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Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Antitumor Activity against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of Response

  1. Author:
    Kang, Z. G.
    Chen, J. J.
    Yu, Y. K.
    Li, B.
    Sun, S. Y.
    Zhang, B. L.
    Cao, L.
  2. Author Address

    [Kang, ZG; Yu, YK; Cao, L] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA [Chen, JJ; Zhang, BL] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA [Kang, ZG; Yu, YK] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21701 USA [Li, B; Sun, SY] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA [Li, B; Sun, SY] Winship Canc Inst, Atlanta, GA USA;Cao, L (reprint author), NCI, Genet Branch, Ctr Canc Res, 37 Convent Dr,MSC 4265,Bldg 37,Rm 6134, Bethesda, MD 20892 USA;caoli@mail.nih.gov
    1. Year: 2011
    2. Date: May
  1. Journal: Clinical Cancer Research
    1. 17
    2. 10
    3. Pages: 3181-3192
  2. Type of Article: Article
  3. ISSN: 1078-0432
  1. Abstract:

    Purpose: Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models. Experimental Design: A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab. Results: We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. Conclusion: Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. Clin Cancer Res; 17(10); 3181-92. (C) 2011 AACR.

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External Sources

  1. DOI: 10.1158/1078-0432.ccr-10-2874
  2. WOS: 000290610000013

Library Notes

  1. Fiscal Year: FY2010-2011
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