title: Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical.
abstract: CD37 is a lineage-specific B-cell antigen that to date has been neglected as an attractive therapeutic target. To exploit this, novel CD37-specific small modular immunopharmaceuticals (CD37-SMIP) that include variable regions linked to modified human IgG(1) hinge, CH(2), and CH(3) domains were designed. The lead CD37-SMIP molecule induces potent apoptosis in the presence of a cross-linker, and antibody-dependent cellular cytotoxicity against B-cell leukemia/lymphoma cell lines and primary chronic lymphocytic leukemia (CLL) cells superior to therapeutic antibodies used in these diseases. The CD37-SMIP-dependent ADCC function in vitro was mediated by natural killer (NK) cells but not naive or activated monocytes. Significant in vivo therapeutic efficacy was demonstrated in a SCID mouse xenograft leukemia/lymphoma model. Depletion of NK cells in this mouse model resulted in diminished efficacy further supported the in vivo importance of NK cells in SMIP therapy. These findings provide strong justification for CD37 as a therapeutic target and introduce small modular immunopharmaceuticals as a novel class of targeted therapies for B-cell malignancies.
authors: Division of Hematology-Oncology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors: Xiaobin
authors: X
authors: Zhao
authors: Rosa
authors: R
authors: Lapalombella
authors: Trupti
authors: T
authors: Joshi
authors: Carolyn
authors: C
authors: Cheney
authors: Aruna
authors: A
authors: Gowda
authors: Martha S
authors: MS
authors: Hayden-Ledbetter
authors: Peter R
authors: PR
authors: Baum
authors: Thomas S
authors: TS
authors: Lin
authors: David
authors: D
authors: Jarjoura
authors: Amy
authors: A
authors: Lehman
authors: Donna
authors: D
authors: Kussewitt
authors: Robert J
authors: RJ
authors: Lee
authors: Michael A
authors: MA
authors: Caligiuri
authors: Susheela
authors: S
authors: Tridandapani
authors: Natarajan
authors: N
authors: Muthusamy
authors: John C
authors: JC
authors: Byrd
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018941:Antigens, CD19 / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D059470:Tetraspanins; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D059470:Tetraspanins; D020169:Caspases