美罗华
CD20
药理学
单克隆抗体
淋巴瘤
抗体
B细胞
医学
化学
癌症研究
免疫学
作者
Che‐Leung Law,Charles G. Cerveny,Kristine A. Gordon,Kerry Klussman,Bruce Mixan,Dana F. Chace,Damon L. Meyer,Svetlana O. Doronina,Clay B. Siegall,Joseph A. Francisco,Peter D. Senter,Alan F. Wahl
标识
DOI:10.1158/1078-0432.ccr-04-1028
摘要
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 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.
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