| The autophilic anti-CD20 antibody DXL625 displays enhanced potency due to lipid raft-dependent induction of apoptosis. | |
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MedLine Citation:
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PMID: 20216307 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Despite widespread use of anti-CD20 antibodies as therapeutic agents for oncologic and autoimmune indications, precise descriptions of killing mechanisms remain incomplete. Complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity are indicated as modes of target cell depletion; however, the importance of apoptosis induction is controversial. Studies showing that the therapeutic anti-CD20 antibody rituximab (Rituxan) mediates apoptosis of tumor cell targets in vitro after cross-linking by anti-Fc reagents suggest that enhancement strategies applied to Fc-independent activities for anti-CD20 antibodies could improve therapeutic efficacy. An anti-CD20 antibody designated DXL625, with autophilic properties such as increased binding avidity, is shown here to independently induce caspase-mediated apoptosis of an established B-cell lymphoma line in vitro. Depletion of membrane cholesterol or chelation of extracellular calcium abrogated the pro-apoptotic activity of DXL625, indicating that intact lipid rafts and calcium are required for this activity. The Fc-mediated complement-dependent and antibody-dependent cellular killing mechanisms are maintained by DXL625 despite conjugation of the parental Rituxan antibody to the autophilic DXL peptide sequence. This study shows a strategy for improving anti-CD20 immunotherapy by endowing therapeutic antibodies with self-interacting properties. |
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Authors:
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Marc G Bingaman; Gargi D Basu; Tiana C Golding; Samuel K Chong; Andrew J Lassen; Thomas J Kindt; Christopher A Lipinski |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Anti-cancer drugs Volume: 21 ISSN: 1473-5741 ISO Abbreviation: Anticancer Drugs Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-04-14 Completed Date: 2010-05-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9100823 Medline TA: Anticancer Drugs Country: England |
Other Details:
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Languages: eng Pagination: 532-42 Citation Subset: IM |
Affiliation:
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InNexus Biotechnology Inc, Scottsdale, Arizona, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibodies, Monoclonal
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pharmacology* Antigens, CD20 / immunology Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Calcium / metabolism Cell Line, Tumor Cell Proliferation / drug effects Humans Membrane Microdomains / drug effects* |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antigens, CD20; 0/Antineoplastic Agents; 0/rituximab; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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