gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

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

Meeting Abstract

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  • corresponding author presenting/speaker Jürgen Krauss - Universitätsklinikum , Essen, Deutschland
  • Michaela A.E. Arndt - Universitätsklinikum , Essen
  • Bang K. Vu - National Cancer Institute at Frederick, Frederick, USA
  • Andrew C.R. Martin - University College London, London, UK
  • Huaitian Liu - National Cancer Institute at Frederick, Frederick, USA
  • Dianne L. Newton - National Cancer Institute at Frederick, Frederick, USA
  • Siegfried Seeber - Universitätsklinikum , Essen
  • Susanna M. Rybak - National Cancer Institute at Frederick, Frederick, USA
  • Juergen Krauss - Universitätsklinikum , Essen

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocOP432

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dkk2006/06dkk542.shtml

Published: March 20, 2006

© 2006 Krauss et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

Text

CD22-specific immunotoxins are highly potent drugs for the treatment of patients with refractory B-cell non-Hodgkin’s lymphoma. However, systemic toxicity and immunogenicity hamper the wide clinical application of these powerful reagents in cancer patients. To overcome these limitations we have developed a dimeric CD22-specific immunoenzyme capable of simultaneously delivering two RNase effector domains on one molecule to CD22+ tumor cells. As targeting moiety we first generated a highly stable humanized scFv by grafting the specificity of the clinically established anti-CD22 mAb RFB4 into robust, pre-selected frameworks from a human antibody phage display library. A derived diabody with further engineered interface (VL36Leu->Tyr) retained the same high affinity as the murine anti-CD22 mAb RFB4 (KD = 0.2 nM) as well as full antigen binding after 8 days of incubation in human serum at 37°C. 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 9-48-fold stronger cytotoxicity than a monovalent rapLRI-scFv counterpart. Our results suggest dimeric antibody-ribonuclease fusion proteins as potent immunotherapeutic reagents with presumably large therapeutic index.

Figure 1 [Fig. 1]