Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIRTM (modular protein technology) platform, to redirect T-cell cytotoxicity towards prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (Prostate Specific Membrane Antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis, and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414, and was effective at low T-effector to tumor target cell ratios. Additionally, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared to other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. Based on these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC.
- Received March 30, 2015.
- Revision received June 6, 2016.
- Accepted June 14, 2016.
- Copyright ©2016, American Association for Cancer Research.