Antibody-drug conjugates (ADCs) represent a cutting-edge advance in cancer therapy. These targeted agents combine a monoclonal antibody and a cytotoxic payload via a chemical linker to deliver cancer drugs directly into cancer cells, maximizing the drug concentration delivered to tumor sites while minimizing damage to healthy cells. Research into next-generation ADCs is surging, with market projections exceeding $50 billion by 2030, driven by innovative therapy approvals and increasing applications.
These innovations include new conjugation techniques, linker chemistry, and payloads. Hundreds of ADCs are currently in development, including variations that use radioactive isotopes instead of cytotoxic payloads, immune-stimulating ADCs, and ADCs with uses beyond cancer. One particularly exciting development is the introduction of pan-cancer ADCs, that shift focus to cancer genetics rather than location of origin, to establish “tumor-agnostic” or “pan-tumor” treatments.
Developing pan-cancer ADCs
The development of next-generation pan-cancer ADCs centers on the idea that different cancers share molecular features and characteristics that may respond to the same targeted therapies despite originating in different tissues. This changes the fundamental strategy for discovering new ADCs. Rather than starting with the tissue of origin, drug developers must identify new molecular targets that are highly expressed in multiple cancer types. They must then establish if these targets are minimally expressed in healthy tissues, accessible to antibody binding, and capable of being internalized by the ADC so the cytotoxic payload can be delivered.
By adopting this approach, research teams can develop more versatile treatment options to address multiple cancers with a single agent. This means that tumor-agnostic therapies have the potential to benefit patients with rare or difficult-to-treat cancers. Additionally, as they directly target the underlying cause of cancer growth, they may result in more effective treatment outcomes, and a tumor-agnostic approach may shorten the drug development process as they remove the need for separate drug trials for every cancer type.
Common ADC targets
- HER2 (Human epidermal growth factor receptor 2): This transmembrane tyrosine kinase receptor protein is a well-established ADC target seen in a variety of cancers, including breast, gastric and lung.
- TROP2 (TACSTD2): A frequently targeted protein which is overexpressed in many solid tumors.
- EGFR (Epidermal growth factor receptor): Targeted in various cancers, this receptor is involved with cell growth and proliferation.
- Muc1: A transmembrane glycoprotein that plays a role in tumor development. Overexpressed in several cancers.
- BCMA, CD19: Expressed by hematological cancers.
- Nectin-4: A target found in solid tumors.
- c-Met: A receptor tyrosine kinase that is overexpressed on the surfaces of many cancers.
Enhertu awarded approval for HER2 solid tumors
In April 2024, Daiichi Sankyo and AstraZeneca's Enhertu (trastuzumab deruxtecan) became the first ADC to receive accelerated approval by the US Food and Drug Administration (FDA) for the treatment of any unresectable or metastatic tumors that express the protein HER2. Previously, it had been approved only for the treatment of breast, lung and gastric tumors.
This approval follows successful results in the DESTINY-PanTumor02 clinical trial (part of a series of international trials to investigate trastuzumab deruxtecan) which demonstrated the drug offered durable clinical benefit and improved patient outcomes, while maintaining levels of safety already observed with the drug.
This decision is significant as it is one of a growing number of “tumor-agnostic” approvals, signalling a “paradigm shift” towards a new pan-cancer approach. Similar recent approvals that target specific genetic mutations or alterations that drive growth within tumors include Rozlytrek, Vitrakvi, and Keytruda.
The importance of biomarker identification in new pan-cancer ADC development
The development of further pan-cancer ADCs relies on specialized, high-quality biomarker testing across cancer types. Biomarkers are essential tools that allow research teams to identify the patient groups that will respond best to treatment, the likely efficacy of treatments, and the potential for resistance to develop. The varying levels of ADC target expression in tumors versus healthy tissues also give an indication of on-target/off-tumor toxicity.
Identifying biomarkers early in the drug development process helps establish a biomarker-guided approach so candidates with the most potential can be pinpointed early on. Essential to effective biomarker identification are robust, advanced preclinical models and screening strategies that faithfully recapitulate original tumors, predict patient responses, and support high-throughput drug screening.
Using organoid and PDX models for biomarker discovery
Biomarkers can be identified through preliminary in vitro screens using organoids, which are followed up with in-depth functional and mechanistic in vivo studies using PDX models. By correlating pharmacology screening data with genomic baseline information, researchers can use organoids to understand genetic response signatures. For example, organoids can be used to identify single genes that correlate with sensitivity to an agent, construct multi-gene biomarker sets to predict sensitivity, and identify signatures composed of gene sets or pathways that differentiate sensitive and insensitive cell lines. In addition, they allow for real-time capturing and monitoring of biomarker changes, which is emerging as a key strategy for improving efficiency, selecting patients for treatment, and defining personalized treatments. In summary, organoid-based in vitro screening offers multiple tracks of unbiased, data-driven statistical analysis, which creates a foundation for later stages of drug development.
Multiple PDX models can then be screened to generate response data which can be correlated with characterization data. Additionally, PDX models can be utilised to further validate biomarkers where aspects of tumor response cannot be recapitulated in vitro. As extensive biobanks of PDX models are now available to research teams, it is possible to select models with the relevant mutations, gene expression, pathway activity and protein expression, so they can access the most relevant models for their studies. When combined with sophisticated statistical methods, such as linear mixed models (LMM), the likelihood of discovering truly predictive biomarkers is further boosted, leading to more reliable results and successful outcomes in this preclinical stage.
Broader organoid and PDX applications during pan-cancer drug development
In addition to biomarker discovery, advanced organoid and PDX models play a crucial role within the wider preclinical drug development pipeline, with organoids well-placed for refining early findings and PDX models for hypothesis testing and building confidence before clinical trials.
As three-dimensional organoid models recapitulate the cellular structures within tumors, they closely mimic the architecture and function of human tissues. This is crucial for research teams looking to understand how ADCs penetrate and disperse within tumors. Additionally, as organoids mimic both tumor and healthy cells, they also allow developers to understand the off-target toxicity of ADCs. Organoids play a crucial role during pan-cancer ADC development as they support high-throughput screening across multiple cancer types.
PDXs offer clinically relevant models for evaluating the efficacy and mechanisms of action of ADCs in vivo. They also provide insights into target distribution and accessibility within the tumor microenvironment, efficacy across diverse patient populations, and off-target toxicity.
By using a range of advanced preclinical models at the right time, the unique strengths of each model can be leveraged. The utilization of well-characterized and annotated organoid and PDX biobanks unlocked rapid screening of multiple ADC candidates across cancer types, to reduce drug development timelines and allow research teams to focus on the most promising drug candidates.
Conclusion
The recent approval of Enhertu across multiple tumor types is part of a wider trend towards new pan-cancer strategies and treatments. To realize the full potential of this advance, improving our understanding of biologic mechanisms underpinning both response and resistance to ADCs via preclinical studies must be a primary goal. Advanced organoid and PDX models and screening strategies are key to this approach, both in the identification and validation of biomarkers, and the understanding of ADC mechanisms of action and resistance. If our understanding deepens, pan-cancer approaches can deliver more effective and versatile therapies to transform patient outcomes.
Navigate the complexities of ADC development
