| Autor: |
Jain R, Rawat A, Verma B, Markiewski MM, Weidanz JA, Jain, Rinki, Rawat, Amit, Verma, Bhavna, Markiewski, Maciej M, Weidanz, Jon A |
| Zdroj: |
JNCI: Journal of the National Cancer Institute; Feb2013, Vol. 105 Issue 3, p202-218, 17p |
| Abstrakt: |
Background: Applications of trastuzumab are limited to breast cancer patients with high Her2-expressing tumors. We developed a T-cell receptor mimic (TCRm) monoclonal antibody (hereafter called RL1B) that targets the Her2-E75 peptide (residues 369-377)-HLA-A2 complex and examined its effects in Her2-expressing cancer cells.Methods: RL1B binding affinity was determined by surface plasmon resonance and specificity was demonstrated using Her2 antigen-positive and negative tumor cell lines. Immunohistochemistry was used to assess binding to frozen sections of human carcinomas (n = 3). Antitumor activity mediated by RL1B and trastuzumab against Her2(+) tumor cell lines was evaluated using the WST-1 cell viability assay and caspase-3 and poly(ADP-ribose) polymerase cleavage assays. A xenograft mouse model (n = 6 per group) was used to assess RL1B antitumor activity. Mechanisms of RL1B-mediated cytotoxicity were evaluated with confocal microscopy, flow cytometry, and histology. All statistical tests were two-sided.Results: RL1B bound with high specificity and affinity to the E75 peptide-HLA-A2 complex in all Her2(+) and HLA-A2(+) cancer cell lines and human carcinomas. Compared with control antibody, RL1B suppressed growth of low Her2-expressing breast tumors in mice (mean volume, RL1B vs control = 241 mm(3) vs 1531 mm(3); P = .0109) and statistically significantly increased mouse survival (P = .0098). It reduced viability compared to control monoclonal antibody-treated cells and statistically significantly increased caspase 3 activation of all Her2(+) carcinoma cell lines tested, whereas trastuzumab induced apoptosis only in high Her2-expressing cancer cells. Mechanisms of RL1B cytotoxicity were associated with antibody internalization and intracellular signaling.Conclusion: The TCRm RL1B could be a new approach to immunotherapy of Her2-expressing malignancies. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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