Novel Approaches in Discovery and Design of Antibody-Based Therapeutics

Abstract We review here new technologies impacting antibody discovery and optimization, specifically next-generation sequencing (NGS). This technology is providing the means to study whole natural and manmade repertoires under a variety of selection conditions or after immunization and is becoming part of the toolbox for the discovery of antibodies. We also discuss novel sources of V regions as substrates for the engineering of therapeutic antibodies, specifically species other than humans and rodents, such as rabbits and chickens. These species have gained attention in recent years due to certain advantages with respect to rodents, such as the capability of generating high-affinity antibodies against epitopes conserved between humans and rodents. Also, chickens and rabbits have simpler V region repertoires than mice, thus facilitating the engineering of antibodies with therapeutic potential. Last, we review molecular modalities beyond natural antibodies, in particular bi- and multispecific modalities. With the relatively recent approval of catumaxomab, the field of bi- and multifunctional molecules has gained momentum; currently, a number of different molecular formats are in the early stages of validation as therapeutics or in clinical trials demonstrating proven superior efficacy in some diseases and potential in new indications in oncology.