The Biologics Boost

Small chemical molecules are the classic active pharmaceutical ingredients and – despite the buzz about biologics and personalized medicine – still account for about 90 percent of all commercialized drugs. However, while biologics represent the minority in terms of sheer number, the financial story is somewhat different. Of the top ten selling drugs of 2012, seven were biologics. And so, for good reason, over the last few years, industry has concentrated much of its efforts on targeted therapies and more clinically efficacious drugs in the form of biologics – or biopharmaceuticals, if you’re old school.

Within the field of biologics, the majority of research and product development is currently focused on recombinant proteins and monoclonal antibodies (mAbs, which accounted for five of the top ten selling drugs of 2012). These large molecule therapeutic proteins are composed of amino acids and can have a size of up to 150 kDa, and are essentially copies or optimized versions of endogenous human proteins. They are used for multiple indications, including cardiovascular diseases, infectious diseases, immune disorders, and cancer. For the treatment of cancers, mAbs have really hit the mark because of their ability to selectively bind to the receptors of cancer cells while leaving healthy cells untargeted and, therefore, safe from attack – the so called “magic bullet”. It is for this reason that biologics often cause fewer side effects than chemotherapy.

In the last 20 years, there have been a total of 40 antibody products and derivatives approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA), and the growth in approved mAbs in the last few years has been exponential. Today, more than 400 antibodies, primarily involving immunological and oncological targets, are under pre-clinical development and clinical trials. These are exciting times to be in the pharmaceutical field.

Working, as I do, in a university laboratory that focuses on pharmaceutical analysis, part of my work has transitioned from the analysis of small molecules to the detailed characterization of biopharmaceuticals, logically mirroring the general trend outlined above. Because biologics exhibit high molecular complexity, they tend to be sensitive to changes in the manufacturing processes, which can lead to considerable micro-heterogeneity. Of course, such heterogeneity must be critically evaluated – levels of impurities (as with any pharmaceutical) and degradation (extremely complex in biologics) have serious health implications.

To meet this essential need, a large panel of separation techniques based on both liquid chromatography (reversed phase, ion exchange, size exclusion, hydrophobic interaction, affinity) and electrophoresis (capillary zone, capillary isoelectric focusing, capillary gel, SDS-PAGE) is being employed for biopharmaceutical characterization and comparability studies. Mass spectrometry (MS) also plays a pivotal role in the structural elucidation of mAbs because it offers an additional degree of separation by mass/charge ratio, greatly facilitating the identification of variants. Indeed, the full characterization of biopharmaceuticals is highly challenging and necessitates high-resolution separation techniques and powerful MS systems.

Despite the challenges and complexity, a study from Tufts University back in 2010 (1) noted (with caveats) that clinical trial success rates for large molecules were more than double that of their small molecule counterparts (survival rates from Phase I to approval of 32 percent and 13 percent, respectively). Why? I believe that it is in part because of the impetus that biologics have provided to the chromatography, electrophoresis, and mass spectrometry communities. The urgent requirement for new solutions generated a spirit of collaboration that has revitalized “snoozing” academic, governmental and industrial laboratories around the world. Examples include many  recent advances in LC (widepore RPLC phases, core-shell technology, inert instrument and columns to limit adsorption, size exclusion and ion exchange materials packed with smaller particles) that aim to meet the requirements of biomolecular analysis. MS devices are also being increasingly adapted for the analysis of large biopolymers (for example, more accurate and higher resolution devices, implementation of new data-dependent acquisition modes, and dedicated software for deconvolution).

The big question is, how can we continue to improve on the Phase I survival rates for the 400 antibodies out there, and the hundreds of other potential biologics that will appear over the next few years? The answer is that we must translate even more of our hard analytical work into product success. In doing so, we will be contributing to something very special – the development of new medicines that save lives.