Monoclonal antibodies and Fc fusion proteins have been successful therapeutics in the field
of cancer and immune disease. As their pharmacological activity is dependent on the Fc fragment governing
their effector functions and long in vivo half-life, the extensive engineering of the Fc for altered
binding of its natural ligands that enable these properties has delivered molecules optimized for their
therapeutic effect. Recently, the IgG1 Fc region itself and its subunits monomeric Fc fragment, CH2 and
monomeric CH3 domain, have been engineered into scaffolds with favorable biophysical properties and
a high potential for de novo antigen recognition. A dimeric Fc fragment with an antigen binding site has
proven suitable for evaluation in animal models and has already entered human trials. Such modified
constant domains can easily be incorporated into an antibody or fused with antibody domains of a second
specificity. The small size of the Fc and its subunits that enhances their tissue penetration, as well
as the unique topology of their binding sites that allows novel modes of contact with the antigen, are attractive
features that prompt their development into promising candidate therapeutics.
Keywords: Directed evolution, Fc fragment, molecular recognition, protein display, protein engineering, rational mutagenesis.
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