| In vitro and in vivo characterization of MDX-1401 for therapy of malignant lymphoma. | |
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MedLine Citation:
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PMID: 19401346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody. EXPERIMENTAL DESIGN: Assays measuring antibody binding to CD30-expressing cells and FcgammaRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model. RESULTS: The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcgammaRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC(50)) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcgammaRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30(+) lymphoma xenografts. CONCLUSIONS: The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma. |
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Authors:
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Pina M Cardarelli; Maria-Cristina Moldovan-Loomis; Ben Preston; Amelia Black; David Passmore; Tseng-Hui Chen; Sharline Chen; Jie Liu; Michelle R Kuhne; Mohan Srinivasan; Albert Assad; Alison Witte; Robert F Graziano; David J King |
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Publication Detail:
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Type: Journal Article Date: 2009-04-28 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 15 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-19 Completed Date: 2009-08-03 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3376-83 Citation Subset: IM |
Affiliation:
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Department of Cell Biology and Pharmacology, Medarex, Sunnyvale, CA 94089, USA. pcardarelli@medarex.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / chemistry, immunology, pharmacology* Antibody Affinity / drug effects, immunology Antibody-Dependent Cell Cytotoxicity / drug effects Antigens, CD30 / immunology Binding Sites, Antibody / immunology CHO Cells Carbohydrates / chemistry, immunology Cell Line, Tumor Cricetinae Cricetulus Dose-Response Relationship, Drug Fucose / chemistry, immunology Humans Lymphoma / drug therapy*, immunology, pathology Male Mice Mice, SCID Receptors, IgG / chemistry, immunology Xenograft Model Antitumor Assays* |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antigens, CD30; 0/Binding Sites, Antibody; 0/Carbohydrates; 0/FCGR3A protein, human; 0/MDX-1401; 0/Receptors, IgG; 3713-31-3/Fucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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