Advanced Drug Modalities Part 3: Antibody-Drug Conjugates (ADCs)
Article summary
Antibody-drug conjugates (ADCs) are an advanced drug modality with unparalleled potential in precision medicine and oncology. ADCs consist of antibody carriers to which cytotoxic payloads are attached via linkers and combine the potency of cytotoxic drugs with the specificity of antibodies to specifically target cancer cells.
The conception of ADCs as a precision medicine therapy begun with Paul Ehrlich’s “magic bullet” more than a century ago and culminated with the first FDA approval of an ADC therapy in 2000, gemtuzumab ozogamicin, for the treatment of acute myeloid leukemia. Today, patients benefit from about a dozen approved ADC therapies, with more than 100 ADC moieties at different stages of clinical trials.
Multi-billion dollar acquisitions and partnerships within the pharmaceutical industry underscore the growing importance and value of ADCs as an advanced drug modality, illustrated by Pfizer's $43 billion acquisition of Seagen in March 2023 and Johnson & Johnson's $2 billion acquisition of Ambrx Biopharma in 2024.
Despite their transformative impact in precision medicine and oncology, ADCs face challenges, including complex pharmacology, limited variety of payloads, and evolving cancer resistance. The limitations and associated challenges are nevertheless being addressed through ongoing research and exploration of new ADC targets, novel linker technologies, and more diverse payloads.
The landscape of antibody therapeutic modalities is rapidly evolving, with the last several decades witnessing the emergence and clinical development of dozens of advanced and emerging antibody drug modalities, including single chain variable fragments (scFvs), Fragment antigen-binding (Fabs), nanobodies, bispecific antibodies, bispecific T-cell engagers (BiTEs), dual affinity retargeting antibodies (DARTs), tandem antibodies, antibody-drug conjugates (ADCs), conditionally active antibodies, and radiolabeled antibodies among others. Among these antibody formats, ADCs can be regarded as the most advanced modality, with about a dozen approved moieties already helping patients in the clinic.
Understanding Antibody-Drug Conjugates (ADCs)
Antibody drug conjugates (ADCs) are a class of advanced therapeutic modalities primarily used in precision oncology. ADCs combine the high specificity of monoclonal antibodies (mAbs) which can discriminate between healthy and diseased tissues, with the high toxicity of certain classes of cytotoxic drugs traditionally used for chemotherapy.
ADCs are composed of an antibody moiety, a linker, and a cytotoxic payload (Figure 1, left). The design of effective ADCs requires a careful consideration of the antibody, linker, and payload individual properties, how the properties of the individual components combine in the ADC, and the nature of the therapeutic target.
Figure 1. Left: Antibody-drug conjugate (ADC) overall structure: antibody moiety, linker, and payload. Right: Primary mechanism of action of ADCs. After recognizing its target antigen on the cancer cell surface, the ADC is internalized and the payload is released. The release of cytotoxic payloads inside the cancer cell leads to cell death. The released cytotoxic payload can cross the cell membrane and impact other cancer cells within the tumor microenvironment, a phenomenon referred to as the bystander effect.
The target. Antibodies cannot effectively cross cell membranes and their target antigens need to be expressed on the cell surface. For an ADC-based targeted therapy to be of value to patients, the targets need to be predominantly expressed on the surface of cancer cells to ensure that healthy cells are not targeted. For example, the human epidermal growth factor 2 (HER2) receptor is significantly overexpressed in certain tumors compared to normal tissues.
The antibody moiety. The antibody moiety defines the specificity, the stability, the circulation half-life, the affinity for the target, and the mechanism of action of ADCs.
Specificity. Antibodies can recognize different regions on their targets, allowing them, for example, to specifically target altered cell surface proteins on cancer cells without interacting with normal proteins on healthy cells.
Circulation half-life. Certain antibody types, for example IgG1, are more stable in the systemic circulation and offer longer half-life compared to other antibody types, allowing higher fraction of the administrated ADCs to reach their targets.
Target affinity. The antibody needs to recognize its target antigen with sufficiently high affinity for the ADC-target complex to be stable enough for internalization in cancer cells. However, the affinity should not be so high as to limit the diffusion of ADCs within the tumor, a phenomenon known as the binding site barrier.
Mechanism of action. The antibody moiety type can also impacts the mechanism of action of ADCs. For example, IgG1 antibodies enable, in addition to their primary mechanism of action, antibody-dependent cell mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and competent-dependent cytotoxicity (CDC) anticancer activities (see below).
What is the binding site barrier? In the context of ADCs, the binding site barrier refers to the impediment caused by the interaction of ADCs with various components within the tumor microenvironment. As ADCs diffuse out of the blood vessel at the periphery of the tumor, they can bind to various components of the tumor microenvironment, limiting their ability to penetrate deeper and consequently limiting their therapeutic effects. Similarly, if the target protein is highly expressed on tumor cells, excessive affinity of the antibody moiety for the target will trap ADCs on the tumor periphery and limit the extent to which ADCs diffuse deeper into the tumor. Overcoming the binding site barrier is central to designing effective drug delivery strategies for solid cancer treatment, aiming to enhance drug distribution within the tumor and improve therapeutic outcomes.
The Linker. Linkers attach the payload to the antibody moiety (Figure 1, left). Its primary function is to keep the payload attached to the antibody moiety in the systemic circulation and to specifically release the payload at the tumor site. Linkers can be cleavable and non-cleavable.
Cleavable linkers exploit the differences between the physicochemical properties of the systemic circulation and tumor cells to release the payloads only after ADCs recognize their targets and are internalized in the tumor cell.
Non-cleavable linkers require complete degradation of the antibody moiety in the lysosome after internalization to release the payload.
The Payload. Payloads are the warheads with cytotoxic properties attached to the antibody moiety via linkers (Figure 1, left). Typically only a small fraction of the administrated ADC reaches the targeted tumor sites after administration in the patient, and highly potent cytotoxic compounds are often preferred as payloads. Increased therapeutic effects can also be achieved by attaching several payload molecules per antibody and the number of payload molecules per antibody is known as the drug to antibody ratio (DAR). Payloads that are able to effectively cross cell membranes after release in the target cancer cell could have the added advantage of impacting surrounding tumor cells via the bystander effect (Figure 1, right and see below).
The most commonly employed cytotoxic drugs used as payloads are either microtubule binding or DNA damage-inducing drugs. Microtubules are a main component of the cytoskeleton and are required for cell division. Microtubule binding drugs thus interfere cell division and are most effective in actively proliferating cancer cells. On the other hand, DNA damage-inducing compounds cause toxicity and cell death independent of cell division, and thus might be more effective against non-actively proliferating cancer cells.
Antibody-Drug Conjugates (ADCs): from Conception to Approved ADC Therapies
ADCs build on concepts advanced by Paul Ehrlich, the German physician regarded as the father of modern drug discovery. Ehrlich introduced the concept of chemotherapy as the use of chemical compounds to treat diseases, and the concept of a magic bullet, a chemical compound that would specifically target diseased cells without affecting healthy cells.
The first clinical trials with ADCs were undertaken in the 1980s, but it wasn’t until the year 2000 when the first breakthrough was achieved with the FDA approval of gemtuzumab ozogamicin. Fast forward to 2024, there are now about a dozen approved ADCs for oncology indications with more than 100 ADC moieties at different stages of clinical trials.
Gemtuzumab ozogamicin, trastuzumab emtansine, and enfortumab vedotin represent pivot points in the clinical development of ADCs:
Gemtuzumab Ozogamicin: Revolutionary Treatment for Acute Myeloid Leukemia
Gemtuzumab ozogamicin, developed by Pfizer and approved by the FDA in 2000, is a landmark in monoclonal antibody therapy for treating acute myeloid leukemia (AML). The antibody targets CD33, a protein predominantly expressed on AML cells. After binding to CD33, the antibody is internalized and releases its payload, calicheamicin, inside the cancer cell. Calicheamicin damages the cancer cell DNA, resulting in cell death.
Trastuzumab Emtansine: A Breakthrough Therapy for HER2-Positive Breast Cancer
Trastuzumab emtansine, was developed by Genentech and approved by the FDA in 2013 for the treatment of HER2-positive metastatic breast cancer. Utilizing the blockbuster antibody trastuzumab, trastuzumab emtansine specifically binds to the HER2 protein overexpressed on breast cancer cells. Its cytotoxic payload, maytansine, is a microtubule binding drug that blocks cell proliferation, eventually leading to cell death.
Enfortumab Vedotin: Transforming Urothelial Cancer Care
Seagen and Astellas Pharma developed enfortumab vedotin, an ADC approved by the FDA in 2019 for the treatment of urothelial cancer. Enfortumab vedotin targets nectin-4, a protein highly expressed on urothelial cancer cells. The payload, monomethyl auristatin E, is a microtubule-binding drug that interferes with cell proliferation, leading to cancer cell death.
Table 1. Approved antibody-drug conjugate (ADC) therapies.
Strategic Dealmaking and Investments in ADCs: Fueling Oncology Innovation and Pharmaceutical Industry Growth
In the last couple of years ADCs have sparked a multi-billion-dollar dealmaking frenzy within the pharmaceutical industry, underscoring their growing importance and value as a class of advanced drug modalities in oncology. This surge in activity is highlighted by significant acquisitions and partnerships, notably Pfizer's monumental $43 billion acquisition of Seagen in March 2023, which added four marketed ADCs to its portfolio. Similarly, AbbVie's acquisition of ImmunoGen for $10.1 billion in November further amplified the focus on ADCs, with both deals significantly exceeding the transaction values of the previous years. Furthermore, 2023 witnessed large partnerships, including Merck & Co.'s $4 billion upfront licensing deal with Daiichi-Sankyo for three clinical-stage ADCs. These acquisitions and partnerships reflect the industry's recognition of ADCs' potential to advance cancer treatment, leveraging their ability to deliver potent cytotoxic drugs directly to cancer cells while minimizing impact on healthy tissue.
The momentum around ADCs continues to build into 2024, driven by both large-scale acquisitions and strategic investments in novel ADC technologies and targets. Johnson & Johnson's $2 billion acquisition of Ambrx Biopharma and Roche's licensing agreement with MediLink Therapeutics exemplify the ongoing commitment to enhancing ADC offerings and capabilities. These developments underscore a broader industry trend toward investing in ADCs as a promising alternative to traditional chemotherapy. Notably, the approval and expanded indications for leading ADCs like Enhertu for various cancers, including HER2-positive breast, gastric, and non-small-cell lung cancer (NSCLC), highlight the significant therapeutic potential and financial opportunity represented by ADCs. The field's evolution is further enriched by smaller deals focusing on advanced linker technologies and new therapeutic targets, indicating a vibrant and dynamic landscape for future ADC development and application.
Understanding the Advantages of Antibody-Drug Conjugates in Targeted Therapy
Antibody Drug Conjugates (ADCs) are an innovative targeted cancer therapy, blending precision medicine with cytotoxic chemotherapy efficiency. This advanced drug modality offers unique advantages over established modalities such as small molecule drugs and monoclonal antibodies (mAbs), and employs multiple mechanisms of action to treat cancer.
A Targeted Approach. ADCs represent an important shift in cancer therapy. This advanced drug modality uniquely combines the precision of mAbs with the efficacy of cytotoxic drugs, offering a targeted approach with clear advantages. In particular, while mAbs can selectively target cancer cells, binding to their cell surface target and antibody internalization does not necessarily lead to a therapeutic effect. On the other hand, while cytotoxic drugs used in traditional chemotherapy can effectively attack cancer cells, these compounds do not discriminate between cancer and healthy cells. ADCs not only enhance the efficacy of cancer treatment but also significantly reduce toxicity by selectively targeting cancer cells while sparing healthy cells.
Complex and Effective Mechanisms of Action. ADCs boast a complex and highly effective primary mechanisms of action that sets them apart from other drug modalities. By targeting specific antigens on cancer cells, ADCs deliver their cytotoxic payload directly to the tumor site while sparing healthy tissues. This process involves ADC internalization and subsequent payload release, which is their primary mechanism of action (Figure 1, right).
In addition to their primary mechanism of action, ADCs can exert a therapeutic effect in a payload-independent manner and employ additional mechanisms to combat cancer effectively. One such mechanism involves the blockade of cell surface receptors. By binding to these receptors, ADCs prevent signaling molecules from binding, thus inhibiting key pathways that cancer cells rely on for growth and survival. Another surface receptor-related mechanism is the prevention of receptor dimerization and activation, a critical process for cell signaling in many types of cancer. For example, the antibody moiety in trastuzumab emtansine binds to its HER2 target and blocks its dimerization and activation of the downstream signaling pathways involved in cell survival and proliferation.
Beyond limiting the physical access to cell surface receptors and their activation, ADCs can actively engage the immune system via their Fc portion (Figure 2). They achieve this through processes like antibody-dependent cell-mediated cytotoxicity (ADCC), where immune cells are recruited to destroy tumor cells bound by the ADC's antibody moiety. Additionally, antibody-dependent cellular phagocytosis (ADCP) is triggered, wherein immune cells recognize the ADC bound on the surface of cancer cells, and engulf and digest these cells. Complement-dependent cytotoxicity (CDC) is another immune-activated pathway, where the ADCs initiate a cascade of immune responses leading to the lysis of cancer cells. These mechanisms collectively enhance the efficacy of ADCs, offering a multi-faceted approach to cancer treatment that goes beyond traditional methods.
The Bystander Effect. The bystander effect of ADCs represents a significant advancement in oncology, significantly enhancing their therapeutic scope. This phenomenon extends the efficacy of ADCs beyond the targeted tumor cells to neighboring cells (Figure 1, right). Once the ADC releases its cytotoxic payload inside a target tumor cell, this payload can diffuse through cellular membranes to reach and impact neighboring cells. This mechanism allows the ADC to extend its anticancer activity beyond just the cells that express the specific antigen, effectively targeting adjacent heterogeneous tumor cells. This diffusion-based process not only broadens the direct cytotoxic impact of ADCs but also contributes to altering the tumor microenvironment, underlining the sophisticated and multifaceted approach of ADCs in contemporary oncology treatments.
Figure 2. Secondary immune system-mediated mechanisms of action of antibody-drug conjugates (ADCs). The Fc region of the antibody moiety can be recognized by specialized immune cells to elicit antibody-dependent cell-phagocytosis (ADCP) and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody moiety can also be recognized by C1q, a protein complex that activates the complement pathway leading to complement-dependent cytotoxicity (CDC) and resulting in cell death.
Harnessing Existing Antibodies. In the development of antibody drug conjugates (ADCs), integrating established mAbs like blockbuster trastuzumab, used in HER2-positive breast cancer, and rituximab, for lymphomas, offers significant advantages. These proven mAbs, with their established safety and efficacy profiles, are being repurposed to form the backbone of ADCs. This approach not only enhances the effectiveness of these therapies but also accelerates the development and approval process. Other successful mAbs like cetuximab and bevacizumab are also being considered for ADC development, leveraging their clinical success to create more targeted and potent cancer treatments. This method exemplifies a smart blend of existing therapeutic knowledge with innovative drug modalities.
Addressing the Limitations of Antibody Drug Conjugates (ADCs) in Cancer Therapy
While ADCs are a rapidly evolving drug modalities with exceptional potential, they face limitations and associated challenges that are being addressed through research and development.
Complex Pharmacokinetics and Pharmacodynamics. ADCs present a challenging aspect in their pharmacokinetics and pharmacodynamics. The clearance of each component (antibody and cytotoxic payload) is influenced by different factors, adding complexity to their design. While the antibody moiety is primarily cleared by the phagocyte (a type of immune cell that can ingest foreign materials) and Fc receptor-mediated recycling systems, leading to a longer half-life, the cytotoxic payload is typically metabolized in the liver and excreted, impacting drug-drug interactions and being affected by liver and kidney functions. Addressing these complexities is required for optimized ADC and is the focus of ongoing research and development efforts.
What is Pharmacokinetics? Pharmacokinetics refers to the movement of drugs within the body and encompasses processes such as absorption, distribution, metabolism, and excretion (ADME). It essentially describes how the body affects a specific drug after administration, including how quickly and for how long the drug is available to exert its effect. Pharmacokinetics basically describe what the body does to the drug.
What is Pharmacodynamics? Pharmacodynamics, involves the study of the biochemical and physiological effects of drugs on the body. It focuses on the mechanisms of drug action and the relationship between drug concentration and effect, including the duration and magnitude of therapeutic and adverse effects. Pharmacodynamics basically describe what the drug does to the body.
Toxicity Challenges. Despite the targeted nature of ADCs, they can be associated with toxicities, which is a major concern in their clinical use. For example, peripheral neuropathy is typically associated with the use of tubulin binding payloads, while myeloid toxicity is common complication from the use of DNA damage-inducing payloads. Beyond these anticipated conditions, premature release of cytotoxic payloads can lead to a range of organ-associated toxicities. Because ADCs are being increasingly used in combination therapies, other toxicities could also occur. To address these issues, ongoing research is focused on developing novel linkers with improved stability and ADCs with better tumor selectivity, ensuring that the cytotoxic agent is released primarily within the tumor cells. Finally, the discovery and development of novel payloads that act via alternative mechanisms is also expected to circumvent some of the safety concerns associated with the currently used highly toxic payloads.
Limited Payload Variety. One of the notable limitations of ADCs is the restricted variety of cytotoxic payloads traditionally used, primarily tubulin binders that block microtubule function, and DNA damage-inducing compounds. This limitation confines the scope of diseases that ADCs can effectively target. However, the landscape is evolving with the exploration of novel payload types, such as antibiotics, small interfering RNAs (siRNAs), and immunomodulators. As an example, immunomodulatory payloads work by stimulating the body's immune response against cancer cells. They are designed to deliver immune-stimulating molecules directly to the tumor site, thereby activating the immune system to target cancer cells. This approach not only broadens the therapeutic potential of ADCs but also aims to provide a more targeted and immune system-friendly treatment option, moving beyond the conventional cytotoxic mechanisms.
Resistance Mechanisms. The treatment of cancer with ADCs is a complex process, offering targeted therapy but also presenting multiple avenues for cancer cells to develop resistance. The efficacy of ADCs depends on several sequential steps: the ADC must bind to a specific antigen on the cancer cell surface, be internalized, transported to and processed within lysosomes, and finally, the released payload must reach and affect its intracellular target. Cancer cells can develop resistance mechanisms at each of these steps:
Altering the Surface of ADC Target Antigens. Cancer cells can accumulate mutations in their DNA which can lead to changes in the ADC’s target antigen, reducing the ADC's ability to recognize the antigen and be internalized. Additionally, cancer cells may downregulate the expression of the target antigen. A well-known example is the downregulation of HER2 in response to trastuzumab emtansine treatment in HER2-positive cancers, leading to reduced drug binding and uptake and reduced ADC efficacy.
Upregulating Multidrug Resistance Proteins (MDRs). MDRs are proteins that transport various molecules across the cell membrane and are often involved in the export of drugs from cells. MDRs actively expel the cytotoxic payload from cancer cells, diminishing the payload’s intracellular concentration and therapeutic impact. In some cases, cancer cells increase the number of MDRs in their membranes, decreasing the intracellular concentration of the payload and eliminating its cytotoxic effects.
Limiting ADC’s Access to Lysosomes. For the payload to exert its cytotoxic effects in cancer cells, the ADC need to be transported to and processed within lysosomes (Figure 1, right). In certain cases, cancer cells can alter their internal trafficking pathways to prevent ADCs from reaching the lysosome. For instance, after an ADC binds to the cancer cell, it may be internalized into vesicles that do not mature into functional lysosomes, preventing proper payload release. In other cases, the ADC may be directed to non-lysosomal pathways, circumventing the intended release and action of the cytotoxic agent.
To counter these resistance mechanisms, ongoing research is exploring new target antigens and new types of payloads. Combining ADCs with other therapeutic agents to target multiple pathways and mechanisms simultaneously is another promising strategy. Understanding the specific mechanisms of resistance in individual cases is crucial for designing effective ADCs and combination therapies, paving the way for more successful cancer treatments.
Development and Manufacturing Challenges. ADCs are complex to develop and manufacture, with challenges arising from their heterogeneity and the need for precise conjugation technologies. The heterogeneity in DAR and conjugation sites can impact their therapeutic efficacy and pharmacokinetics. Advances in site-specific conjugation technologies are being explored to address these issues, aiming for more homogeneous ADCs with improved stability and efficacy.
Limited Tumor Penetration. The range of viable targets for ADCs has been traditionally limited, though recent research is expanding this range to include components of the tumor microenvironment. However, the large molecular weight of antibodies used in ADCs poses challenges for penetration through the blood capillary and tumor matrix, especially for solid tumors. Miniaturizing antibodies or using smaller molecular weight fragments like single chain variable region fragments are strategies being explored to enhance tumor penetration. These approaches aim to improve delivery efficiency to tumor tissues but can also result in reduced half-life and loss of Fc-mediated immune effects. Balancing these factors is a key focus in ongoing ADC research and development.
Conclusion
In conclusion, Antibody Drug Conjugates (ADCs) are at the forefront of innovation in targeted oncology therapies, offering a promising bridge between the specificity of monoclonal antibodies and the potent cytotoxicity of chemotherapy drugs. As the pharmaceutical and biotech industries continue to invest in and develop this advanced therapeutic modality, the landscape of cancer treatment is being transformed. Despite facing challenges in pharmacokinetics, toxicity, resistance, and manufacturing, the ongoing advancements in ADC technology are paving the way for more effective, targeted, and less toxic treatments. By harnessing the power of precision medicine, ADCs are not just a testament to the progress in the fight against cancer but also a beacon of hope for patients worldwide, promising a future where cancer therapy is as effective as it is specific, minimizing harm while maximizing therapeutic potential.
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