In search of magic bullets: the golden age of immunotherapeutics

Abstract

Once upon a time, immunology was a black box, inflammatory and autoimmune diseases were a mystery, and relatively blunt tools were used to treat these diseases. In the last 40 years, advances in molecular biology, DNA recombination technology, and genome sequencing allowed immunologists to open the box. As the complexity and diversity of the immune response are unveiled, targeted cellular and molecular therapies now offer rational approaches to treat immune-mediated diseases. Here, we discuss how the tried and true bench-to-bedside strategies resulted in some spectacular successes, along with some puzzling failures. Conversely, the advent of targeted therapies in the clinic has led to a wealth of information that changes how we think about the pathogenesis of immune-mediated diseases and how we categorize disease. In turn, these insights can inform next-generation drug discovery and refine targeted therapies for the appropriate patient subsets.

Figure 1. Timeline of targeted therapies

Selected examples of recombinant cytokines and cytokine receptors, monoclonal antibodies (mAbs) and small molecules illustrate the evolution of targeted therapies.

Figure 2

Lessons learnt and Challenges ahead.

Figure 3. Flow of information in development of targeted therapies

Advances in molecular biology revealed a number of targets that were identified at the bench and led to successful drugs at the bedside (‘bench to bedside’) Conversely though, advances in sequencing technology led to the discovery of various genetic disorders that also provided convincing targets for intervention. Such “experiments of nature” facilitated the understanding of what the consequence of interfering with a target might be and thus provided impetus to go back to the bench (‘bedside to bench to bedside’). In other circumstances, development of a targeted therapy did not have the expected result. Fortunately, in a number of cases this led investigators to go back to the bedside and rethink disease mechanisms, and find the right disease for the therapy (‘bench to bedside to bedside’).