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Antibody dependent cellular cytotoxicity

Shin-Ichiro Fujii, Satoru Yamasaki, Yusuke Sato, Kanako Shimizu
Vaccines against a variety of infectious diseases have been developed and tested. Although there have been some notable successes, most are less than optimal or have failed outright. There has been discussion about whether either B cells or dendritic cells (DCs) could be useful for the development of antimicrobial vaccines with the production of high titers of antibodies. Invariant (i)NKT cells have direct antimicrobial effects as well as adjuvant activity, and iNKT-stimulated antigen-presenting cells (APCs) can determine the form of the ensuing humoral and cellular immune responses...
2018: Frontiers in Immunology
Mouldy Sioud, Phuong Westby, Vlada Vasovic, Yngvar Fløisand, Qian Peng
mAbs have emerged as a promising strategy for the treatment of cancer. However, in several malignancies, no effective antitumor mAbs are yet available. Identifying therapeutic mAbs that recognize common tumor antigens could render the treatment widely applicable. Here, a human single-chain variable fragment (scFv) antibody library was sequentially affinity selected against a panel of human cancer cell lines and an antibody fragment (named MS5) that bound to solid and blood cancer cells was identified. The MS5 scFv was fused to the human IgG1 Fc domain to generate an antibody (MS5-Fc fusion) that induced antibody-dependent cellular cytotoxicity and phagocytosis of cancer cells by macrophages...
April 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rory D de Vries, Arwen F Altenburg, Nella J Nieuwkoop, Erwin de Bruin, Stella E van Trierum, Mark R Pronk, Mart M Lamers, Mathilde Richard, David F Nieuwenhuijse, Marion P G Koopmans, Joost H C M Kreijtz, Ron A M Fouchier, Albert D M E Osterhaus, Gerd Sutter, Guus F Rimmelzwaan
Background: Highly pathogenic avian influenza viruses continue to circulate in poultry and wild birds and occasionally infect humans, sometimes with fatal outcome. Development of vaccines is a priority to prepare for potential pandemics, however complicated by antigenic variation of the surface glycoprotein hemagglutinin. We report the immunological profile induced by human immunization with Modified Vaccinia virus Ankara expressing the hemagglutinin gene of H5N1 virus A/Vietnam/1194/04 (rMVA-H5)...
April 18, 2018: Journal of Infectious Diseases
Delfina Costa, Roberta Venè, Roberto Benelli, Emanuele Romairone, Stefano Scabini, Silvia Catellani, Barbara Rebesco, Luca Mastracci, Federica Grillo, Simona Minghelli, Fabrizio Loiacono, Maria Raffaella Zocchi, Alessandro Poggi
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16)...
2018: Frontiers in Immunology
Kevin C Conlon, Milos D Miljkovic, Thomas A Waldmann
Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate the immune system of cancer patients has been an important treatment modality and continues to be a key contributor to current clinical cancer research. Interferon alpha (IFNα) is approved for adjuvant treatment of completely resected high-risk melanoma patients and several refractory malignancies. High-dose interleukin-2 (HDIL-2) is approved for treatment of metastatic renal cell cancer and melanoma, but both agents are currently less commonly used with the development of newer agents...
June 11, 2018: Journal of Interferon & Cytokine Research
Nicole C McKenzie, Nichollas E Scott, Alan John, Jonathan M White, Ethan D Goddard-Borger
Many monoclonal antibodies (mAbs) used in cancer immunotherapy mediate tumour cell lysis by recruiting natural killer (NK) cells; a phenomenon known as antibody-dependent cellular cytotoxicity (ADCC). Eliminating core-fucose from the N-glycans of a mAb enhances its capacity to induce ADCC. As such, inhibitors of fucosylation are highly desirable for the production of mAbs for research and therapeutic use. Herein, we describe a simple synthesis of 6,6,6-trifluoro-l-fucose (F3Fuc), a metabolic inhibitor of fucosylation, and demonstrate the utility of this molecule in the production of low-fucose mAbs from murine hybridoma cell lines...
May 23, 2018: Carbohydrate Research
Serena Varesano, Maria Raffaella Zocchi, Alessandro Poggi
New successful anti-cancer strategies are based on the stimulation of immune reaction against tumors: however, preclinical testing of such treatments is still a challenge. To improve the screening of anti-cancer drugs, three-dimensional (3D) culture systems, including spheroids, have been validated as preclinical models. We propose the spheroid 3D system to test anti-tumor drug-induced immune responses. We show that colorectal carcinoma (CRC) spheroids, generated with the epithelial growth factor (EGF), can be co-cultured with Vδ2 T cells to evaluate the anti-tumor activity of these effector lymphocytes...
2018: Frontiers in Immunology
Hillary A Vanderven, Kathleen Wragg, Fernanda Ana-Sosa-Batiz, Anne B Kristensen, Sinthujan Jegaskanda, Adam K Wheatley, Deborah Wentworth, Bruce D Wines, P Mark Hogarth, Steve Rockman, Stephen J Kent
Background: New treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralising antibody responses to past strains in influenza-infected subjects. The effect of Flu-IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear. Methods: We studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fc receptors and mediate antibody-dependent cellular cytotoxicity in vitro...
May 31, 2018: Journal of Infectious Diseases
Hao-Ching Hsiao, Xuejun Fan, Robert E Jordan, Ningyan Zhang, Zhiqiang An
BACKGROUND: Proteolytic impairment of the Fc effector functions of therapeutic monoclonal antibodies (mAbs) can compromise their antitumor efficacy in the tumor microenvironment and may represent an unappreciated mechanism of host immune evasion. Pertuzumab is a human epidermal growth factor receptor 2 (HER2)-targeting antibody and has been widely used in the clinic in combination with trastuzumab for treatment of HER2-overexpressing breast cancer. Pertuzumab susceptibility to proteolytic hinge cleavage and its impact on the drug's efficacy has not been previously studied...
June 1, 2018: Breast Cancer Research: BCR
Xi Chen, Xianqiong Zou, Guangying Qi, Ying Tang, Yong Guo, Jia Si, Lihua Liang
LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma...
May 25, 2018: Cellular Physiology and Biochemistry
Sundar Jagannath, Jacob Laubach, Ellice Wong, Keith Stockerl-Goldstein, Cara Rosenbaum, Madhav Dhodapkar, Ying-Ming Jou, Mark Lynch, Michael Robbins, Suresh Shelat, Kenneth C Anderson, Paul G Richardson
Smouldering multiple myeloma (SMM) is associated with increased risk of progression to multiple myeloma within 2 years, with no approved treatments. Elotuzumab has been shown to promote natural killer (NK) cell stimulation and antibody-dependent cellular cytotoxicity (ADCC) in vitro. CD56dim (CD56dim /CD16+ /CD3- /CD45+ ) NK cells represent the primary subset responsible for elotuzumab-induced ADCC. In this phase II, non-randomized study (NCT01441973), patients with SMM received elotuzumab 20 mg/kg intravenously (cycle 1: days 1, 8; monthly thereafter) or 10 mg/kg (cycles 1, 2: weekly; every 2 weeks thereafter)...
May 29, 2018: British Journal of Haematology
Jocelyn Ollier, Thibault Kervarrec, Mahtab Samimi, Houssem Benlalam, Pascal Aumont, Régine Vivien, Antoine Touzé, Nathalie Labarrière, Henri Vié, Béatrice Clémenceau
The recent success of checkpoint inhibitors in the treatment of Merkel cell carcinoma (MCC) confirms that MCC tumors can be immunogenic. However, no treatment directly targeting the tumor is available for use in combination with these checkpoint inhibitors to enhance their efficacity. This study was carried out to characterize MCC line sensitivity to cellular lysis and to identify cell surface antigens that could be used for direct targeting of this tumor. For five representative MCC lines, the absence or low expression of MICA, MICB, HLA-I, and ICAM-1 was associated with low level of recognition by NK cells and T lymphocytes...
May 28, 2018: Cancer Immunology, Immunotherapy: CII
Jiulong Zhang, Zhouqi Du, Shuang Pan, Menghao Shi, Jie Li, Chunrong Yang, Haiyang Hu, Mingxi Qiao, Dawei Chen, Xiuli Zhao
The therapeutic efficacy of chemotherapy is dramatically hindered by multidrug resistance (MDR), which is induced by overexpression of P-glycoprotein (P-gp). Co-delivery of antitumor drug and siRNA is an effective strategy recently applied in overcoming P-gp related MDR. In this study, a multifunctional drug delivery system with both pH-sensitive feature and active targetability was designed, in which MDR1-siRNA and DOX were successfully loaded. The resulting carrier Eph A10 antibody conjugated pH-sensitive doxrobicin (DOX), MDR1 siRNA co-loading lipoplexes (shorten as DOX+siRNA/ePL) with high serum stability had a favorable psychemical properity...
May 25, 2018: ACS Applied Materials & Interfaces
Ingrid J G Burvenich, William Farrugia, Zhanqi Liu, Dahna Makris, Dylan King, Benjamin Gloria, Angelo Perani, Laura C Allan, Andrew M Scott, Paul A Ramsland
Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of Fc mutations targeting the neonatal Fc receptor (FcRn) site on a Lewis Y binding IgG1, hu3S193. The hu3S193 variants displayed shortened in vivo half-lives and may have potential for radioimaging or radiotherapy of Lewis Y positive tumors. Here we report Fc crystal structures of wild-type hu3S193, seven FcRn binding site variants, and a variant lacking C1q binding or complement-dependent cytotoxicity (CDC) activity...
May 24, 2018: Biochemical Journal
Shanshan Li, Bingchen Yu, Jiajia Wang, Yueqin Zheng, Huajie Zhang, Margaret J Walker, Zhengnan Yuan, He Zhu, Jun Zhang, Peng George Wang, Binghe Wang
Installation of an antibody-recruiting moiety on the surface of disease-relevant cells can lead to the selective destruction of targets by the immune system. Such an approach can be an alternative strategy to traditional chemotherapeutics in cancer therapy and possibly other diseases. Herein we describe the development of a new strategy to selectively label targets with an antibody-recruiting moiety through its covalent and stable installation, complementing existing methods of employing reversible binding...
May 24, 2018: ACS Chemical Biology
Desheng Kong, Yan Wang, Ping Ji, Wei Li, Tianlei Ying, Jinghe Huang, Chen Wang, Yanling Wu, Yanping Wang, Weizao Chen, Yanling Hao, Kunxue Hong, Yiming Shao, Dimiter S Dimitrov, Shibo Jiang, Liying Ma
OBJECTIVE: Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody-dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the non-defucosylated molecule LSEVh-LS...
May 11, 2018: AIDS
Sofia Romano, Vera Moura, Sérgio Simões, João Nuno Moreira, João Gonçalves
Nucleolin arises as a relevant target for cancer therapy, as it is overexpressed at the surface of cancer and angiogenic endothelial cells thus enabling a dual cellular targeting strategy. Immunotherapeutic strategies, albeit of proven therapeutic relevance, have been scarcely explored against this target. Therefore, this work aimed at engineering an anti-nucleolin VHH-based antibody capable of triggering anticancer immune responses. Herein, anti-nucleolin VHHs have been generated upon grafting F3 peptide-derived nucleolin-binding sequences onto a VHH CDR1 or CDR3...
May 10, 2018: Scientific Reports
Łukasz Opaliński, Jakub Szymczyk, Martyna Szczepara, Marika Kucińska, Daniel Krowarsch, Małgorzata Zakrzewska, Jacek Otlewski
Fibroblast growth factor receptor 1 (FGFR1) is a plasma membrane protein that transmits signals from the extracellular environment, regulating cell homeostasis and function. Dysregulation of FGFR1 leads to the development of human cancers and noncancerous diseases. Numerous tumors overproduce FGFR1, making this receptor a perspective target for cancer therapies. Antibody-drug conjugates (ADCs) are highly potent and selective anticancer agents. ADCs are composed of antibodies (targeting factors) fused to highly cytotoxic drugs (warheads)...
May 10, 2018: International Journal of Molecular Sciences
William Vermi, Alessandra Micheletti, Giulia Finotti, Cristina Tecchio, Federica Calzetti, Sara Costa, Mattia Bugatti, Stefano Calza, Claudio Agostinelli, Stefano Pileri, Piera Balzarini, Alessandra Tucci, Giuseppe Rossi, Lara Furlani, Giuseppe Todeschini, Alberto Zamò, Fabio Facchetti, Luisa Lorenzi, Silvia Lonardi, Marco A Cassatella
Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extra-nodal, forms...
May 10, 2018: Cancer Research
Natasha A Pereira, Kah Fai Chan, Pao Chun Lin, Zhiwei Song
Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity...
May 7, 2018: MAbs
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