Structure-Based Drug Discovery

Gary L. Gilliland, Jinquan Luo, Omid Vafa, Juan Carlos Almagro, Gilliland, Gary L., Luo, Jinquan, Vafa, Omid, Almagro, Juan Carlos

Antibodies make up the largest, growing segment of protein therapeutics in the pharmaceutical and biotechnology industries. The development or engineering of therapeutic antibodies is based to a large extent on our knowledge of antibody structure and requires sophisticated methods that continue to evolve. In this chapter, after a review of what is known about the structure and functional properties of antibodies, the current, state-of-the-art antibody engineering methods are described. These methods include antibody humanization, antigen-affinity optimization, Fc engineering for modulated effector function and extended half-life, and engineering for improved stability and biophysical properties. X-ray crystallographic structures of antibody fragments and their complexes can play a critical role in guiding and, in some cases, accelerating these processes. These approaches represent guidelines for developing antibody therapeutics with the desired affinity, effector function, and biophysical properties.