Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates.

Abstract

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 IC(50) values ranging from 50 ng/mL to 1 microg/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 G(2)-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 (IC(50) > 50 microg/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.

• Authors: Che-Leung Law, Charles G Cerveny, Kristine A Gordon, Kerry Klussman, Bruce J Mixan, Dana F Chace, Damon L Meyer, Svetlana O Doronina, Clay B Siegall, Joseph A Francisco, Peter D Senter, Alan F Wahl
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 23 Pg. 7842-51 (Dec 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15585616 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Antineoplastic Agents
• Oligopeptides
• Rituximab
• Doxorubicin
• monomethyl auristatin E

Topics

• Animals
• Antibodies, Monoclonal (metabolism, pharmacology)
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20 (immunology)
• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Doxorubicin (pharmacology)
• Drug Delivery Systems
• G2 Phase (drug effects)
• Humans
• Lymphoma, B-Cell (drug therapy, immunology)
• Mice
• Oligopeptides (adverse effects, chemistry, metabolism, pharmacology)
• Rituximab
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays