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A new DNA vaccine fused with the C3d-p28 induces a Th2 immune response against amyloid-beta

Neural Regeneration Research 2013年第27期8卷 2581-2590页

作者： Wanshu Guo Sha Sha Tongzi Jiang Xiaona Xing Yunpeng Cao Department of Neurology First Affiliated Hospital of China Medical University Department of Neurology First People's Hospital of Shenyang City

To enhance anti-amyloid-beta （Aβ） antibody generation and induce a Th2 immune response, we constructed a new DNA vaccine p（Aβ3-10 ）10-C3d-p28.3 encoding ten repeats of Aβ3-10 and three copies of C3d-p28 as a molecular adjuvant. In this study, we administered this adjuvant intramus-cularly to female C57BL/6J mice at 8-10 weeks of age. Enzyme linked immunosorbent assay was used to detect the titer of serum anti-Aβ antibody, isotypes, and cytokines in splenic T cel s. A 3-（4,5-cimethylthiazol-2-yl）-2,5-diphenyl tetrazolium bromide assay was used to detect the prolifera-tion rate of splenic T cel s. Brain sections from a 12-month-old APP/PS1 transgenic mouse were used for detecting the binding capacities of anti-Aβ antibodies to Aβ plaques. The p（Aβ3-10）10-C3d-p28.3 vaccine induced high titers of anti-amyloid-βantibodies, which bound to Aβplaques in APP/PS1 transgenic mouse brain tissue, demonstrating that the vaccine is effective against plaques in a mouse model of Alzheimer’s disease. Moreover, the vaccine elicited a pre-dominantly IgG1 humoral response and low levels of interferon-γ in ex vivo cultured splenocytes, indicating that the vaccine could shift the cel ular immune response towards a Th2 phenotype. This indicated that the vaccine did not elicit a detrimental immune response and had a favorable safety profile. Our results indicate that the p（Aβ3-10）10-C3d-p28.3 vaccine is a promising immunothera-peutic option for Aβvaccination in Alzheimer’s disease.

关键词： neural regeneration Alzheimer's disease amyloid-β C57BL/6J mice DNA vaccine activeimmunotherapy passive immunotherapy C3d-p28 molecular adjuvant Th2 immune response grants-supported paper neuroregeneration

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immunotherapy of hepatoma with a monoclonal antibody against murine endoglin

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World Journal of Gastroenterology 2007年第17期13卷 2479-2483页

作者： Guang-Hong Tan Feng-Ying Huang Hua Wang Yong-Hao Huang Ying-Ying Lin Yue-Nan Li Hainan Provincial Key Laboratory of Tropical Medicine Hainan Medical CollegeHaikou 571101 Hainan Province China Pediatric Department ofAffiliated Hospital Hainan Medical College Haikou 570102Hainan Province China

AIM: To explore the capability of a monoclonal antibody (mAb) against murine endoglin to inhibit tumor angiogenesis and suppression of hepatoma growth in murine models. METHODS: A monoclonal antibody against murine endoglin was purified by affinity chromatography and passively transfused through tail veins in two murine hepatoma models. Tumor volume and survival time were observed at three-day intervals for 48 d. Microvessels in tumor tissues were detected by immunohistochemistry against CD31, and angiogenesis in vivo was determined by alginate encapsulated assay. In addition, tumor cell apoptosis was detected by TUNEL assay. RESULTS: passive immunotherapy with anti-endoglin mAb could effectively suppress tumor growth, and prolonged the survival time of hepatoma-bearing mice. Angiogenesis was apparently inhibited within the tumor tissues, and the vascularization of alginate beads was also reduced in the mice passively transfused with anti- endoglin mAb. In addition, increased apoptotic cells were observed within the tumor tissues from the mice passively transfused with anti-endoglin mAb. CONCLUSION: passive immunotherapy with anti- endoglin mAb effectively inhibits tumor growth via inhibiting tumor angiogenesis and increasing tumor cell apoptosis, which may be highly correlated with the blockage of endoglin-related signal pathway induced bya nti-endoglin mAb.

关键词： Monoclonal antibody Endoglin passive immunotherapy Tumor angiogenesis Apoptosis

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A concise review of immunotherapy for glioblastoma

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Neuroimmunology and Neuroinflammation 2018年第6期5卷 18-28页

作者： Omer Sager Ferrat Dincoglan Selcuk Demiral Bora Uysal Hakan Gamsiz Bahar Dirican Murat Beyzadeoglu Department of Radiation Oncology University of Health SciencesGulhane Medical FacultyAnkara 06018Turkey

Glioblastoma(GB)is the most common and aggressive form of primary brain tumors in adults with a universally poor prognosis despite multimodal management including surgery,chemotherapy and radiation *** the novel therapeutic strategies,immunotherapy deserves particular attention with its potential to evoke biologic response and harness the host immune *** success achieved for other tumors has elicited great enthusiasm and prompted research on immunotherapy for *** the central nervous system has traditionally been thought of as an immune-privileged site,our understanding is being refined with emerging *** studies have been conducted and more are under way to establish the role of immunotherapy in management of *** of GB has yet resulted in mixed success with conflicting research findings,emphasizing the need for extensive study before its integration into routine clinical *** there is a lot of room for improvement,immunotherapy for GB may be feasible and serve as a viable management strategy broadening and strengthening the therapeutic armamentarium to combat this deadly ***,we present a concise review of immunotherapy for GB.

关键词： Glioblastoma immunotherapy glioma vaccine passive immunotherapy active immunotherapy cytokine therapy central nervous system

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Phase I Dose Escalation Study with the Lewis Y Carbohydrate Specific Humanized Antibody IGN311

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Journal of Cancer Therapy 2011年第5期2卷 760-771页

作者： Daniel Oruzio Gunter Waxenecker Christoph Aulmann Bruno Markl Theodor Wagner Geert Mudde Manfred Schuster Norbert Eller Andrea Mayer Stefan Stranner Gottfried Himmler Hans Loibner Günter Schlimok Ralf Kircheis Andreas Nechansky Zentralklinikum AugsburgGermany Igeneon ViennaAustria AGES Pharmed ViennaAustria S-TARget ViennaAustria Apeiron ViennaAustria CDMS ViennaAustria Immatics TubingenGermany f-Star ViennaAustria ViroLogik ErlangenGermany Meridian Biopharmaceuticals ViennaAustria.

Purpose: Investigation of safety, tolerability, pharmacokinetics, and anti-tumor activity of the Lewis Y-specific, fully humanized monoclonal antibody (mAb) IGN311 in patients with Lewis Y positive tumors in a Phase I clinical trial. Experimental Design: Twelve patients (pts) were enrolled in an open-label, uncontrolled, dose escalating Phase I study. Three pts received 50 mg, three pts 100 mg and six pts 200 mg IGN311 by i.v. infusion on days 1 and 15. Blood samples were taken immediately before infusion, and 0.5, 4, 8, 24 hours post infusion, as well as on days 3, 5 and 8 after the first and second infusion, respectively, and day 29. A final visit was scheduled for day 43. Results: No drug related adverse events were observed in the 50 mg and 100 mg dose groups. Three out of six patients in the 200 mg dose group showed drug related adverse reactions with nausea, vomiting and hypotension in one patient (NCI CTC grade 3) being the dose limiting toxicities. t1/2 of IGN311 was ~20 days after second infusion of IGN311. Sera of patients receiving IGN311 were capable of lysing Lewis Y positive tumor cells in vitro by both, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Circulating tumor cells found in the peripheral blood in two out of twelve pts prior to treatment were reduced after treatment to below the quantification limit of the detection method. None of the patients showed an increase in the number of disseminated tumor cells during treatment period. Conclusions: The good safety and PK profile, the biological activity regarding CDC and ADCC mediated tumor cell lysis, and the elimination of circulating tumor cells warrant further clinical investigation of IGN311.

关键词： passive immunotherapy Therapeutic Monoclonal Antibody Disseminated Tumor Cells Phase I Study Lewis Y Carbohydrate HAHA (Human Anti-Human Antibodies)

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