Antibody-drug conjugates (ADCs) continue to push the boundaries of targeted cancer therapy and the World ADC Conference in London showcased the latest advances in preclinical and translational development shaping the field. Across the diverse themes explored during the event, one message stood out clearly: development must begin with the clinical endpoint in mind. The emphasis was firmly on more predictive, patient-centric models and tools that better capture tumour biology, inform ADC design and ultimately improve the likelihood of successful clinical translation.

Across sessions ranging from patient-derived organoids to circulating tumour cells, experts from leading organisations highlighted strategies to improve predictivity, safety and clinical translation.

Patient-derived organoids in the clinic

Isabella Zampeta, Scientific Business Development Manager at HUB Organoids, discussed preclinical models with a particular focus on patient-derived organoids (PDOs). She emphasised the limitations of conventional models, explaining: "It is costly, it is lengthy and it's a risk. With only 8 percent of drugs progressing beyond early clinical trials, much of that failure is due to models that do not capture the biology of the patient."

With only 8 percent of drugs progressing beyond early clinical trials, much of that failure is due to models that do not capture the biology of the patient.

PDOs, however, offer a patient-centric platform that retains the genetic, epigenetic and antigenic signatures of tumours, enabling more predictive target evaluation and screening.

Zampeta described their versatility across the development pipeline, from target identification and efficacy testing to toxicity assessment and resistance modelling.

"We can compare tumour organoids to matched normal tissue, helping to predict both on-target efficacy and off-target toxicity," she said.

Organoids also enable the creation of acquired resistance models, providing scientists with key insights into therapeutic failure. Reinforcing their clinical relevance, she cited studies showing strong correlations between organoid responses and patient outcomes, highlighting the platform's value in guiding trial design, biomarker selection and payload optimisation.

Isabella Zampeta, Scientific Business Development Manager at HUB Organoids, delivering her talk on patient derived organoids.

Modelling bone marrow toxicity for safer ADCs

Suzanne Randle, Associate Director at AstraZeneca, tackled one of the most persistent challenges in ADC development: bone marrow toxicity. Randle explained that hematotoxicity - manifesting as neutropenia, thrombocytopenia, anaemia and lymphopenia - is often driven by off-target payload uptake rather than the intended target.

Hematotoxicity - manifesting as neutropenia, thrombocytopenia, anaemia and lymphopenia - is often driven by off-target payload uptake rather than the intended target.

"Many toxicities are off-target within the bone marrow and generally are driven by payloads," she said, highlighting the difficulty of predicting clinical risks.

Randle described a tiered approach to safety assessment, beginning with high-throughput suspension cultures of human CD34+ stem cells for early payload ranking and IC50-based risk prediction. More complex 3D microphysiological niches and organ-on-chip systems allow long-term, multi-lineage differentiation and capture clinically relevant effects.

"ADC dynamics in vitro can be quite challenging if you're looking at an off-target mechanism," said Randle, highlighting the importance of careful data interpretation.

She also talked about how fluorescence-based internalisation assays help distinguish target-mediated, Fc receptor-mediated and non-specific uptake, giving researchers actionable insights for payload selection and ADC design.

Together, these approaches aim to maximise the therapeutic index while reducing reliance on animal studies.

In her presentation, Suzanne Randle, Associate Director at AstraZeneca, tackled one of the most persistent challenges in ADC development: bone marrow toxicity.

Preclinical considerations for novel ADC payloads

Next, Niresh Hariparsad, Head of Oncology R&D at AstraZeneca, provided a detailed overview of the challenges in preclinical characterisation of novel ADC payloads. He discussed how systemic exposure alone does not necessarily reflect the true driver of efficacy - the payload concentration at the site of action.

"Very often, you're making these assessments based on systemic exposure, but what really causes the effect is the concentration at the site of action," he said.

Very often, you're making these assessments based on systemic exposure, but what really causes the effect is the concentration at the site of action.

He explained that efflux transporters and lysosomal trapping can limit the availability of ADC payloads, complicating their effectiveness. Basic compounds, for example, may become sequestered in lysosomes rather than reaching their intended site of action. Designing effective ADCs therefore requires careful balancing of properties such as permeability, bystander activity, stability and systemic exposure to achieve both efficacy and safety.

The key takeaway from this session was that mechanistic understanding of both extracellular and intracellular behaviour is essential for optimising efficacy and safety and predicting clinical outcomes with confidence.

Niresh Hariparsad, Head of Oncology R&D at AstraZeneca, delivered a detailed talk on the challenges in preclinical characterisation of novel ADC payloads.

ADC C9: a pan-cancer approach

Ali Salanti, CEO of Var2 Pharmaceuticals, introduced ADC C9, a pan-cancer therapeutic targeting the ofCS modification, an oncofetal glycosaminoglycan modification broadly expressed in tumours but largely absent from normal tissues. ofCS represents a highly differentiated therapeutic target, with the underlying biology originating from malaria research. This work led to the identification of ofCS as a conserved, tumour-associated structure with pan-cancer relevance.

Preclinical studies demonstrated broad and uniform tumour staining with minimal off-target binding.

Preclinical studies demonstrated broad and uniform tumour staining with minimal off-target binding. No adjustments were made to ADC or payload levels and patient selection was not based on expression, allowing the therapy to be applicable across a wide patient population.

The monovalent IgG format was chosen to improve tumour penetration and prevent perivascular trapping. The ADC showed tumour-restricted biodistribution, efficient internalisation, bystander activity and synergy in combination treatments. Genetic knockout experiments also indicated that tumours may find it difficult to evade targeting without compromising their viability, suggesting the potential for durable responses.

With GMP manufacturing and toxicology studies in progress, ADC C9 is moving towards first-in-human evaluation.

In his presentation, Ali Salanti, CEO of Var2 Pharmaceuticals, introduced ADC C9, a pan-cancer therapeutic targeting the ofCS modification.

Tracking tumour cells to improve ADCs

Finally, Lavanya Sivapalan, Senior Director for R&D and Laboratory Services at CelLBxHealth, highlighted circulating tumour cells (CTCs) as a dynamic biomarker for guiding ADC therapy.

Firstly, she acknowledged that patient selection remains a major challenge, as traditional tissue biopsies assume stable antigen expression, while tumours are biologically heterogeneous and continuously evolving. Static tissue assessments can therefore miss key changes in target expression over time.

CTCs provide a real-time window into tumour biology, offering mechanistic insight at the DNA, RNA and protein level.

Despite this, CTCs provide a real-time window into tumour biology, offering mechanistic insight at the DNA, RNA and protein level. Unlike ctDNA, which only captures mutations, CTCs reveal where targets are expressed on living cancer cells and the density of that expression. CelLBxHealth's Parsortix platform performs epitope-independent enrichment, capturing epithelial, mesenchymal and EMT-transitioning CTCs, as well as clusters. This approach allows the identification of clinically relevant subpopulations and can uncover resistance mechanisms driven by the payload rather than the antigen.

By integrating CTC analysis into ADC development, researchers can identify non-responding patients early, enable adaptive treatment strategies and implement rational ADC sequencing based on mechanistic resistance patterns.

"Circulating tumour cells provide a very promising solution to enable multidimensional measurements of antigen distribution, DNA damage response, apoptosis as well as phenotypic evolution," concluded Sivapalan.

Lavanya Sivapalan, Senior Director for R&D and Laboratory Services at CelLBxHealth, delivered a presentation on circulating tumour cells (CTCs) as a dynamic biomarker for guiding ADC therapy.

Final thoughts

Across the preclinical and translational sessions at the World ADC Conference, it was clear that advancing ADC development requires models and tools that more accurately reflect human biology. Patient-derived organoids and circulating tumour cells are enabling deeper insight into tumour heterogeneity, target expression and resistance mechanisms, while sophisticated bone marrow models and mechanistic payload studies are improving safety predictions and the therapeutic index. Innovative ADC designs, such as the pan-cancer ADC C9, demonstrate the potential of precise target selection, optimised antibody formats and tumour-restricted biodistribution to maximise efficacy and durability. Together, these approaches move the field towards more predictive, patient-centric preclinical strategies that not only enhance our understanding of ADC biology but also increase confidence in successfully translating therapies into the clinic.

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