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HER2-Affitoxin: A Potent Therapeutic Agent for the Treatment of HER2-Overexpressing Tumors

  1. Author:
    Zielinski, R.
    Lyakhov, I.
    Hassan, M.
    Kuban, M.
    Shafer-Weaver, K.
    Gandjbakhche, A.
    Capala, J.

  2. Author Address

    [Capala, J] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA [Hassan, M; Gandjbakhche, A] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA [Zielinski, R] John Paul II Catholic Univ Lublin, Dept Mol Biol, Lublin, Poland [Lyakhov, I] NCI Frederick, Prot Chem Lab, Frederick, MD USA [Shafer-Weaver, K] NCI Frederick, Lab Cell Mediated Immun, SAIC Frederick Inc, Frederick, MD USA;Capala, J (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room B3B37D, Bethesda, MD 20892 USA;capalaj@mail.nih.gov
    1. Year: 2011
    2. Date: Aug
  2. Journal: Clinical Cancer Research
    1. 17
    2. 15
    3. Pages: 5071-5081
  4. Type of Article: Article
  5. ISSN: 1078-0432
  1. Abstract:

    Purpose: Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific Affibody and modified Pseudomonas aeruginosa exotoxin A (PE 38), which, after binding to HER2, is internalized and delivered to the cytosol of the tumor cell, where it blocks protein synthesis by ADP ribosylation of eEF-2. Experimental Design: The effect of the Affitoxin on cell viability was assessed using CellTiter-Glo (Promega). To assess HER2-specific efficacy, athymic nude mice bearing BT-474 breast cancer, SK-OV-3 ovarian cancer, and NCI-N87 gastric carcinoma xenografts were treated with the Affitoxin (HER2- or Tag-specific), which was injected every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays. Results: In vitro experiments proved that HER2-Affitoxin is a potent agent that eliminates HER2-overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation (T(1/2) < 10 minutes) and was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose. Conclusions: Our findings showed that HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies. Clin Cancer Res; 17(15); 5071-81. (C)2011 AACR.

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External Sources

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  2. DOI: 10.1158/1078-0432.ccr-10-2887
  3. View record in Web of Science®
  4. WOS: 000293335800019

Library Notes

  1. Fiscal Year: FY2010-2011
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