Two-in-One antibodies with dual action Fabs

•Multi-specific antibodies can arise spontaneously.•Dual action Fabs can be engineered in vitro.•Dual action Fabs are non-promiscuous and specific for two distinct antigens.•Two-in-One antibodies may have effects not possible with two-antibody combinations.

Mechanisms and biological roles of antibody multi-specificity are topics of high interest. Evidence of conformational flexibility in antigen-combining sites and their utility in the recognition of different antigens appeared two decades ago. In the last three years an appreciation has emerged that recognition of very much more diverse protein antigens is within the scope of multi-specificity and also that this is sometimes, but not always, associated with structural plasticity. The ability to invent non-promiscuous, high affinity antibodies which are ‘specific’ for more than one antigen such as the recently described dual-specific Two-in-One DAF antibodies, provides not only insights into the evolution of antibody specificity but also a promise of powerful medicines fully within the paradigm of targeted therapies.