Overcoming Challenges in Developing RDCs: WuXi AppTec’s CRDMO Model

Radionuclide drug conjugates (RDCs) have recently emerged as a promising approach in oncology, attracting increasing attention. By integrating precision diagnosis with targeted therapy, RDCs offer a new therapeutic paradigm for cancer patients. As of the end of 2025, 11 RDC drugs have been approved globally, validating their clinical value and potential.

Despite this progress, development challenges remain. An RDC is structurally complex, typically consisting of a targeting ligand (typically a peptide or small molecule), a linker, a chelator, and a radioactive isotope. These components must be precisely assembled, placing high requirements on process development and manufacturing capabilities.

Several years ago, a biotech company encountered such challenges while developing a cyclic peptide-based RDC.

Initially, the biotech was working with another partner. However, after more than a year, the progress remained stalled, and key molecules required for downstream development were not delivered.

After a prolonged delay, the biotech selected WuXi AppTec.

An Integrated Platform Brings the Project Back on Track

Upon taking over the project, WuXi TIDES, WuXi AppTec’s integrated CRDMO platform focused on oligonucleotides, peptides, and related synthetic conjugates, moved swiftly. The team’s immediate priority was to optimize the lead structure to identify a preclinical candidate (PCC).

The initial hurdle was the uncertainty in raw material supply.

A key unnatural amino acid (UAA) required for the project faced unstable external supply and long procurement periods, which posed a risk of delaying progress.

To mitigate this risk, the discovery team at WuXi TIDES developed a synthetic route internally for the UAA, establishing a stable supply chain. 

With a reliable material supply in place, the discovery team delivered more than 200 cyclic peptide variants with over 95% purity within 4 months—one month ahead of the client’s expectation. They worked with WuXi Testing team to refine the molecular properties and advanced lead compounds with optimized in vitro and in vivo profiles. Through the combined efforts of all teams, the client ultimately nominated a preclinical candidate.

Following candidate selection, the project was advanced to the process development stage.

In traditional models, this handoff often leads to inefficiencies due to revalidation and fragmented results exchange. WuXi AppTec’s integrated, end-to-end CRDMO model is designed to eliminate such discontinuities, enabling seamless collaboration across teams.

Leveraging this model, the process development team directly received all related information from the discovery team, ensuring continuity across project stages and reducing contamination risk from cross supplier handovers.

During process development, the team went beyond conventional synthetic approaches and explored alternative strategies.

Traditional approaches require sequential isolation, purification, and drying steps after each reaction, which are time-consuming operations that also incur cumulative material losses.

To address this, the team implemented a telescoping process strategy. Commonly used in small molecule development, telescope process allows intermediates to proceed directly into subsequent reactions without isolation, through solution-phase transfers or direct carryover. This eliminates the need for solid isolation, filtration, and drying.

Drawing on WuXi AppTec’s extensive experience in small molecule process development, the team quickly validated the applicability of the telescope process for RDCs and successfully implemented it in this project.

The results were significant: the telescope process reduced the synthesis cycle by 30% and decreased material usage by approximately 30%, minimizing losses associated with intermediate steps.

Addressing Challenges to Enable High-Quality Delivery

Another key challenge throughout the project was impurity control.

Due to the presence of metal-chelating structures, during production and purification, RDC molecules are capable of binding the intended radionuclide, while also exhibiting affinity for trace metals from the environment. These unintended metal complexes form structurally similar impurities that are difficult to separate and accurately identify.

To address this, WuXi TIDES incorporated impurity control into the overall process design from the outset.

Cross-functional teams collaborated to tackle this issue from different dimensions. The analytical-purification method was developed to distinguish structurally similar metal-chelated species and precursors. The drug substance team optimized solvent systems, operational procedures, and reaction conditions to minimize the introduction of exogenous metals. The formulation and analytical teams also carefully screened containers and materials to further minimize potential interference.

Through project-specific solutions and a series of process optimizations, the crude purity reached 99%, while overall yield increased from 29% to 44%.

When the first batch of API was successfully delivered, the client was excited to see that the project, which had once stalled for over a year at another provider, was completed at WuXi AppTec.

Following the successful delivery, the client subsequently entrusted several additional projects to WuXi AppTec, turning a single collaboration into a long-term partnership built on trust.

Today, WuXi TIDES has established integrated capabilities covering RDC discovery, process development, and manufacturing, enabling global customers to efficiently advance RDC projects.

As emerging modalities such as RDCs continue to evolve, the complexity of drug development is increasing. From molecular design to process development, and from scale-up to quality control, each stage demands higher levels of coordination and efficiency.

With its integrated, end-to-end CRDMO platform, WuXi AppTec combines comprehensive capabilities into a cohesive development pathway to address these challenges and deliver speed, quality and value while advancing programs.

Looking ahead, as increasingly complex molecules emerge, WuXi AppTec will continue to work with global customers to translate scientific challenges into executable development strategies, enabling the acceleration of innovative therapies from the laboratory toward the clinic, and ultimately to patients.