[cv]

Engineering Antibody Fc Domains for Enhanced Immune Effector Functions

The success of an antibody therapeutic in cancer treatment is often due not only to its ability to bind to and neutralize a particular target of interest, but also to its ability to engage, and activate, immune effector cells for potent clearance of the tumor.  Here, the antibody acts as an adaptor molecule, simultaneously binding a target antigen through its variable regions and activating an immune response through interaction of its conserved Fc region with the Fc receptors on cells of the immune system.  The aim of my project is to develop more potent antibody therapeutics by enhancing this antibody-mediated immune cell activation.  To accomplish this, we are engineering human antibody (IgG1) Fc domains for increased affinity and specificity for binding to the activating Fc receptors (FcγRIIIA and FcγRIIA) as compared to the lone inhibitory receptor (FcγRIIB), which has been hypothesized will stimulate a stronger immune response.  To this end, we are using yeast surface display of fully-assembled human IgG and directed evolution to select for Fc variants with the desired binding properties.  As a second aim, we are using the same system to develop aglycosylated antibody Fc domain variants that can be recognized by Fc receptors.  Such variants could allow for the recombinant expression of therapeutic antibodies in alternative expression systems, potentially decreasing their cost of manufacture.