Preclinical Development Regression of Human Prostate Cancer Xenografts inMice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens

For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. AMG 212/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinesehamster ovary cells stably expressinghumanor cynomolgusmonkeyPSMA,T cells redirectedbyAMG 212/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1,MDAPCa 2b, C4-2, PC-3-huPSMA, andLnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/mL (1.8–72 pmol/L). No lysis of PSMA-negative human PCa cell lines PC-3 and DU145 was observed. The subcutaneous (s.c.) formation of tumors from PC-3huPSMAcells inNOD/SCIDmicewas significantly preventedbyoncedaily intravenous (i.v.) injection ofAMG 212/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed inNOD/SCIDmice bearingestablished s.c. 22Rv1xenografts after repeateddaily treatmentwith AMG 212/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells 3 days before BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or AMG 212/BAY2010112. On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa. Mol Cancer Ther; 11(12); 2664–73. 2012 AACR.