionuclide Drug Conjugates

The categorization of RDCs is largely based on their intended clinical application, with distinct classifications for therapeutic and diagnostic applications. This dual functionality is critical, as RDCs provide avenues for both imaging to localize disease and therapy to treat it.

Therapeutic RDCs

Therapeutic RDCs are designed to deliver cytotoxic radiation to tumor cells. These constructs typically employ radionuclides that emit beta (β⁻) or alpha (α) particles—each having unique radiation properties that determine the range and type of tissue damage.
For instance, isotopes such as 90Y and 131I are frequently used in therapeutic RDC designs due to their favorable decay energy and established track records in clinical settings. In one comprehensive review, numerous therapeutic RDCs investigated in clinical trials were mentioned, including those based on radionuclides like 111In, 131I (in various constructs including 131I-BC-2, 131I-BC-4, and 131I-tenatumomab), and even 211At for advanced therapies.
Moreover, recent developments include RDCs that focus on targeting antigens with high specificity. An example of this is the investigation of novel investigational drugs such as 89Zr-DFO-SC16.56 and ABD-147, which are designed to target DLL3 expressed in solid tumors, notably in SCLC, delivering cytotoxic radiation while minimizing damage to healthy tissue.
Another innovative therapeutic application involves supermolecular systems. In one recent study, a new RDC system, referred to as 131I-ER-Fu NPs, was developed by labeling erlotinib with 131I and combining it with floxuridine in a nanoplatform, thereby harnessing the benefits of both small molecule and nanoplatform-based RDCs for treating non-small cell lung cancer (NSCLC). This approach leverages controlled assembly by hydrogen bond interactions, prolonging circulation lifetime, and enhancing tumor specificity.

Diagnostic RDCs

Diagnostic RDCs are tailored for imaging purposes, where the goal is to accurately localize tumors or assess disease burden non-invasively. These RDCs are typically developed using radionuclides that emit positrons or gamma rays, which can be detected by PET or SPECT imaging systems.
A prime example is the utilization of radioisotopes like 64Cu and 89Zr in conjugate systems, where the radiolabeled compound provides clear imaging contrast and can also be used to screen patients for subsequent targeted therapy. Although the primary focus for diagnostic RDCs has been on imaging applications, the same conjugation principles apply: a targeting ligand is coupled with a diagnostic radionuclide via a stable linker to ensure accurate biodistribution and retention in target lesions.
In addition, the theranostic concept in radiopharmaceutical development enables some RDCs to serve in a dual role—providing diagnostic imaging in one formulation and delivering therapeutic radiation in another when the therapeutic isotope is substituted for the diagnostic one. This adaptability is crucial for personalized treatment strategies, whereby diagnostic RDC imaging can guide therapy decisions and monitor treatment response.

Current Research and Development

The research and development landscape for RDCs is marked by several notable investigational agents, advancing through preclinical studies and early clinical trials. These developments span both academic and industry-driven projects, reflecting the integration of advanced conjugation chemistry, novel radionuclides, and innovative drug delivery systems.

Notable RDCs in Development

Recent literature and ongoing studies reveal a range of RDCs under development:

DLL3-Targeting RDCs for Solid Tumors
Among the forefront RDCs, those targeting the DLL3 antigen have gained interest, specifically in the context of small-cell lung cancer. Two investigational RDCs, 89Zr-DFO-SC16.56 and ABD-147, have been reported. These RDCs are designed to selectively deliver radioactivity to solid tumors with high DLL3 expression, lowering the risk of radiotoxicity to non-target tissues.
The choice of 89Zr, a radionuclide with a favorable half-life for imaging and therapeutic evaluation, coupled with optimized chelators such as DFO (desferrioxamine), underscores the progress in linker and conjugation chemistry that ensures the stability and specificity of these constructs.

Therapeutic RDCs Incorporating 131I, 90Y, and Other Radionuclides
A plethora of RDCs have been developed using varied radionuclides to offer a broad therapeutic index. As highlighted, clinical trials have evaluated RDCs such as 111In-DTPA-BC-2, 131I-BC-2, 131I-BC-4, 90Y-BC4, 131I-81C6, 131I-ch81C6, and 211At-ch81C6.
These agents differ in pharmacokinetic properties and radionuclide emission characteristics. For example, 90Y emits high-energy beta particles allowing for deep tissue penetration, whereas 211At provides highly potent alpha radiation for targeted therapies that demand short-range, high-impact cytotoxic effects. Such diversity enables the tailoring of treatment regimens based on tumor size, location, and specific molecular characteristics.

Supermolecular and Nanoplatform-Based RDC Systems
An innovative study developed a supermolecular RDC system by conjugating erlotinib with 131I, and then combining with floxuridine to form nanoplatform-based nanoparticles (131I-ER-Fu NPs). This design integrates the clear structure definition, enhanced tumor retention, and rapid non-target clearance often seen with nanoplatform RDCs, while retaining the advantages of classical RDC approaches.
The supermolecular assembly approach not only demonstrates improved quality control and extended circulation time but also facilitates a modular strategy that could be adapted to different tumor types by substituting the targeting moiety or altering the payload radionuclide.

Additional Investigational Constructs
Beyond the specific examples mentioned above, several other RDCs are under investigation. These include formulations using innovative radionuclides such as 211At and 131I in various conjugate designs. The studies also explore the conjugation of radionuclides to various targeting ligands—not only antibodies but also peptides and small molecules—which allows for the exploration of diverse tumor targets and microenvironment factors.
Such developments are emblematic of a broader trend where traditional cytotoxic chemotherapeutic strategies are being supplanted by highly targeted, low-toxicity radiopharmaceutical agents, offering a new paradigm in oncologic therapy.

Clinical Trials and Studies

The transition of RDCs from preclinical research to clinical trials is being actively pursued in various settings. Clinical studies have begun evaluating the safety, efficacy, and pharmacokinetic profiles of these RDCs:

Clinical Trial Data and Preclinical Models
Preclinical studies have validated that RDCs can selectively accumulate in tumors while achieving sufficient clearance from non-target tissues. For instance, animal models have demonstrated that RDCs such as the 131I-ER-Fu NPs system exhibit both low biological toxicity and enhanced antitumor effects compared to conventional therapies.
In early-phase clinical trials, RDCs targeting DLL3 (e.g., 89Zr-DFO-SC16.56 and ABD-147) are being evaluated for safety and efficacy. These studies assess not only the overall response in tumor reduction but also the dosimetry, biodistribution, and potential adverse effects related to off-target radiation exposure.

Multimodal Assessments in Trials
Many clinical trials involving RDCs incorporate multimodal assessments that integrate both imaging and therapeutic endpoints. By using diagnostic radionuclides for initial patient screening and then employing therapeutic radionuclides in treatment formulations, researchers can conduct adaptive trials. These trials refine dosing strategies based on real-time imaging feedback, improving the therapeutic ratio.
Additionally, clinical evaluations integrate metrics such as tumor uptake quantified via PET or SPECT imaging, measured in standardized uptake values, and correlations with clinical outcomes such as progression-free survival and overall response rates. These comprehensive approaches ensure that RDCs are not only potent in vitro but also translate effectively in clinical settings.

Regulatory-Driven Clinical Studies
The clinical trial landscape for RDCs is being shaped by regulatory initiatives that emphasize quality assurance, controlled manufacturing processes, and rigorous dosimetry assessments. Regulatory science-based approaches are being implemented to guide the nonclinical and clinical evaluation of RDCs, ensuring that these novel agents meet stringent safety and efficacy criteria.
The evolving regulatory frameworks also pave the way for accelerated clinical trials, especially in areas with high unmet needs such as metastatic solid tumors. Early-phase trials focusing on safety and response biomarkers are establishing the groundwork for larger, multi-center studies. Collaboration between academic institutions, industry, and regulatory bodies is a key factor in the successful clinical translation of these agents.

Challenges and Opportunities

The development of RDCs presents a promising therapeutic strategy; however, several challenges—both technical and regulatory—must be addressed to fully harness their potential. At the same time, the field is ripe with opportunities for innovation and improved clinical outcomes.

Technical and Regulatory Challenges

Conjugation Chemistry and Stability
One of the most significant technical challenges is achieving a stable and reproducible conjugation between the radionuclide and the targeting moiety. Unstable linkers may result in premature detachment of the radioactive payload, leading to off-target toxicity and reduced therapeutic efficacy.
Advances in site-specific conjugation techniques, such as the use of optimized chelators (e.g., DFO for 89Zr or specialized bifunctional chelators for 131I), are critical for maintaining the integrity of RDCs during circulation and ensuring targeted delivery. The development of multi-step chemical methods for synthesizing robust RDCs remains an active area of research.

Pharmacokinetics and Biodistribution
Achieving the appropriate pharmacokinetic profile is paramount. RDCs must circulate long enough to home into tumor tissues yet be cleared swiftly from non-target tissues to minimize radiotoxicity. This balance requires careful optimization of antibody or ligand size, linker length, and radionuclide half-life.
Nanoplatform-based RDC systems, such as those incorporating a supermolecular assembly approach, offer promising avenues to address these issues by allowing for controlled release, prolonged circulation, and enhanced tumoral retention. However, translating these findings from preclinical models to human patients introduces further challenges that must be addressed through rigorous phase I clinical studies.

Dosimetry and Safety Assessments
Accurate dosimetry—estimating the absorbed dose of radiation in both tumor and healthy tissue—is essential for the safe implementation of RDC therapy. Regulatory requirements demand comprehensive non-clinical studies that characterize dose distributions.
These studies are complex as the physical decay characteristics of different radionuclides, such as 90Y, 131I, and 211At, differ considerably. Standardization of dosimetric methods and the adoption of advanced imaging techniques play an important role in correlating administered activity with expected biological effects.
Additionally, integrating radiological safety assessments with pharmacodynamic outcomes is an evolving regulatory challenge that calls for novel analytical methods and cross-disciplinary expertise.

Regulatory Pathways and Manufacturing
The manufacturing of RDCs poses its own set of challenges. Production methods must be robust, reproducible, and scalable while ensuring that the quality of the radionuclide, the conjugation process, and the final product meets regulatory standards.
Regulatory agencies require extensive documentation for quality control, including stability testing, purity assessments, and radiochemical yield profiles. As RDCs combine elements of both biologics and radiopharmaceuticals, they often fall under complex regulatory frameworks that integrate aspects of both drug and device evaluation. This complexity can delay clinical translation and requires ongoing dialogue between developers and regulatory authorities to streamline approval processes.

Future Directions and Innovations

Integration of Theranostic Platforms
One promising direction is the further development of integrated theranostic RDC platforms that enable seamless transition between diagnostic imaging and therapeutic delivery. By interchanging the radionuclide component (e.g., substituting a diagnostic isotope with a therapeutic one in the same chemical construct), clinicians can tailor treatment in real time.
Such strategies not only facilitate personalized treatment regimens but also provide critical data on biodistribution and dosimetry that can inform subsequent treatment cycles. The continued refinement of such methodologies is expected to significantly advance the field in the next decade.

Advances in Nanotechnology and Supermolecular Assemblies
The integration of nanotechnology with RDC development is an area of high potential. Nanoplatform-based systems, such as the 131I-ER-Fu NPs, are designed to harness the benefits of both nanoparticles and traditional RDC constructs. These systems offer enhanced targeting capabilities, improved control over pharmacokinetics, and the potential for multi-drug payloads that can address tumor heterogeneity.
Future research will likely focus on the design of modular, controllable systems that combine multiple therapeutic modalities, such as a combination of chemotherapy and radiotherapy, to overcome resistance mechanisms in refractory tumors. The development of these advanced platforms also promises improvements in quality control and manufacturing reproducibility.

Optimized Linker Technologies and Site-Specific Conjugation
Future innovations in linker chemistry are expected to further enhance the stability and efficacy of RDCs. Site-specific conjugation methods that ensure homogeneity in the final product will be critical for reducing off-target toxicity and improving therapy predictability.
Innovations in chelator design and the utilization of novel conjugation techniques such as enzymatic coupling could lead to RDCs with more predictable pharmacokinetic profiles and lower immunogenicity. These technological advancements, when paired with computational modeling and in silico dosimetric evaluations, will lead to optimized RDC constructs ready for clinical use.

Regulatory Science and Accelerated Approval Pathways
Regulatory agencies are beginning to recognize the potential of RDCs and are updating guidelines to accommodate the complexities of combined radiopharmaceutical and biologic products. The future regulatory landscape is expected to include more harmonized requirements that reduce development time without compromising safety.
In parallel, early dialogues between industry and regulators can pave the way for expedited study designs and accelerated approval pathways. Greater reliance on real-world evidence (RWE) and advanced imaging biomarkers is anticipated to streamline clinical trials in RDC-based therapies, ultimately improving access for patients with high unmet need conditions.

Collaborative Networks and Patient-Centric Approaches
As the field matures, collaborative networks that integrate academic research, industry expertise, and clinical practice will be crucial. Such collaborations are expected to facilitate the standardization of methodologies, promote data sharing, and ultimately lead to improved patient outcomes.
Patient-centric approaches that incorporate feedback into the design of RDC clinical trials will also be instrumental. By involving patients early in the development process, clinicians and researchers can more effectively tailor therapies to meet the needs of diverse populations, ensuring that RDCs address both efficacy and quality-of-life considerations.

Conclusion

Radionuclide Drug Conjugates are emerging as a versatile and potent class of therapeutic agents, with applications spanning both targeted cancer therapy and diagnostic imaging. In summary, RDCs are defined by the strategic coupling of a targeting agent with a radionuclide through a stable linker, enabling the localized delivery of ionizing radiation to tumor cells while minimizing systemic harm. Their historical evolution—from early radioimmunoconjugates to today's advanced constructs incorporating site-specific conjugation and nanoplatform-based designs—reflects significant technological progress and a deepening understanding of the tumor microenvironment.

The current landscape of RDC research features several types of RDCs, classified broadly into therapeutic and diagnostic agents. Therapeutic RDCs primarily employ radionuclides such as 131I, 90Y, and 211At to deliver cytotoxic radiation and are being developed for targets like DLL3 among others, while diagnostic RDCs are optimized for non-invasive imaging using isotopes like 64Cu and 89Zr. Notable investigational RDCs include the DLL3-targeting agents 89Zr-DFO-SC16.56 and ABD-147, as well as innovative supermolecular constructs exemplified by the 131I-ER-Fu NPs system.

From a clinical development perspective, RDCs have progressed from promising preclinical models to early-phase clinical trials, where multimodal evaluations of safety, dosimetry, and efficacy are refining their use in personalized cancer therapies. Yet, several technical and regulatory challenges remain—ranging from ensuring robust conjugation stability and optimized pharmacokinetics to meeting rigorous quality assurance and dosimetry requirements. The field is looking forward to innovations in nanotechnology, linker chemistry, and harmonized regulatory frameworks that promise to overcome these hurdles.

Ultimately, the future of RDC development is bright. With ongoing advances in theranostic platforms, emerging nanoplatform assemblies, and the integration of patient-centric clinical trial designs, RDCs are poised to revolutionize the way we diagnose and treat complex solid tumors and other diseases. Collaborative efforts involving academia, industry, and regulatory organizations will be essential in realizing the full potential of RDCs, ensuring that they translate into safe, effective, and widely accessible therapies in the near future.

In conclusion, RDCs represent an exciting frontier at the convergence of nuclear medicine, targeted therapy, and precision diagnostics. Their development is supported by robust scientific research, innovative chemical engineering, and evolving regulatory science—all geared toward improving outcomes for patients with some of the most difficult-to-treat cancers. As the field continues to innovate and address current challenges, RDCs are expected to play an increasingly critical role in the future of personalized medicine, reshaping therapeutic paradigms and advancing global oncology care.