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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1807-1814. Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-07-2466. This Article Full Text (PDF) All Versions of this Article: 2003-07-2466v1 103/5/1807    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 DiJoseph, J. F Articles by Damle, N. K Search for Related Content PubMed PubMed Citation Articles by DiJoseph, J. F Articles by Damle, N. K Social Bookmarking                   What's this? Submitted July 22, 2003 Accepted October 1, 2003 Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B lymphoid malignancies John F DiJoseph, Douglas C Armellino, Erwin R Boghaert, Kiran Khandke, Maureen M Dougher, Latha Sridharan, Arthur Kunz, Philip R Hamann, Boris Gorovits, Chadrasekhar Udata, Justin K Moran, Andrew G Popplewell, Sue Stephens, Philip Frost, and Nitin K Damle* Department of Oncology Discovery, Wyeth Research, Pearl River, NY, USA Department of Chemical Sciences, Wyeth Research, Pearl River, NY, USA Department of Drug Metabolism, Wyeth Research, Pearl River, NY, USA Department of Bioprocess Development, Wyeth Research, Pearl River, NY, USA Department of Research & Development, Celltech, Slough, Berkshire, United Kingdom * Corresponding author; email: damlen{at}wyeth.com. Antibody-targeted chemotherapy with gemtuzumab ozogamicin (Mylotarg or CMA-676, a CD33-targeted immunoconjugate of N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH, a potent DNA-binding cytotoxic anti-tumor antibiotic) is a clinically validated therapeutic option for AML patients. Here, we describe the preclinical profile of another immunoconjugate of CalichDMH, CMC-544, targeted to CD22 expressed by B lymphoid malignancies. CMC-544 is comprised of a humanized IgG4 anti-CD22 mAb, G5/44, covalently linked to CalichDMH via an acid-labile AcBut linker. Both CMC-544 and unconjugated G5/44 bound human CD22 with subnanomolar affinity. CMC-544, but not unconjugated G5/44, exerted potent cytotoxicity against CD22+ B-cell lymphoma (BCL) cell lines (IC50: 6 to 600 pM CalichDMH). CMC-544 caused a potent inhibition of growth of small but established BCL xenografts leading to cures (therapeutic index >10). CMC-544 prevented the establishment of BCL xenografts and also caused regression of large BCLs (>1.5 g of tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44 and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong anti-tumor profile of CMC-544 supports its clinical evaluation as a treatment option for B lymphoid malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Martin, R. R. Furman, M. Coleman, and J. P. Leonard Phase I to III Trials of Anti B Cell Therapy in Non Hodgkin's Lymphoma Clin. Cancer Res., September 15, 2007; 13(18): 5636s - 5642s. [Abstract] [Full Text] [PDF] A. G. Polson, S.-F. Yu, K. Elkins, B. Zheng, S. Clark, G. S. Ingle, D. S. Slaga, L. Giere, C. Du, C. Tan, et al. 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Maloney Immunotherapy for Non-Hodgkin's Lymphoma: Monoclonal Antibodies and Vaccines J. Clin. Oncol., September 10, 2005; 23(26): 6421 - 6428. [Abstract] [Full Text] [PDF] J. F. DiJoseph, M. E. Goad, M. M. Dougher, E. R. Boghaert, A. Kunz, P. R. Hamann, and N. K. Damle Potent and Specific Antitumor Efficacy of CMC-544, a CD22-Targeted Immunoconjugate of Calicheamicin, against Systemically Disseminated B-Cell Lymphoma Clin. Cancer Res., December 15, 2004; 10(24): 8620 - 8629. [Abstract] [Full Text] [PDF] E. R. Boghaert, L. Sridharan, D. C. Armellino, K. M. Khandke, J. F. DiJoseph, A. Kunz, M. M. Dougher, F. Jiang, L. B. Kalyandrug, P. R. Hamann, et al. Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl {gamma} Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts Clin. Cancer Res., July 1, 2004; 10(13): 4538 - 4549. [Abstract] [Full Text] [PDF]

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