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Efficient killing of CD22(+) tumor cells by a humanized diabody-RNase fusion protein

  1. Author:
    Krauss, J.
    Arndt, M. A. E.
    Vu, B. K.
    Newton, D. L.
    Seeber, S.
    Rybak, S. M.

  2. Author Address

    Univ Essen Gesamthsch, Dept Med Oncol & Canc Res, D-45122 Essen, Germany. Univ Essen Gesamthsch, Inst Immunol, D-45122 Essen, Germany. NCI, SAIC, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Frederick, MD 21702 USA Krauss, J, Univ Essen Gesamthsch, Dept Med Oncol & Canc Res, D-45122 Essen, Germany
    1. Year: 2005
    2. Date: JUN 3
  2. Journal: Biochemical and Biophysical Research Communications
    1. 331
    2. 2
    3. Pages: 595-602
  4. Type of Article: Article
  1. Abstract:

    We report on the generation of a dimeric immunoenzyme capable of simultaneously delivering two ribonuclease (RNase) effector domains on one molecule to CD22(+) tumor cells. As targeting moiety a diabody derived from the previously humanized scFv SGIII with grafted specificity of the murine anti-CD22 mAb RFB4 was constructed. Further engineering the interface of this construct (V(L)36(Leu→ Tyr)) resulted in a highly robust bivalent molecule that retained the same high affinity as the murine mAb RFB4 (K-D = 0.2 nM). A dimeric immunoenzyme comprising this diabody and Rana pipiens liver ribonuclease I (rapLRI) was generated, expressed as soluble protein in bacteria, and purified to homogeneity. The dimeric fusion protein killed several CD22(+) tumor cell lines with high efficacy (IC50 = 3-20 nM) and exhibited 9- to 48-fold stronger cytotoxicity than a monovalent rapLRI-scFv counterpart. Our results demonstrate that engineering of dimeric antibody ribonuclease fusion proteins can markedly enhance their biological efficacy. © 2005 Elsevier Inc. All rights reserved

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External Sources

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  2. DOI: 10.1016/j.bbrc.2005.03.215
  3. View record in Web of Science®
  4. WOS: 000228961000034

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