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Prepublished online as a Blood First Edition Paper on April 24, 2003May 8, 2003; DOI 10.1182/blood-2003-01-0039. This Article Full Text (PDF) All Versions of this Article: 2003-01-0039v1 2003-01-0039v2 102/4/1458    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Francisco, J. A Articles by Wahl, A. F Search for Related Content PubMed PubMed Citation Articles by Francisco, J. A Articles by Wahl, A. F Social Bookmarking                   What's this? Submitted January 7, 2003 Accepted April 3, 2003 cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity Joseph A Francisco, Charles G Cerveny, Damon L Meyer, Bruce J Mixan, Kerry Klussman, Dana F Chace, Starr X Rejniak, Kristine A Gordon, Ronald DeBlanc, Brian E Toki, Che-Leung Law, Svetlana O Doronina, Clay B Siegall, Peter D Senter, and Alan F Wahl* Seattle Genetics Inc., Bothell, WA, USA * Corresponding author; email: awahl{at}seagen.com. The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30-positive cell lines in vitro and has pronounced antitumor activity in SCID mouse xenograft models of Hodgkin's disease. We have significantly enhanced these activities by conjugating to cAC10 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC10-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC10 via a valine-citrulline peptide linker. The drug is stably attached to the antibody, showing only a 2% release of MMAE following a 10 day incubation in human plasma, but is readily cleaved by lysosomal proteases following receptor-mediated internalization. Release of MMAE into the cytosol induces G2/M phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC10-vcMMAE is highly potent and selective against CD30-positive tumor lines (IC50 <10 ng/ml) but was >300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin's disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg of cAC10-vcMMAE showed no signs of toxicity. These data indicate that cAC10-vcMMAE may be a highly effective and selective therapy for the treatment of CD30-positive neoplasias. 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