According to the National Cancer Institute, more than 1.6 million Americans will be diagnosed with cancer this year. While there are many types of cancer treatments available today, targeted cancer therapies have emerged as a very promising approach.
Targeted cancer therapies are drugs designed specifically to block the growth of cancer cells. Unlike chemotherapies which attack and kill healthy cells along with the cancerous ones, targeted therapies are engineered to only inhibit specific molecules. Among the different types of targeted therapies approved for use in cancer treatment are monoclonal antibodies (mAbs), which are linked with a toxic molecule, such as a radioactive substance or drug compound, in order to deliver it to the targeted cancer cells.
Leveraging Molecular Targets
Advances in this form of precision medicine have led to the development of antibody drug conjugates (ADCs), a class of powerful biopharmaceutical drugs composed of mAbs linked to a cytotoxic payload, which is designed to kill tumor cells. As opposed to traditional small-molecule chemotherapy, ADCs minimize the risk of harming non-cancerous cells. What’s more, because of their precise approach, they enable the use of more potent chemical agents. As a result of these benefits, ADCs are one of the most novel and exciting areas in current biological study for the treatment of numerous diseases, including many types of cancer.
As promising as ADCs are, the road to their production is steeped in challenges. ADC creation hinges on the chemical conjugation – very precise linking of just the right combination of molecules. Antibodies already exist as a complex population of ‘variants’ due to posttranslational modifications and degradation during expression, processing and storage. ADCs have an additional layer of complexity due to variation in the drug-to-antibody ratio (DAR).
DAR is the average number of drugs conjugated to the antibodies and is a critical measurement, as it directly impacts the efficacy of the treatment. For example, a high drug proportion can negatively affect pharmacokinetics while a low one can hinder potency. Now each variant of the antibody can itself have multiple variants based on how many drug molecules are conjugated to it. Precise and reproducible analysis is critical to understand the dosage of drug that will be administered, not to mention for FDA acceptance, Quality Control and release testing.
The inherent complexity of ADC populations is itself a significant challenge to analytical techniques. Liquid chromatography–mass spectrometry (LC-MS, or HPLC-MS), is commonly used to measure the DAR and drug load distribution of ADCs to identify various species. However, as mentioned above, the complexity and heterogeneity of ADCs present a challenge for the conventional analysis tools widely used by the life science industry. For example, the high salt content required for ADC separation makes it incompatible with traditional MS techniques.
Overcoming Analytical Hurdles Using Integrated Microfluidics
Our ZipChip™ offers an ideal solution for ADC analysis. Launched earlier this year, ZipChip uses integrated microfluidic technology to prepare, separate and electrospray biological samples directly into traditional MS, resulting in near-native intact ADC variants with a full mass spectrum behind every peak. What’s more, the analysis process requires no sample prep, is tolerant of salt and production detergents typically present and can be completed in as little as three minutes.
This is a noteworthy improvement over conventional processes which typically involve time-consuming sample preparation. When dealing with ADCs, accurate and efficient sample prep can be particularly challenging due to the complex nature of antibodies. This can significantly slow down the drug development phase for those in need of immediate treatment. With ZipChip, not only is much of this time saved, but analysis timeframes are considerably reduced, with our device bringing them from 30 minutes to just three – a mere fraction of the time.
The incorporation of ZipChip and microfluidic-based analysis into the characterization process is enabling drug developers to overcome many of the challenges inherent in the analysis of ADC variants and ensure effective treatment of life-threatening diseases.
Our science founder, J. Michael Ramsey, and his team at the University of North Carolina at Chapel Hill, further demonstrated the analytical power of employing capillary electrophoresis-mass spectrometry (CE-MS) in an integrated microfluidics platform in a paper published this year in Analytical Chemistry. The paper, titled Characterization of Intact Antibody Drug Conjugate Variants Using Microfluidic Capillary Electrophoresis–Mass Spectrometry, reinforces the favorable comparison between microfluidic CE-MS data and more traditional forms of analysis for ADCs, such as infusion ESI-MS and imaging CE (iCE). We invite you to learn more by reading the full publication through the link above.
Chris Petty, VP Business Development and Marketing