Novel humanized and highly efficient bispecific antibodies mediate killing of prostate stem cell antigen-expressing tumor cells by CD8+ and CD4+ T cells

• Published in: The Journal of immunology (1950) 2012-09, Vol.189 (6), p.3249-3259
• Main Authors: Feldmann, Anja, Arndt, Claudia, Töpfer, Katrin, Stamova, Slava, Krone, Franziska, Cartellieri, Marc, Koristka, Stefanie, Michalk, Irene, Lindemann, Dirk, Schmitz, Marc, Temme, Achim, Bornhäuser, Martin, Ehninger, Gerhard, Bachmann, Michael
• Format: Article
• Language: English
• Subjects: Antibodies, Bispecific - physiology; Antibodies, Monoclonal, Humanized - physiology; Antigens, Neoplasm - biosynthesis; Antigens, Neoplasm - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Death - immunology; Epitopes, T-Lymphocyte - immunology; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - biosynthesis; GPI-Linked Proteins - immunology; Humans; Male; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - immunology; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Stem Cells - immunology; Stem Cells - pathology; Tumor Stem Cell Assay - methods
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200341

Prostate cancer is the most common noncutaneous malignancy in men. The prostate stem cell Ag (PSCA) is a promising target for immunotherapy of advanced disease. Based on a novel mAb directed to PSCA, we established and compared a series of murine and humanized anti-CD3-anti-PSCA single-chain bispecific Abs. Their capability to redirect T cells for killing of tumor cells was analyzed. During these studies, we identified a novel bispecific humanized Ab that efficiently retargets T cells to tumor cells in a strictly Ag-dependent manner and at femtomolar concentrations. T cell activation, cytokine release, and lysis of target cells depend on a cross-linkage of redirected T cells with tumor cells, whereas binding of the anti-CD3 domain alone does not lead to an activation or cytokine release. Interestingly, both CD8+ and CD4+ T cells are activated in parallel and can efficiently mediate the lysis of tumor cells. However, the onset of killing via CD4+ T cells is delayed. Furthermore, redirecting T cells via the novel humanized bispecific Abs results in a delay of tumor growth in xenografted nude mice.