The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells.
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.
Luqman
Mohammad
M
Disease Area Oncology, Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA. mohammad.luqman@novartis.com
Klabunde
Sha
S
Lin
Karen
K
Georgakis
Georgios V
GV
Cherukuri
Anu
A
Holash
Jocelyn
J
Goldbeck
Cheryl
C
Xu
Xiaomei
X
Kadel
Edward E
EE
Lee
Sang Hoon
SH
Aukerman
Sharon Lea
SL
Jallal
Bahija
B
Aziz
Natasha
N
Weng
Wen-Kai
WK
Wierda
William
W
O'Brien
Susan
S
Younes
Anas
A
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
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D000069283:Rituximab