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Harnessing the fc? 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 Fc?R is overexpressed on malignant B cells in CLL and mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fc?). To exploit this internalization and trafficking pathway for targeted drug delivery, we engineered an IgM-derived protein scaffold (Fc?) and linked it with the cytotoxic agent monomethylauristatin F. This Fc?-drug conjugate was selectively toxic for Fc?R-expressing cell lines in vitro and for CLL cells but not autologous normal T cells ex vivo. Notably, the cytotoxic activity of the Fc?-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 Fc?-drug conjugate in immunodeficient NOD/SCID/IL-2R?(null) (NSG) mice engrafted with peripheral blood cells from patients with leukemia. Three intravenous injections of the Fc?-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 Fc?R. Fc?R-targeted drug delivery showed potent and specific therapeutic activity in CLL, thus providing proof of concept for Fc?R as a valuable therapeutic target in CLL and for IgM-based antibody-drug conjugates as a new targeting platform.

SUBMITTER: Vire B

PROVIDER: S-EPMC4268434 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Harnessing the fcμ receptor for potent and selective cytotoxic therapy of chronic lymphocytic leukemia.

Vire Bérengère B Skarzynski Martin M Thomas Joshua D JD Nelson Christopher G CG David Alexandre A Aue Georg G Burke Terrence R TR Rader Christoph C Wiestner Adrian A

Cancer research 20141024 24

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-dru ...[more]

PMID: 25344228

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Project description:Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Dataset Information

Harnessing the fc? receptor for potent and selective cytotoxic therapy of chronic lymphocytic leukemia.

Publications

Harnessing the fcμ receptor for potent and selective cytotoxic therapy of chronic lymphocytic leukemia.

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