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Updated: Mar 18, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant
Gabriela Hernandez-Hoyos1, Toddy Sewell1, Robert Bader1
1Emergent BioSolutions, Seattle, Washington.
Abstract:
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 ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward 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. In addition, 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 with 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. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR.
Insights
A novel bispecific antibody, MOR209/ES414, effectively targets prostate cancer cells by redirecting T-cells. This immunotherapy approach shows promise for treating metastatic, castration-resistant prostate cancer (mCRPC) in preclinical models.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Metastatic, castration-resistant prostate cancer (mCRPC) presents a significant unmet medical need with limited therapeutic options.
- Current immunotherapies have shown restricted efficacy in mCRPC, necessitating novel treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of a novel humanized bispecific antibody, MOR209/ES414, for treating prostate cancer.
- To assess the ability of MOR209/ES414 to redirect T-cell cytotoxicity towards prostate cancer cells expressing prostate-specific membrane antigen (PSMA).
Main Methods:
- Development of MOR209/ES414 using the ADAPTIR platform, targeting CD3ε on T cells and PSMA on cancer cells.
- In vitro assessment of T-cell mediated tumor lysis, activation, and proliferation.
- In vivo evaluation in murine xenograft models of human prostate cancer with human T-cell transfer.
Main Results:
- MOR209/ES414 induced potent, dose-dependent tumor lysis and T-cell activation at low concentrations.
- Effective tumor lysis was observed across a wide range of PSMA expression levels.
- In vivo studies demonstrated significant inhibition of tumor growth, prolonged survival, and reduced PSA levels in the presence of human T cells.
Conclusions:
- MOR209/ES414 exhibits potent preclinical anti-tumor activity against prostate cancer.
- The bispecific antibody demonstrates favorable characteristics, including high sensitivity and limited cytokine induction.
- These findings support further clinical investigation of MOR209/ES414 for castration-resistant prostate cancer treatment.
