Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab

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BlankBlood, 15 October 2006, Vol. 108, No. 8, pp. 2736-2744.

Prepublished online as a Blood First Edition Paper on June 15, 2006; DOI

10.1182/blood-2006-04-017921.

Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks

effector cell functions but retains direct antilymphoma activity and increases

the potency of rituximab

Rhona Stein, Zhengxing Qu, Chen, Solis, Hans J. Hansen, and M.

Goldenberg

From the Garden State Cancer Center, Center for Molecular Medicine and

Immunology, Belleville, NJ; and Immunomedics, Plains, NJ.

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, hL243gamma 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 immunologic systems in the patient and effector

mechanism-related toxicity. In vitro studies show that replacing the Fc region

of hL243gamma 1, 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, antiproliferative capacity (in vitro

and in vivo), and the ability to induce apoptosis concurrent with activation of

the AKT survival pathway. Growth inhibition was evaluated compared with and in

combination with the anti-CD20 mAb rituximab, with the combination being more

effective than rituximab alone in inhibiting proliferation. Thus, hL243gamma 4P

is indistinguishable from hL243gamma 1 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 hL243gamma 4P

with rituximab offers the prospect for improved patient outcome.