Dataset Information

Immunotoxicity assessment of rice-derived recombinant human serum albumin using human peripheral blood mononuclear cells.

ABSTRACT: Human serum albumin (HSA) is extensively used in clinics to treat a variety of diseases, such as hypoproteinemia, hemorrhagic shock, serious burn injuries, cirrhotic ascites and fetal erythroblastosis. To address supply shortages and high safety risks from limited human donors, we recently developed recombinant technology to produce HSA from rice endosperm. To assess the risk potential of HSA derived from Oryza sativa (OsrHSA) before a First-in-human (FIH) trial, we compared OsrHSA and plasma-derived HSA (pHSA), evaluating the potential for an immune reaction and toxicity using human peripheral blood mononuclear cells (PBMCs). The results indicated that neither OsrHSA nor pHSA stimulated T cell proliferation at 1x and 5x dosages. We also found no significant differences in the profiles of the CD4(+) and CD8(+) T cell subsets between OsrHSA- and pHSA-treated cells. Furthermore, the results showed that there were no significant differences between OsrHSA and pHSA in the production of cytokines such as interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), interleukin (IL)-10 and IL-4. Our results demonstrated that OsrHSA has equivalent immunotoxicity to pHSA when using the PBMC model. Moreover, this ex vivo system could provide an alternative approach to predict potential risks in novel biopharmaceutical development.

SUBMITTER: Fu K

PROVIDER: S-EPMC4123919 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Immunotoxicity assessment of rice-derived recombinant human serum albumin using human peripheral blood mononuclear cells.

Fu Kai K Cheng Qin Q Liu Zhenwei Z Chen Zhen Z Wang Yan Y Ruan Honggang H Zhou Lu L Xiong Jie J Xiao Ruijing R Liu Shengwu S Zhang Qiuping Q Yang Daichang D

PloS one 20140806 8

Human serum albumin (HSA) is extensively used in clinics to treat a variety of diseases, such as hypoproteinemia, hemorrhagic shock, serious burn injuries, cirrhotic ascites and fetal erythroblastosis. To address supply shortages and high safety risks from limited human donors, we recently developed recombinant technology to produce HSA from rice endosperm. To assess the risk potential of HSA derived from Oryza sativa (OsrHSA) before a First-in-human (FIH) trial, we compared OsrHSA and plasma-de ...[more]

PMID: 25099245

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Project description:Abstract Introduction: Despite state-of-the-art surgical methods combined with radio- and chemotherapy the clinical prognosis of brain cancer patients remains poor. The brain is an immune privileged site and brain cancers are known to form a highly immunosuppressive microenvironment, suggesting that patients could benefit from immunomodulatory drugs. Multiple therapies targeting the immune system are currently under development, including application of a potent activator of immune responses, interleukin (IL)-12. This cytokine stimulates the cytotoxic function of lymphocytes and can trigger rejection of gliomas in preclinical studies. Even though IL-12 has a relatively short half-life, systemic IL-12 can quickly lead to severe adverse reactions. Local application or targeting is therefore mandatory. Local IL-12 therapy is currently tested in early stage clinical trials of intratumoral genetherapy using viral vectors (ClinicalTrials.gov identifiers NCT02026271 and NCT02062827). An alternative approach is the use of convection-enhanced delivery (CED). This way IL-12 could be dosed precisely to the tumour focus with minimal systemic leakage. Furthermore, to increase the local half-life of IL-12, we have fused it with the Fc part of human IgG4 (IL-12Fc). Using CED, we are aiming to validate efficacy and safety of local IL-12Fc monotherapy in a preclinical setting with canine brain tumours. Materials and Methods: Canine peripheral blood mononuclear cells (PBMCs) were stimulated with increasing concentrations of human IL-12Fc or with recombinant human or canine IL-12 in presence or absence of concanavalin A. Interferon-γ (IFN-γ) production was measured by ELISA. Phosphorylation of STAT4 was measured by western blot. Porcine PBMCs were stimulated in the presence of recombinant porcine IL-2 and IL-18. IFN-γ production was measured by ELISA. Results: Human IL-12Fc is able to stimulate canine and porcine PBMCs to secrete IFN-γ in a dose-dependent manner. Furthermore, stimulation with hIL-12Fc leads to phosphorylation of STAT4. Conclusions: Human IL-12 immunotherapeutics are able to stimulate canine PBMCs and thus therapy of spontaneous brain tumours in dogs can be used for preclinical testing. To estimate leakage and brain perfusion in the dog and ultimately in humans, we will next test CED of hIL-12Fc in large white landrace pigs. We are aiming to initiate a trial to assess the efficacy of local delivery of human IL-12Fc as therapy for canine brain tumours.

Dataset Information

Immunotoxicity assessment of rice-derived recombinant human serum albumin using human peripheral blood mononuclear cells.

Publications

Immunotoxicity assessment of rice-derived recombinant human serum albumin using human peripheral blood mononuclear cells.

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