Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates
| Autor: | Svetlana O. Doronina, Bruce Mixan, Dana F. Chace, Che-Leung Law, Clay B. Siegall, Peter D. Senter, Joseph A. Francisco, Kristine A. Gordon, Alan F. Wahl, Charles G. Cerveny, Damon L. Meyer, Kerry Klussman |
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| Rok vydání: | 2004 |
| Předmět: |
G2 Phase
Cancer Research Lymphoma B-Cell medicine.drug_class Antineoplastic Agents Apoptosis Pharmacology Monoclonal antibody Antibodies Monoclonal Murine-Derived Mice chemistry.chemical_compound Drug Delivery Systems immune system diseases hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans Doxorubicin Cytotoxicity CD20 biology business.industry Antibodies Monoclonal Antigens CD20 Xenograft Model Antitumor Assays Virology Oncology Monomethyl auristatin E chemistry Monoclonal Drug delivery biology.protein Rituximab business Oligopeptides Cell Division medicine.drug |
| Zdroj: | Clinical Cancer Research. 10:7842-7851 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-04-1028 |
| Popis: | The anti-CD20 antibody rituximab is useful in the treatment of certain B-cell malignancies, most notably non-Hodgkin’s lymphoma. Its efficacy has been increased when used in combination with chemotherapy, yet anti-CD20 monoclonal antibodies (mAbs) directly conjugated with drugs such as doxorubicin (Dox) have failed to deliver drug or to demonstrate antitumor activity. We have produced anti-CD20 antibody-drug conjugates that possess potent antitumor activity by using the anti-mitotic agent, monomethyl auristatin E (MMAE), linked via the lysosomally cleavable dipeptide, valine-citrulline (vc). Two anti-CD20 conjugates, rituximab-vcMMAE and 1F5-vcMMAE, were selectively cytotoxic against CD20+ B-lymphoma cell lines, with IC50 values ranging from 50 ng/mL to 1 μg/mL. Unlike rituximab, which showed diffuse surface localization, rituximab-vcMMAE capped and was internalized within 4 hours after binding to CD20+ B cells. Internalization of rituximab-vcMMAE was followed by rapid G2-M phase arrest and onset of apoptosis. Anti-CD20 antibody-drug conjugates prepared with Dox were internalized and localized as with rituximab-vcMMAE, yet these were not effective for drug delivery (IC50 > 50 μg/mL). Consistent with in vitro activity, rituximab-vcMMAE showed antitumor efficacy in xenograft models of CD20-positive lymphoma at doses where rituximab or rituximab-Dox conjugates were ineffective. These data indicate that anti-CD20–based antibody-drug conjugates are effective antitumor agents when prepared with a stable, enzyme-cleavable peptide linkage to highly potent cytotoxic agents such as MMAE. |
| Databáze: | OpenAIRE |
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