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

Copyright © 2014, American Association for Cancer Research.