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

Abstract

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.

• Authors: Anja Feldmann, Claudia Arndt, Katrin Töpfer, Slava Stamova, Franziska Krone, Marc Cartellieri, Stefanie Koristka, Irene Michalk, Dirk Lindemann, Marc Schmitz, Achim Temme, Martin Bornhäuser, Gerhard Ehninger, Michael Bachmann
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 6 Pg. 3249-59 (Sep 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22875801 (Publication Type: Journal Article)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal, Humanized
• Antigens, Neoplasm
• Epitopes, T-Lymphocyte
• GPI-Linked Proteins
• Neoplasm Proteins
• PSCA protein, human

Topics

• Antibodies, Bispecific (physiology)
• Antibodies, Monoclonal, Humanized (physiology)
• Antigens, Neoplasm (biosynthesis, immunology)
• CD4-Positive T-Lymphocytes (immunology, pathology)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Cell Death (immunology)
• Epitopes, T-Lymphocyte (immunology)
• GPI-Linked Proteins (antagonists & inhibitors, biosynthesis, immunology)
• Humans
• Male
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, immunology)
• Prostatic Neoplasms (immunology, pathology)
• Stem Cells (immunology, pathology)
• Tumor Stem Cell Assay (methods)