New research improves the safety and effectiveness of ADC cancer treatments

Antibody-drug conjugates (ADCs) represent a significant advancement in drug discovery, combining the precision of monoclonal antibodies with the cancer-killing power of cytotoxic drugs. While these therapies hold great promise for improving cancer treatment outcomes, their development presents significant challenges, especially in achieving the optimal balance between efficacy and safety.

To explore these challenges further, we spoke with Cheng Wang, a postdoctoral researcher at the University at Buffalo. Wang’s research focuses on developing mechanistic mathematical models to quantitatively characterise ADC-induced toxicities. Wang discusses how his work is providing critical insights and tools to help advance the development of safer and more effective ADC therapies.

A focus on ADC toxicities

ADC toxicities result from the unintended effects of the cytotoxic payload or the breakdown of the linker that attaches it to the antibody. The cytotoxic payload is a potent drug or compound attached to the antibody in an ADC, designed to selectively target and kill cancer cells by binding to specific proteins on their surface. Once inside the cancer cell, the payload is released and exerts its cell-killing effects. However, if the payload is released prematurely or impacts healthy cells, it can lead to harmful side effects. These toxicities can affect healthy tissues, leading to side effects such as liver damage, peripheral neuropathy, and immune-related issues. Properly managing these toxicities is crucial to enhancing the safety and therapeutic effectiveness of ADC treatments.

“My research focuses on developing mechanistic mathematical models to quantitatively characterise ADC-induced toxicities, with the goal of enhancing the therapeutic index of ADC therapeutics,” explains Wang. This work is crucial for addressing a key challenge in ADC development: the toxic side effects from the release of cytotoxic payloads. By gaining a deeper understanding of the mechanisms behind these toxicities, Wang’s models provide a pathway for optimising ADC designs and dosing strategies to reduce adverse effects.

Understanding exposure-AE relationships in ADCs

A key focus of Wang’s research is the examination of exposure-adverse event (AE) relationships, which provide a valuable framework for understanding how the levels of ADC exposure in the body are linked to specific toxicities. Wang found that if an ADC with a particular payload is associated with payload-driven toxicity, prioritising the use of more stable linkers can enhance safety. Furthermore, data from Phase I trials can serve as benchmarks for comparing exposure-AE relationships in new ADCs using the same linker-payload combinations. This type of analysis is crucial for drug developers, providing a framework to identify and mitigate toxicity risks early in the design process. It also enables a more targeted approach to ADC optimisation, minimising the need for trial-and-error experimentation.

Dosing strategies to minimise toxicity

Understanding exposure-toxicity relationships is crucial for refining dosing strategies, particularly during the early stages of ADC development. “Toxicity enrichment is crucial for any kind of medicine,” says Wang. He further explained that knowing the toxic exposure levels associated with specific adverse events allows developers to optimise dosing regimens, helping to avoid severe toxicities and mitigate overlapping toxicities, particularly in combination therapies. “Most patients are given combination therapies to enhance efficacy,” explains Wang. “But these can increase the risk of overlapping toxicities. For example, pairing ADCs with other therapies that share similar toxicity profiles, such as peripheral neurotoxicity, should be avoided.”

In addition to combination therapy considerations, Wang highlighted the importance of addressing dose-limiting toxicities (DLTs). Reducing DLT-related exposures can significantly improve ADC tolerability. For example, adjusting payload binding fragments has been shown to increase the maximum tolerated dose of certain ADCs by minimising toxic payload concentrations. This optimisation ensures that ADCs can be dosed effectively without compromising patient safety, a critical factor for clinical success.

Accelerating safer ADC development

Wang’s findings also have profound implications for accelerating the development of safer ADCs. By identifying analytes correlated with toxicities, his research provides a roadmap for prioritising areas of investigation, particularly when budget constraints or other limitations arise. “This provides a strong starting point for new ADC development,” Wang explained. “Even when constrained by budget or other limitations, our meta-analysis can help prioritise which analytes to investigate in patient samples.”

This targeted approach not only streamlines research efforts but also provides developers with critical data to minimise toxicities associated with specific linker-payload combinations.

Optimising the therapeutic window

A crucial aspect of ADC development is optimising the therapeutic window—the balance between efficacy and toxicity. Wang highlighted several key considerations for achieving this balance, focusing on the three main components of ADCs: the antibody, linker, and payload.

“The target should have high expression in the tumour compared to normal tissue. The linker must be stable enough to prevent premature release of the payload but also capable of inducing the ‘bystander effect.’ This occurs when the ADC is cleaved in neighbouring tumour cells, allowing the payload to diffuse into those cells, even if they have lower receptor expression. Additionally, the payload needs to be potent, soluble, and able to cross the cell membrane.”

This interplay between the chemical and physiological properties of each ADC component is critical for designing ADCs that are both effective and safe. Wang’s work highlights the need to approach ADC optimisation holistically, considering how each component interacts with the others.

Laying the groundwork for future ADC research

As investment in ADC development continues to grow, Wang’s research offers a foundation for future advancements. His quantitative framework serves as a guide for investigating more complex mechanistic models to address the site-specific toxicities of ADCs. “This is a trending area, and our quantitative framework has paved the way for future investigations using more complex models. The current analysis is somewhat shallow, as it primarily looks at exposure levels in plasma. However, toxicity can occur in different organs, such as cardio-toxicity in the heart and neuro-toxicity in the nerves. To better understand these effects, we need more detailed, mechanistic models,” Wang said.

Wang envisions a future where deeper, more detailed models are developed to uncover the mechanistic drivers of ADC-related toxicities. “While our findings highlight correlations, proving causation requires controlled experiments. This analysis lays the groundwork for those deeper investigations,” explains Wang. The broader implications of Wang’s research extend to the entire field of oncology drug discovery. By refining ADC design and development processes, his work is contributing to the creation of safer, more effective cancer therapies. One particularly promising area of application is the development of ADCs for specific cancer types. Wang’s findings provide a roadmap for tailoring ADC designs to the unique characteristics of each cancer, improving both efficacy and safety.

A collaborative effort

While Wang’s work represents a significant step forward, he acknowledges that it is part of a larger collaborative effort within the scientific community. His findings build on existing research and provide a foundation for future investigations, paving the way for continued innovation in ADC development.

Wang’s research is a testament to the power of quantitative analysis in advancing ADC therapeutics. By identifying toxicity drivers, refining dosing strategies, and optimising ADC components, his work provides invaluable tools for improving the safety and efficacy of these groundbreaking treatments.

Readers can access the full study here to explore the detailed findings of Wang’s research.