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 novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although 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 natural killer 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.
1] Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA [2] Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
K A
KA
Beckwith
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
F W
FW
Frissora
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
M R
MR
Stefanovski
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
W H
WH
Towns
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
C
C
Cheney
Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
X
X
Mo
ImmunoGen, Inc., Waltham, MA, USA.
J
J
Deckert
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA.
C M
CM
Croce
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
J M
JM
Flynn
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
L A
LA
Andritsos
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
J A
JA
Jones
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
K J
KJ
Maddocks
Department of Pathology, The Ohio State University, Columbus, OH, USA.
G
G
Lozanski
1] Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA [2] Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
J C
JC
Byrd
1] Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA [2] Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA.
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N
Muthusamy
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000235:genetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D059470:Tetraspanins / Q000037:antagonists & inhibitors* / Q000235:genetics*
D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C059071:CD37 protein, human; D059470:Tetraspanins; C585625:naratuximab emtansine