Radio Tracers and Antibody Drug Conjugate drug development

Introduction

Antibody Drug Conjugates (ADCs) are a rapidly emerging class of targeted biological agents, designed to deliver a potent cytotoxic agent to cancer cells with minimal damage to surrounding tissue. ADCs are made up of three fundamental components: an antibody, a linker, and a payload, the choice of which dictates the clinical behavior of the drug. For example, when considering the most successful application of HER2-positive breast cancer, the ADC Trastuzumab Emtansine (T-DM1) combines the monoclonal antibody Trastuzumab with the cytotoxic agent DM1, via a stable linker.

The antibody targets HER2-expressing tumor cells, effectively delivering the small-molecule cytotoxic payload directly to these cells whilst minimizing off-target effects. Since its conception around the year 2000, ADC drug development has seen rapid growth as a successful therapeutic intervention, creating opportunities for drug developers to design specific, potent, and innovative next-generation targeted treatments. The penetration of the drug into the solid tumor microenvironment presents a challenge for ADC drug development, however, with many research programs coming to a halt due to a lack of in vivo insight into whether or not the antibody is actually engaging the target.

However, ongoing advances in radiochemistry continue to expand the possibilities for more precise and informative ADC imaging and analysis. Radioactive tracers, or radiotracers, are now frequently being used during ADC drug development. Defined as the radioactive element of a compound which can be added to a material, or in this case, an antibody, to monitor the material’s distribution as it progresses through the body. Radiolabeling ADCs in this way supports preclinical validation, patient selection, and companion diagnostics, guiding decision-making and de-risking ADC clinical trial execution. 

The role of radiotracers in ADC development

As previously discussed, radiotracer ADC research studies leverage the tools and techniques of radiochemistry to label antibody-drug conjugates with radioisotopes to track their behavior in vivo. Through this application of radiochemical labeling strategies, researchers can visualize and quantify how ADCs distribute, accumulate, and metabolize. Traditionally, preclinical studies have focused on the concept of efficacy and the evaluation of tumor growth inhibition, leaving gaps in our understanding of how exactly these complex molecules behave within the body.

ADCs can vary significantly in their biodistribution, biotransformation, and pharmacokinetics, influenced by the specific characteristics of the three fundamental components, linker chemistry, payload properties, and conjugation methods. By integrating radiochemistry approaches into ADC development, scientists and pharmaceutical sponsors can gain a deeper understanding of these varying characteristics.

Benefits of using radiotracers in ADC drug development include:

• Real-time visualization of ADC biodistribution in vivo without the need for repeat biopsies
• Precise measurements of ADC uptake
• Confirmation that the ADC binds specifically to the intended target antigen in vivo
• Helps to optimize dosing regime and schedule based on tissue distribution and clearance
• Provides detailed data on circulation half-life, metabolism, and tumor penetration
• Early insight into the potential therapeutic response of off-target effects
• Identifies patients whose tumors express the target antigen at specific levels for ADC therapy
• Supports regulatory submission by providing robust imaging and pharmacokinetic/pharmacodynamic evidence
• Helps with the study of ADC internalization, intracellular trafficking, and payload release
• Facilitates head-to-toe comparison of different ADC constructs and formulations

Real-world research insights from in vivo validation

[68Ga]Ga-PSMA-11 was approved in the United States in 2020 by the Food and Drug Administration (FDA) as the first 68Ga-radiopharmaceutical for the PET imaging of PSMA-positive prostate cancer. This radiotracer revolutionized prostate cancer imaging, facilitating the development of PSMA-targeted ADCs.

In a HER2-targeting immuno-PET study, Zr-89–labeled antibodies were used to measure dose-dependent target engagement in patients. Imaging revealed saturable tumor uptake at higher mass doses, confirming target specificity and informing dose optimization strategies, insights which would not have been possible from biopsy alone.

Challenges developers face

Whilst a promising area for drug development, ADC drug development research studies can be complex and often come rife with challenges. Developers continue to experience delays in the form of drug resistance, poor intracellular trafficking, narrow therapeutic windows, off-target accumulation, and molecular heterogeneity, complex issues arising from the specific structure of ADC components.

While drug developers may be aware of the risks, they can be difficult to detect in traditional in vivo methods alone, which is what makes the use of radiotracers so compelling. Radiotracers are becoming indispensable in ADC development, enabling non-invasive and quantifiable evaluation of ADC behavior before advancing to costly clinical studies.

Aligning your ADC drug development goals with Perceptive Discovery leverages our radiochemistry and in vivo expertise to drive the success of your clinical trial. Clinically relevant models are specifically chosen in line with tumor biology and immune context, supporting the translation of preclinical research findings into human outcomes. 

Perceptive’s strengths in this space

Perceptive Discovery combines radiolabeling expertise, biodistribution studies, and an advanced in vivo imaging infrastructure to deliver an end-to-end platform for tracking and optimizing ADC development. From targeted small molecules to monoclonal antibodies, peptides, and live cell labeling, we provide expertise across a diverse range of chemical entities.

Advantages of partnering with Perceptive:

• Expertise in PET/SPECT imaging workflows to capture radiotracer performance
• 900+ agents radiolabeled
• Extensive experience with US and UK/EU GMP regulatory requirements
• 80+ IND submissions supported for novel radiotracers
• Centralized imaging platforms ensure standardization and reproducibility across sites
• Data-driven insights into biodistribution modeling, dosimetry, and patient population analysis
• Significant supply chain capabilities, supporting 300 global production centers
• External manufacturing offering covering the US, EU, APAC, and Oceania, including site identification, qualification, set up, validation, and oversight
• Connecting imaging, biomarker, and clinical trial data into a holistic development view.

From preclinical modeling to clinical imaging endpoints, Perceptive supports ADC programs across the development continuum. Few imaging providers can match our depth of expertise in imaging science and radiotracer analytics, making Perceptive the partner of choice for next-generation targeted therapies.

Resources

ASCO. Rise of Antibody-Drug Conjugates: The Present and Future. https://ascopubs.org/doi/10.1200/EDBK_390094 

Antibodies. Introduction to Antibody-Drug Conjugates. https://pubmed.ncbi.nlm.nih.gov/34842621/ 

Journal of Medical Chemistry. [52Mn]Mn-BPPA-Trastuzumab: A Promising HER2-Specific PET Radiotracer. https://pubmed.ncbi.nlm.nih.gov/38690886/ 

Pharmaceuticals. [68Ga]Ga-PSMA-11: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging of Prostate Cancer. https://pmc.ncbi.nlm.nih.gov/articles/PMC8401928/