The coming of age of engineered multivalent antibodies

•36 out of 39 approved therapeutic antibodies are native full-length IgG.•Antibody engineering may increase potency and improve safety of native antibodies.•Next generation antibodies may be even more efficient therapeutic molecules.•18 engineered antibodies with promising preclinical results are in clinical trials.•In December 2014, blinatumomab became the first bispecific antibody approved in US. The development of monoclonal antibody (mAb) technology has had a profound impact on medicine. The therapeutic use of first-generation mAb achieved considerable success in the treatment of major diseases, including cancer, inflammation, autoimmune, cardiovascular, and infectious diseases. Next-generation antibodies have been engineered to further increase potency, improve the safety profile and acquire non-natural properties, and constitute a thriving area of mAb research and development. Currently, a variety of alternative antibody formats with modified architectures have been generated and are moving fast into the clinic. In fact, the bispecific antibody blinatumomab was the first in its class to be approved by the US Food and Drug Administration (FDA) as recently as December 2014. Here, we outline the fundamental strategies used for designing the next generation of therapeutic antibodies, as well as the most relevant results obtained in preclinical studies and clinical trials.