Harnessing the Fcm Receptor for Potent and Selective Cytotoxic Therapy of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy in need of new, effective, and safe therapies. The recently identified IgM receptor FcmR is overexpressed on malignant B cells in CLL and mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fcm). To exploit this internalization and trafficking pathway for targeted drug delivery, we engineered an IgM-derived protein scaffold (Fcm) and linked it with the cytotoxic agent monomethylauristatin F. This Fcm–drug conjugate was selectively toxic for FcmRexpressing cell lines in vitro and for CLL cells but not autologous normal T cells ex vivo. Notably, the cytotoxic activity of the Fcm–drug conjugate wasmaintained in CLL cells carrying a 17p deletion, which predicts resistance to standard chemotherapy. Next, we tested the possible therapeutic application of the Fcm–drug conjugate in immunodeficient NOD/SCID/IL-2Rg (NSG) mice engrafted with peripheral blood cells from patients with leukemia. Three intravenous injections of the Fcm–drug conjugate over a 10-day period were well tolerated and selectively killed the human CLL cells but not the coengrafted autologous human T cells. In summary, we developed a novel strategy for targeted cytotoxic therapy of CLL based on the unique properties of FcmR. FcmRtargeted drug delivery showed potent and specific therapeutic activity in CLL, thus providing proof of concept for FcmR as a valuable therapeutic target in CLL and for IgM-based antibody–drug conjugates as a new targeting platform. Cancer Res; 74(24); 7510–20. 2014 AACR.