Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

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Abstract

Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro.

Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT.

Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo.

Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.

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Most cited references 34

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TRIM24 links a noncanonical histone signature to breast cancer

Wen-Wei Tsai, Zhanxin Wang, Teresa Yiu … (2010)

Recognition of modified histone species by distinct structural domains within “reader” proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here, we report that chromatin regulator TRIM24 functions as a reader of dual histone marks via tandem Plant Homeodomain (PHD) and Bromodomain (Bromo). The three-dimensional structure of TRIM24 PHD-Bromo revealed a single functional unit for combinatorial recognition of unmodified H3K4 (H3K4me0) and acetylated H3K23 (H3K23ac) within the same histone tail. TRIM24 binds chromatin and estrogen receptor to activate estrogen-dependent genes associated with cellular proliferation and tumor development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation via a noncanonical histone signature, establishing a new paradigm by which chromatin readers may influence cancer pathogenesis.

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Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.

Scott Tagawa, Neeta Taskar, Shankar Vallabhajosula … (2013)

To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of (177)Lu-J591 (15 patients at 65 mCi/m(2), 17 at 70 mCi/m(2)) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m(2) to verify response rate and examine biomarkers. Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received (177)Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m(2)) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. A single dose of (177)Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising. ©2013 AACR.

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Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases.

D Bostwick, A Pacelli, K. G. Murphy … (1998)

Prostate-specific membrane antigen (PSMA) is an integral membrane protein highly specific for the prostate. PSMA may be clinically useful for predicting outcome in patients with prostate cancer. We compared the expression of PSMA in prostate adenocarcinoma and lymph node metastases in a large series of patients with node-positive cancer. We studied 232 patients with node-positive adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy at the Mayo Clinic between 1987 and 1992. Immunohistochemistry was performed using monoclonal antibody 7E11-5.3 directed against PSMA. For each case, the percentage of immunoreactive cells in benign prostate tissue, adenocarcinoma, and lymph node metastases was estimated in 10% increments. Intensity was recorded using a scale of 0 to 3 (0 = no staining, 3 = highest). Cytoplasmic immunoreactivity for PSMA was observed in all cases in benign epithelium and cancer, and most lymph node metastases. The number of cells stained was lowest in benign epithelium; cancer and lymph node metastases were similar (46.2% +/- 27.5% versus 79.3% +/- 18.5% versus 76.4% +/- 26.1%, respectively; all pairs P < 0.05). Intensity of staining was greatest in primary cancer and lowest in lymph node metastases. PSMA is expressed in benign prostatic epithelium and primary cancer in all cases and in 98% of cases with lymph node metastases. Expression of PSMA was greatest in primary cancer for both percentage and intensity of immunoreactive cells. PSMA expression allows the identification of benign and malignant prostatic epithelium and may be a potentially valuable marker in the treatment of patients with prostate cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2019

Publication date (Electronic): 7 February 2019

Volume: 9

Issue: 5

Pages: 1247-1263

Affiliations

[1 ]Department of Urology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, P.R. China

[2 ]Department of Dermatology, First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, P.R. China

[3 ]State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi'an, P.R. China

[4 ]Department of Urology, Tangdu Hospital, Fourth Military Medical University, 710038 Xi'an, P.R. China

[5 ]Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 710038 Xi'an, P.R. China

[6 ]Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, P.R. China.

[7 ]Department of Physiology and Pathophysiology, Fourth Military Medical University, 710032 Xi'an, P.R. China

[8 ]OriMAbs Ltd. Science center, Room 544. 3624 Market Street, PA 19104, USA

Author notes

✉ Corresponding authors: Weihong Wen, Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an, China 710032. Tel.: +86 29 84774532; Fax: +86 29 83253816; Email: wenweih@ 123456fmmu.edu.cn ; Weijun Qin, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, China 710032. Tel.: +86 29 84775321; Email: qinweij@ 123456fmmu.edu.cn ; Aizhi Zhao, OriMAbs Ltd. Science center, Room 544. 3624 Market Street, PA 19104, USA. Tel: 215-966-6286; Email: zhaoaizhi@ 123456orimabs.com .

^# These authors contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: thnov09p1247

DOI: 10.7150/thno.29884

PMC ID: 6401511

PubMed ID: 30867828

SO-VID: d5d7736b-9857-4686-bbfc-c1677232fc2c

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This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 34

TRIM24 links a noncanonical histone signature to breast cancer

Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.

Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases.

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