SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on May 8, 2003April 24, 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-W. Lee, H. D. Han, M. M. K. Shahzad, S. W. Kim, L. S. Mangala, A. M. Nick, C. Lu, R. R. Langley, R. Schmandt, H.-S. Kim, et al. EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma J Natl Cancer Inst, September 2, 2009; 101(17): 1193 - 1205. [Abstract] [Full Text] [PDF] E. Oflazoglu, I. J. Stone, K. Gordon, C. G. Wood, E. A. Repasky, I. S. Grewal, C.-L. Law, and H.-P. Gerber Potent Anticarcinoma Activity of the Humanized Anti-CD70 Antibody h1F6 Conjugated to the Tubulin Inhibitor Auristatin via an Uncleavable Linker Clin. Cancer Res., October 1, 2008; 14(19): 6171 - 6180. [Abstract] [Full Text] [PDF] K. M. Kim, C. F. McDonagh, L. Westendorf, L. L. Brown, D. Sussman, T. Feist, R. Lyon, S. C. Alley, N. M. Okeley, X. Zhang, et al. Anti-CD30 diabody-drug conjugates with potent antitumor activity Mol. Cancer Ther., August 1, 2008; 7(8): 2486 - 2497. [Abstract] [Full Text] [PDF] 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. Sanderson, K. A. Gordon, J. Andreyka, C. G. Cerveny, C. Yu, T. S. Lewis, D. L. Meyer, R. F. Zabinski, S. O. Doronina, et al. Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-specific Cytotoxicity by Peptide-linked Anti-CD30-Auristatin Conjugates J. Biol. Chem., April 14, 2006; 281(15): 10540 - 10547. [Abstract] [Full Text] [PDF] C.-L. Law, K. A. Gordon, B. E. Toki, A. K. Yamane, M. A. Hering, C. G. Cerveny, J. M. Petroziello, M. C. Ryan, L. Smith, R. Simon, et al. Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates Cancer Res., February 15, 2006; 66(4): 2328 - 2337. [Abstract] [Full Text] [PDF] S. Nagata, T. Ise, M. Onda, K. Nakamura, M. Ho, A. Raubitschek, and I. H. Pastan Cell membrane-specific epitopes on CD30: Potentially superior targets for immunotherapy PNAS, May 31, 2005; 102(22): 7946 - 7951. [Abstract] [Full Text] [PDF] R. J. Sanderson, M. A. Hering, S. F. James, M. 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]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020