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Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2003-01-0039. This Article Full Text 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 Citation Map 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. Related Collections Immunobiology Neoplasia Apoptosis Cell Cycle Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2003, Vol. 102, No. 4, pp. 1458-1465 NEOPLASIA 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, Ron DeBlanc, Brian E. Toki, Che-Leung Law, Svetlana O. Doronina, Clay B. Siegall, Peter D. Senter, and Alan F. Wahl From Seattle Genetics, Bothell, WA. The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30+ cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin 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 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following 10-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G2/M-phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC10-vcMMAE was highly potent and selective against CD30+ tumor lines (IC50 less than 10 ng/mL) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg 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+ neoplasias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. F. McDonagh, E. Turcott, L. Westendorf, J. B. Webster, S. C. Alley, K. Kim, J. Andreyka, I. Stone, K. J. Hamblett, J. A. Francisco, et al. Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment Protein Eng. Des. Sel., July 1, 2006; 19(7): 299 - 307. [Abstract] [Full Text] [PDF] D. Ma, C. E. Hopf, A. D. Malewicz, G. P. Donovan, P. D. Senter, W. F. Goeckeler, P. J. Maddon, and W. C. Olson Potent Antitumor Activity of an Auristatin-Conjugated, Fully Human Monoclonal Antibody to Prostate-Specific Membrane Antigen Clin. Cancer Res., April 15, 2006; 12(8): 2591 - 2596. [Abstract] [Full Text] [PDF] M. S. K. Sutherland, R. J. 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M.C. Sun, S. O. Doronina, A. W. Siadak, P. D. Senter, and A. F. Wahl In vivo Drug-Linker Stability of an Anti-CD30 Dipeptide-Linked Auristatin Immunoconjugate Clin. Cancer Res., January 15, 2005; 11(2): 843 - 852. [Abstract] [Full Text] [PDF] N. L. Bartlett Therapies for Relapsed Hodgkin Lymphoma: Transplant and Non-Transplant Approaches Including Immunotherapy Hematology, January 1, 2005; 2005(1): 245 - 251. [Abstract] [Full Text] [PDF] C.-L. Law, C. G. Cerveny, K. A. Gordon, K. Klussman, B. J. Mixan, D. F. Chace, D. L. Meyer, S. O. Doronina, C. B. Siegall, J. A. Francisco, et al. Efficient Elimination of B-Lineage Lymphomas by Anti-CD20-Auristatin Conjugates Clin. Cancer Res., December 1, 2004; 10(23): 7842 - 7851. [Abstract] [Full Text] [PDF] K. J. Hamblett, P. D. Senter, D. F. Chace, M. M. C. Sun, J. Lenox, C. G. Cerveny, K. M. Kissler, S. X. Bernhardt, A. K. Kopcha, R. F. Zabinski, et al. Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate Clin. Cancer Res., October 15, 2004; 10(20): 7063 - 7070. [Abstract] [Full Text] [PDF] D. E.H. Afar, V. Bhaskar, E. Ibsen, D. Breinberg, S. M. Henshall, J. G. Kench, M. Drobnjak, R. Powers, M. Wong, F. Evangelista, et al. Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer Mol. Cancer Ther., August 1, 2004; 3(8): 921 - 932. [Abstract] [Full Text] [PDF]

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