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      A novel multifunctional anti-CEA-IL15 molecule displays potent antitumor activities

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          Abstract

          Introduction

          Interleukin-15 (IL-15) is an immunomodulatory cytokine. It can activate and expand cytotoxic CD8 T lymphocytes and natural killer cells, leading to potent antitumor effects. Various forms of IL-15 are now in different stages of development for cancer immunotherapy. One of the major issues with IL-15 or IL15–IL15Rα fusion is high toxicity due to systemic activation of immune cells.

          Materials and methods

          In this study, we engineered a nanobody–cytokine fusion molecule, anti-CEA-IL15, in which an anti-CEA nanobody was linked to an IL15Rα–IL15 fusion. The nanobody–cytokine fusion exhibited multiple mechanisms to kill tumor cells, including promoting immune cell proliferation and directing antibody-dependent cytotoxicity against CEA-positive tumor cells.

          Results

          In xenograft models, anti-CEA-IL15 was localized in the tumor microenvironment and exhibited more potent antitumor activities than non-targeting IL-15, supporting potential application of this multifunctional fusion molecule in tumor immunotherapy.

          Conclusion

          We generated and validated a tumortargeting fusion protein, anti-CEA-IL15, which has potent cytokine activity to activate and mobilize the immune system to fight cancer cells. Such strategies may also be applied to other cytokines and tumor-targeting molecules to increase antitumor efficacy.

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          Most cited references 38

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          A function for interleukin 2 in Foxp3-expressing regulatory T cells.

          Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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            The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues.

            The human CEA family has been fully characterized. It comprises 29 genes of which 18 are expressed; 7 belonging to the CEA subgroup and 11 to the pregnancy specific glycoprotein subgroup. CEA is an important tumor marker for colorectal and some other carcinomas. The CEA subgroup members are cell membrane associated and show a complex expression pattern in normal and cancerous tissues with notably CEA showing a selective epithelial expression. Several CEA subgroup members possess cell adhesion properties and the primordial member, biliary glycoprotein, seems to function in signal transduction or regulation of signal transduction possibly in association with other CEA sub-family members. A modified ITAM/ITIM motif is identified in the cytoplasmatic domain of BGP. A role of CEA in innate immunity is envisioned. Copyright 1999 Academic Press.
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              The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design.

              Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                29 August 2018
                : 12
                : 2645-2654
                Affiliations
                [1 ]School of Pharmaceutical Sciences, wangzh357@ 123456mail.sysue.edu.cn
                [2 ]Center for Cellular and Structural Biology, Sun Yat-Sen University, Guangzhou, People’s Republic of China, wangzh357@ 123456mail.sysue.edu.cn
                Author notes
                Correspondence: Zhong Wang, School of Pharmaceutical Sciences, Sun Yat-Sen University, No 132, Waihuan East Road, Higher Education Mega Center, Guangzhou 510006, People’s Republic of China, Tel +86 136 5096 1576, Email wangzh357@ 123456mail.sysue.edu.cn
                Article
                dddt-12-2645
                10.2147/DDDT.S166373
                6120566
                © 2018 Liu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                antibody–cytokine fusion, immunotherapy, cea, nanobody, il-15

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