The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
Open Access
- 14 May 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (10), 2928-2937
- https://doi.org/10.1158/1078-0432.CCR-20-3725
Abstract
Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy. Experimental Design: We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated. Results: AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6-42 pmol/L. In vivo, AMG160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68-labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs. Conclusions: The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.Keywords
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Funding Information
- Amgen Inc
- Cactus Life Sciences
This publication has 42 references indexed in Scilit:
- Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancerNature Communications, 2014
- The prostate-specific membrane antigen: Lessons and current clinical implications from 20 years of researchUrologic Oncology: Seminars and Original Investigations, 2013
- Alpha Emitter Radium-223 and Survival in Metastatic Prostate CancerNew England Journal of Medicine, 2013
- Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate AntigensMolecular Cancer Therapeutics, 2012
- Increased Survival with Enzalutamide in Prostate Cancer after ChemotherapyNew England Journal of Medicine, 2012
- International Harmonization of Toxicologic Pathology NomenclatureToxicologic Pathology, 2012
- Strategies for extended serum half-life of protein therapeuticsCurrent Opinion in Biotechnology, 2011
- Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trialThe Lancet, 2010
- Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer modelsThe Prostate, 2003
- Upregulation of prostate-specific membrane antigen after androgen-deprivation therapyUrology, 1996