title: A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies.
abstract: The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human Fcγ receptors. The resulting mAb 37.1 showed high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. Furthermore, the Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. In all assays, mAb 37.1 was superior to rituximab in terms of potency and maximal cell lysis. A single dose of mAb CD37.1 administered to human CD37-transgenic mice resulted in a reversible, dose-dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC activities very similar to those of mAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys. In conclusion, the remarkable preclinical pharmacodynamic and antitumor effects of mAb 37.1 warrant clinical development for B-cell malignancies.
authors.affiliation: Department of NBE Discovery, Boehringer Ingelheim RCV, Vienna, Austria. karl-heinz.heider@boehringer-ingelheim.com
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Heider
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kiefer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Matthias
authors.initials: M
authors.lastname: Volden
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Elinborg
authors.initials: E
authors.lastname: Ostermann
authors.forename: Anke
authors.initials: A
authors.lastname: Baum
authors.forename: Herbert
authors.initials: H
authors.lastname: Lamche
authors.forename: Zaruhi
authors.initials: Z
authors.lastname: Küpcü
authors.forename: Alexander
authors.initials: A
authors.lastname: Jacobi
authors.forename: Steffen
authors.initials: S
authors.lastname: Müller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hirt
authors.forename: Günther R
authors.initials: GR
authors.lastname: Adolf
authors.forename: Eric
authors.initials: E
authors.lastname: Borges
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab; D059470:Tetraspanins / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C059071:CD37 protein, human; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; D059470:Tetraspanins; D000069283:Rituximab