Siltuximab (CNTO 328): a promising option for human malignancies

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Siltuximab (CNTO 328): a promising option for human malignancies

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Author(s): Runzhe Chen , Baoan Chen

Publication date (Electronic): 02 July 2015

Journal: Drug Design, Development and Therapy

Publisher: Dove Medical Press

Keywords: interleukin-6, Castleman’s disease, clinical trials

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Abstract

Siltuximab (CNTO 328) is a promising antibody-drug conjugate targeting cytokine interleukin-6 (IL-6). It is highly binding to IL-6 and thus neutralizing IL-6 bioactivity and promoting death of tumor cell. In this review, we mainly focus on the mechanisms, clinical studies, and adverse effect of siltuximab in the treatment of human malignancies. We also provide our recommendations for siltuximab treatment in the future.

Most cited references 32

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Paraneoplastic thrombocytosis in ovarian cancer.

Rebecca L. Stone, Alpa Nick, Iain A McNeish … (2012)

The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.).

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Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

Frits van Rhee, Raymond S M Wong, Nikhil Munshi … (2014)

Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease.

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JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells.

Kai Li, Donagh P Berry, Acácio Rodrigues … (2013)

Interleukin (IL)-6 overexpression and constitutive STAT3 activation occur in many cancers, including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from patients with prostate cancer secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high-grade disease. In a murine xenograft model used to determine the in vivo effects of pSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require pSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Des Devel Ther

Journal ID (iso-abbrev): Drug Des Devel Ther

Journal ID (publisher-id): Drug Design, Development and Therapy

Title: Drug Design, Development and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1177-8881

Publication date Collection: 2015

Publication date (Electronic): 02 July 2015

Volume: 9

Pages: 3455-3458

Affiliations

Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China

Author notes

Correspondence: Baoan Chen, Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, Jiangsu Province, People’s Republic of China, Tel +86 25 8327 2006, Fax +86 25 8327 2011, Email cba8888@ 123456hotmail.com

Article

Publisher ID: dddt-9-3455

DOI: 10.2147/DDDT.S86438

PMC ID: 4494175

SO-VID: 374aa6e7-dd73-4743-91d1-d80a6bd016e3

License:

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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Siltuximab (CNTO 328): a promising option for human malignancies

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Abstract

Most cited references 32

Paraneoplastic thrombocytosis in ovarian cancer.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells.

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