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.

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.

• Authors: Pamela A Davol, Janelle A Smith, Nicola Kouttab, Gerald J Elfenbein, Lawrence G Lum
• Journal: Clinical prostate cancer (Clin Prostate Cancer) Vol. 3 Issue 2 Pg. 112-21 (Sep 2004) ISSN: 1540-0352 [Print] United States
• PMID: 15479495 (Publication Type: Comparative Study, Journal Article, 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.)

Chemical References

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

Topics

• 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, mortality, therapy)
• Receptor, ErbB-2 (immunology)
• Sensitivity and Specificity
• T-Lymphocytes (drug effects, immunology)