Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody

Stefan Stangl, Mathias Gehrmann, Julia Riegger, Kristin Kuhs, Isabelle Riederer, Wolfgang Sievert, Kathrin Hube, Ralph Mocikat, Ralf Dressel, Elisabeth Kremmer, Alan G. Pockley, Lars Friedrich, Laszlo Vigh, Arne Skerra, Gabriele Multhoff

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Immunization of mice with a 14-mer peptide TKDNNLLGRFELSG, termed "TKD," comprising amino acids 450-461 (aa450-461) in the C terminus of inducible Hsp70, resulted in the generation of an IgG1 mousemAb cmHsp70.1. The epitope recognized by cmHsp70.1 mAb, whichhas beenconfirmed tobelocated in theTKD sequence by SPOT analysis, is frequently detectable on the cell surface of human and mouse tumors, but not on isogenic cells and normal tissues, and membrane Hsp70 might thus serve as a tumor-specific target structure. As shown for human tumors, Hsp70 is associated with cholesterol-rich microdomains in the plasma membrane of mouse tumors. Herein, we show that the cmHsp70.1 mAb can selectively induce antibody-dependent cellular cytotoxicity (ADCC) of membrane Hsp70+ mouse tumor cells by unstimulated mouse spleen cells. Tumor killing could be further enhanced by activating the effector cells with TKD and IL-2. Three consecutive injections of the cmHsp70.1 mAb into mice bearing CT26 tumors significantly inhibited tumor growth and enhanced the overall survival. These effects were associated with infiltrations of NK cells, macrophages, and granulocytes. The Hsp70 specificity of the ADCC response was confirmed by preventingthe antitumor response in tumor-bearingmiceby coinjecting the cognate TKD peptide with the cmHsp70.1 mAb, and by blocking the binding of cmHsp70.1 mAb to CT26 tumor cells using either TKD peptide or the C-terminal substrate-binding domain of Hsp70.

Original languageEnglish
Pages (from-to)733-738
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number2
DOIs
Publication statusPublished - Jan 11 2011

Keywords

  • Cellular cytotoxicity
  • Epitope mapping
  • Immunotherapy
  • Surface antigen
  • Syngeneic tumor model
  • Tumor antibody dependent

ASJC Scopus subject areas

  • General

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  • Cite this

    Stangl, S., Gehrmann, M., Riegger, J., Kuhs, K., Riederer, I., Sievert, W., Hube, K., Mocikat, R., Dressel, R., Kremmer, E., Pockley, A. G., Friedrich, L., Vigh, L., Skerra, A., & Multhoff, G. (2011). Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proceedings of the National Academy of Sciences of the United States of America, 108(2), 733-738. https://doi.org/10.1073/pnas.1016065108