MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer
- PMID: 27406985
- DOI: 10.1158/1535-7163.MCT-15-0242
MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer
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.
©2016 American Association for Cancer Research.
Similar articles
-
The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer.Clin Cancer Res. 2021 May 15;27(10):2928-2937. doi: 10.1158/1078-0432.CCR-20-3725. Epub 2021 Jan 27. Clin Cancer Res. 2021. PMID: 33504551
-
Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release.J Immunother Cancer. 2021 Jun;9(6):e002488. doi: 10.1136/jitc-2021-002488. J Immunother Cancer. 2021. PMID: 34088740 Free PMC article.
-
A PSMA-Targeting CD3 Bispecific Antibody Induces Antitumor Responses that Are Enhanced by 4-1BB Costimulation.Cancer Immunol Res. 2020 May;8(5):596-608. doi: 10.1158/2326-6066.CIR-19-0518. Epub 2020 Mar 17. Cancer Immunol Res. 2020. PMID: 32184296
-
Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease.Eur Urol. 2018 May;73(5):648-652. doi: 10.1016/j.eururo.2017.12.008. Epub 2017 Dec 21. Eur Urol. 2018. PMID: 29275833 Free PMC article. Review.
-
PSMA-based Therapies and Novel Therapies in Advanced Prostate Cancer: The Now and the Future.Curr Treat Options Oncol. 2025 May;26(5):375-384. doi: 10.1007/s11864-025-01317-5. Epub 2025 Apr 23. Curr Treat Options Oncol. 2025. PMID: 40266437 Free PMC article. Review.
Cited by
-
Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436.Cancers (Basel). 2021 Oct 21;13(21):5287. doi: 10.3390/cancers13215287. Cancers (Basel). 2021. PMID: 34771451 Free PMC article.
-
Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies.Vaccines (Basel). 2021 Jul 2;9(7):724. doi: 10.3390/vaccines9070724. Vaccines (Basel). 2021. PMID: 34358141 Free PMC article. Review.
-
Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives.Cancers (Basel). 2021 Feb 1;13(3):549. doi: 10.3390/cancers13030549. Cancers (Basel). 2021. PMID: 33535627 Free PMC article. Review.
-
T cell-redirecting bispecific antibodies in cancer immunotherapy: recent advances.J Cancer Res Clin Oncol. 2019 Apr;145(4):941-956. doi: 10.1007/s00432-019-02867-6. Epub 2019 Feb 23. J Cancer Res Clin Oncol. 2019. PMID: 30798356 Free PMC article. Review.
-
A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer.Cancer Immunol Res. 2025 Feb 3;13(2):258-272. doi: 10.1158/2326-6066.CIR-24-0273. Cancer Immunol Res. 2025. PMID: 39545924 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous