Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin.
In 1997, a chimeric anti-CD20 monoclonal antibody (mAb) (Rituxan) was approved for the treatment of low-grade/follicular B-cell lymphoma. Rituxan has a long half-life and low immunogenicity, and it mediates effector function. Rituxan induces apoptosis in some tumor cell lines in vitro. Previous studies with mAbs that react with neoplastic B cells have demonstrated that homodimers of immunoglobulin G ([IgG](2)) often inhibit cell growth more effectively than their monomeric (IgG)(1) counterparts. In this study, the ability of IgG or F(ab')(2) homodimers vs monomers of Rituxan were compared for their ability to inhibit the growth of several different B-lymphoma cell lines in vitro. It was found that homodimers of Rituxan had superior antigrowth activity in vitro and that F(ab')(2) homodimers were the most active. Homodimers, but not monomers, of Rituxan induced both apoptosis and necrosis of several B-cell lymphoma lines in vitro; the inhibition of cell growth was not dependent upon the presence of Fc receptors or upon 10-fold or greater differences in the density of CD20 on the target cells. Rituxan homodimers, compared with monomers, also rendered drug-resistant CD20(+) B-lymphoma cells more sensitive to chemotherapeutic agents and synergized with an anti-CD22 immunotoxin in vitro.
Ghetie
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MA
Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, TX 75390-8576, USA.
Bright
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H
Vitetta
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D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015815:Cell Adhesion Molecules; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D037102:Lectins; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011961:Receptors, Fc / Q000378:metabolism; D012276:Ricin / Q000494:pharmacology; D000069283:Rituximab; D051918:Sialic Acid Binding Ig-like Lectin 2; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; D015815:Cell Adhesion Molecules; D000922:Immunotoxins; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D051918:Sialic Acid Binding Ig-like Lectin 2; D000069283:Rituximab; D012276:Ricin