Submitted April 19, 2006
Accepted May 31, 2006
Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct anti-lymphoma activity and increases the potency of rituximab
Rhona Stein*, Zhengxing Qu, Susan Chen, David Solis, Hans J Hansen, and David M Goldenberg
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA
Immunomedics, Inc., Morris Plains, NJ, USA
* Corresponding author; email: rstein{at}gscancer.org.
HLA-DR is under investigation as a target for monoclonal antibody (MAb) therapy of malignancies. Here we describe a humanized IgG4 form of the anti-HLA-DR MAb L243, hL243
4P (IMMU-114), generated to provide an agent with selectivity toward neoplastic cells that can kill without complement-dependent cytotoxicity (CDC) or antibody-dependent cellular-cytotoxicity (ADCC), so as to reduce reliance on intact immunological systems in the patient and effector mechanism-related toxicity. In vitro studies show that replacing the Fc region of hL2431, a humanized IgG1 anti-HLA-DR MAb, with the IgG4 isotype abrogates the effector cell functions of the antibody (ADCC and CDC), while retaining its antigen-binding properties, anti-proliferative capacity (in vitro and in vivo), and the ability to induce apoptosis concurrent with activation of the AKT survival pathway. Growth inhibition was evaluated in comparison to and in combination with the anti-CD20 MAb rituximab, with the combination being more effective than rituximab alone in inhibiting proliferation. Thus, hL2434P is indistinguishable from hL2431 and the parental murine MAb in assays dependent on antigen recognition. The abrogation of ADCC and CDC, which are believed to play a major role in side effects of MAb therapy, may make this antibody an attractive clinical agent. In addition, combination of hL2434P with rituximab offers the prospect for improved patient outcome.
