Antibody–antigen pair probed by combinatorial approach and rational design: Bringing together structural insights, directed evolution, and novel functionality

► Antibodies are extraordinary template for combinatorial and rational improvements. ► Reactibodies are novel catalytic scavengers with predefined specificity. ► Catalytic antibodies towards distinct pathogens – elaboration of catalytic vaccines. ► 2D screening – antibody versus antigen in solving of the “Chicken and Egg” problem. The unique hypervariability of the immunoglobulin (Ig) superfamily provides a means to create both binding and catalytic antibodies with almost any desired specificity and activity. The diversity of antigens and concept of adaptive response suggest that it is possible to find an antigen pair to any raised Ig. In the current review we discuss combinatorial approaches, which makes it possible to obtain an antibody with predefined properties, followed by 3D structure-based rational design to enhance or dramatically change its characteristics. A similar strategy, but applied to the second partner of the antibody–antigen pair, may result in selection of complementary substrates to the chosen Ig. Finally, 2D screening may be performed solving the “Chicken and Egg” problem when neither antibody nor antigen is known.