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Mol Cancer Ther. 2015 Jul;14(7):1650-60. doi: 10.1158/1535-7163.MCT-15-0067. Epub 2015 May 1.

AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML.

Author information

1
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California. dpereira@agensys.com.
2
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
3
Princess Margaret Cancer Centre, University Health Network, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
4
Division of Hematology-Oncology, University of California, San Diego, Moores Cancer Center, La Jolla, California.

Abstract

CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody-drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34(+)CD38(-) leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML.

PMID:
25934707
PMCID:
PMC4557793
DOI:
10.1158/1535-7163.MCT-15-0067
[Indexed for MEDLINE]
Free PMC Article

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