The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and nov...

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Main Authors:	Beckwith, Kyle A., Frissora, Frank W., Stefanovski, Matthew R., Towns, William H., Cheney, Carolyn, Mo, Xiaokui, Deckert, Jutta, Croce, Carlo M., Flynn, Joseph M., Andritsos, Leslie A., Jones, Jeffrey A., Maddocks, Kami J., Lozanski, Gerard, Byrd, John C., Muthusamy, Natarajan
Format:	Online
Language:	English
Published:	2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090271/

id	pubmed-4090271
recordtype	oai_dc
spelling	pubmed-40902712015-01-01 The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model Beckwith, Kyle A. Frissora, Frank W. Stefanovski, Matthew R. Towns, William H. Cheney, Carolyn Mo, Xiaokui Deckert, Jutta Croce, Carlo M. Flynn, Joseph M. Andritsos, Leslie A. Jones, Jeffrey A. Maddocks, Kami J. Lozanski, Gerard Byrd, John C. Muthusamy, Natarajan Article Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. While several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood, and promotes killing by macrophages and NK cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies. 2014-01-21 2014-07 /pmc/articles/PMC4090271/ /pubmed/24445867 http://dx.doi.org/10.1038/leu.2014.32 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Beckwith, Kyle A. Frissora, Frank W. Stefanovski, Matthew R. Towns, William H. Cheney, Carolyn Mo, Xiaokui Deckert, Jutta Croce, Carlo M. Flynn, Joseph M. Andritsos, Leslie A. Jones, Jeffrey A. Maddocks, Kami J. Lozanski, Gerard Byrd, John C. Muthusamy, Natarajan
spellingShingle	Beckwith, Kyle A. Frissora, Frank W. Stefanovski, Matthew R. Towns, William H. Cheney, Carolyn Mo, Xiaokui Deckert, Jutta Croce, Carlo M. Flynn, Joseph M. Andritsos, Leslie A. Jones, Jeffrey A. Maddocks, Kami J. Lozanski, Gerard Byrd, John C. Muthusamy, Natarajan The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
author_facet	Beckwith, Kyle A. Frissora, Frank W. Stefanovski, Matthew R. Towns, William H. Cheney, Carolyn Mo, Xiaokui Deckert, Jutta Croce, Carlo M. Flynn, Joseph M. Andritsos, Leslie A. Jones, Jeffrey A. Maddocks, Kami J. Lozanski, Gerard Byrd, John C. Muthusamy, Natarajan
author_sort	Beckwith, Kyle A.
title	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
title_short	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
title_full	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
title_fullStr	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
title_full_unstemmed	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model
title_sort	cd37-targeted antibody-drug conjugate imgn529 is highly active against human cll and in a novel cd37 transgenic murine leukemia model
description	Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. While several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood, and promotes killing by macrophages and NK cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090271/
_version_	1613110917782831104

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

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