Antibody-drug conjugates (ADCs) have emerged as a groundbreaking advancement in oncology, promising improved patient outcomes and quality of life. However, developing these complex therapeutics involves numerous challenges and considerations. As we venture further into this field, it is essential to consider the many challenges and the evolving nature of ADC development. With the promise of ADCs comes many scientific, regulatory, and clinical considerations that must be navigated to transform these biopharmaceuticals from a concept into a cure.
Here Abzena’s VP and Bristol Site Head, Dr Ian Glassford and Scientific Leader for Regulatory, Dr Jeffrey Mocny, delve into ten critical aspects of ADC development and bring to light the indispensable factors that are shaping the future of targeted therapies. From the therapeutic window to market demands, clinical efficacy, and beyond, each element underscores the importance of innovation and patient-centricity in forging the path forward.
1. Understanding the therapeutic window: data is reshaping our understanding of the ADC therapeutic window – the range of dosages of a drug or a treatment that provides effective therapy with minimal to acceptable side effects. It’s crucial to balance safety and efficacy in drug design, a task that requires ongoing analysis and data-driven refinements. The goal is a dynamic therapeutic window that adapts to emerging clinical data, ensuring personalized treatment strategies that can significantly improve patient outcomes.
2. Comparing ADCs and small molecules: when looking at oncology trials, ADCs often show higher objective response rates (ORR) – the proportion of patients whose cancer reduces or disappears after treatment – compared to their small molecule counterparts. This indicates a potential for greater patient benefit, but requires careful data analysis for accurate comparisons.
3. Dose optimization: for effective ADC development, there’s a heightened focus on fine-tuning dosing regimens to maximize the therapeutic index – the ratio of drug efficacy to its toxicity. This trend toward precision dosing is exemplified by the case of Sotorasib, a targeted therapy for a specific mutation in non-small cell lung cancer. After its initial approval, the FDA required further studies to explore dose optimization, comparing the approved dosage to lower doses used in earlier trial phases. These studies aim to identify the most effective dose that minimizes side effects, ensuring a better balance between treatment benefits and patient safety.
4. Maximum tolerated doses (MTD) and payload-linker stability: contrary to expectations, ADCs do not necessarily increase the MTD compared to equivalent small molecules. Factors like payload-linker stability and deconjugation in plasma play a crucial role here. A stable payload-linker ensures that the drug remains attached to the antibody until it reaches the target cancer cells, minimizing premature release and reducing toxic side effects in non-target cells. This stability is key to maximizing the therapeutic efficacy of the ADC while keeping the side effects within the tolerable range.
At Abzena we employ a matrix evaluation and developability approach to determine the optimal design of the linker payload architecture. This process includes in silico, in vitro, and ex vivo activity and safety assessments to support candidate ranking and lead selection. Such comprehensive evaluation and development strategies streamline and de-risk the scaling and manufacturing of linker payloads, ensuring that our ADCs not only meet the therapeutic goals but also adhere to safety standards.
5. Innovative conjugation technologies: the shift towards site-selective conjugation in ADC development aims to produce more uniformly structured ADCs, enhancing their efficacy and safety. By attaching the cytotoxic payload to specific sites on the antibody, these technologies ensure a more predictable drug release and interaction with cancer cells. This uniformity reduces the risk of overdosing and minimizes off-target effects, thereby enhancing the safety profile.
Abzena’s ThioBridge™ platform exemplifies the advancements in this field, overcoming limitations of earlier conjugation methods. ThioBridge™ employs site-specific conjugation to antibody interchain disulfides, leading to a more uniform Drug-to-Antibody Ratio (DAR) and offering stable attachment. This technology also allows for optimized pharmacokinetic profiles with flexibility in payload and spacer design providing an innovative approach to ADC development enhancing both the efficacy and safety of ADCs.
6. Clinical data and efficacy: recent clinical findings have prompted an evaluation of ADC maximum tolerated doses (MTD), which appear to align more closely with those of traditional small molecule drugs than previously anticipated. This realization has pivotal implications for the design and optimization of ADCs, underscoring the necessity for rigorous clinical trials to investigate efficacy at varying dosages.
7. Optimizing downstream development: manufacturing ADCs becomes more challenging as their complexity increases. Streamlining downstream development is crucial for timely market entry. Advancements in artificial intelligence and machine learning are accelerating the development timeline by automating manufacturing processes.
8. Increasingly potent compounds: the use of highly potent active pharmaceutical ingredients (HPAPIs) in ADCs is a growing trend. HPAPIs enable lower dosages with reduced side effects. However, their potency also brings heightened safety risks during manufacturing. These challenges are addressed by implementing strict safety procedures, conducting extensive risk assessments, and using specialised equipment for safe handling.
9. Market growth and demand: the ADC market is rapidly expanding, driven by a demand for more targeted oncology treatments. This growth is a testament to the confidence in ADCs’ ability to offer safer, more effective treatments with reduced side effects, meeting the needs of a patient population seeking more sophisticated and less invasive treatment options.
10. Patient-centric approach: at every stage of ADC development and manufacture, the patient journey is paramount. From ensuring the drug meets patient needs to considering the administration and dosing, a holistic understanding of the patient’s experience is essential. The ultimate goal is to accelerate the delivery of the drug to the patients without compromising on quality or efficacy.
With over a dozen ADCs already licensed, the future of this field is bright. Innovations in linkers, payloads, and targeting mechanisms are expanding the reach of ADCs beyond oncology to other therapeutic areas. Realizing the full potential of ADCs requires ongoing innovation, particularly in targeting strategies and linker technologies.
The growth trajectory of ADCs suggests a future where individual patient needs are met with treatments as unique as their conditions. The path to realizing the full promise of ADCs is charted through relentless innovation and an unwavering commitment to patient-centric care. In this rapidly evolving field, remaining agile, informed, and ready to embrace new technologies and strategies is key. It is through this dedication to innovation and adaptability that ADC development will continue to break new ground, offering hope with unparalleled precision and efficacy.
Are you trying to develop a new ADC? Find out about our capabilities in ADC development and how our experts can help accelerate your biologic or bioconjugate from concept to clinic.
