Humanized IgG1 M195 (HuG1-M195), a complementarity determining region-grafted recombinant monoclonal antibody, is reactive with CD33, an antigen expressed on myelogenous leukemia cells. M195 is in use in trials for the therapy of acute myelogenous leukemia. Since biological activity of IgG may depend, in part, on multimeric Fab and Fc clustering, homodimeric forms of HuG1-M195 were constructed by introducing a mutation in the gamma 1 chain CH3 region gene to change a serine to a cysteine, allowing interchain disulfide bond formation at the COOH terminal of the IgG. Despite similar avidity, the homodimeric IgG showed a dramatic improvement in the ability to internalize and retain radioisotope in target leukemia cells. Moreover, homodimers were 100-fold more potent at complement-mediated leukemia cell killing and antibody-dependent cellular cytotoxicity using human effectors. Therefore, genetically engineered multimeric constructs of IgG may have advantages relative to those forms that are found naturally.
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October 01 1992
Engineered humanized dimeric forms of IgG are more effective antibodies.
P C Caron,
P C Caron
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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W Laird,
W Laird
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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M S Co,
M S Co
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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N M Avdalovic,
N M Avdalovic
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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C Queen,
C Queen
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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D A Scheinberg
D A Scheinberg
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
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P C Caron
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
W Laird
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
M S Co
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
N M Avdalovic
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
C Queen
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
D A Scheinberg
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1992) 176 (4): 1191–1195.
Citation
P C Caron, W Laird, M S Co, N M Avdalovic, C Queen, D A Scheinberg; Engineered humanized dimeric forms of IgG are more effective antibodies.. J Exp Med 1 October 1992; 176 (4): 1191–1195. doi: https://doi.org/10.1084/jem.176.4.1191
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