title: Harnessing the fcμ receptor for potent and selective cytotoxic therapy of chronic lymphocytic leukemia.
abstract: 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 NOD/SCID/IL-2Rγ(null) (NSG) mice engrafted with peripheral blood cells from patients with leukemia. 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 coengrafted 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.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Vire
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Skarzynski
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Thomas
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nelson
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: David
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Aue
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.|Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D016503:Drug Delivery Systems; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D036102:Peripheral Blood Stem Cell Transplantation; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007075:Immunoglobulin M; D011961:Receptors, Fc; C035311:immunoglobulin M receptor