Interest in targeted radioligands and bioconjugates is growing, with the antibody-drug conjugate (ADC) pipeline alone growing from hundreds to thousands of candidates in recent years. Advances in linker chemistry and new payload classes, including topoisomerase I inhibitors (TOP1), have helped fuel this expansion and opened new possibilities for precision cancer medicines.
Yet despite rapid advances and notable successes, familiar roadblocks continue to prevent many targeted medicines from reaching patients. Off-target toxicity, tumour heterogeneity and drug resistance remain substantial challenges, while developers must also engineer linkers that support effective targeting and payload delivery.
At ELRIG Drug Discovery 2026, our track, 'Targeted potency: Advances in radioligands and bioconjugates', explored how developers are tackling these challenges. Experts from Bicycle Therapeutics, Artios Therapeutics, Lonza and more shared approaches that combined creative problem-solving with the careful management of competing design priorities and a consistent focus on tolerability and patient safety.
Getting past potency
The discovery of potent payloads such as TOP1 inhibitors and alpha-emitting radionuclides like lead-212 has opened exciting new possibilities in precision medicine, but potency is also a double-edged sword. Promising drug candidates can fail when their therapeutic effects are outweighed by toxicity in healthy tissues.
Alonso Haysom Rodriguez, Research Scientist at Bicycle Therapeutics illustrated this challenge through the development of BT1702, a therapeutic radioconjugate designed to deliver the alpha-emitting radionuclide lead-212 to tumours expressing membrane type-1 matrix metalloproteinase (MT1-MMP).
MT1-MMP is a membrane-anchored protein associated with tumour invasiveness and overexpressed in several cancers, including osteosarcoma and oesophageal and lung cancers.
Bicycle's constrained peptides offer high specificity and rapid tumour penetration, making them well suited to targeted radionuclide delivery. But early development also revealed unwanted kidney accumulation in animal models.
‘That prompted months of lab work from Bicycle’s medicinal chemists,’ said Alonso.
The team had to tune tumour retention to the isotope's half-life, ensuring the molecule remained in the tumour long enough to maximise its cytotoxic effect, while promoting rapid clearance from healthy tissues and limiting kidney exposure.This challenge echoed throughout the track: as payloads become more potent, the demands on lead optimisation increase. Highly cytotoxic payloads need to be conjugated with molecules that can effectively control when, where and for how long they are activated.
Making precision multidimensional
Target affinity has long been top-of-mind for teams developing precision medicines, but while its importance has not diminished, new modalities bring new challenges. Clinical success increasingly depends on controlling not only what a drug binds to, but where it travels, how it behaves inside cells and how effectively it delivers its payload.
This multidimensional approach to precision engineering was spotlighted by Bin Liu, Scientific Director of WuXi AppTec, who presented the company’s development of tissue-specific peptide–oligonucleotide conjugates for siRNA delivery.
Starting from an initial peptide, the team used affinity maturation and the incorporation of non-canonical amino acids to generate a stable lead that bound around 60 times more tightly to the target. However, high affinity wasn't enough: the researchers needed to establish the drug's cellular behaviour.
Specifically, they needed to establish whether receptor binding translated into cellular uptake, and whether the siRNA could escape the endosomal pathway and reach its intracellular target.
To achieve this, the conjugate had to be considered as a whole. Even promising peptides and oligonucleotides did not necessarily perform well when brought together, meaning the linker architecture joining them also had to be refined to preserve the functionality of both components.
Using fluorescence imaging and competition assays to assess internalisation, alongside measurements of knockdown efficiency, the team demonstrated that the conjugate could enter target cells and deliver biologically active siRNA.
The case study illustrates an important shift in how precision medicines are designed. Binding affinity remains essential, but it is only one dimension of a drug's performance, alongside properties such as biodistribution, cellular uptake and intracellular trafficking. And as conjugates become more complex, seemingly secondary features such as linker architecture are becoming integral to how the drug behaves as a whole.
Programmable medicines
As developers increasingly view targeted medicines as whole systems rather than distinct components, they are gaining new opportunities to configure medicines around the biology of specific tumours.
Remon van Geel, Director of Biochemistry for Lonza, illustrated this shift through the development of dual-payload ADCs designed to address tumour heterogeneity and drug resistance. Rather than using an antibody to deliver a single cytotoxic agent, the platform enables two payloads with complementary mechanisms of action to be incorporated into the same conjugate.
This creates a new level of flexibility. Developers can select payloads whose mechanisms complement each other, while also tuning their ratios, potency and bystander properties. In principle, these variables can be configured around the particular biological challenges presented by different cancers.
The strategy is already showing promising preclinical results. In animal models of breast and ovarian cancer, an ADC combining two payloads – one inhibiting the cell cycle and the other damaging DNA – outperformed the corresponding single-payload ADCs, achieving full tumour regression.
This idea of programmability can even extend beyond the components of the medicine itself. Manuel Pinto, Principal Scientist at Avacta Therapeutics, presented the company’s PreCISION approach. PreCISION exploits FAP, an enzyme expressed by cancer-associated fibroblasts in the tumour microenvironment. Its chemistry is designed so that FAP cleavage releases the payload within the tumour microenvironment, where the active drug can diffuse into and kill neighbouring cells. In this case, a feature of tumour biology becomes part of the drug's activation mechanism.
As our understanding of tumour biology deepens, new payloads emerge and linker engineering becomes more sophisticated, these relationships are likely to become increasingly important. Binders, linkers and payloads may remain modular building blocks, but they can no longer be optimised in isolation. Instead, developers are gaining the tools to programme where a medicine travels, where it becomes active and which mechanisms it deploys – configuring the whole therapeutic system around the biology it is designed to attack.
What's next?
The rapid expansion of bioconjugates and radioligands is being underpinned by new payloads, but also by a shift in how teams approach their development. Increasingly, developers are taking a flexible, holistic approach to molecule design, considering not just the potency of the payload or the specificity of the binder, but how each component works together and interacts with the distinct biological challenges that cancer presents.
As these technologies progress, this systems-level approach could expand what targeted medicines can address, from hard-to-treat cancers to some of the field's most persistent challenges, including tumour heterogeneity and drug resistance.