Over the past decades, monoclonal antibodies (monoclonals) have become invaluable for basic research, diagnostics, clinicians, and thousands of patients suffering from severe afflictions. Monoclonals are widely used laboratory reagents, and it is fair to say that the availability of a good monoclonal has led to increased understanding of the target biology as many experimental approaches, ranging from classical western blots to chromatin immnunoprecipitation assays, are enabled. Beyond basic research, therapeutic monoclonals are increasingly used as drugs and will account for over 50 billion USD in sales in 2013, and this fi gure is forecast to grow at double-digit rate, higher than any other therapeutic class. Since OKT3 (Muromonab-CD3, Johnson & Jonson/Ortho Biotech), the fi rst monoclonal approved for human use, 34 other monoclonals have been approved.
This is the tip of the iceberg, as it is estimated that over 400 monoclonals are in clinical development worldwide. This brisk success is explained by several factors. First and most importantly, their specificity and low off-target toxicity often provide monoclonals with an exceptional “therapeutic window,” i.e., the ability to dose them effectively with acceptable side effects. Monoclonals are also embraced because of their prolonged half-life and, more generally, as their pharmacokinetic properties are more predictable than for other classes of drugs. Consequently, the rate of success for the clinical development of monoclonals is signifi cantly higher than for small molecule drugs or for other biologicals.
With the progress of genetic and protein engineering, academic labs and the biopharmaceutical industry have advanced many novel antibody formats and antibody-based approaches. These comprise multi-specifi c antibodies, fragments, antibody–drug conjugates, antibodies with enhanced effector function, and so on. However, despite these evolutions, being able to generate high-quality monoclonals against carefully selected epitopes remains the absolute foundation for subsequent improvements. Equally important is the meticulous characterization of candidate monoclonals. We actually contend that because of the greatly expanded toolkit for improving monoclonals, epitope selection and biochemical characterization has now become even more important for generating well-differentiated monoclonals. One can directly witness this notion at the bench with antibodies raised against the same target that perform very differently in various assays but also in the clinic, where monoclonals against different epitopes can exert very different responses in patients (e.g., the three anti-CD20 monoclonals Rituximab, Ofatumumb, and GA-101 by Roche, Genmab/GSK, and Roche respectively).