Anti-CD3 x anti-HER2 bispecific antibody effectively redirects armed T cells to inhibit tumor development and growth in hormone-refractory prostate cancer-bearing severe combined immunodeficient beige mice

Clin Prostate Cancer. 2004 Sep;3(2):112-21. doi: 10.3816/cgc.2004.n.021.

Abstract

The bispecific antibody (BiAb) anti-CD3 x anti-Her2/neu (Her2Bi), combines Her2/neu targeting with nonmajor histocompatibility complex-restricted cytotoxicity mediated by activated T cells (ATCs). To evaluate this adaptive immunotherapeutic strategy for augmenting antitumor immune response toward hormone-refractory prostate cancer (HRPC), normal donor or patient T cells were activated with anti-CD3, expanded ex vivo in interleukin-2, and then armed with Her2Bi (5-500 ng per million ATCs). In vitro, arming ATCs with Her2Bi increased the percent specific cytotoxicity toward PC-3 prostate adenocarcinoma cells 2-3 fold and increased the secretion of Th1 cytokines granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interferon-gamma when compared with unarmed ATCs or ATCs armed with an irrelevant BiAb. Her2Bi-armed ATCs administered with PC-3 (Winn Assay) or injected intratumorally prevented development or induced remissions, respectively, of PC-3 tumors in severe combined immunodeficient beige mice. Intravenously administered Her2Bi-armed ATCs localized to PC-3 xenografts mediated cytotoxicity toward tumor cells and produced significant tumor growth delay of PC-3 tumors, but not Her2/neu-negative LS174T colon adenocarcinoma xenografts. By flow cytometry analyses, Her2Bi-armed ATCs had a proliferative advantage over unarmed ATCs and persisted in the circulation and tumor tissues longer than unarmed ATCs. These findings suggest that Her2Bi-armed ATC therapy may be an effective, nontoxic, tumor-specific treatment for Her2-positive HRPC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies, Bispecific / pharmacology*
  • Antineoplastic Agents, Hormonal / pharmacology
  • CD3 Complex / immunology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cryopreservation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Immunohistochemistry
  • Immunotherapy / methods*
  • Male
  • Mice
  • Mice, SCID
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / therapy*
  • Receptor, ErbB-2 / immunology*
  • Sensitivity and Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Bispecific
  • Antineoplastic Agents, Hormonal
  • CD3 Complex
  • Receptor, ErbB-2