Fcγ receptors polymorphisms: clinical and functional implications in the use of therapeutic monoclonal antibodies

Polymorphisms in FcγRIIα (CD32) and FcγRIIIα (CD16) receptors are associated with responses to the CD20 directed IgG1 monoclonal antibody rituximab among patients with indolent lymphoma. Rituximab is an important therapeutic for Waldenström’s macroglobulinemia (WM). The contribution of FcγRIIIα-158 polymorphisms, as well as at other positions, in response to rituximab has not been reported for WM. In these studies, we sequenced all coding regions of the FcγRIIIα from a series of 58 patients with WM to first define potential polymorphisms, and then correlated these findings to their response to rituximab. We observed single nucleotide variations in five codons of the FcγRIIα. Two were commonly observed and predicted for amino acid polymorphisms at FcγRIIIα-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcγRIIIα-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcγRIIIα-158 F/F were always FcγRIIIα-48 L/L (p V/F > F/F). Συμπεραίνουμε επομένως, ότι οι V/V και V/F έχουν μεγαλύτερη πιθανότητα κλινικής ανταπόκρισης στη θεραπεία με ριτουξιμάμπη, που οφείλεται: (α) στην αυξημένη έκφραση του CD16 στην επιφάνεια των NK κυττάρων τους, (β) στην καλύτερη σύνδεση της ριτουξιμάμπης και (γ) σε μεγαλύτερη ADCC