Early detection of pulmonary ADC toxicity with high-content imaging of alveolar macrophages

What are ADCs?

Antibody-drug conjugates (ADCs) have revolutionised cancer therapy, offering targeted and effective treatment options. By leveraging monoclonal antibodies (mAbs) to deliver cytotoxic agents directly to cancer cells, ADCs aim to minimise damage to healthy tissues, thereby reducing the adverse side effects typically associated with conventional chemotherapy. This is achieved by utilising specific antigens on cancer cell surfaces, allowing the ADC to bind selectively to these cancerous cells.

Despite their promise, a significant proportion of ADCs fail during development, with toxicity being a major hurdle¹ . These failures highlight the need for advanced approaches to designing ADCs that can balance efficacy with safety.

Challenge: off-target toxicity with ADCs

A significant hurdle in ADCs development is the issue of off-target toxicity. This occurs when ADCs interact with healthy cells expressing similar antigens or due to the premature release of the toxic payload. Such toxicities can limit the therapeutic window of these promising drugs. 

For example, ADCs are the leading cause of interstitial lung disease (ILD)². ILD can involve direct cytotoxicity to parenchyma of the lung, alterations to health and permeability of endothelial cells, inflammation (alveolitis), and accumulation of immune cells that together, results in fibrosis and impaired lung function³. The ability to accurately predict and assess these toxicities early in the drug development process is essential for moving ADCs through the pipeline safely and efficiently.

Why focus on alveolar macrophages for assessing off-target effects?

Understanding alveolar macrophage function is crucial for assessing off-target ADC effects. These immune cells play a central role in ADC uptake, processing, and potential payload release, impacting surrounding lung tissue. Prior research indicates that ADC internalisation by macrophages can contribute to interstitial lung disease by increasing local cytotoxicity and inflammation⁴. Current ADC toxicity screening models lack immune cells, limiting their predictive accuracy for lung injury.

ImmuONE’s morph_ONE^TM assay uses alveolar macrophages to detect these off-target effects early in the development process.

For example, in studies involving Trastuzumab deruxtecan (T-DXd), the morph_ONE^TM assay successfully identified that at high concentrations, adaptive macrophage morphology changes are seen rather than cytotoxic effects. Such findings highlight the assay’s capability to detect nuanced cellular responses that may not be immediately apparent with traditional toxicity assays. This focus on respiratory effects is vital for ensuring that ADCs develop with a more comprehensive understanding of their safety profiles.

Detecting ADC’s off-target effects early using HCIA (morph_ONE^TM)

ImmuONE’s morph_ONE^TM high-content imaging assay analyses alveolar macrophage morphology to provide insights into biological pathways, including particle overload, inflammation, phospholipidosis and apoptosis. Using advanced imaging, it captures detailed cellular images, assessing cell morphology and health indicators like nuclear integrity, cytoplasm condition, mitochondrial activity, and membrane permeability.

Implementing the morph_ONE^TM assay early in the ADC development process offers several benefits. By identifying potential off-target toxicities before progressing to animal studies, developers can refine candidate selection, prioritise safer compounds, and optimise dosing strategies. A proactive approach at this stage not only enhances the safety and efficacy of ADCs but also increases the likelihood of successful clinical trials.

Early detection of potential toxicities can significantly reduce development costs and timelines. By eliminating less promising candidates early, resources can be focused on compounds with a higher likelihood of success. This efficiency is crucial in the competitive pharmaceutical industry, where time-to-market can be a critical factor in a drug’s commercial success.