Monoclonal antibodies have dominated the biopharmaceutical market for over two decades. Few people doubt that their future success in fields such as oncology, inflammation, and autoimmune diseases owes much to the development of antibodies conjugated to cytotoxic drugs. Like all great innovations, this is a breathtakingly simple concept: Combine the targeting specificity of an antibody with a small-molecule drug as an effector component joined to that antibody by means of a small chemical or peptide linker, and you have a therapeutic strategy suitable for any indication in which cells produce disease-specific antigens. The resulting compound structures are known as antibody–drug conjugates (ADCs), and they direct cytotoxic effectors to specific disease-causing cells, such as cancer and hyperactive immune cells, which are subsequently induced to undergo apoptosis (
1
). By targeting cell-surface proteins such as receptors or adhesion molecules that are solely expressed on disease cells, but not surrounding...
Lonza
Development of highly potent active pharmaceutical ingredients (HPAPIs) is clearly a pharmaceutical industry trend. Highly potent drug products involve active agents and APIs that are so potent therapeutically (or simply just outright toxic) even in small dose that special precautions are required during their manufacture — particularly when handling the active agents. Such requirements include maximal containment and isolation of the process stream. Worker exposure and environmental release clearly pose problems. The necessity and intensity of containment efforts with HPAPIs largely define products based on them. Specialized analytical techniques, equipment and knowledge are also required with ADCs.
Among HPAPI drugs, exemplary products include highly potent proteins such as some hormones; biological toxins such as botulinum toxin; and antibody–drug conjugates (ADCs), formerly commonly referred to as immunotoxins. ADCs are by far the fastest growing class of HPAPI drugs, and perhaps the fastest-gro...
Figure 1: Schematic of lysine and cysteine conjugates and their expected DAR profiles.
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Bringing a new biologic drug to market is a long and expensive process, with research and development (R&D) cycles that can span up to 15 years and may cost over a billion dollars. Biologic drug development also involves significantly more complex manufacturing and CMC components than does development of small molecules. Nonetheless, the pharmaceutical industry is increasingly shifting its R&D efforts to focus on biologic drugs. According to a recent report from Tufts Center for Study of Drug Development, the number of clinical trials involving biologic drugs has risen by over 155% from 355 in 2001 to more than 900 in 2012 (
1
). The same report reveals that biologics accounted for 71% of revenue from the world’s top-10 selling drugs in 2012 compared with a mere 7% in 2001. Worldwide sales of biologic drugs increased from US$36 billion to $163 billion during the same period.
Biologic drugs represent ...
+1Bioconjugates represent an important and growing class of pharmaceuticals that include PEGylated proteins, vaccines, and antibody-drug conjugates (ADCs) (
1–8
). Numerous protein conjugation techniques exist (
9
). Among the more important conjugation chemistries used for protein therapeutics are N-hydroxysuccinimide (NHS), aldehyde, and maleimide (
10–13
).
To date, process development of industrial biopharmaceutical conjugation reactions has largely been empirical in nature. Typically, many experiments testing different reaction parameters are required to identify optimal process conditions. In some instances, nonmechanistic statistical models can be used, often using JMP or similar software. However, such mathematical descriptions can suffer from a number of deficiencies. In particular, it is difficult for a statistical model to fully capture the complex dynamic behavior seen for many multistep conjugation reactions and hence allow limited extrapolation.
Kinetic models have shown promising results to a...
Antibody–drug conjugates (ADCs) use the targeting ability of a monoclonal antibody (MAb) to deliver a highly biologically active drug to diseased cells while sparing healthy cells, creating potent and effective therapies. This emerging class of novel drugs currently focuses almost exclusively on cancer treatment. Two blockbuster ADCs — brentuximab vedotin (Adcetris from Seattle Genetics) for treatment of rare lymphomas and ado-trastuzumab emtansine (Kadcyla from Genentech/ Roche, manufactured by Lonza) for treatment of HER2-positive metastatic breast cancer — have improved treatment options for many patients and constituted the majority of the US$454 million ADC market in 2013, according to the UK-based market research firm Roots Analysis (
1
). With more than 30 ADCs in clinical testing and many more in preclinical development, Roots Analysis estimates that by 2018 sales of ADCs will climb to $5 billion/year.
Although the basic principle seems straightforward, drug developers have had to overcome many ch...
+1 Figure 1: Aggregation propensity of ADC
products developed by Innate Pharma and
Adcetris
Antibody–drug conjugates (ADCs) are monoclonal antibodies coupled to cytotoxic agents with stable linkers. ADCs travel to target cells, where the antibody binds to its antigen expressed on the cell surface. Upon binding, the full ADC can be internalized by a process called receptor-mediated endocytosis. That process is followed by lysosomal degradation of ADC complexes, which ultimately leads to release of the cytotoxic agent and apoptosis of the target cell. Drugs used in ADCs can be up to a thousand times more potent than current chemotherapeutics (
1
).
A well-known example of an ADC is brentuximab vedotin, which is often referred to by its trade name, Adcetris (from Seattle Genetics). The US Food and Drug Administration approved this ADC in 2011 for treatment of relapsed or refractory cases of classical Hodgkin lymphoma. It is directed at CD30, which is expressed on the surface of malignant cells, and is linked to...
+8 Abzena.com
Antibody–drug conjugates (ADCs) for treatment of cancer combine the tumor-targeting properties of antibodies with the cell-killing properties of cytotoxic drugs. By targeting a drug to a tumor, it is possible to reduce systemic toxicity and thereby enable administration of drugs that are otherwise too toxic to be effective therapies. Although the concept of an ADC is simple, in reality developing an effective treatment is somewhat more challenging. Whether an ADC has sufficient efficacy at a tolerable dose depends on four key factors: the target antigen, the antibody, the drug, and the linker between the antibody and the drug.
The Target Antigen
The target antigen should be either specific to or highly expressed on cancer cells (with low levels in normal tissue), not secreted into the circulation and, what is most important, internalized upon antibody binding. Despite all efforts made to identify antigen targets that are suitable for antibody-based therapies in cancer, very few have been found ...
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Antibody–drug conjugates (ADCs) are an exciting new area of therapeutics. They bring the “magic bullet” that was promised by Paul Ehrlich over a hundred years ago to reality by targeting cancer cells to deliver chemotherapies without poisoning a patient’s whole body. ADCs offer a promising form of therapy by providing higher safety margins than traditional chemotherapeutics alone, and they make selectivity possible. We should be able to personalize a therapy to the specific cancer expressed in a given individual.
Why choose to work with a contract manufacturing organization (CMO) for developing and manufacturing your ADC products? These are complex molecules, requiring expertise both in handling biologics (the antibody portion of the drug) and highly potent active pharmaceutical ingredients (HPAPI), as well as drug linkers and associated chemistry. Specialized containment is required to protect personnel handling highly potent ingredients. Conjugates with both biological and chemical a...
