A new era of targeted therapy with antibody–drug conjugates

insights from industryGrace LiuTechnical Account ManagerSino Biological

In this interview, Grace Liu from Sino Biological shares her expertise on Antibody-Drug Conjugates (ADCs), a revolutionary cancer therapy combining precision targeting with potent cytotoxic drugs. With a strong background in medical science and immunotherapy, Grace highlights the science, challenges, and innovations driving ADC development and Sino Biological’s role in advancing this transformative field.

Can you please introduce yourself and tell us a bit about your background?

My name is Grace Liu. I joined Sino Biological in 2022 to support CRO services and manage projects across the western and central US regions. I obtained my Ph.D. in Medical Science from Baylor College of Medicine in Houston, Texas.

Before joining Sino Biological, I worked as a postdoctoral fellow at the Houston Methodist Research Institute, where I focused on developing sustained drug-eluting devices for cancer immunotherapy.

Can you please explain what ADCs are?

Antibody-drug conjugates (ADCs) represent a promising cancer treatment modality designed to deliver highly potent cytotoxic agents directly to tumor cells. This approach maximizes therapeutic efficacy while minimizing systemic toxicity.

A narrow therapeutic window often constrains conventional cancer chemotherapy due to its lack of specificity for tumor cells. As a result, chemotherapeutic agents frequently harm normal cells with high mitotic rates, leading to a wide range of adverse effects. Therefore, there is a critical need for more selective therapeutic options.

Referred to as "magic bullets," ADCs consist of a monoclonal antibody (mAb) that serves as a carrier conjugated to a cytotoxic drug (referred to as the payload) via a chemical linker. ADCs leverage the mAb's specificity for a tumor-associated antigen to achieve targeted cytotoxic drug delivery to tumor cells.

Once an ADC binds to its target antigen on a tumor cell, the ADC–antigen complex undergoes internalization through receptor-mediated endocytosis into an early endosome. The endosome then matures and fuses with a lysosome. The ADC releases its payload within the lysosome, which becomes an active-free drug that diffuses into the cytoplasm. This active drug exerts its cytotoxic effects, ultimately leading to cell death.

What are the key components of ADCs?

ADCs have three main elements: a monoclonal antibody (mAb) backbone, a cytotoxic payload, and a linker. The creation of ADCs goes beyond a simple combination, with the key challenge being the balance between efficacy and safety.

What role does the mAb play in ADC therapy?

Acting as the tumor-targeting vehicle, the mAb component of the ADC should possess high antigen specificity, strong antigen-binding affinity, and efficient internalization, among other properties. mAbs that recognize antigens predominantly overexpressed on the surface of tumor cells are preferable for ADCs, ensuring tumor-specific delivery of payloads and a wide therapeutic window.

Target antigens of approved ADCs include HER2, TROP2, Nectin-4, EGFR, TF, and FRα for solid tumors, and CD19, CD22, CD33, CD30, BCMA, and CD79b for hematologic malignancies. Internalization efficiency is critical for ADC efficacy.

Higher antigen-binding affinity often promotes rapid internalization, but excessively strong binding can hinder ADC penetration into solid tumors, a phenomenon known as the binding site barrier effect. Therefore, various parameters must be carefully balanced to optimize mAb design.

Desirable characteristics of the antibody moiety include minimal immunogenicity and a long circulating half-life. Humanized and fully human antibodies, which are less immunogenic than murine or chimeric mAbs, are most commonly used as the ADC backbone. The IgG1 subtype is preferred for its strong effector functions and stability in systemic circulation, with a half-life of 21 days.

What is the role of the linker in ADCs?

The linker connects the cytotoxic payload to the mAb. It has two primary purposes: ensuring stability in plasma to prevent premature drug release and enabling efficient release of the payload upon internalization within tumor cells.

Currently, linkers are categorized into two types: cleavable and non-cleavable. Cleavable linkers are designed to break down in response to tumor-associated factors and include acid-labile linkers (e.g., hydrazones), reducible/glutathione-sensitive linkers (e.g., disulfides), and protease-sensitive/peptide linkers (e.g., valine–citrulline dipeptides).

Non-cleavable linkers rely on complete degradation of the mAb in lysosomes, releasing the cytotoxic cargo linked to an amino acid residue (typically cysteine or lysine) from the degraded mAb.

Non-cleavable linkers offer greater plasma stability and reduced off-target toxicity but can restrict payloads to those effective despite chemical modification. Cleavable linkers enable efficient and controlled payload release and are compatible with a broader range of drugs, but their flexibility increases the risk of premature drug release and systemic toxicity.

Careful design is essential to balance linker stability and payload release efficiency. Most approved drugs and nearly all ADCs in clinical trials employ cleavable linkers, particularly enzyme-cleavable linkers.

What is the function of the payload in ADCs?

The payload is the effector component of ADCs, typically a highly potent cytotoxic drug with half-maximal inhibitory concentration (IC50) values at sub-nanomolar or picomolar levels, compared to the micromolar IC50 of conventional chemotherapeutics.

High potency is essential since only approximately 2% of the administered ADC dose reaches the tumor site, and mAbs can carry only a limited number of payload molecules.

Current ADC payloads fall into two categories: tubulin inhibitors and DNA-damaging agents. Tubulin inhibitors, such as auristatins (e.g., MMAE and MMAF) and maytansinoids (e.g., DM1 and DM4), disrupt microtubule assembly, causing mitotic arrest and cell death.

DNA-damaging agents include calicheamicins, which induce double-strand breaks; pyrrolobenzodiazepines (PBDs), which create DNA cross-links; duocarmycins, which cause DNA alkylation; and camptothecins (e.g., DXd and SN-38), which inhibit topoisomerase I, leading to DNA breaks.

Emerging payloads include immune stimulants (e.g., STING agonists and TLR agonists) and proteolysis-targeting chimeras (PROTACs).

The drug-to-antibody ratio (DAR), representing the average number of payload molecules attached to each mAb, is a critical parameter for ADC design. While higher DAR values can increase potency, they may also result in excessive hydrophobicity, leading to antibody aggregation, accelerated clearance, and toxicity.

Optimizing the DAR is essential to balance efficacy and safety. Other important payload characteristics include conjugation compatibility, aqueous solubility, and stability as conjugates.

Why do ADCs attract attention in healthcare?

Antibody-drug conjugates (ADCs) represent a breakthrough in the era of targeted therapy, offering significant potential to meet the growing demand for enhanced efficacy and safety in cancer treatment. ADCs are designed as a form of "targeted chemotherapy," combining the potency of chemotherapeutic agents with the specificity of monoclonal antibodies (mAbs) to direct therapeutic action toward tumor cells.

This targeted delivery approach has garnered widespread attention due to its clinical benefits and substantial advantages over conventional chemotherapy.

For instance, ADCs can potentially improve objective response rates and the durability of responses in both liquid and solid tumors, whether used as monotherapies or combined with chemotherapies or immune checkpoint inhibitors.

In addition, as personalized medicine advances and benefits from extensive individualized data, ADCs capable of targeting specific cancer subtypes could become increasingly powerful tools in the fight against cancer.

Despite their promise, ADCs face numerous challenges. These include difficulties in selecting and validating appropriate target antigens, complexities in design, cost-intensive and time-consuming development and production processes, and technical issues such as linker stability, ADC heterogeneity, toxicity, and resistance.

Developing more effective and safer ADCs requires optimizing antibodies, designing robust linkers, refining conjugation chemistry, and selecting suitable payload classes. Moreover, a deeper understanding of cancer biology and the landscape of potential targets is critical.

Significant efforts are underway to overcome these obstacles. ADCs' targeted nature, efficacy, personalized approach, innovative potential, and considerable market opportunities, combined with the scope for further improvement, make them a compelling focus of research and development. This has attracted significant attention from various stakeholders in the healthcare sector.

What is the current status of ADCs in therapeutics? 

In 2000, gemtuzumab ozogamicin (Mylotarg^®) became the first antibody-drug conjugate (ADC) approved by the United States Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia.

As of April 2024, 13 ADCs have been clinically approved worldwide for treating various hematologic malignancies and solid tumors. Additionally, more than 100 ADCs are currently under evaluation in clinical trials for a broader range of cancers, with many demonstrating remarkable success in advanced phases of development.² 

Table 1. Approved ADCs worldwide.¹ Source: Sino Biological Inc.

Despite these achievements and a promising outlook, the field faces significant challenges, including addressing tumor heterogeneity, overcoming drug resistance, and mitigating treatment-related adverse effects.

Progress in ADC technology and a more nuanced understanding of ADC mechanisms are key factors driving the development of next-generation ADCs with improved targeting capabilities, greater potency, and enhanced safety profiles.

One area of innovation in next-generation ADCs is the development of bispecific ADCs, which are categorized into two types based on their mechanisms of action. The first category includes bispecific ADCs that target two different antigens, an approach designed to improve selectivity for tumor cells over normal tissue and to kill a broader spectrum of tumor cells when the target antigens are heterogeneously expressed within the tumor.

The second category involves biparatopic ADCs, which recognize two distinct epitopes of the same antigen. This strategy is intended to enhance the ADC's internalization and trafficking to lysosomes, thereby maximizing the delivery of the cytotoxic payload into tumor cells.

Beyond oncology, there is increasing interest in applying ADCs to non-oncological diseases, such as autoimmune disorders and bacterial infections. For example, antibodies conjugated with anti-inflammatory agents like glucocorticoids allow selective drug delivery to activated immune cells.

This approach reduces inflammatory responses while minimizing side effects, offering potential in the treatment of inflammatory diseases. Similarly, antibody–antibiotic conjugates (AACs) are being developed to effectively eliminate intracellular bacteria, representing a promising therapeutic platform to enhance antibiotic efficacy against difficult-to-treat bacterial infections.

How is Sino Biological involved in advancing the development of ADCs? 

Developing antibody-drug conjugates (ADCs) is a complex process that requires careful consideration of several factors, including the target, antibody, payload, and linker. Additionally, due to their structural diversity and complexity, ADCs face unique formulation, manufacturing, and quality control challenges.

As a leading supplier in the pharmaceutical industry, Sino Biological plays a pivotal role in every key aspect of ADC development. The company offers comprehensive ADC development solutions tailored to the specific needs of pharmaceutical and biotechnology companies.

These solutions span the entire development journey, from early discovery to clinical studies (Figure 1). Sino Biological’s services are designed to help clients accelerate their progress throughout the ADC development process.

Figure 1. ADC development solutions at Sino Biological. Image Credit: Sino Biological Inc.

References

1. Senior, M. (2024). Cancer-targeting antibody–drug conjugates drive dealmaking frenzy. Nature Biotechnology, [online] pp.1–5. https://doi.org/10.1038/s41587-024-02168-5.
2. Tsuchikama, K., et al. (2024). Exploring the next generation of antibody–drug conjugates. Nature Reviews Clinical Oncology, [online] pp.1–21. https://doi.org/10.1038/s41571-023-00850-2.

About Grace Liu

Grace Liu joined Sino Biological in 2022, supporting CRO services and project management in the western and central US regions. Grace received her Ph.D. in Medical Science from Baylor College of Medicine in Houston (TX, USA). Prior to joining Sino Biological, she worked in the Houston Methodist Research Institute (TX, USA) as a postdoctoral fellow focused on sustained drug-eluting devices for cancer immunotherapy. In this interview, Grace discusses how biomarkers play a crucial role in cancer prevention and diagnosis, and how they can help guide treatment decisions.

About Sino Biological Inc.

Sino Biological is an international reagent supplier and service provider. The company specializes in recombinant protein production and antibody development. All of Sino Biological's products are independently developed and produced, including recombinant proteins, antibodies and cDNA clones. Sino Biological is the researchers' one-stop technical services shop for the advanced technology platforms they need to make advancements. In addition, Sino Biological offer pharmaceutical companies and biotechnology firms pre-clinical production technology services for hundreds of monoclonal antibody drug candidates.

Sino Biological's core business

Sino Biological is committed to providing high-quality recombinant protein and antibody reagents and to being a one-stop technical services shop for life science researchers around the world. All of our products are independently developed and produced. In addition, we offer pharmaceutical companies and biotechnology firms pre-clinical production technology services for hundreds of monoclonal antibody drug candidates. Our product quality control indicators meet rigorous requirements for clinical use samples. It takes only a few weeks for us to produce 1 to 30 grams of purified monoclonal antibody from gene sequencing.

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