How Specialized Software Can Help Companies Better Identify Biologic Antibody-Drug Conjugates
At medical schools and research facilities across the country, physicians and scientists are trying to discover ways to ensure that treatments are more specific and targeted than ever before. Gone are the days when experts are content with a “one-drug-fits-all” style pharmacology. In cancer therapy, these experts are turning to antibody-drug conjugates to serve their needs for specificity1 in the hope that these therapies will eliminate the often terrible side effects of chemotherapy and result in long-lasting relief from cancer.
Biologic antibody-drug conjugates are generally composed of four components: the antibody that targets highly expressed antigens on a tumor (enabling the drug complex to distinguish diseases from healthy cells), an attachment site, linker (which attaches the antibody and the drug) and finally, the drug itself.2 Taken together, the result of these chemistries allows for specific targeting of a cancer cell and subsequently, specific release of the drug via mechanisms, such as hydrolysis or reduction. Alternatively, researchers can design linker conjugates that are non-cleavable, an advantage for increasing plasma stability and drug specificity.3
Initial Challenges Are Deepened Using Biologic Antibody-drug Conjugates
Protein therapeutics are notoriously finicky and as such, present researchers with a number of challenges. As one scientist notes, “relatively small changes of external variables…can destabilize protein structure,”4 leading to protein aggregation, a phenomenon which can occur in vivo with disastrous effects. With potent drug conjugates, misfolded or aggregated antibody drug conjugates could result in the release of cytotoxic drug elements. When no longer targeted to tumor cells, these elements can cause widespread damage wherever they are released. In extreme cases, the injuries caused by these off-target release events can exacerbate the symptoms of disease and might affect the likelihood of patients to continue with a specific therapy.
To ensure both safety, effectiveness and patient comfort, it is essential for companies to experiment with a number of different excipients in combination with antibody-drug conjugates. Excipients are specifically important for eliminating chemical instabilities, increasing conformational stability and optimizing interfacial stability, all factors that are essential for maximizing the specificity of binding of a monoclonal antibody to its antigen and the subsequent release of the drug. To consider the importance of these excipients, researchers should think of antibody-drug conjugates as human faces: there can be a great diversity in how a face appears; however, the process of reproducing a singular face must be the same in the context of antibody-drug conjugates, especially within patients.
The Goldilocks Dilemma
So which excipients should one consider in determining how to modify antibody-drug conjugates? Before addressing this issue, a good first step would be to make use of powerful software that keeps track of prior workflows. The data stored in workflows is quickly customizable and the results of activity experiments are easily stored, monitored and assessed. From this robust data trove, scientists can begin to identify changes to antibody-drug conjugates that will have minimal effects. A categorization of “critical qualities” versus “non-critical qualities” could then be devised in order to more quickly determine how to stabilize and improve biologic ADCs.
For example, high mannose type glycans are often critically important when added to biologics because they reduce the amount of time a drug remains in the body.5 In certain disease contexts, researchers may want to increase or decrease the half-life of an antibody-drug conjugate. In doing so they may better understand how high mannose type glycans affect previous biologics and antibody-drug conjugates can powerfully inform the eventual structure of a drug.
Using software that records experimental protocols and the subsequent activities of antibody-drug conjugates, researchers can also determine how specific antimicrobials/preservatives, buffering agents and surfactants that assist in protein folding are also likely to affect the ADCs being studied. In general, there are many factors that can affect protein folding, subsequent potency and safety profile of a drug. Various combinations of these factors can be tested in an effort to improve a specific antibody-drug conjugate formulation.
The BIOVIA Biologics Solution is an innovative platform that supports the discovery and manufacture of biotherapeutics by enabling researchers to document and manage data. It can help monitor assays to enable them to make the most informed decisions about excipient additions and the general development of biologic therapies. To learn more about how BIOVIA Biologics Solution can assist your company, please contact us today.
- “Lonza Annual Report,” 2013, https://www.zonebourse.com/LONZA-GROUP-AG-2956013/pdf/425850/Lonza%20Group%20AG_Rapport-annuel.pdf ↩
- “The Chemistry Behind Antibody-Drug Conjugation,” http://www.scripps.edu/baran/images/grpmtgpdf/Sella_May_14.pdf ↩
- “Antibody Drug Conjugate: Design and Selection of Linker, Payload and Conjugation Chemistry,” March 2015, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365093/ ↩
- “Excipients and their Effects on the Quality of Biologics,” http://bit.ly/22CNaqo ↩
- ”Critical Quality Attributes,” 2015, http://www.amgenbiosimilars.com/the-science/critical-quality-attributes/ ↩