Immune Inhibitor Fc Domains

FcγRIIb (IIb), also called CD32b, is a receptor on B cells that, when engaged by Fc domains, blocks that activation of immune pathways that play an important role in autoimmune, allergic and inflammatory diseases.

Xencor has discovered IIb immune inhibitor Fc variants with a 400-fold increase in binding affinity to FcγRIIb derived from just two amino acid changes.

Targeting FcγRIIb by itself does not trigger its inhibitory properties. FcγRIIb must be associated with other specific partner proteins on the cell surface to mediate its inhibition. Xencor has created antibodies that target a B-cell surface target through their Fv domain and recruit the FcγRIIb to associate with that target. This coupling of the two proteins, in some cases, will then trigger the inhibitory properties of FcγRIIb. We have also discovered a new mechanism of action in which high FcγRIIb binding on endothelial cells causes extremely rapid clearance of antibody: target complexes from circulation.

Our IIb technology has been applied to two drug candidates in our pipeline. XmAb5871 targets CD19 on B cells through its variable domain and its Fc domain recruits FcγRIIb to inhibit B-cell activation for the treatment of autoimmune diseases. XmAb7195 targets IgE and rapidly clears IgE from the circulation and inhibits activation of IgE-positive B cells to prevent production of IgE.