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.
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.
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California. dpereira@agensys.com.
Daniel S
DS
Pereira
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Claudia I
CI
Guevara
Princess Margaret Cancer Centre, University Health Network, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Liqing
L
Jin
Princess Margaret Cancer Centre, University Health Network, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Nathan
N
Mbong
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Alla
A
Verlinsky
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Ssucheng J
SJ
Hsu
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Hector
H
Aviña
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Sher
S
Karki
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Joseph D
JD
Abad
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Peng
P
Yang
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Sung-Ju
SJ
Moon
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Faisal
F
Malik
Division of Hematology-Oncology, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Michael Y
MY
Choi
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Zili
Z
An
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Kendall
K
Morrison
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Pia M
PM
Challita-Eid
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Fernando
F
Doñate
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
Ingrid B J
IB
Joseph
Division of Hematology-Oncology, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Thomas J
TJ
Kipps
Princess Margaret Cancer Centre, University Health Network, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
John E
JE
Dick
Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.
David R
DR
Stover
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009842:Oligopeptides / Q000276:immunology / Q000378:metabolism; D059470:Tetraspanins / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C000607292:AGS67E; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D018796:Immunoconjugates; D009842:Oligopeptides; D059470:Tetraspanins; C495575:monomethyl auristatin E