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Unveiling the potential of the antibody drug conjugate

In the ever-evolving landscape of cancer therapeutics, antibody-drug conjugates (ADCs) have emerged as a promising class of treatments. ADCs combine the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, offering a novel approach to targeted therapy. Antibody-drug conjugates have shown tremendous promise in the fight against cancer, with the potential to be a game-changer in the targeted treatment of a range of non-oncological indications.

An analysis of data from the CAS Content Collection™ relating to antibody-drug conjugate research and development shows strong growth with a 30% increase in the number of publications (mainly journal articles and patents) in the last three years. The United States, China, and Japan are leading the way with journal and patent publications (Figure 1). Interestingly, patents now outnumber journal publications, which indicates the transfer of accumulated scientific knowledge into patentable applications. The range of antibody-drug conjugate patents within the CAS Content Collection is becoming increasingly diverse, with researchers exploring different linker technologies, conjugation techniques, and target antigen moieties.

world map
Figure 1. Top countries with respect to the numbers of ADC-related journal articles (blue) and patents

With a plethora of antibody-drug conjugates in preclinical and clinical development, these remarkable compounds have attracted the attention of researchers and pharmaceutical companies. According to PitchBook, there has been a dramatic increase in private investment since 2018 (Figure 2), highlighting significant interest in antibody-drug conjugates for their therapeutic and commercial potential. The global antibody-drug conjugate market was estimated to be worth $8.6 billion in 2022 and is forecasted to reach $23.9 billion by 2032, growing at a CAGR of 10.7% in that time. Antibody-drug conjugates are attracting attention across global markets, with World ADC Asia holding dedicated conferences to unite leaders in the antibody-drug conjugate field.

ADC Pie chart
Figure 2. Capital invested by global region for the period 2012-2022 in the ADC field: (A) Venture capital investment and (B) Total capital investments

Inside the Trojan Horse: Understanding antibody-drug conjugates

To grasp the significance of antibody-drug conjugates, it is important to understand how they work. This dynamic therapy consists of three main components: a monoclonal antibody, a cytotoxic drug payload, and a linker molecule (Figure 3). The monoclonal antibody is designed to specifically recognize antigens overexpressed on the surface of cancer cells, allowing for selective targeting. The cytotoxic payload is often a potent chemotherapy drug that is highly effective at killing cancer cells. Finally, the linker serves as a bridge between the two other components, maintaining stability during circulation while releasing the payload upon internalization.

Structure and mechanism of action of ADCs
Figure 3. Structure and mechanism of action of ADCs.

Like immunotherapies such as immune checkpoint inhibitors, antibody-drug conjugates promise to revolutionize cancer treatment. However, the two classes of compounds operate through distinct mechanisms. While immunotherapies boost the patient's immune response against cancer cells, the antibody-drug conjugate operates as a 'Trojan Horse,' delivering a lethal strike directly to the cancer cells.

Success stories in antibody-drug conjugate treatment

The antibody-drug conjugates in clinical development today have been over a century in the making. Since German scientist Paul Ehrlich proposed the concept of a “magic bullet” in the early 1900s, researchers have strived to develop therapies capable of selectively targeting pathogens or diseased cells without injuring the rest of the organism. Since then, key discoveries in antibody-drug conjugate research and development have led to the approval of groundbreaking drugs such as Takeda’s lymphoma agent Adcetris® (brentuximab vedotin) and Genentech’s Kadcycla® (trastuzumab emtansine), approved for the treatment of human epidermal growth factor receptor 2–positive breast cancer in 2013. Since 2020, eight further antibody-drug conjugates have been approved for a range of solid tumors and hematological malignancies. Currently, there are 15 approved antibody-drug conjucates that have received regulatory approval anywhere in the world (Figure 4).

Timeline of key events and discoveries in ADC research and development.
Figure 4. Timeline of key events and discoveries in ADC research and development.

With antibody-drug conjugates, the elusive magic bullet is within reach. The targeted nature of these compounds allows for selective delivery of the cytotoxic payload to the diseased cells, minimizing the exposure of healthy cells to the drug. This targeted approach not only enhances the efficacy of the therapy but also reduces the risk of off-target effects and systemic toxicity. By sparing healthy cells, antibody-drug conjugates offer the potential for more tolerable treatment regimens and reduced side effects.

Challenges and limitations of antibody-drug conjugates

While the potential of antibody-drug conjugates is undeniable, there are several challenges and limitations that need to be addressed in their development. To start, the manufacture of antibody-drug conjugates involves multiple steps, including antibody production, drug synthesis, and conjugation. This complexity can lead to high manufacturing costs, making these therapies less accessible to patients in certain regions or healthcare systems.

Selecting suitable antigens remains another hurdle, as effective targeting relies on the antigen's specificity to cancer cells. This selectivity is crucial to ensure the precision of the therapy and minimize off-target effects. However, not all cancers have well-defined target antigens, and the heterogeneity of antigen expression within tumors can further complicate target selection.

Furthermore, the choice of cytotoxic payload is critical for the success of an antibody-drug conjugate. The cytotoxic drug should have high lethality against cancer cells while maintaining stability during conjugation and circulation. Achieving this balance of potency, stability, and release kinetics is a significant challenge in antibody-drug conjugate development.

Yet another challenge faced by researchers is the development of drug resistance to antibody-drug conjugates. Cancer cells can develop various mechanisms to evade the cytotoxic effects of antibody-drug conjugates, such as downregulating the target antigen or increasing drug efflux. These resistance mechanisms can limit the effectiveness of these therapies and reduce treatment efficacy over time.

The promising future of antibody-drug conjugates in oncology and beyond

The future of the antibody-drug conjugate is bright, with several exciting advancements on the horizon. Researchers are exploring innovative strategies to optimize antibody-drug conjugate design, including the use of alternative cytotoxic drugs, novel linkers, and improved antibody engineering techniques.

Combination therapies integrating antibody-drug conjugates with immunotherapies or other targeted agents could present synergistic effects, amplifying their clinical impact. Researchers believe that the ADC brentuximab vedotin and chemotherapy gemcitabine–a combination studied in various types of cancers–work well together as they each target different cancer cell types, delivering a two-pronged strike against diseases such as Hodgkin’s lymphoma. Antibody-drug conjugates have also shown promise when combined with checkpoint inhibitors such as the PD-1 inhibitors, pembrolizumab and nivolumab, with these combinations being explored in various stages of clinical trials. Such combinations are an attractive treatment option for frail or elderly patients who are at higher risk of severe toxicity from chemotherapy. Though most oncology trials are in early phase development (Figure 5), the staggering range of drug candidates and cancer types being explored highlights the enormous potential of antibody-drug conjugates yet to be realized.

Percentage of ADC clinical trials
Figure 5. Percentage of ADC clinical trials in various phases for the treatment of specific solid tumors and hematological malignancies.

Beyond oncology, the expansion of antibody-drug conjugates into new therapeutic areas is on the horizon. The technology is currently being explored in the fight against infectious diseases. Antibiotic resistance has compromised the efficacy of bacterial infection treatment, leading to the development of antibody-antibiotic conjugates (AACs) as a solution. Like antibody-drug conjugates, AACs employ antibodies to deliver antibiotics to target bacteria, combining antibody specificity with antibiotic potency via a specialized linker. While research into AACs is limited, these exciting new compounds may effectively treat bacterial biofilms, a major global healthcare challenge.

Antibody-drug conjugates are also being explored as immunomodulatory agents, enabling the targeted delivery of anti-inflammatory drugs such as glucocorticoids while minimizing the systemic adverse effects typically associated with these agents. Several antibody-drug conjugate strategies are being tested in a range of conditions, from rheumatoid arthritis to myasthenia gravis (Table 1).

Examples of ADC strategy tested to modulate pathogenic cellular activity in non-oncology indications.
Figure 6. Examples of ADC strategy tested to modulate pathogenic cellular activity in non-oncology indications.

With antibody-drug conjugate technology continuing to evolve, these compounds are a promising therapeutic modality with vast potential beyond oncology. While their development has ongoing challenges and limitations, the success of approved drugs and the growing pipeline of investigational ADCs demonstrate their potential to transform to meet clinical needs and improve patient outcomes.

To learn more about the exciting and ever-evolving antibody-drug conjugate landscape, see our peer-reviewed publication in Bioconjugate Chemistry.

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