title: Dual-targeting immunotherapy of lymphoma: potent cytotoxicity of anti-CD20/CD74 bispecific antibodies in mantle cell and other lymphomas.
abstract: We describe the use of novel bispecific hexavalent Abs (HexAbs) to enhance anticancer immunotherapy. Two bispecific HexAbs [IgG-(Fab)(4) constructed from veltuzumab (anti-CD20 IgG) and milatuzumab (anti-CD74 IgG)] show enhanced cytotoxicity in mantle cell lymphoma (MCL) and other lymphoma/leukemia cell lines, as well as patient tumor samples, without a crosslinking Ab, compared with their parental mAb counterparts, alone or in combination. The bispecific HexAbs have different properties from and are more potent than their parental mAbs in vitro. The juxtaposition of CD20 and CD74 on MCL cells by the HexAbs resulted in homotypic adhesion and triggered intracellular changes that include loss of mitochondrial transmembrane potential, production of reactive oxygen species, rapid and sustained phosphorylation of ERKs and JNK, down-regulation of pAkt and Bcl-xL, actin reorganization, and lysosomal membrane permeabilization, culminating in cell death. They also displayed different potencies in depleting lymphoma cells and normal B cells from whole blood ex vivo and significantly extended the survival of nude mice bearing MCL xenografts in a dose-dependent manner, thus indicating stability and antitumor activity in vivo. Such bispecific HexAbs may constitute a new class of therapeutic agents for improved cancer immunotherapy, as shown here for MCL and other CD20(+)/CD74(+) malignancies.
authors.affiliation: Immunomedics Inc, Morris Plains, NJ, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
mesh_terms: D008841:Actin Cytoskeleton / Q000276:immunology / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000276:immunology / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D003603:Cytotoxins; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; C045084:invariant chain; C540932:milatuzumab; C493846:veltuzumab