title: The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells.
abstract: B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-alpha, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA. mohammad.luqman@novartis.com
authors.forename: Mohammad
authors.initials: M
authors.lastname: Luqman
authors.forename: Sha
authors.initials: S
authors.lastname: Klabunde
authors.forename: Karen
authors.initials: K
authors.lastname: Lin
authors.forename: Georgios V
authors.initials: GV
authors.lastname: Georgakis
authors.forename: Anu
authors.initials: A
authors.lastname: Cherukuri
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.forename: Cheryl
authors.initials: C
authors.lastname: Goldbeck
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xu
authors.forename: Edward E
authors.initials: EE
authors.lastname: Kadel
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Sharon Lea
authors.initials: SL
authors.lastname: Aukerman
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Natasha
authors.initials: N
authors.lastname: Aziz
authors.forename: Wen-Kai
authors.initials: WK
authors.lastname: Weng
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D019013:CD40 Antigens / Q000276:immunology*; D005260:Female; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D000069283:Rituximab