HCD122 Shows Activity Against CLL Cells

[Guest guest]

[This agent was formerly known as CHIR-12.12.]

Blood First Edition Paper, prepublished online May 22, 2008

Submitted April 12, 2007

Accepted March 4, 2008

The anti-leukemia activity of a human anti-CD40 antagonist antibody,

HCD122, on human chronic lymphocytic leukemia cells

Mohammad Luqman*, Sha Klabunde, Lin, Georgios V. Georgakis, Anu

Cherukuri, Jocelyn Holash, Cheryl Goldbeck, Xiaomei Xu, E.

Kadel III, Sang Hoon Lee, Sharon Lea Aukerman, Bahija Jallal, Natasha

Aziz, Wen-Kai Weng, Wierda, OBrien, and Anas Younes

Disease Area Oncology, Novartis Institutes for Biomedical Research,

Emeryville, CA, United States

Dept. of Leukemia, UT MD Cancer Center, Houston, TX, United

States

Department of Internal Medicine, Stanford University Medical Center,

Palo Alto, CA, United States

Lymphoma and Myeloma, UT MD Cancer Center, Houston, TX,

United States

* Corresponding author; email: mohammad.luqman@....

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.